Disrupting glioblastoma networks with tumor treating fields (TTFields) in in vitro models.

PURPOSE: This study investigates the biological effect of Tumor Treating Fields (TTFields) on key drivers of glioblastoma's malignancy-tumor microtube (TM) formation-and on the function and overall integrity of the tumor cell network. METHOD: Using a two-dimensional monoculture GB cell network model (2DTM) of primary glioblastoma cell (GBC) cultures (S24, BG5 or T269), we evaluated the effects of TTFields on cell density, interconnectivity and structural integrity of the tumor network. We also analyzed calcium (Ca2+) transient dynamics and network morphology, validating findings in patient-derived tumoroids and brain tumor organoids. RESULTS: In the 2DTM assay, TTFields reduced cell density by 85-88% and disrupted network interconnectivity, particularly in cells with multiple TMs. A "crooked TM" phenotype emerged in 5-6% of treated cells, rarely seen in controls. Ca2+ transients were significantly compromised, with global Ca2+ activity reduced by 51-83%, active and periodic cells by over 50%, and intercellular co-activity by 52% in S24, and almost completely in BG5 GBCs. The effects were more pronounced at 200 kHz compared to a 50 kHz TTFields. Similar reductions in Ca2+ activity were observed in patient-derived tumoroids. In brain tumor organoids, TTFields significantly reduced tumor cell proliferation and infiltration. CONCLUSION: Our comprehensive study provides new insights into the multiple effects of Inovitro-modeled TTFields on glioma progression, morphology and network dynamics in vitro. Future in vivo studies to verify our in vitro findings may provide the basis for a deeper understanding and optimization of TTFields as a therapeutic modality in the treatment of GB.

Global post­marketing safety surveillance of Tumor Treating Fields (TTFields) therapy in over 25,000 patients with CNS malignancies treated between 2011-2022.

BACKGROUND: Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes. TTFields therapy is approved for recurrent glioblastoma (rGBM), and newly-diagnosed (nd) GBM (with concomitant temozolomide for ndGBM; US), and for grade IV glioma (EU). We present an updated global, post-marketing surveillance safety analysis of patients with CNS malignancies treated with TTFields therapy. METHODS: Safety data were collected from routine post-marketing activities for patients in North America, Europe, Israel, and Japan (October 2011-October 2022). Adverse events (AEs) were stratified by age, sex, and diagnosis. RESULTS: Overall, 25,898 patients were included (diagnoses: ndGBM [68%], rGBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other CNS malignancies [2%]). Median (range) age was 59 (3-103) years; 66% patients were male. Most (69%) patients were 18-65 years; 0.4% were < 18 years; 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%) patients, respectively. Most common treatment-related AEs were beneath-array skin reactions (43%), electric sensation (tingling; 14%), and heat sensation (warmth; 12%). Treatment-related skin reactions were comparable in pediatric (39%), adult (42%), and elderly (45%) groups, and in males (41%) and females (46%); and similar across diagnostic subgroups (ndGBM, 46%; rGBM, 34%; anaplastic astrocytoma/oligodendroglioma, 42%; other, 40%). No TTFields-related systemic AEs were reported. CONCLUSIONS: This long-term, real-world analysis of > 25,000 patients demonstrated good tolerability of TTFields in patients with CNS malignancies. Most therapy-related AEs were manageable localized, non-serious skin events. The TTFields therapy safety profile remained consistent across subgroups (age, sex, and diagnosis), indicative of its broad applicability.

Cilia at the Crossroads of Tumor Treating Fields and Chemotherapy.

Glioblastoma (GBM), the most common and lethal primary brain tumor in adults, requires multi-treatment intervention which unfortunately barely shifts the needle in overall survival. The treatment options after diagnosis and surgical resection (if possible) include irradiation, temozolomide (TMZ) chemotherapy, and now tumor treating fields (TTFields). TTFields are electric fields delivered locoregionally to the head/tumor via a wearable medical device (Optune®). Overall, the concomitant treatment of TTFields and TMZ target tumor cells but spare normal cell types in the brain. Here, we examine whether primary cilia, microtubule-based "antennas" found on both normal brain cells and GBM cells, play specific roles in sensitizing tumor cells to treatment. We discuss evidence supporting GBM cilia being exploited by tumor cells to promote their growth and treatment resistance. We review how primary cilia on normal brain and GBM cells are affected by GBM treatments as monotherapy or concomitant modalities. We also focus on latest findings indicating a differential regulation of GBM ciliogenesis by TTFields and TMZ. Future studies await arrival of intracranial TTFields models to determine if GBM cilia carry a prognostic capacity.

