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Effect of craniectomy after tumor resection. Percentage of tissue exposed to field strengths above the corresponding value on the abscissa (craniectomy—stippled line; no craniectomy—solid line). Rows represent different tissues and columns the L/R and A/P electrode pairs, as indicated. Craniectomy significantly increases the field strength in the peritumoral region compared to the situation with no craniectomy. The field strengths in healthy tissues were largely unaffected.
Source publication
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 cli...
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Citations
... Therefore, minimizing the thickness and conductivity of edema might be beneficial in improving AEF treatment outcomes. TTFields-enhancing techniques such as skull remodeling (Korshoej et al 2016, Mikic et al 2021 might help to compensate for the field strength loss caused by the peritumoral edema. Beyond the stifling effects of peritumoral edema on the efficacy of AEF, the edema has other clinically-relevant implications including promoting GBM cell infiltration (Ohmura et al 2023), which has been found to be associated with GBM recurrence/progression (Qin et al 2021). ...
Objective. Alternating electric fields (AEF) therapy is a treatment modality for patients with glioblastoma. Tumor characteristics such as size, location, and extent of peritumoral edema may affect the AEF strength and distribution. We evaluated the sensitivity of the AEFs in a realistic 3D rat glioma model with respect to these properties. Approach. The electric properties of the peritumoral edema were varied based on calculated and literature-reported values. Models with different tumor composition, size, and location were created. The resulting AEFs were evaluated in 3D rat glioma models. Main Results. In all cases, a pair of 5-mm-diameter electrodes induced an average field strength >1 V/cm. The simulation results showed that a negative relationship between edema conductivity and field strength was found. As the tumor core size was increased, the average field strength increased while the fraction of the shell achieving >1.5 V/cm decreased. Increasing peritumoral edema thickness decreased the shell’s mean field strength. Compared to rostrally/caudally, shifting the tumor location laterally/medially and ventrally (with respect to the electrodes) caused higher deviation in field strength. Significance. This study identifies tumor properties that are key drivers influencing AEF strength and distribution. The findings might be potential preclinical implications.
... The fluid movements during these diseases are slow, thus enabling the use of a quasi-static poroelastic model (Mokhtarudin and Payne 2015). On the other hand, computational simulations for DC operation involves the investigation of the effectiveness of this operation during traumatic brain injury (Fletcher et al. 2014(Fletcher et al. , 2016Lambride et al. 2020), brain tumour (Korshoej et al. 2016) and brain tissue swelling after ischaemic stroke (Nadzri et al. 2021(Nadzri et al. , 2022, as well as during the designing of cranial implants (Matzkin et al. 2020;Wu et al. 2022) and during neurosurgical training purposes (Chawla et al. 2022). The DC operation during brain tissue swelling after ischaemic stroke can be further investigated to evaluate its outcome in terms of brain tissue displacement and the changes in ICP. ...
Brain oedema or tissue swelling that develops after ischaemic stroke can cause detrimental effects, including brain herniation and increased intracranial pressure (ICP). These effects can be reduced by performing a decompressive craniectomy (DC) operation, in which a portion of the skull is removed to allow swollen brain tissue to expand outside the skull. In this study, a poroelastic model is used to investigate the effect of brain ischaemic infarct size and location on the severity of brain tissue swelling. Furthermore, the model will also be used to evaluate the effectiveness of DC surgery as a treatment for brain tissue swelling after ischaemia. The poroelastic model consists of two equations: one describing the elasticity of the brain tissue and the other describing the changes in the interstitial tissue pressure. The model is applied on an idealized brain geometry, and it is found that infarcts with radius larger than approximately 14 mm and located near the lateral ventricle produce worse brain midline shift, measured through lateral ventricle compression. Furthermore, the model is also able to show the positive effect of DC treatment in reducing the brain midline shift by allowing part of the brain tissue to expand through the skull opening. However, the model does not show a decrease in the interstitial pressure during DC treatment. Further improvement and validation could enhance the capability of the proposed poroelastic model in predicting the occurrence of brain tissue swelling and DC treatment post ischaemia.
... Computational studies indicate that SR-surgery significantly increases the electric field strength in superficial tumors (30%-100%) with a minimal effect on WM and gray matter. 41,[47][48][49] The highest field enhancement was observed when SR surgery was performed directly above the tumor with the transducer arrays overlapping the skull defect, thus using the "edge effect. " 41 Furthermore, a higher field enhancement was observed with several small burr holes compared with one craniectomy with same defect surface area. ...
... " 41 Furthermore, a higher field enhancement was observed with several small burr holes compared with one craniectomy with same defect surface area. 47,48 SR surgery was recently evaluated in a safety and feasibility study for rGBM. The study concluded that SR surgery in combination with TTFields therapy was safe and probably effective. ...
