Clinical Practice Experience With NovoTTF-100A™ System for Glioblastoma: The Patient Registry Dataset (PRiDe)

Mrugala, Maciej M.; Engelhard, Herbert H.; Tran, David; Kew, Yvonne; Cavaliere, Robert; Villanó, John L.; Bota, Daniela; Rudnick, Jeremy; Sumrall, Ashley; Zhu, Jay Jiguang; Butowski, Nicholas

doi:10.1053/j.seminoncol.2014.09.010

Cited by 125 publications

(111 citation statements)

References 28 publications

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“…The compliance with TTFields therapy in the clinical trials was tightly linked to the survival outcomes; monthly compliance above 75% was associated with higher overall survival 9,10,31 . Our cell culture experiments revealed that the surviving cells recover with a delay of 24 h after end of TTFields application.…”

Section: Discussionmentioning

confidence: 99%

“…For clinical use they are applied at tumor specific frequencies via ceramic electrodes, so-called transducer arrays, adhered to the shaved scalp of the patient. The therapy compliance was tightly linked to the outcome and monthly compliance above 75% was associated with higher overall survival 9,10 . In addition, this important development in the treatment of GBM patients, the therapy may be further improved by its combination with synergistic therapies.…”

Section: Introductionmentioning

confidence: 99%

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Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

et al. 2018

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Tumor treating fields (TTFields) are approved for glioblastoma (GBM) therapy. TTFields disrupt cell division by inhibiting spindle fiber formation. Spindle assembly checkpoint (SAC) inhibition combined with antimitotic drugs synergistically decreases glioma cell growth in cell culture and mice. We hypothesized that SAC inhibition will increase TTFields efficacy. Human GBM cells (U-87 MG, GaMG) were treated with TTFields (200 kHz, 1.7 V/cm) and/or the SAC inhibitor MPS1-IN-3 (IN-3, 4 µM). Cells were counted after 24, 48, and 72 h of treatment and at 24 and 72 h after end of treatment (EOT). Flow cytometry, immunofluorescence microscopy, Annexin-V staining and TUNEL assay were used to detect alterations in cell cycle and apoptosis after 72 h of treatment. The TTFields/IN-3 combination decreased cell proliferation after 72 h compared to either treatment alone (−78.6% vs. TTFields, P = 0.0337; −52.6% vs. IN-3, P = 0.0205), and reduced the number of viable cells (62% less than seeded). There was a significant cell cycle shift from G1 to G2/M phase (P < 0.0001). The apoptotic rate increased to 44% (TTFields 14%, P = 0.0002; IN-3 4%, P < 0.0001). Cell growth recovered 24 h after EOT with TTFields and IN-3 alone, but the combination led to further decrease by 92% at 72 h EOT if IN-3 treatment was continued (P = 0.0288). The combination of TTFields and SAC inhibition led to earlier and prolonged effects that significantly augmented the efficacy of TTFields and highlights a potential new targeted multimodal treatment for GBM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

et al. 2018

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“…This trial lead to the approval of the Optune™ system for the treatment of recurrent GBM by the FDA. The analysis of a patient registry dataset (PRiDe) with 457 recurrent GBM patients who were treated with TTFields showed that ≥75% compliance, i.e., application for ≥18 hour per day, was a favourable prognostic factor (Mrugala et al 2014). A recent a Phase III clinical trial (EF-14) of TTFields in patients with newly diagnosed GBM was terminated during interim analysis due to early success (Stupp et al 2014).…”

Section: Introductionmentioning

confidence: 99%

The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study

et al. 2015

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Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic and approved treatment for recurrent glioblastoma multiforme (GBM) patients. In vitro studies have shown that inhibition of cell division in glioma is achieved when the applied alternating electric field has a frequency in the range of 200 kHz and an amplitude of 1 - 3 V/cm. Our aim is to calculate the electric field distribution in the brain during TTFields therapy and to investigate the dependence of these predictions on the heterogeneous, anisotropic dielectric properties used in the computational model. A realistic head model was developed by segmenting MR images and by incorporating anisotropic conductivity values for the brain tissues. The finite element method (FEM) was used to solve for the electric potential within a volume mesh that consisted of the head tissues, a virtual lesion with an active tumour shell surrounding a necrotic core, and the transducer arrays. The induced electric field distribution is highly non-uniform. Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less. A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature. Comparing results to a previously developed head model suggests significant inter-subject variability. This modelling study predicts that during treatment with TTFields the electric field in the tumour exceeds 1 V/cm, independent of modelling assumptions. In the future, computational models may be useful to optimize delivery of TTFields.

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“…Additionally, a surface electrical system called Optune that disrupts mitotic spindle formation and cytokinesis has been approved by the FDA for treatment of recurrent GBM after demonstrating survival rates comparable to those achieved with physician's choice chemotherapy [51] and for upfront treatment of GBM after demonstrating a survival advantage when added to standard chemoradiation [2••].…”

Section: Other Targeted Therapies In Gliomasmentioning

confidence: 99%

Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future

Chen

Cohen

Colman

2016

Curr. Treat. Options in Oncol.

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High-grade gliomas remain incurable despite current therapies, which are plagued by high morbidity and mortality. Molecular categorization of glioma subtypes using mutations in isocitrate dehydrogenase 1/2 (IDH1/2), TP53, and ATRX; codeletion of chromosomes 1p and 19q; DNA methylation; and amplification of genes such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, alpha polypeptide provides a more accurate prognostication and biologic classification than classical histopathological diagnoses, and a number of molecular markers are being incorporated in the new World Health Organization classification of gliomas. However, despite the improved understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways, these observations have so far failed to result in the successful application of targeted therapies, as has occurred in other solid tumors. To date, the only targeted therapy for gliomas approved by the US Food and Drug Administration is bevacizumab, which targets vascular endothelial growth factor. EGFR remains a dominant molecular alteration in specific glioma subtypes and represents a potentially promising target, with drugs of multiple types targeting EGFR in development including vaccines, antibody drug conjugates, and chimeric antigen receptor (CAR) T cells, despite the prior failures of EGFR tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens and tumor-specific antigens, pulsed dendritic cells, heat shock protein-tumor conjugates, and CAR T cells. Mutations in the IDH1/2 genes are central to gliomagenesis in a high proportion of grade II and III gliomas, and ongoing trials are examining vaccines against IDH1, small molecular inhibitors of IDH1 and IDH2, and metabolic components including NAD+ depletion to target IDH-mutated gliomas. The central role of DNA methylation in a subset of gliomas may be targetable, but better understanding of the relation between epigenetic alterations and resulting tumor biology appears necessary. Ultimately, given the prior failure of single-agent targeted therapy in high-grade gliomas, it appears that novel combinatorial therapy or targeted drugs with immunomodulatory or epigenetic approaches will likely be necessary to successfully combat these challenging tumors.

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Clinical Practice Experience With NovoTTF-100A™ System for Glioblastoma: The Patient Registry Dataset (PRiDe)

Cited by 125 publications

References 28 publications

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study

Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future

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