Optimization of tumor-treating field therapy for triple-negative breast cancer cells in vitro via frequency modulation.

PURPOSE: Currently, 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: TTFields were highly efficacious against TNBC growth, FM TTFields showed minimal effects on epithelial cells similar to unmodulated treatment.

Tumor Treating Fields (TTFields) increase the effectiveness of temozolomide and lomustine in glioblastoma cell lines.

PURPOSE: Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is approved for treatment of newly-diagnosed glioblastoma (GBM) concurrent with maintenance temozolomide (TMZ). Recently, the benefit of TMZ in combination with lomustine (CCNU) was demonstrated in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. The addition of adjuvant TTFields to TMZ plus CCNU further improved patient outcomes, leading to a CE mark for this regimen. The current in vitro study aimed to elucidate the mechanism underlying the benefit of this treatment protocol. METHODS: Human GBM cell lines with different MGMT promoter methylation statuses were treated with TTFields, TMZ, and CCNU, and effectiveness was tested by cell count, apoptosis, colony formation, and DNA damage measurements. Expression levels of relevant DNA-repair proteins were examined by western blot analysis. RESULTS: TTFields concomitant with TMZ displayed an additive effect, irrespective of MGMT expression levels. TTFields concomitant with CCNU or with CCNU plus TMZ was additive in MGMT-expressing cells and synergistic in MGMT-non-expressing cells. TTFields downregulated the FA-BRCA pathway and increased DNA damage induced by the chemotherapy combination. CONCLUSIONS: The results support the clinical benefit demonstrated for TTFields concomitant with TMZ plus CCNU. Since the FA-BRCA pathway is required for repair of DNA cross-links induced by CCNU in the absence of MGMT, the synergy demonstrated in MGMT promoter methylated cells when TTFields and CCNU were co-applied may be attributed to the BRCAness state induced by TTFields.

Association of Tumor Treating Fields (TTFields) therapy with survival in newly diagnosed glioblastoma: a systematic review and meta-analysis.

PURPOSE: Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015 based on the randomized controlled EF-14 study. Subsequent approvals worldwide and increased adoption over time have raised the question of whether a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role. METHODS: We conducted a literature search to identify clinical studies evaluating overall survival (OS) in TTFields-treated patients. Comparative and single-cohort studies were analyzed. Survival curves were pooled using a distribution-free random-effects method. RESULTS: Among nine studies, seven (N = 1430 patients) compared the addition of TTFields therapy to standard of care (SOC) chemoradiotherapy versus SOC alone and were included in a pooled analysis for OS. Meta-analysis of comparative studies indicated a significant improvement in OS for patients receiving TTFields and SOC versus SOC alone (HR: 0.63; 95% CI 0.53-0.75; p < 0.001). Among real-world post-approval studies, the pooled median OS was 22.6 months (95% CI 17.6-41.2) for TTFields-treated patients, and 17.4 months (95% CI 14.4-21.6) for those not receiving TTFields. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, for patients included in studies reporting data on device usage (N = 1015), an average usage rate of ≥ 75% was consistently associated with prolonged survival (p < 0.001). CONCLUSIONS: Meta-analysis of comparative TTFields studies suggests survival may be improved with the addition of TTFields to SOC for patients with newly diagnosed GBM.

Aurora B Kinase Inhibition by AZD1152 Concomitant with Tumor Treating Fields Is Effective in the Treatment of Cultures from Primary and Recurrent Glioblastomas.