Tumor Treating Fields (TTFields) is currently a Category 1A treatment recommendation by the U.S. 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 anti-tumor 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.
... Electric fields of intermediate frequency (200 kHz) produced from low voltage (2 V) sources impede the growth of high grade gliomas, including GBM, while non-neoplastic neurons and brain tissue remains relatively unaffected (Di Sebastiano et al 2018, Deweyert et al 2019. We and others have demonstrated computer simulations to be useful tools to analyze and plan electric field distributions in realistic preclinical and clinical scenarios (Miranda et al 2014, Korshoej et al 2016, Wenger et al 2018, Iredale et al 2020, 2022. Electric field simulations of single electrode in vitro IMT models suggest that while the coverage is sufficient for preclinical models, improvements in the extent of such coverage would be required to advance to human scale tumors (Di Sebastiano et al 2018, Deweyert et al 2019, Iredale et al 2020, 2022. ...
Objective: The treatment of glioblastoma (GBM) using low intensity electric fields (~1 V/cm) is being investigated using multiple implanted bioelectrodes, which was termed intratumoral modulation therapy (IMT). Previous IMT studies theoretically optimized treatment parameters to maximize coverage with rotating fields, which required experimental investigation. In this study, we employed computer simulations to generate spatiotemporally dynamic electric fields, designed and purpose-built an IMT device for in vitro experiments, and evaluated the human GBM cellular responses to these fields.
Approach: After measuring the electrical conductivity of the in vitro culturing medium, we designed experiments to evaluate the efficacy of various spatiotemporally dynamic fields: (a) different rotating field magnitudes, (b) rotating vs. non-rotating fields, (c) 200 kHz vs. 10 kHz stimulation, and (d) constructive vs. destructive interference. A custom printed circuit board (PCB) was fabricated to enable four-electrode IMT in a 24-well plate. Patient-derived GBM cells were treated and analyzed for viability using bioluminescence imaging.
Main results: The optimal PCB design had electrodes placed 6.3 mm from the center. Spatiotemporally dynamic IMT fields at magnitudes of 1, 1.5, and 2 V/cm reduced GBM cell viability to 58%, 37% and 2% of sham controls respectively. Rotating vs. non-rotating, and 200 kHz vs. 10 kHz fields showed no statistical difference. The rotating configuration yielded a significant reduction (p<0.01) in cell viability (47±4%) compared to the voltage matched (99±2%) and power matched (66±3%) destructive interference cases.
Significance: We found the most important factors in GBM cell susceptibility to IMT are electric field strength and homogeneity. Spatiotemporally dynamic electric fields have been evaluated in this study, where improvements to electric field coverage with lower power consumption and minimal field cancellations has been demonstrated. The impact of this optimized paradigm on cell susceptibility justifies its future use in preclinical and clinical trial investigations.
... Clinical evidence has demonstrated that field intensity delivered to the site of the tumor is correlated with overall survival [18][19][20]. Accordingly, one active area of research in TTF is cranial remodeling interventions, in which the calvarial bone is either surgically thinned and/or burr holes or small craniectomies are strategically placed either during the initial tumor resection or re-resections with the aim of enhancing TTF penetrance and intensity [20][21][22]. ...
Diffuse intrinsic pontine glioma (DIPG) carries an extremely poor prognosis, with 2-year survival rates of <10% despite the maximal radiation therapy. DIPG cells have previously been shown to be sensitive to low-intensity electric fields in vitro. Accordingly, we sought to determine if the endoscopic endonasal (EE) implantation of an electrode array in the clivus would be feasible for the application of tumor-treating fields (TTF) in DIPG. Anatomic constraints are the main limitation in pediatric EE approaches. In our Boston Children's Hospital's DIPG cohort, we measured the average intercarotid distance (1.68 ± 0.36 cm), clival width (1.62 ± 0.19 cm), and clival length from the base of the sella (1.43 ± 0.69 cm). Using a linear regression model, we found that only clival length and sphenoid pneumatization were significantly associated with age (R 2 = 0.568, p = 0.005 *; R 2 = 0.605, p = 0.0002 *). Critically, neither of these parameters represent limitations to the implantation of a device within the dimensions of those currently available. Our findings confirm that the anatomy present within this age group is amenable to the placement of a 2 × 1 cm electrode array in 94% of patients examined. Our work serves to demonstrate the feasibility of implantable transclival devices for the provision of TTFs as a novel adjunctive therapy for DIPG.
