Tumor-treating fields dosimetry in glioblastoma: Insights into treatment planning, optimization, and dose-response relationships.

Tumor-treating fields (TTFields) are currently a Category 1A treatment recommendation by the US National Comprehensive Cancer Center for patients with newly diagnosed glioblastoma. Although the mechanism of action of TTFields has been partly elucidated, tangible and standardized metrics are lacking to assess antitumor dose and effects of the treatment. This paper outlines and evaluates the current standards and methodologies in the estimation of the TTFields distribution and dose measurement in the brain and highlights the most important principles governing TTFields dosimetry. The focus is on clinical utility to facilitate a practical understanding of these principles and how they can be used to guide treatment. The current evidence for a correlation between TTFields dose, tumor growth, and clinical outcome will be presented and discussed. Furthermore, we will provide perspectives and updated insights into the planning and optimization of TTFields therapy for glioblastoma by reviewing how the dose and thermal effects of TTFields are affected by factors such as tumor location and morphology, peritumoral edema, electrode array position, treatment duration (compliance), array "edge effect," electrical duty cycle, and skull-remodeling surgery. Finally, perspectives are provided on how to optimize the efficacy of future TTFields therapy.

Guidelines for Burr Hole Surgery in Combination With Tumor Treating Fields for Glioblastoma: A Computational Study on Dose Optimization and Array Layout Planning.

Tumor treating fields (TTFields) is an anti-cancer technology increasingly used for the treatment of glioblastoma. Recently, cranial burr holes have been used experimentally to enhance the intensity (dose) of TTFields in the underlying tumor region. In the present study, we used computational finite element methods to systematically characterize the impact of the burr hole position and the TTFields transducer array layout on the TTFields distribution calculated in a realistic human head model. We investigated a multitude of burr hole positions and layouts to illustrate the basic principles of optimal treatment planning. The goal of the paper was to provide simple rules of thumb for physicians to use when planning the TTFields in combination with skull remodeling surgery. Our study suggests a number of key findings, namely that (1) burr holes should be placed directly above the region of interest, (2) field enhancement occurs mainly underneath the holes, (3) the ipsilateral array should directly overlap the holes and the contralateral array should be placed directly opposite, (4) arrays in a pair should be placed at far distance and not close to each other to avoid current shunting, and finally (5) rotation arrays around their central normal axis can be done without diminishing the enhancing effect of the burr holes. Minor deviations and adjustments (<3 cm) of arrays reduces the enhancement to some extent although the procedure is still effective in these settings. In conclusion, our study provides simple guiding principles for implementation of dose-enhanced TTFields in combination with burr-holes. Future studies are required to validate our findings in additional models at the patient specific level.

[Tumor treating fields in cancer treatment in Denmark].

Tumor treating fields (TTFields) is a new non-invasive approach to cancer treatment. TTFields is low-intensity (1-5 V/m), intermediate frequency (150-200 kHz) alternating electric fields delivered locally to the tumour to selectively kill dividing cells and disrupt cancer growth. TTFields has proven safe and effective for newly diagnosed glioblastoma and is currently being tried for multiple other tumours. This review presents an introduction to TTFields, covering the main indications, the application method, the mechanism of action, the clinical results and the perspectives for implementation in Danish cancer treatment.

[Tumor treating fields in cancer treatment in Denmark].

Tumor treating fields (TTFields) is a new non-invasive approach to cancer treatment. TTFields are low-intensity (1-5 V/m), intermediate frequency (150-200 kHz) alternating electric fields delivered locally to the tumour to selectively kill dividing cells and disrupt cancer growth. TTFields has proven safe and effective for newly diagnosed glioblastoma and is currently being tried for multiple other tumours. This review presents an introduction to TTFields, covering the main indications, the application method, the mechanism of action, the clinical results and the perspectives for implementation in Danish cancer treatment.

Optimization of tumor treating fields using singular value decomposition and minimization of field anisotropy.

