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Martin Glas - One of the best experts on this subject based on the ideXlab platform.
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abstract ct258 ef 32 trident a pivotal randomized trial of radiation therapy concomitant with temozolomide Tumor Treating Fields ttFields in newly diagnosed glioblastoma
Clinical Trials, 2021Co-Authors: Wenyin Shi, Lawrence Kleinberg, Suriya A Jeyapalan, Samuel Goldlust, Seema Nagpal, Stephanie E Combs, David Roberge, Ryo Nishigawa, Rachel Grossman, Martin GlasAbstract:Purpose: Tumor Treating Fields (TTFields) is a non-invasive, loco-regional antimitotic treatment approved as a standard-of-care for newly diagnosed glioblastoma (ndGBM). In the Phase 3 EF-14 trial, TTFields (200 kHz) plus temozolomide (TMZ) post-surgery and chemoradiation significantly increased survival of ndGBM patients compared to TMZ alone. The addition of TTFields was not associated with any increases in systemic toxicity. TTFields-related adverse events (AEs) were mainly dermatological. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of TTFields concomitant with RT and TMZ will be investigated in the TRIDENT trial. Methodology: TRIDENT (NCT04471844) is an international, pivotal randomized trial comparing standard RT with concomitant TMZ vs the triple combination of RT with concomitant TMZ and TTFields. RT is delivered through the TTFields transducer arrays. Patients in both arms will receive maintenance TTFields and TMZ. TTFields (200 KHz) will be delivered >18 hours/day using the Optune device. TTFields treatment will be continued until the second disease recurrence. Patients with pathologically confirmed ndGBM, ≥ 18 years (≥ 22 years in the US), KPS ≥ 70, either sex, post-surgery or biopsy, and candidates for RT/TMZ therapy will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points include progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), PFS (PFS6M, PF12M, PFS2Y); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM Tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields/RT/TMZ will significantly improve OS versus RT/TMZ. Sample size (N=950; 475/arm) will detect a HR Citation Format: Wenyin Shi, Lawrence Kleinberg, Suriya A. Jeyapalan, Samuel A. Goldlust, Seema Nagpal, Stephanie E. Combs, David Roberge, Ryo Nishigawa, Rachel Grossman, Martin Glas. EF-32 (TRIDENT): A pivotal randomized trial of radiation therapy concomitant with temozolomide +/- Tumor Treating Fields (TTFields) in newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT258.
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abstract lb 167 post marketing safety surveillance of Tumor Treating Fields ttFields in patients with high grade glioma in clinical practice
Cancer Research, 2020Co-Authors: Wenyin Shi, Rimas V. Lukas, Jayjiguang Zhu, Deborah T Blumenthal, Nancy Ann Oberheim Bush, Seid Kebir, Yoshihiro Muragaki, Martin GlasAbstract:Introduction: Tumor Treating Fields (TTFields) are an antineoplastic treatment delivering low-intensity, intermediate-frequency, alternating electric Fields through 2 pairs of transducer arrays locoregionally applied to Tumor bed. TTFields are FDA-approved for glioblastoma (GBM; 200 kHz) and mesothelioma (150 kHz). Safety and effectiveness were demonstrated in the Phase 3 EF-11 and EF-14 trials in recurrent GBM (rGBM) and in newly diagnosed GBM (ndGBM), respectively. The main TTFields-related adverse event (AE) was array-associated manageable scalp irritation. We report AEs from TTFields-treated patients in the real-world, clinical practice setting. Methods: Unsolicited, global, post-market surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1, stratified by region (US, EMEA [Europe, Middle East, Africa], or Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma, anaplastic oligodendroglioma, or other brain Tumors [includes brain metastases from different cancer types]), and age (years; Citation Format: Wenyin Shi, Deborah T. Blumenthal, Nancy Ann Oberheim Bush, Sied Kebir, Rimas V. Lukas, Yoshihiro Muragaki, Jay-Jiguang Zhu, Martin Glas. Post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-167.