Tumor Treating Fields (TTFields) were incorporated into the treatment of glioblastoma, the most malignant brain tumor, after showing an effect on progression-free and overall survival in a phase III clinical trial. The combination of TTFields and an antimitotic drug might further improve this approach. Here, we tested the combination of TTFields with AZD1152, an Aurora B kinase inhibitor, in primary cultures of newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM). AZD1152 concentration was titrated for each cell line and 5-30 nM were used alone or in addition to TTFields (1.6 V/cm RMS; 200 kHz) applied for 72 h using the inovitro™ system. Cell morphological changes were visualized by conventional and confocal laser microscopy. The cytotoxic effects were determined by cell viability assays. Primary cultures of ndGBM and rGBM varied in p53 mutational status; ploidy; EGFR expression and MGMT-promoter methylation status. Nevertheless; in all primary cultures; a significant cytotoxic effect was found following TTFields treatment alone and in all but one, a significant effect after treatment with AZD1152 alone was also observed. Moreover, in all primary cultures the combined treatment had the most pronounced cytotoxic effect in parallel with morphological changes. The combined treatment of TTFields and AZD1152 led to a significant reduction in the number of ndGBM and rGBM cells compared to each treatment alone. Further evaluation of this approach, which has to be considered as a proof of concept, is warranted, before entering into early clinical trials.

Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study.

Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We conducted a pilot clinical trial of concurrent chemoradiation with TTFields and report pattern of progression. MATERIALS AND METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from the primary enhancing lesion. RESULTS: Thirty patients were enrolled on the trial. Twenty were male with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 15.2 months (1.7-23.6 months). Ten (33.3%) patients had a methylated promoter status. Twenty-seven patients (90%) had progression, with median PFS of 9.3 months (range 8.5 to 11.6 months). Six patients presented with distant recurrence, with median distance from primary lesion of 5.05 cm (2.26-6.95 cm). One infratentorial progression was noted. CONCLUSIONS: We observed improved local control using concurrent chemoradiation with TTFields for patients with newly diagnosed when compared to historical controls. Further data are needed to validate this finding. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.

The safety profile of Tumor Treating Fields (TTFields) therapy in glioblastoma patients with ventriculoperitoneal shunts.

INTRODUCTION: Tumor Treating Fields (TTFields, 200 kHz) therapy is a noninvasive, locoregional cancer treatment approved for use in newly diagnosed glioblastoma (GBM), recurrent GBM, and malignant pleural mesothelioma. GBM patients with hydrocephalus may require implantation of a ventriculoperitoneal (VP) shunt, however, the current TTFields therapy label does not include the use of VP shunts in GBM patients due to insufficient safety data. This analysis evaluates the safety of TTFields therapy use in this population. METHODS: Unsolicited post-marketing global surveillance data from patients with GBM and a VP shunt (programmable/non-programmable) who received TTFields therapy between November 2012-April 2021 were retrospectively analyzed. Adverse events (AEs) were assessed using the Medical Dictionary for Regulatory Activities version 24.0. RESULTS: Overall, 156 patients with VP shunts were identified and included in this analysis. In total, 77% reported ≥ 1 AE; the most common TTFields therapy-related AEs were non-serious and localized, beneath-array skin AEs (43%). The incidence and categories of AEs were comparable between patients with or without VP shunts. Six patients with VP shunts experienced seven serious TTFields therapy-related AEs: skin erosion at the shunt site (n = 3); wound dehiscence at the shunt site (n = 2) and at the resection scar (n = 2). No shunt malfunctions were deemed related to TTFields therapy. CONCLUSIONS: In the real-world setting, TTFields therapy in GBM patients with VP shunts demonstrated good tolerability and a favorable safety profile. There was no evidence that TTFields therapy disrupted VP shunt effectiveness. These results suggest TTFields therapy may be safely used in patients with VP shunts.

Tumor treating fields therapy is feasible and safe in a 3-year-old patient with diffuse midline glioma H3K27M - a case report.

Since high grade gliomas are aggressive brain tumors, intensive search for new treatment options is ongoing. For adult patients with newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM), low intensity intermediate frequency alternating electric fields, known as tumor treating fields (TTFields) have been established as a new treatment modality. Tumor treating fields significantly increase survival rates in combination with adjuvant temozolomide (TMZ) in adult and GBM patients. Here, we report about feasibility and safety of treatment on a pediatric patient with diffuse midline glioma who is receiving TTFields therapy in combination with temozolomide.

Tumor Treating Fields (TTFields) Concomitant with Immune Checkpoint Inhibitors Are Therapeutically Effective in Non-Small Cell Lung Cancer (NSCLC) In Vivo Model.

Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields induce anti-mitotic effects through the disruption of the mitotic spindle and abnormal chromosome segregation, which trigger several forms of cell death, including immunogenic cell death (ICD). The efficacy of TTFields concomitant with anti-programmed death-1 (anti-PD-1) treatment was previously shown in vivo and is currently under clinical investigation. Here, the potential of TTFields concomitant with anti- PD-1/anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-programmed death-ligand 1 (anti-PD-L1) immune checkpoint inhibitors (ICI) to improve therapeutic efficacy was examined in lung tumor-bearing mice. Increased circulating levels of high mobility group box 1 protein (HMGB1) and elevated intratumoral levels of phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α) were found in the TTFields-treated mice, indicative of ICD induction. The concomitant application of TTFields and ICI led to a significant decrease in tumor volume as compared to all other groups. In addition, significant increases in the number of tumor-infiltrating immune cells, specifically cytotoxic T-cells, were observed in the TTFields plus anti-PD-1/anti-CTLA-4 or anti-PD-L1 groups. Correspondingly, cytotoxic T-cells isolated from these tumors showed higher levels of IFN-γ production. Collectively, these results suggest that TTFields have an immunoactivating role that may be leveraged for concomitant treatment with ICI to achieve better tumor control by enhancing antitumor immunity.

PTEN mutations predict benefit from tumor treating fields (TTFields) therapy in patients with recurrent glioblastoma.

INTRODUCTION: Optimal treatment for recurrent glioblastoma isocitrate dehydrogenase 1 and 2 wild-type (rGBM IDH-WT) is not standardized, resulting in multiple therapeutic approaches. A phase III clinical trial showed that tumor treating fields (TTFields) monotherapy provided comparable survival benefits to physician's chemotherapy choice in rGBM. However, patients did not equally benefit from TTFields, highlighting the importance of identifying predictive biomarkers of TTFields efficacy. METHODS: A retrospective review of an institutional database with 530 patients with infiltrating gliomas was performed. Patients with IDH-WT rGBM receiving TTFields at first recurrence were included. Tumors were evaluated by next-generation sequencing for mutations in 205 cancer-related genes. Post-progression survival (PPS) was examined using the log-rank test and multivariate Cox-regression analysis. RESULTS: 149 rGBM patients were identified of which 29 (19%) were treated with TTFields. No significant difference in median PPS was observed between rGBM patients who received versus did not receive TTFields (13.9 versus 10.9 months, p = 0.068). However, within the TTFields-treated group (n = 29), PPS was improved in PTEN-mutant (n = 14) versus PTEN-WT (n = 15) rGBM, (22.2 versus 11.6 months, p = 0.017). Within the PTEN-mutant group (n = 70, 47%), patients treated with TTFields (n = 14) had longer median PPS (22.2 versus 9.3 months, p = 0.005). No PPS benefit was observed in PTEN-WT patients receiving TTFields (n = 79, 53%). CONCLUSIONS: TTFields therapy conferred a significant PPS benefit in PTEN-mutant rGBM. Understanding the molecular mechanisms underpinning the differences in response to TTFields therapy could help elucidate the mechanism of action of TTFields and identify the rGBM patients most likely to benefit from this therapeutic option.

Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice.

INTRODUCTION: Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting. METHODS: Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 [pediatric], 18-64 [adults], ≥ 65 [elderly]; years of age). RESULTS: Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively). CONCLUSIONS: This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma.

INTRODUCTION: Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-sparing radiation with concurrent TTFields. METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m2 daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma. RESULTS: We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70-90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months). CONCLUSIONS: Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.

Use of FET PET in glioblastoma patients undergoing neurooncological treatment including tumour-treating fields: initial experience.

PURPOSE: We present our first clinical experience with O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET in patients with high-grade glioma treated with various neurooncological therapies including tumour-treating fields (TTFields) for the differentiation of tumour progression from treatment-related changes. METHODS: We retrospectively assessed 12 patients (mean age 51 ± 12 years, range 33-72 years) with high-grade glioma (11 glioblastomas, 1 gliosarcoma) in whom the treatment regimen included TTFields and who had undergone FET PET scans for differentiation of tumour progression from treatment-related changes. Mean and maximum tumour-to-brain ratios (TBRmean, TBRmax) were calculated. The definitive diagnosis (tumour progression or posttherapeutic changes) was confirmed either by histopathology (4 of 12 patients) or on clinical follow-up. RESULTS: In all nine patients with confirmed tumour progression, the corresponding FET PET showed increased uptake (TBRmax 3.5 ± 0.6, TBRmean 2.7 ± 0.7). In one of these nine patients, FET PET was consistent with treatment-related changes, whereas standard MRI showed a newly diagnosed contrast-enhancing lesion. In two patients treated solely with TTFields without any other concurrent neurooncological therapy, serial FET PET revealed a decrease in metabolic activity over a follow-up of 6 months or no FET uptake without any signs of tumour progression or residual tumour on conventional MRI. CONCLUSION: FET PET may add valuable information in monitoring therapy in individual patients with high-grade glioma undergoing neurooncological treatment including TTFields.