Tumor treating fields (TTFields) are increasingly used to treat newly diagnosed and recurrent glioblastoma (GBM). Recently, the authors proposed a new and comprehensive method for efficacy estimation based on singular value decomposition of the sequential field distributions. The method accounts for all efficacy parameters known to affect anti-cancer efficacy of TTFields, i.e. intensity, exposure time, and spatial field correlation. In this paper, we describe a further development, which enables individual optimization of the TTFields activation cycle. The method calculates the optimal device settings to obtain a desired average field intensity in the tumor, while minimizing unwanted field correlation. Finite element (FE) methods were used to estimate the electrical field distribution in the head. The computational head model was based on MRI data from a GBM patient. Sequential field vectors were post-processed using singular value decomposition. A linear transformation was applied to the resulting field matrix to reduce fractional anisotropy (FA) of the principal field components in the tumor. Results were computed for four realistic transducer array layouts. The optimization method significantly reduced FA and maintained the average field intensity in the tumor. The algorithm produced linear gain factors to be applied to the transducer array pairs producing the sequential fields. FA minimization was associated with an increase in total current delivered through the head during a activation cycle. Minimized FA can be obtained for an unchanged total current level, albeit with a reduction in average field intensity. We present an algorithm for optimization of the TTFields activation cycle settings. The method can be used to minimize the spatial correlation between sequential TTFields, while adjusting the total current level and mean field intensity to a desired level. Future studies are needed to validate clinical impact and assess sensitivity towards model parameters.

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

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

Estimating the Intensity and Anisotropy of Tumor Treating Fields Jsing Singular Value Decomposition. Towards a More Comprehensive Estimation of Anti-tumor Efficacy.

Tumor treating fields (TTFields) is an anticancer treatment that inhibits tumor growth with alternating electrical fields. Finite element (FE) methods have been used to estimate the TTFields intensity as a measure of treatment "dose". However, TTFields efficacy also depends on field direction and exposure time. Here we propose a new FE based approach, which uses all these parameters to quantify the average field intensity and the amount of unwanted directional field correlation (fractional anisotropy, FA). The method is based on principal component decomposition of the sequential TTFields over one duty cycle. Using a realistic head model of a glioblastoma patient, we observed significant unwanted FA in many regions of the brain, which may potentially affect therapeutic efficacy. FA varied between different array layouts and indicated a different order of array performance than predicted from the field intensity. Tumor resection nullified differences in field distributions between layouts and increased FA considerably. Our results question the rationale for the use of macroscopically orthogonal array layouts to reduce field correlation and rather indicate that arrays should be placed to maximize pathology coverage and field intensity. The proposed calculation framework has several potential applications, incl. improved treatment planning, technology development, and accurate prognostication models. Future studies are required to validate the method.

Importance of electrode position for the distribution of tumor treating fields (TTFields) in a human brain. Identification of effective layouts through systematic analysis of array positions for multiple tumor locations.

Tumor treating fields (TTFields) is a new modality used for the treatment of glioblastoma. It is based on antineoplastic low-intensity electric fields induced by two pairs of electrode arrays placed on the patient's scalp. The layout of the arrays greatly impacts the intensity (dose) of TTFields in the pathology. The present study systematically characterizes the impact of array position on the TTFields distribution calculated in a realistic human head model using finite element methods. We investigate systematic rotations of arrays around a central craniocaudal axis of the head and identify optimal layouts for a large range of (nineteen) different frontoparietal tumor positions. In addition, we present comprehensive graphical representations and animations to support the users' understanding of TTFields. For most tumors, we identified two optimal array positions. These positions varied with the translation of the tumor in the anterior-posterior direction but not in the left-right direction. The two optimal directions were oriented approximately orthogonally and when combining two pairs of orthogonal arrays, equivalent to clinical TTFields therapy, we correspondingly found a single optimum position. In most cases, an oblique layout with the fields oriented at forty-five degrees to the sagittal plane was superior to the commonly used anterior-posterior and left-right combinations of arrays. The oblique configuration may be used as an effective and viable configuration for most frontoparietal tumors. Our results may be applied to assist clinical decision-making in various challenging situations associated with TTFields. This includes situations in which circumstances, such as therapy-induced skin rash, scar tissue or shunt therapy, etc., require layouts alternative to the prescribed. More accurate distributions should, however, be based on patient-specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity.

A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred From Computational Modeling.