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prevention and management of dermatologic adverse events associated with Tumor Treating Fields in patients with glioblastoma
Frontiers in Oncology, 2020Co-Authors: Mario E Lacouture, Suriya A Jeyapalan, Fabio M Iwamoto, Milan J Anadkat, Matthew T Ballo, Renato V La Rocca, Margaret Schwartz, Jennifer Serventi, Martin GlasAbstract:Importance: Tumor Treating Fields (TTFields) are an anti-mitotic treatment approved for Treating newly diagnosed and recurrent glioblastoma, and mesothelioma. TTFields in glioblastoma comprise alternating electric Fields (200 kHz) delivered continuously, ideally for ≥18 h/day, to the Tumor bed via transducer arrays placed on the shaved scalp. When applied locoregionally to the Tumor bed and combined with systemic temozolomide chemotherapy, TTFields improved overall survival vs. temozolomide alone in patients with newly diagnosed glioblastoma. Improved efficacy outcomes with TTFields were demonstrated, while maintaining a well-tolerated and manageable safety profile. The most commonly-reported TTFields-associated adverse events (AEs) are beneath-array dermatologic events. Since survival benefit from TTFields increases with duration-of-use, prevention and management of skin AEs are critical to maximize adherence. This paper describes TTFields-associated dermatological AEs and recommends prevention and management strategies based on clinical trial evidence and real-world clinical experience. Observations: TTFields-associated skin reactions include contact dermatitis (irritant/allergic), hyperhidrosis, xerosis or pruritus, and more rarely, skin erosions/ulcers and infections. Skin AEs may be prevented through skin-care and shifting (~2 cm) of array position during changes. TTFields-related skin AE management should be based on clinical phenotype and severity. Depending on diagnosis, recommended treatments include antibiotics, skin barrier films, moisturizers, topical corticosteroids, and antiperspirants. Water-based lotions, soaps, foams, and solutions with minimal impact on electrical impedance are preferred with TTFields use over petroleum-based ointments, which increase impedance. Conclusions: Early identification, prophylactic measures, and symptomatic skin AE management help patients maximize TTFields usage, while maintaining quality-of-life and optimizing therapeutic benefit. Implications for practice: TTFields confer a survival benefit in patients with glioblastoma that correlates positively with duration of daily use. Skin events (rash) are the primary treatment-related AE that can limit duration of use. The recommendations described here will help healthcare professionals to recognize, prevent, and manage dermatologic AEs associated with TTFields treatment. These recommendations may improve cutaneous health and support adherence to therapy, both of which would maximize treatment outcomes.
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global post marketing safety surveillance of Tumor Treating Fields ttFields in patients with high grade glioma in clinical practice
Journal of Neuro-oncology, 2020Co-Authors: Wenyin Shi, Rimas V. Lukas, Jayjiguang Zhu, Deborah T Blumenthal, Nancy Ann Oberheim Bush, Seid Kebir, Yoshihiro Muragaki, Martin GlasAbstract: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. 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 ( 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.
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phase iii trident trial radiation and temozolomide Tumor Treating Fields in newly diagnosed glioblastoma
Journal of Clinical Oncology, 2020Co-Authors: Wenyin Shi, David A. Reardon, Lawrence Kleinberg, Suriya A Jeyapalan, Samuel Goldlust, Seema Nagpal, Stephanie E Combs, David Roberge, Ryo Nishigawa, Martin GlasAbstract:TPS2580Background: Tumor Treating Fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard of care for glioblastoma (GBM). In the EF-14 phase III trial, TTFields (...
Eilon D Kirson - One of the best experts on this subject based on the ideXlab platform.