Proliferation arrest, selectivity, and chemosensitivity enhancement of cancer cells treated by a low-intensity alternating electric field.

Elimination of serious side effects is a desired feature of cancer therapy. Alternating electric field treatment is one approach to the non-invasive treatment of cancer. The efficacy and safety of this novel therapy are confirmed for the treatment of glioblastoma multiforme. In the current study, we co-cultured cancer cells and normal cells to investigate the selectivity and chemosensitivity enhancement of an electric field treatment. Cancer cells (cell line: HeLa and Huh7) and fibroblasts (cell line: HEL299) were cultured in an in-house-developed cell culture device embedded with stimulating electrodes. A low-intensity alternating electric field was applied to the culture. The field significantly induced proliferation arrest of the cancer cells, while had limited influence on the fibroblasts. Moreover, in combination with the anti-cancer drug, damage to the cancer cells was enhanced by the electric field. Thus, a lower dosage of the drug could be applied to achieve the same treatment effectiveness. This study provides evidence that low-intensity electric field treatment selectively induced proliferation arrest and enhanced the chemosensitivity of the cancer cells. This electro-chemotherapy could be developed and applied as a regional cancer therapy with minimal side effects.

Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study.

BACKGROUND: Tumor Treating Fields (TTFields) are an anti-mitotic therapy comprising continuous delivery of low-intensity alternating electric fields at intermediate frequencies to the tumor region by a home-use medical device. METHODS: The INNOVATE (EF-22) Study was a phase 2, single arm clinical trial, which tested the safety and efficacy of TTFields (200 kHz) in combination with weekly paclitaxel (weekly for 8 weeks and then on days 1, 8, 15 of each subsequent 28 day-cycle; starting dose 80 mg/m2) in 31 patients with recurrent, platinum-resistant ovarian carcinoma. The primary endpoint was safety and secondary endpoints included OS, PFS and RR. RESULTS: Median age was 60 (range: 45-77), 24 patients (77%) had serous histology, 16 patients (52%) ECOG score 0 and 15 (48%) ECOG 1, the median number of prior chemotherapy lines was 4 (range: 1-11). All patients received prior platinum-based chemotherapy and 30 (97%) received prior taxanes. No serious adverse events related to TTFields were reported. There was no increase in grade 3-4 adverse events compared to the frequency of such events reported in the literature with single agent weekly paclitaxel. Twenty-six patients (84%) had the expected TTFields-related dermatitis but only one patient permanently discontinued TTFields due to dermatitis. The median PFS was 8.9 months, 7 patients (25%) had partial response and the clinical benefit rate was 71%. The median overall survival was not reached: the one-year survival rate was 61%. CONCLUSION: TTFields combined with weekly paclitaxel were safe in platinum-resistant recurrent ovarian cancer and warrants evaluation in a randomized phase 3 trial.

Acceptance and compliance of TTFields treatment among high grade glioma patients.

BACKGROUND: Tumor treating fields (TTFields) significantly prolong both progression-free and overall survival in patients with newly diagnosed glioblastoma (GBM). TTFields are delivered to the brain tumor via skin transducer arrays and should be applied for a minimum of 18 h per day (≥ 75% compliance). This may cause limited acceptance by patients because of obstacles in daily routine. So far, there are limited data on factors influencing therapy acceptance and compliance. METHODS: In this retrospective study, fourty-one patients with primary GBM or recurrent high grade glioma (rHGG) have been treated with TTFields in our department. Compliance reports were generated at the monthly routine check of the device. We investigated demographic data, stage of disease and therapy duration in regard to treatment compliance. RESULTS: Thirty percent of patients with primary diagnosis of GBM were informed about TTFields. Acceptance rate among these patients was 36%. In this study, TTFields were prescribed in newly diagnosed GBM patients (57%) and in rHGG. Mean treatment compliance was 87% in the total population independent of age, sex and stage of disease. Compliance was not negatively correlated with time on treatment. CONCLUSION: TTFields are effective in newly diagnosed GBM, therefore acceptance and compliance is important for GBM treatment. We experienced moderate acceptance rate for TTFields, which is influenced by factors such as social support, comorbidities and independence in daily life. Overall therapy compliance lies above 75% and is not influenced by age, sex, stage of disease or duration of therapy. Improved patient consultation strategies will increase acceptance and compliance for better outcome.