Tumor-treating fields (TTFields) are a cancer treatment modality that uses alternating electric fields of intermediate frequency (∼100-500 kHz) and low intensity (1-3 V/cm) to disrupt cell division. TTFields are delivered by transducer arrays placed on the skin close to the tumor and act regionally and noninvasively to inhibit tumor growth. TTFields therapy is U.S. Food and Drug Administration approved for the treatment of glioblastoma multiforme, the most common and aggressive primary human brain cancer. Clinical trials testing the safety and efficacy of TTFields for other solid tumor types are underway. The objective of this paper is to review computational approaches used to characterize TTFields. The review covers studies of the macroscopic spatial distribution of TTFields generated in the human head, and of the microscopic field distribution in tumor cells. In addition, preclinical and clinical findings related to TTFields and principles of its operation are summarized. Particular emphasis is put on outlining the potential clinical value inferred from computational modeling.

Impact of tumor position, conductivity distribution and tissue homogeneity on the distribution of tumor treating fields in a human brain: A computer modeling study.

BACKGROUND: Tumor treating fields (TTFields) are increasingly used in the treatment of glioblastoma. TTFields inhibit cancer growth through induction of alternating electrical fields. To optimize TTFields efficacy, it is necessary to understand the factors determining the strength and distribution of TTFields. In this study, we provide simple guiding principles for clinicians to assess the distribution and the local efficacy of TTFields in various clinical scenarios. METHODS: We calculated the TTFields distribution using finite element methods applied to a realistic head model. Dielectric property estimates were taken from the literature. Twentyfour tumors were virtually introduced at locations systematically varied relative to the applied field. In addition, we investigated the impact of central tumor necrosis on the induced field. RESULTS: Local field "hot spots" occurred at the sulcal fundi and in deep tumors embedded in white matter. The field strength was not higher for tumors close to the active electrode. Left/right field directions were generally superior to anterior/posterior directions. Central necrosis focally enhanced the field near tumor boundaries perpendicular to the applied field and introduced significant field non-uniformity within the tumor. CONCLUSIONS: The TTFields distribution is largely determined by local conductivity differences. The well conducting tumor tissue creates a preferred pathway for current flow, which increases the field intensity in the tumor boundaries and surrounding regions perpendicular to the applied field. The cerebrospinal fluid plays a significant role in shaping the current pathways and funnels currents through the ventricles and sulci towards deeper regions, which thereby experience higher fields. Clinicians may apply these principles to better understand how TTFields will affect individual patients and possibly predict where local recurrence may occur. Accurate predictions should, however, be based on patient specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity.

Enhancing Predicted Efficacy of Tumor Treating Fields Therapy of Glioblastoma Using Targeted Surgical Craniectomy: A Computer Modeling Study.

OBJECTIVE: The present work proposes a new clinical approach to TTFields therapy of glioblastoma. The approach combines targeted surgical skull removal (craniectomy) with TTFields therapy to enhance the induced electrical field in the underlying tumor tissue. Using computer simulations, we explore the potential of the intervention to improve the clinical efficacy of TTFields therapy of brain cancer. METHODS: We used finite element analysis to calculate the electrical field distribution in realistic head models based on MRI data from two patients: One with left cortical/subcortical glioblastoma and one with deeply seated right thalamic anaplastic astrocytoma. Field strength was assessed in the tumor regions before and after virtual removal of bone areas of varying shape and size (10 to 100 mm) immediately above the tumor. Field strength was evaluated before and after tumor resection to assess realistic clinical scenarios. RESULTS: For the superficial tumor, removal of a standard craniotomy bone flap increased the electrical field strength by 60-70% in the tumor. The percentage of tissue in expected growth arrest or regression was increased from negligible values to 30-50%. The observed effects were highly focal and targeted at the regions of pathology underlying the craniectomy. No significant changes were observed in surrounding healthy tissues. Median field strengths in tumor tissue increased with increasing craniectomy diameter up to 50-70 mm. Multiple smaller burr holes were more efficient than single craniectomies of equivalent area. Craniectomy caused no significant field enhancement in the deeply seated tumor, but rather a focal enhancement in the brain tissue underlying the skull defect. CONCLUSIONS: Our results provide theoretical evidence that small and clinically feasible craniectomies may provide significant enhancement of TTFields intensity in cerebral hemispheric tumors without severely compromising brain protection or causing unacceptable heating in healthy tissues. A clinical trial is being planned to validate safety and efficacy.

Simultaneous PET-MRI: a new approach for functional and morphological imaging.

Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.