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abstract ct173 Tumor Treating Fields 150 khz concurrent with standard of care treatment for stage 4 non small cell lung cancer nsclc following platinum failure the phase iii lunar study
Cancer Research, 2019Co-Authors: Uri Weinberg, Zeev Bomzon, Ori Farber, Moshe Giladi, Eilon D KirsonAbstract:Background Tumor Treating Fields (TTFields) is a non-invasive, anti-mitotic treatment that disrupts the formation of the mitotic spindle and dislocation of intracellular constituents. TTFields plus temozolomide significantly extended survival in newly diagnosed glioblastoma. Efficacy of TTFields in NSCLC has been shown in preclinical in vitro and in vivo models. In a Phase I/II pilot study [NCT00749346} of advanced NSCLC, TTFields in combination with pemetrexed detected no serious adverse events and median overall survival (OS) was 13.8 months. In the Phase III LUNAR study [NCT02973789], we investigated if the addition of TTFields to immune checkpoint inhibitors or docetaxel following platinum doublet failure will increase overall survival (OS). Methods Patients (N=534), with squamous or non-squamous NSCLC, are stratified by their selected standard therapy (immune checkpoint inhibitors or docetaxel), histology (squamous vs. non-squamous) and geographical region. Key inclusion criteria are disease progression while on or after platinum-based therapy, ECOG 0-2, no electronic medical devices in the upper torso, and absence of brain metastasis. Docetaxel or immune checkpoint inhibitors are given at standard doses. TTFields (150 kHz) are applied to the upper torso for at >18 hours/day, allowing patients to maintain daily activities. TTFields are continued until progression in the thorax and/or liver. Follow up is performed once q6 weeks, including CT scans of the chest and abdomen. On progression in the thorax and/or liver, patients have 3 post-progression follow up visits and are then followed monthly for survival. The primary endpoint is superiority in OS between patients treated with TTFields in combination with the standard of care treatments versus standard of care treatments alone. Key secondary endpoints compare the OS in patients treated with TTFields and docetaxel versus docetaxel alone, and patients treated with TTFields and immune checkpoint inhibitors vs those treated with immune checkpoint inhibitors alone. An exploratory analysis will test non-inferiority of TTFields with docetaxel compared to checkpoint inhibitors alone. Secondary endpoints include progression-free survival, radiological response rate, quality of life based on the EORTC QLQ C30 questionnaire and severity and frequency of adverse events. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group. Citation Format: Uri Weinberg, Ori Farber, Moshe Giladi, Zeev Bomzon, Eilon Kirson. Tumor Treating Fields (150 kHz) concurrent with standard of care treatment for stage 4 non-small cell lung cancer (NSCLC) following platinum failure: The Phase III LUNAR study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT173.
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Supplementary_file_questionnaire – Supplemental material for Tumor Treating Fields for Glioblastoma Treatment: Patient Satisfaction and Compliance With the Second-Generation Optune® System
2019Co-Authors: Adrian Kinzel, Michael Ambrogi, Michael Varshaver, Eilon D KirsonAbstract:Supplemental material, Supplementary_file_questionnaire for Tumor Treating Fields for Glioblastoma Treatment: Patient Satisfaction and Compliance With the Second-Generation Optune® System by Adrian Kinzel, Michael Ambrogi, Michael Varshaver and Eilon D Kirson in Clinical Medicine Insights: Oncology
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Tumor Treating Fields for Glioblastoma Treatment: Patient Satisfaction and Compliance With the Second-Generation Optune System
'SAGE Publications', 2019Co-Authors: Adrian Kinzel, Michael Ambrogi, Michael Varshaver, Eilon D KirsonAbstract:Background: Tumor Treating Fields (TTFields) are a non-invasive antimitotic therapy that delivers alternating electric Fields via the Optune ® system. The Phase III EF-14 trial in newly diagnosed glioblastoma multiforme (GBM) showed significantly improved progression-free, overall and long-term survival when Optune was used together with maintenance temozolomide (TMZ) compared with TMZ alone. Compliance (average monthly use) was associated with better clinical outcome. The first-generation Optune system weighed approximately 6 pounds (~2.7 kg). The second-generation redesigned Optune system weighs 2.7 pounds (~1.2 kg). We tested and compared GBM patient experience with the second-generation system versus the first-generation system. Methods: Ten newly diagnosed and recurrent GBM patients in Germany (median age: 52.9 years [31-79]) were prospectively monitored over the first month of transitioning from the first-generation to the second-generation Optune system. Questionnaires using a numerical analog scale assessed feedback at baseline (first generation) and after 1 month of second-generation use. Results: After transitioning to the second-generation system, compliance improved by more than 10% in four patients, was maintained in five patients and decreased by more than 10% in one patient. Following transition, eight out of nine patients reported a reduction in the triggering of malfunction alarms. Self-reported patient feedback showed improved handling and portability (weight, mobility) of the second- versus the first-generation Optune system. Conclusions: This patient user survey suggests that patient satisfaction with the second-generation Optune system is improved versus the first-generation system. Improved features of the new system help patients achieve and maintain a higher rate of treatment compliance
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AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields)