... Consistent with this line of thinking, a study utilizing targeted craniectomies in conjunction with TTF to bypass the skull was conceptualized and has shown promising results both in silico and in a phase I clinical trial 13 . It is prudent to note that while this method may provide an avenue for substantially higher field strengths in hemispheric tumors, modeling suggests that achieving therapeutic field strengths in deep brain targets remains unlikely 14 . ...
... The TER quantifies the effects of an electric field on a tumor: TER values above 0 indicate a reduction in tumor growth, TER of 1 corresponds with complete growth arrest, and TER values above 1 indicate tumor shrinkage. Complete proliferation arrest (TER of 1) occurs in glioma cell cultures when fields reach 2.25 V/cm in the treated tumor 6 and this value has been used as a benchmark in other studies 14 . We therefore calculated the percentage of the ROI receiving field strengths over 2.25 V/cm and the percentage for which TER > 1 as primary outcome measures. ...
... As discussed above, the therapeutic enhancement ratio (TER) quantifies how electric field strength (E) affects tumor growth with Kirson et al. having reported TER values for tumor cell cultures resulting from the application of electric fields of various strengths 6 . Similar to the procedure described by Korshoej et al. 14 we fitted a third-degree polynomial to the in vitro data: (Fig. 6). Data was available for E values from 1.10 to 2.40 V/cm, so we set TER for E lower than 1.10 V/cm to 0, and for E higher than 2.40 V/cm to the value at E = 2.40 V/cm: TER(2.40) ...
Increasing the intensity of tumor treating fields (TTF) within a tumor bed improves clinical efficacy, but reaching sufficiently high field intensities to achieve growth arrest remains challenging due in part to the insulating nature of the cranium. Using MRI-derived finite element models (FEMs) and simulations, we optimized an exhaustive set of intracranial electrode locations to obtain maximum TTF intensities in three clinically challenging high-grade glioma (HGG) cases (i.e., thalamic, left temporal, brainstem). Electric field strengths were converted into therapeutic enhancement ratios (TER) to evaluate the predicted impact of stimulation on tumor growth. Concurrently, conventional transcranial configurations were simulated/optimized for comparison. Optimized intracranial TTF were able to achieve field strengths that have previously been shown capable of inducing complete growth arrest, in 98–100% of the tumor volumes using only 0.54–0.64 A current. The reconceptualization of TTF as a targeted, intracranial therapy has the potential to provide a meaningful survival benefit to patients with HGG and other brain tumors, including those in surgically challenging, deep, or anatomically eloquent locations which may preclude surgical resection. Accordingly, such an approach may ultimately represent a paradigm shift in the use of TTFs for the treatment of brain cancer.
... By using realistic computational head models and finite element method it was concluded that SR-surgery could potentially increase the TTFields intensity by 60-70% in superficial tumors. Furthermore, it was concluded that several small burrholes would induce a greater increase in field strength than one large craniectomy per skull defect area, which is an important clinical safety consideration [4]. Computational studies also indicated that TTFields electrode array placement could be optimized when taking SR-surgery into account [5]. ...
... A five burrhole SR-surgery configuration was chosen as shown in Fig. 1, based on previous research indicating higher efficacy compared to complete craniectomy [4]. The general rationale behind this configuration was to induce significant field enhancement in the peritumor and tumor region without compromising patient safety and with no requirement for protective headgear. ...
Skullremodeling surgery (SR-surgery) includes removing bone from the skull to enhance TTFields. In our phase 1 trial (NCT02893137) we tested multiple SR-configurations (craniectomy, burrholes, and skull thinning) with TTFields concluding it to be safe. To examine the efficacy, we recently initiated an investigator-initiated, randomized, comparative, multi-center phase 2 trial (NCT04223999).
To ensure uniformity, SR-surgery will be standardized to 5 burrholes of 15 mm diameter placed cross-diagonally in a 45×45 mm square above the tumor. The configuration was chosen as a combination of maximizing the overall cm ³ while not compromising patient safety.
To create a standard operating procedure for the trial, we wanted to examine how the electric field was affected by this SR-surgery configuration, its location, and the electrode array placement. We created E-field simulations based on a computational head model, that mimicked a trial patient’s tumor resection cavity, residual tumor, and SR-surgery. SR-surgery was virtually applied at several locations with different electrode positions to investigate the impact on the electric field in the residual tumor tissue, resection cavity, and grey- and white matter. The electrode arrays were moved by 15-degree stepwise rotation around a central craniocaudal axis in the same horizontal plane, corresponding to 0–180 degrees for a total of 13 different positions. Control simulations without SR-surgery were also performed.
In general, we found that SR-surgery increased the electric field strength significantly in the residual tumor and resection cavity with minimal effect on the healthy white and grey matter tissue. The highest electric field values were observed in the residual tumor and resection cavity when the burrholes were placed directly above the pathological tissue and the edge electrodes of both pairs were placed on top or close to the burrholes with the reference electrode directly opposite on the head.
