Hadas Sara Hershkovich

Using computational phantoms to improve delivery of Tumor Treating Fields (TTFields) to patients

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.

First steps to creating a platform for high throughput simulation of TTFields

Tumor Treating Fields (TTFields) are low intensity alternating electric fields in the 100-500 KHz frequency range that are known to have an anti-mitotic effect on cancerous cells. In the USA, TTFields are approved by the Food and Drug Administration (FDA) for the treatment of glioblastoma (GBM) in both the newly diagnosed and recurrent settings. Optimizing treatment with TTFields requires a deep understanding of how TTFields distribute within the brain. To address this issue, simulations using realistic head models have been performed. However, the preparation of such models is time-consuming and requires a high level of expertise, limiting the usefulness of these models for systematic studies in which the testing of multiple cases is required. Here we present a platform for rapidly simulating TTFields distributions in multiple scenarios. This platform enables high throughput computational simulations to be performed, allowing comparison of field distributions within the head in multiple clinically relevant scenarios. The simulation setup is simple and intuitive, allowing non-expert users to run simulations and evaluate results, thereby providing a valuable tool for studying how to optimize TTFields delivery in the clinic.

Abstract 4111: Water content based Electrical Properties Tomography (wEPT) for modelling delivery of Tumor Treating Fields to the brain

Objective: The purpose of this study was to investigate the application of Water content based Electrical Properties Tomography for mapping electrical properties (EPs) of brain tissues in the frequency range of 100-1000 kHz. Background: TTFields are electric fields with frequencies of 100-500 kHz that disrupt mitosis. TTFields are approved for the treatment of glioblastoma multiforme. Determining the EPs of brain tissues is important for understanding how TTFields distribute within the head. The EPs of tissues are heterogeneous, especially in the region of the tumor. Therefore methods that map EPs within the brain with high spatial resolution are desired. Water content based EP tomography (wEPT) is a method that utilizes the ratio of two T1w MRI images with different relaxation times (TRs) to map EPs based on empirically derived relationships between T1, water content (WC) and EPs. wEPT has been applied to map EPs of healthy brain at 128 MHz using typical WC and EP values of healthy tissues reported in the literature to derive the empirical models. Here we adapted wEPT to map EPs in the 100-1000 kHz range utilizing in-house measurements of WC and EPs from healthy bovine and tumor-bearing rat brain tissue. Methods: The empirical model connecting MRI images, WC and EPs in the 100-1000 kHz range were created using 32 tissue samples derived from three 3 calf brains and 1 CSF sample of a pig. For each sample, T1w MRIs with TRs {700, 4000} ms were acquired and the image ratio (Ir) between the images was calculated. EPs of samples were measured using parallel plates, and WC was measured by the wet-dry weight method. Curve fitting yielded empirical models connecting Ir, WC and EP. Next, T1w MRIs of in-vivo tumor-bearing rat brains and 6 ex-vivo pieces of calf brain were acquired, and the empirical curves described above were used to map WC and EP within the rat brains and the pieces of calf brain. EPs and WC were measured on 6 small samples excised from each imaged brain. For each sample, measured values were compared to the median WC and EPs extracted from the corresponding Regions of Interest (ROIs) in the wEPT map. Results: Anatomical structures and the tumor were clearly visible in wEPT maps. WC estimated using wEPT agreed well with measurements on excised samples. There was a clear connection between EPs estimated with wEPT and the measured values. However, in some samples large differences between wEPT-derived EP values and measurements were found. In particular, the differences between tumor and healthy tissues conductivity estimated using wEPT was significantly higher than the measured difference in conductivities within the corresponding excised samples. Conclusion: wEPT maps WC in healthy and tumor brain tissues and provides information on local electrical properties at frequencies of 100-1000 kHz. Further investigation is needed to clarify the relationship between WC and EP within this frequency range. Citation Format: Catherine Tempel-Brami, Cornelia Wenger, Hadas S. Hershkovich, Moshe Giladi, Ze9ev Bomzon. Water content based Electrical Properties Tomography (wEPT) for modelling delivery of Tumor Treating Fields to the brain [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 4111.

Abstract 2051: Tumor-treating fields (TTFields) intensity in the gross tumor volume and peritumoral brain zone: implications for local recurrence in glioblastoma

The purpose of this study was to simulate the intensity of TTFields delivered to the brain during the course of glioblastoma (GBM) treatment and to determine whether therapeutic intensities are delivered to the proximal peri-tumoral brain zone (PBZ). Background: TTFields are low-intensity (1-3 V/cm), intermediate frequency (200kHz), alternating electric fields delivered orthogonally in a localized manner during the course of GBM therapy. A recent phase 3 randomized, controlled trial conducted in patients newly diagnosed with GBM was stopped early for efficacy when the end points for progression-free survival (PFS) and overall survival (OS) were met at the interim analysis. Patients receiving TTFields in combination with temozolomide (TMZ) had a significantly longer PFS and OS compared with patients receiving TMZ alone. More than 90% of GBM recur at the margin of a resection cavity or within the PBZ where the presence of infiltrating tumor cells, inflammatory cells and tumorigenic stromal cells are thought to promote recurrence. Phantom model simulation studies suggest that field intensities >1V/cm are delivered to the brain in a non-uniform distribution, however the field distribution to the gross tumor volume (GTV) and PBZ have not been previously evaluated. Methods: Two MRI cases (frontal and posterior-parietal tumors) were used to generate TTFields treatment array layout maps using NovoTAL(TM) System planning software, targeting areas of contrast enhancement on T1 sequences. Simulations for the respective array layouts were created for solid tumors, resection cavities and for tumors with a necrotic core (modified Colin27 model, meshed and solved using the Sim4Life software solver package). Two orthogonal fields (left-right and antero-posterior) at a field frequency of 200 kHz were employed for all simulations. Field intensity was determined in the GTV, tumor margin(TM) and proximal PBZ (20mm) for all models. Results: Transducer array layout maps generated by the NovoTAL software deliver therapeutic intensities of TTFields in both L-R and A-P directions. Bi-directional intensities exceed therapeutic levels (>1 V/cm) in the GTV (median 1.84 V/cm), TM (median 1.9 V/cm) and PBZ (median 2.09 V/cm) in all solid tumors and in the PBZ (median 1.83 V/cm) surrounding a gross total resection (GTR) cavity. The highest areas of field intensity are observed directly adjacent to resection cavities and the ventricles. Conclusions: The delivery of therapeutic intensities of TTFields to patients who have undergone a GTR, subtotal resection or who have inoperable GBM, targets therapy to the area of active disease and importantly, to the PBZ. TTFields target residual tumor cells in the GTV and may also disrupt infiltrating tumor cells in the PBZ. Clinically, this may decrease local GBM recurrence rates and prospective clinical studies are warranted to explore this further. Citation Format: Aafia Chaudhry, Zeev Bomzon, Hadas Sara Hershkovich, Dario Garcia-Carracedo, Cornelia Wenger, Uri Weinberg, Yoram Palti. Tumor-treating fields (TTFields) intensity in the gross tumor volume and peritumoral brain zone: implications for local recurrence in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2051.