Nature Publishing Group, 2018Co-Authors: Anna Shteingauz, Moshe Giladi, Einav Zeevi, Rosa S Schneiderman, Yaara Porat, Mijal Munster, Tali Voloshin, Noa Kaynan, Karnit Gotlib, Eilon D KirsonAbstract:Abstract Tumor Treating Fields (TTFields), an approved treatment modality for glioblastoma, are delivered via non-invasive application of low-intensity, intermediate-frequency, alternating electric Fields. TTFields application leads to abnormal mitosis, aneuploidy, and increased cell granularity, which are often associated with enhancement of autophagy. In this work, we evaluated whether TTFields effected the regulation of autophagy in glioma cells. We found that autophagy is upregulated in glioma cells treated with TTFields as demonstrated by immunoblot analysis of the lipidated microtubule-associated protein light chain 3 (LC3-II). Fluorescence and transmission electron microscopy demonstrated the presence of LC3 puncta and typical autophagosome-like structures in TTFields-treated cells. Utilizing time-lapse microscopy, we found that the significant increase in the formation of LC3 puncta was specific to cells that divided during TTFields application. Evaluation of selected cell stress parameters revealed an increase in the expression of the endoplasmic reticulum (ER) stress marker GRP78 and decreased intracellular ATP levels, both of which are indicative of increased proteotoxic stress. Pathway analysis demonstrated that TTFields-induced upregulation of autophagy is dependent on AMP-activated protein kinase (AMPK) activation. Depletion of AMPK or autophagy-related protein 7 (ATG7) inhibited the upregulation of autophagy in response to TTFields, as well as sensitized cells to the treatment, suggesting that cancer cells utilize autophagy as a resistance mechanism to TTFields. Combining TTFields with the autophagy inhibitor chloroquine (CQ) resulted in a significant dose-dependent reduction in cell growth compared with either TTFields or CQ alone. These results suggest that dividing cells upregulate autophagy in response to aneuploidy and ER stress induced by TTFields, and that AMPK serves as a key regulator of this process
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Tumor Treating Fields ttFields delay dna damage repair following radiation treatment of glioma cells
Radiation Oncology, 2017Co-Authors: Moshe Giladi, Zeev Bomzon, Rosa S Schneiderman, Yaara Porat, Mijal Munster, Tali Voloshin, Roni Blat, Katarzyna Zielinskachomej, Petra Haag, Eilon D KirsonAbstract:Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric Fields using insulated transducer arrays placed directly on the skin in the region surrounding the Tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity. The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy). TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the “skin sparing effect”. Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions. Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.
Uri Weinberg - One of the best experts on this subject based on the ideXlab platform.
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abstract ct173 Tumor Treating Fields 150 khz concurrent with standard of care treatment for stage 4 non small cell lung cancer nsclc following platinum failure the phase iii lunar study
Cancer Research, 2019Co-Authors: Uri Weinberg, Zeev Bomzon, Ori Farber, Moshe Giladi, Eilon D KirsonAbstract:Background Tumor Treating Fields (TTFields) is a non-invasive, anti-mitotic treatment that disrupts the formation of the mitotic spindle and dislocation of intracellular constituents. TTFields plus temozolomide significantly extended survival in newly diagnosed glioblastoma. Efficacy of TTFields in NSCLC has been shown in preclinical in vitro and in vivo models. In a Phase I/II pilot study [NCT00749346} of advanced NSCLC, TTFields in combination with pemetrexed detected no serious adverse events and median overall survival (OS) was 13.8 months. In the Phase III LUNAR study [NCT02973789], we investigated if the addition of TTFields to immune checkpoint inhibitors or docetaxel following platinum doublet failure will increase overall survival (OS). Methods Patients (N=534), with squamous or non-squamous NSCLC, are stratified by their selected standard therapy (immune checkpoint inhibitors or docetaxel), histology (squamous vs. non-squamous) and geographical region. Key inclusion criteria are disease progression while on or after platinum-based therapy, ECOG 0-2, no electronic medical devices in the upper torso, and absence of brain metastasis. Docetaxel or immune checkpoint inhibitors are given at standard doses. TTFields (150 kHz) are applied to the upper torso for at >18 hours/day, allowing patients to maintain daily activities. TTFields are continued until progression in the thorax and/or liver. Follow up is performed once q6 weeks, including CT scans of the chest and abdomen. On progression in the thorax and/or liver, patients have 3 post-progression follow up visits and are then followed monthly for survival. The primary endpoint is superiority in OS between patients treated with TTFields in combination with the standard of care treatments versus standard of care treatments alone. Key secondary endpoints compare the OS in patients treated with TTFields and docetaxel versus docetaxel alone, and patients treated with TTFields and immune checkpoint inhibitors vs those treated with immune checkpoint inhibitors alone. An exploratory analysis will test non-inferiority of TTFields with docetaxel compared to checkpoint inhibitors alone. Secondary endpoints include progression-free survival, radiological response rate, quality of life based on the EORTC QLQ C30 questionnaire and severity and frequency of adverse events. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group. Citation Format: Uri Weinberg, Ori Farber, Moshe Giladi, Zeev Bomzon, Eilon Kirson. Tumor Treating Fields (150 kHz) concurrent with standard of care treatment for stage 4 non-small cell lung cancer (NSCLC) following platinum failure: The Phase III LUNAR study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT173.