... Therefore, computational modeling of the distribution of the electric field and thermogenic effects in such patients is important, because overheating in patients with skull defects will force the application of a lower voltage, which might decrease the focal electric field in the tumor. 14,17 In this study, we applied the FEM approach to ascertain the electric field distribution inside GBM head models, with or without skull defects, and the impact of an insulation layer thereon. This may provide new insights into the application scope of TTFields, and the strategy of utilizing skull defects to maintain field strength, avoid overheating, and maximize antineoplastic efficiency. ...
Background:
Tumor treating fields (TTFields) is an FDA-approved adjuvant therapy for glioblastoma. The distribution of an applied electric field has been shown to be governed by distinct tissue structures and electrical conductivity. Of all the tissues the skull plays a significant role in modifying the distribution of the electric field due to its large impedance. In this study, we studied how remodeling of the skull would affect the therapeutic outcome of TTFields, using a computational approach.
Methods:
Head models were created from the head template ICBM152 and five realistic head models. The electric field distribution was simulated using the default TTFields array layout. To study the impact of the skull on the electric field, we compared three cases, namely, intact skull, defective skull, and insulating process, wherein a thin electrical insulating layer was added between the transducer and the hydrogel. The electric field strength and heating power were calculated using the FEM (finite element method).
Results:
Removing the skull flap increased the average field strength at the tumor site, without increasing the field strength of "brain". The ATVs of the supratentorial tumors were enhanced significantly. Meanwhile, the heating power of the gels increased, especially those overlapping the skull defect site. Insulation lightly decreased the electric field strength and significantly decreased the heating power in deep tumor models.
Conclusion:
Our simulation results showed that a skull defect was beneficial for superficial tumors but had an adverse effect on deep tumors. Skull removal should be considered as an optional approach in future TTFields therapy to enhance its efficacy. An insulation process could be used as a joint option to reduce the thermogenic effect of skull defect. If excessive increase in heating power is observed in certain patients, insulating material could be used to mitigate overheating without sacrificing the therapeutic effect of TTFields.
... Most TTFields modeling studies set the constant current source as a stimulation condition [5,[13][14][15], and only a few simulation models selected the constant voltage source [16]. To compare the differences in simulated EF between the two stimulation conditions, and further validate the accuracy of the simulation model, we modeled the two stimulation conditions respectively. ...
Tumor-treating Fields (TTFields) is a promising cancer therapy technique in clinical application. Computational simulation of TTFields has been used to predict the electric field (EF) distribution in the human body and to optimize the treatment parameters. However, there are only a few studies to validate the accuracy of the simulation model. Here we propose a measurement platform with technical details for validating the simulation model of TTFields. We further constructed homogeneous agar phantoms with different conductivity for voltage measurement. With the measured voltages from six equidistance recording points in the cylinder phantom, we calculated the EF intensity in the phantoms at different frequencies. Comparing the measured values with the simulated values obtained from two types of source simulation, we found that the current source simulation model of TTFields is a reliable method for evaluating the EF intensity distribution.
... An enhancing effect of TTF after skull remodeling surgery was described. For superficial tumors, removal of a standard craniotomy bone flap increased the electrical field strength by up to 70% (51). A phase 1 safety study on 15 patients with recurrent GBM confirmed the safety of this approach (52) and a phase 2 study was announced (53). ...
Introduction
Tumor-treating fields (TTFs) are a specific local oncological treatment modality in glioblastoma multiforme WHO° IV (GBM). Their mechanism of action is based on the effect of electrical fields interfering with the mitotic activity of malignant cells. Prospective studies have demonstrated efficacy, but TTF benefits are still controversially discussed. This treatment was implemented in our center as the standard of care in January 2016. We thus discuss the current state of the art and our long-term experience in the routine application of TTF.
Methods
The data of 48 patients suffering from GBM and treated with TTF were assessed and compared with previously published studies. Up-to-date information from open sources was evaluated.
Results
A total of 31 males and 17 females harboring a GBM were treated with TTF, between January 2016 and August 2021, in our center. In 98% of cases, TTFs were started within 6 weeks after concomitant radiochemotherapy (Stupp protocol). Mean overall survival was 22.6 months (95% CI: 17.3–27.9). Current indications, benefits, and restrictions were evaluated. Future TTF opportunities and ongoing studies were reviewed.
Conclusion
TTFs are a feasible and routinely applicable specific oncological treatment option for glioblastoma multiforme WHO° IV. Further research is ongoing to extend the indications and the efficacy of TTF.