Tumor-treating fields as a fourth treating modality for glioblastoma: a meta-analysis.

BACKGROUND: We aim to review the available literature on patients suffering from glioblastoma treated with tumor-treating fields (TTFields) plus radio chemotherapy or conventional radio chemotherapy alone, to compare the efficacy and safety of the two methods. METHODS: A systematic literature search was performed in PubMed, Cochrane library, and Scopus databases, in accordance with the PRISMA guidelines. Six studies met the inclusion criteria incorporating 1806 patients for the qualitative analysis and 1769 for the quantitative analysis. RESULTS: This study reveals increased median overall survival (weighted mean difference (WMD) 3.29 [95% confidence interval (CI) 2.37, 4.21]; p < 0.00001), survival at 1 year (odds ratio (OR) 1.81 [95% CI 1.41, 2.32]; p < 0.00001) and 2 years (OR 2.33 [95% CI 1.73, 3.14]; p < 0.00001), and median progression-free survival (WMD 2.35 [95% CI 1.76, 2.93]; p < 0.00001) along with progression-free survival at 6 months (WMD 6.86 [95% CI 5.91, 7.81]; p < 0.00001) for the patients treated with TTFields. Survival at 3 years was comparable between the two groups. TTFields were associated with fewer adverse events compared to chemotherapy along with similar incidence of skin irritation. CONCLUSIONS: TTFields are a safe and efficient novel treatment modality. More randomized controlled studies, with longer follow-up, are necessary to further assess the clinical outcomes of TTFields.

Planning TTFields treatment using the NovoTAL system-clinical case series beyond the use of MRI contrast enhancement.

BACKGROUND: Gliomas are the most common primary brain tumors in adults and invariably carry a poor prognosis. Recent clinical studies have demonstrated the safety and compelling survival benefit when tumor treating fields (TTFields) are added to temozolomide for patients with newly diagnosed glioblastoma. TTFields are low-intensity, intermediate frequency (200 kHz) alternating electric fields, delivered directly to a patient's brain through the local application of non-invasive transducer arrays. Experimental simulations have demonstrated that TTFields distribute in a non-uniform manner within the brain. To ensure patients receive the maximal therapeutic level of TTFields at the site of their tumor, tumor burden is mapped and an optimal array layout is personalized using the NovoTAL software. The NovoTAL software utilizes magnetic resonance imaging (MRI) measurements for head size and tumor location obtained from axial and coronal T1 postcontrast sequences to determine the optimal paired transducer array configuration that will deliver the maximal field intensity at the site of the tumor. In clinical practice, physicians planning treatment with TTFields may determine that disease activity is more accurately represented in noncontrast-enhancing sequences. Here we present and discuss a series of 8 cases where a treating physician has utilized non-contrast enhancement and advanced imaging to inform TTFields treatment planning based on a clinical evaluation of where a patient is believed to have active tumor. This case series is, to our knowledge, the first report of this kind in the literature. CASE PRESENTATIONS: All patients presented with gliomas (grades 2-4) and ranged in age from 49 to 65 years; 5 were male and 3, female. Each patient had previously received standard therapy including surgery, radiation therapy and/or chemotherapy prior to initiation of TTFields. The majority had progressed on prior therapy. A standard pre- and postcontrast MRI scan was acquired and used for TTFields treatment planning. CONCLUSION: This paper details important approaches for integrating clinical considerations, nonmeasurable disease and advanced imaging into the treatment planning workflow for TTFields. As TTFields become integrated into standard care pathways for glioblastoma, this case series demonstrates that treatment planning beyond the extent of contrast enhancement is clinically feasible and should be prospectively compared to standard treatment planning in a clinical trial setting, in order to determine the impact on patient outcomes.