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using computational phantoms to improve delivery of Tumor Treating Fields ttFields to patients
International Conference of the IEEE Engineering in Medicine and Biology Society, 2016Co-Authors: Zeev Bomzon, Uri Weinberg, Hadas Sara Hershkovich, Noa Urman, Aafia Chaudhry, Dario Garciacarracedo, Anders Rosendal Korshoej, Cornelia Wenger, Pedro C Miranda, Yoram WassermanAbstract:This paper reviews the state-of-the-art in simulation-based studies of Tumor Treating Fields (TTFields) and highlights major aspects of TTFields in which simulation-based studies could affect clinical outcomes. A major challenge is how to simulate multiple scenarios rapidly for TTFields delivery. Overcoming this challenge will enable a better understanding of how TTFields distribution is correlated with disease progression, leading to better transducer array designs and field optimization procedures, ultimately improving patient outcomes.
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novottf 100a system Tumor Treating Fields transducer array layout planning for glioblastoma a novotal system user study
World Journal of Surgical Oncology, 2015Co-Authors: Aafia Chaudhry, Uri Weinberg, Eilon D Kirson, Michael Varshaver, Laura Benson, Ori Farber, Yoram PaltiAbstract:Background Optune™, previously known as the NovoTTF-100A System™, generates Tumor Treating Fields (TTFields), an effective anti-mitotic therapy for glioblastoma. The system delivers intermediate frequency, alternating electric Fields to the supratentorial brain. Patient therapy is personalized by configuring transducer array layout placement on the scalp to the Tumor site using MRI measurements and the NovoTAL System. Transducer array layout mapping optimizes therapy by maximizing electric field intensity to the Tumor site. This study evaluated physician performance in conducting transducer array layout mapping using the NovoTAL System compared with mapping performed by the Novocure in-house clinical team.
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modelling Tumor Treating Fields for the treatment of lung based Tumors
International Conference of the IEEE Engineering in Medicine and Biology Society, 2015Co-Authors: Zeev Bomzon, Uri Weinberg, Noa Urman, Cornelia Wenger, Pedro C Miranda, Yoram Wasserman, M Giladi, Eilon D Kirson, Yoram PaltiAbstract:Tumor Treating Fields (TTFields), low-intensity electric Fields in the frequency range of 100-500 kHz, exhibit antimitotic activity in cancer cells. TTFields were approved by the U. S. Food and Drug Administration for the treatment of recurrent glioblastoma in 2011. Preclinical evidence and pilot studies suggest that TTFields could be effective for Treating certain types of lung cancer, and that treatment efficacy depends on the electric field intensity. To optimize TTFields delivery to the lungs, it is important to understand how TTFields distribute within the chest. Here we present simulations showing how TTFields are distributed in the thorax and torso, and demonstrate how the electric field distribution within the body can be controlled by personalizing the layout of the arrays used to deliver the field.
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alternating electric Fields Tumor Treating Fields therapy can improve chemotherapy treatment efficacy in non small cell lung cancer both in vitro and in vivo
Seminars in Oncology, 2014Co-Authors: M Giladi, Uri Weinberg, Michal Munster, Rosa S Schneiderman, Aviran Itzhaki, Shay Cahal, Tali Voloshin, Y Porat, Roni Blatt, Amir OnnAbstract:Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-Treating Fields (TTFields) are low-intensity, intermediate-frequency alternating electric Fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.
Edwin Chang - One of the best experts on this subject based on the ideXlab platform.
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Tumor Treating Fields ttFields impairs aberrant glycolysis in glioblastoma as evaluated by 18f dasa 23 a non invasive probe of pyruvate kinase m2 pkm2 expression
Neoplasia, 2021Co-Authors: Chirag B. Patel, Edwin Chang, Corinne Beinat, Yuanyang Xie, Sanjiv S GambhirAbstract:Abstract Despite the anti-proliferative and survival benefits from Tumor Treating Fields (TTFields) in human glioblastoma (hGBM), little is known about the effects of this form of alternating electric Fields therapy on the aberrant glycolysis of hGBM. [18F]FDG is the most common radiotracer in cancer metabolic imaging, but its utility in hGBM is impaired due to high glucose uptake in normal brain tissue. With TTFields, radiochemistry, Western blot, and immunofluorescence microscopy, we identified pyruvate kinase M2 (PKM2) as a biomarker of hGBM response to therapeutic TTFields. We used [18F]DASA-23, a novel radiotracer that measures PKM2 expression and which has been shown to be safe in humans, to detect a shift away from hGBM aberrant glycolysis in response to TTFields. Compared to unexposed hGBM, [18F]DASA-23 uptake was reduced in hGBM exposed to TTFields (53%, P 0.05) for 3 d. A 6-d TTFields exposure resulted in a 31% reduction (P = 0.043) in 60-min uptake of [18F]DASA-23. [18F]DASA-23 was retained after a 10 but not 30-min wash-out period. Compared to [18F]FDG, [18F]DASA-23 demonstrated a 4- to 9-fold greater uptake, implying an improved Tumor-to-background ratio. Furthermore, compared to no-TTFields exposure, a 6-d TTFields exposure caused a 35% reduction in [18F]DASA-23 30-min uptake compared to only an 8% reduction in [18F]FDG 30-min uptake. Quantitative Western blot analysis and qualitative immunofluorescence for PKM2 confirmed the TTFields-induced reduction in PKM2 expression. This is the first study to demonstrate that TTFields impairs hGBM aberrant glycolytic metabolism through reduced PKM2 expression, which can be non-invasively detected by the [18F]DASA-23 radiotracer.
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abstract 250 Tumor Treating Fields increases membrane permeability in glioblastoma cells
Cancer Research, 2019Co-Authors: Edwin Chang, Christoph Pohling, Chirag J. Patel, Caroline Young, Jonathan Song, Thomas Flores, Yitian Zeng, Lydiamarie Joubert, Hamed Arami, Arutselvan NatarajanAbstract:INTRODUCTION: Glioblastoma multiforme (GBM) is the most lethal primary brain cancer (median survival: 15-17 months, 5-year survival: 5%). Standard interventions consist of aggressive surgical resection, radiotherapy, and chemotherapy; however, GBM is heterogeneous and present therapies are often ineffective. Novel approaches need consideration. We investigated two such novel approaches: Withaferin A and Tumor Treating Fields (TTFields). Withaferin A is a steroidal lactone originating from extracts of the winter cherry plant (Withania somnifera). Extracts such as AshwaMAX can contain up to 4.3% (w/w) Withaferin A. Recently, the U.S. Food and Drug Administration approved another approach to Treating glioblastoma: Tumor Treating Fields (TTFields). TTFields involves the delivery of alternating electric Fields to the Tumor but mechanisms of action are not fully understood. METHODS: To investigate these two therapies, we used human glioblastoma cells (GBM2, GBM39, and U87-MG) isolated from primary Tumors. Cells were modified to express firefly luciferase. Proliferation was monitored by: bioluminescent imaging, cell counting via hemocytometer, or cell titer blue viability assay. TTFields were imposed on cell cultures by the inovitroTM device from Novocure Ltd. RESULTS: Both AshwaMAX and Withaferin A inhibited growth of GBM cell lines (IC50 ~0.25 µM). In exploring Withaferin A and TTFields interventions in GBM cell culture, we discovered that the steroid worked synergistically with TTFields (p CONCLUSIONS: In summary, increased membrane permeability by TTFields helps to explain previous reports of additive vs. synergistic effects between TTFields and chemotherapies, including Withaferin A. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies. Citation Format: Edwin Chang, Chirag Patel, Christoph Pohling, Caroline Young, Jonathan Song, Thomas A. Flores, Yitian Zeng, Lydia Marie Joubert, Hamed Arami, Arutselvan Natarajan, Robert Sinclair, Sanjiv S. Gambhir. Tumor Treating Fields increases membrane permeability in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 250.
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abstract 5271 molecular imaging of pyruvate kinase m2 pkm2 with 18f dasa 23 detects temozolomide and Tumor Treating Fields ttFields induced changes in glycolysis in glioblastoma
Cancer Research, 2019Co-Authors: Chirag B. Patel, Edwin Chang, Corinne Beinat, Yuanyang Xie, Sanjiv S GambhirAbstract:Introduction: Pyruvate kinase M2 (PKM2) is an enzyme that catalyzes the final step in glycolysis, a key step in Tumor metabolism and growth, making PKM2 an important marker of cancer glycolytic reprogramming. The 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) radiotracer has been developed to measure the expression of PKM2. Glioblastoma (GBM) is traditionally treated with surgical resection, temozolomide (TMZ) chemotherapy, and radiation therapy. Tumor Treating Fields (TTFields), the application of alternating electric Fields (100-500 kHz, 1-4 V/cm) to Tumors, is emerging as the fourth therapeutic modality in GBM. There is an important need to assess early on whether a patient’s GBM is responding to a given standard-of-care or experimental therapy. In this study we evaluated the ability of [18F]DASA-23 to detect changes in metabolism in response to standard-of-care (TMZ) and emerging (TTFields) therapies, in cell culture and an orthotopic murine model of human GBM. Methods: Human U87-MG GBM cells were subjected to either 200 kHz TTFields or the IC50 of TMZ for three or six days (n≥3/condition), followed by evaluation of 30-minute cellular uptake of [18F]DASA-23. In parallel experiments, immunofluorescence for PKM2 was performed to confirm the [18F]DASA-23 uptake results. Finally, U87-MG human GBM cells were orthotopically implanted in nude mice (N=5), and evaluated with 7T small animal magnetic resonance imaging (MRI) and [18F]DASA-23 microPET/CT before and one week post-initiation of vehicle or TMZ therapy. Results: There was a significant interaction between the treatment (vehicle, TMZ, or TTFields) and treatment duration (3 or 6 days) on PKM2 expression as measured by cellular uptake of [18F]DASA-23 (p=0.005, 2-way ANOVA). Immunofluorescence for PKM2 in TTFields-exposed and unexposed U87-MG cells revealed reduced cell count and less intense PKM2 staining due to TTFields. In the orthotopic mouse model, the Tumor/normal brain (T/N) [18F]DASA-23 uptake ratio (unitless) at one week post-treatment was divided by the pre-treatment T/N ratio. The resulting ratio of ratios was significantly smaller in the TMZ cohort (1.0±0.4) compared to in the vehicle cohort (2.2±0.2), p=0.004. Conclusion: Together, these data suggest the potential for non-invasive assessment of GBM’s response to various therapies using [18F]DASA-23, a radiotracer that measures PKM2 expression. Clinical studies are currently being completed to evaluate the diagnostic ability of [18F]DASA-23 in patients with intracranial malignancies and future studies will evaluate the ability of [18F]DASA-23 to predict responders vs. non-responders to therapy in recurrent GBM. Citation Format: Chirag B. Patel, Corinne Beinat, Yuanyang Xie, Edwin Chang, Sanjiv S. Gambhir. Molecular imaging of pyruvate kinase M2 (PKM2) with [18F]DASA-23 detects temozolomide- and Tumor Treating Fields (TTFields)-induced changes in glycolysis in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5271.
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Tumor Treating Fields increases membrane permeability in glioblastoma cells
Cell death discovery, 2018Co-Authors: Edwin Chang, Christoph Pohling, Chirag B. Patel, Caroline Young, Jonathan Song, Thomas Flores, Yitian Zeng, Lydiamarie Joubert, Hamed Arami, Arutselvan NatarajanAbstract:Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to Treating glioblastoma; namely, Tumor Treating Fields (TTFields). TTFields involves the delivery of alternating electric Fields to the Tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric Fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate Tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.
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Abstract 5828: Withaferin A and Tumor Treating Fields synergistically inhibit glioma proliferation
Experimental and Molecular Therapeutics, 2018Co-Authors: Edwin Chang, Christoph Pohling, Nooshin Beygui, Chirag J. Patel, Sanjiv S. GambhirAbstract:Glioblastoma multiforme (GBM) is the most lethal primary brain cancer (median survival: 15-17 months, 5-year survival: 5-10%). Current interventions consist of equally aggressive surgical resection, radiotherapy, and chemotherapy. However, this cancer is heterogeneous and not easily accessible so standardized, non-specific therapies are often ineffective. Novel, unorthodox approaches against GBM need consideration. Withaferin A is a steroidal lactone that originates from the roots and leaves of the winter cherry plant (Withania somnifera). Within Ayurvedic medicine, Withania somnifera extracts are applied to many disorders including several cancers. Extracts such as AshwaMAX can contain up to 4.3% (w/w) Withaferin A, a biologically active compound from Withania somnifera. Tumor Treating Fields (TTFields) are thought to disrupt mitotic spindle formation and stymie proliferation of actively dividing cancer cells. We report on the anti-cancer properties of both Withaferin A and TTFields. We also examined the hypothesis that combining TTFields with Withaferin A would synergistically inhibit GBM growth. We used GBM cells (U87-MG, GBM2, and GBM39) and breast adenocarcinoma cells (MDA-MB-231) isolated from human primary Tumors. Each GBM cell line was modified to express firefly luciferase. Proliferative potential was assessed by bioluminescent imaging (BLI), cell counting via hemocytometer, or through the CellTiter-Blue® viability assay. Intracranial orthotopic U87-MG GBM xenografts were grown in the right frontal lobe of female nude mice (n=5/experiment). TTFields were imposed on cell cultures with the inovitroTM system from Novocure Ltd. Neurosphere cultures (U87-MG, GBM2, and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM (Withaferin A equivalent), respectively, and by Withaferin A with IC50 of 0.31, 0.28, and 0.25 µM, respectively. Oral gavage, every other day, of AshwaMAX (40mg/kg per dose) significantly reduced BLI signal (n=5 mice/group, p Citation Format: Edwin Chang, Chirag Patel, Christoph Pohling, Nooshin Beygui, Dong Ho Ha, Sanjiiv S. Gambhir. Withaferin A and Tumor Treating Fields synergistically inhibit glioma proliferation [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 5828.
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403 phase 3 trial of Tumor Treating Fields concomitant with weekly paclitaxel for platinum resistant ovarian cancer engot ov50 gog 329 innovate 3
International Journal of Gynecologic Cancer, 2020Co-Authors: Ignace Vergote, Jalid Sehouli, R Fossati, Robert L Coleman, Bradley J Monk, Larry J Copeland, David M OmalleyAbstract:Introduction/Background Tumor Treating Fields (TTFields) are a non-invasive, antimitotic cancer therapy. The Phase 2 INNOVATE study demonstrated safety of TTFields/weekly paclitaxel in 31 PROC (platinum-resistant ovarian cancer) patients (Vergote Gyn Onc 2018); efficacy: median PFS 8.9 months, 25% partial response,71% clinical benefit and 61% 1-year survival rate. This phase 3 ENGOT-ov50/GOG-329/INNOVATE-3 study [NCT03940196] investigates TTFields plus weekly paclitaxel in PROC patients. Methodology Patients (N=540) will have PROC (RECIST V1.1) within 6 months of last platinum therapy with maximum of 2–5 prior lines of systemic therapy, ECOG 0–1 and no peripheral neuropathy >grade1. Patients with primary refractory disease will be excluded. Patients will be randomized 1:1 to weekly paclitaxel alone or weekly paclitaxel (starting of dose 80 mg/m2 weekly for 8 weeks, and then on Days 1, 8, and 15 for subsequent 28-day cycle ) plus TTFields (200 kHz for 18 hours/day and continued if no progression in the abdominal or pelvic regions (‘in-field region’) per RECIST V1.1. Clinical follow-up will be performed q4w, with radiological follow-up (CT or MRI scans of the abdomen and chest) q8w. The primary endpoint is overall survival. Secondary endpoints: PFS, objective response rate, AEs, and quality of life (EORTC QLQ-C30 with QLQ-OV28). Sample size (n=540) will detect an increase in median OS from 12 to 16 months (HR 0.75). Data Monitoring Committee (DMC) meeting (March 2020) concluded that data to-date showed no safety issues and recommended trial continuation. Results TiP N/A Conclusion TiP N/A Disclosures
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meta analysis of toxicity data in thoracic and abdominal malignancies from clinical trials in Tumor Treating Fields
Journal of Clinical Oncology, 2019Co-Authors: Ignace Vergote, Miklos Pless, Fernando Rivera, Giovanni Luca CeresoliAbstract:e14658Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, antimitotic treatment modality, which has been approved for the treatment of glioblastoma (GBM) by the FDA. Mil...
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Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma results of the innovate pilot study
Gynecologic Oncology, 2018Co-Authors: Ignace Vergote, Roger Von Moos, Luis Manso, Els Van Nieuwenhuysen, Nicole Concin, C SessaAbstract:Abstract 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.
