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.

Temperature and Impedance Variations During Tumor Treating Fields (TTFields) Treatment.

Tumor Treating Fields (TTFields) is an FDA-approved cancer treatment technique used for glioblastoma multiforme (GBM). It consists in the application of alternating (100-500 kHz) and low-intensity (1-3 V/cm) electric fields (EFs) to interfere with the mitotic process of tumoral cells. In patients, these fields are applied via transducer arrays strategically positioned on the scalp using the NovoTAL™ system. It is recommended that the patient stays under the application of these fields for as long as possible. Inevitably, the temperature of the scalp increases because of the Joule effect, and it will remain above basal values for most part of the day. Furthermore, it is also known that the impedance of the head changes throughout treatment and that it might also play a role in the temperature variations. The goals of this work were to investigate how to realistically account for these increases and to quantify their impact in the choice of optimal arrays positions using a realistic head model with arrays positions obtained through NovoTAL™. We also studied the impedance variations based on the log files of patients who participated in the EF-14 clinical trial. Our computational results indicated that the layouts in which the arrays were very close to each other led to the appearance of a temperature hotspot that limited how much current could be injected which could consequently reduce treatment efficacy. Based on these data, we suggest that the arrays should be placed at least 1 cm apart from each other. The analysis of the impedance showed that the variations seen during treatment could be explained by three main factors: slow and long-term variations, array placement, and circadian rhythm. Our work indicates that both the temperature and impedance variations should be accounted for to improve the accuracy of computational results when investigating TTFields.

A computational study of the relation between the power density in the tumor and the maximum temperature in the scalp during Tumor Treating Fields (TTFields) therapy.

In this work we investigated the relation between the power density in the tumor and the maximum temperature reached in the scalp during TTFields treatment for glioblastoma. We used a realistic head model to perform the simulations in COMSOL Multiphysics and we solved Pennes' equation to obtain the temperature distribution. Our results indicate that there might be a linear relation between these two quantities and that TTFields are safe from a thermal point of view.

The impact of the uncertainty of biological tissue thermal parameters on the estimated maximum temperature during TTFields treatment.

In this work we evaluated the maximum temperature reached by the head tissues and transducers during TTFields treatment when the thermal parameters were changed. We used Pennes' equation to obtain the temperature distribution and we ran our studies using COMSOL Multiphysics. We observed that, among the parameters we tested, changes in the scalp thermal conductivity and grey matter blood perfusion were the ones that led to the highest temperature variations.Clinical Relevance- This work shows that the uncertainty regarding the thermal parameters of biological tissues might lead to significant changes in the temperature distribution when modeling heat transfer during TTFields therapy.

Heat transfer during TTFields treatment: Influence of the uncertainty of the electric and thermal parameters on the predicted temperature distribution.

BACKGROUND AND OBJECTIVES: Tumor Treating Fields (TTFields) is a technique currently used in the treatment of glioblastoma. It consists in applying an electric field (EF) with a frequency of 200 kHz using two pairs of transducer arrays placed on the head. Current should be injected at least 18 h/day and induce a minimum EF intensity of 1 V/cm at the tumor bed for the treatment to be effective. To avoid scalp burns, Optune, the device used to apply this technique in patients, monitors the temperature of the transducers and keeps them below 41 °C by reducing the injected current. The goal of this study was to quantify the impact of the uncertainty associated with the electric and thermal parameters on the predicted temperature of the transducers and of each tissue when TTFields were applied. METHODS: We used a realistic head model, added the two pairs of transducers arrays on the scalp and a virtual lesion, mimicking a glioblastoma tumor in the right hemisphere. Minimum, standard and maximum values for the electric and thermal properties of each tissue were taken from the literature after an extensive review. We used finite element methods (COMSOL Multiphysics) to solve Laplace's equation for the electric potential and Pennes' equation for the temperature distribution. RESULTS: We observed that the electric conductivity of the scalp and skull, as well as scalp's blood perfusion and thermal conductivity were the parameters to which tissue and transducers temperature were most sensitive to. Considering all simulations, scalp's maximum temperature was around 43.5 °C, skull's 42 °C, CSF's 41.2 °C and brain's 39.3 °C. According to the literature, for this temperature range, some physiological changes are predicted only for the brain. The average temperature of the transducers varied between 38.1 °C and 41.6 °C which suggests that modelling TTFields current injection is very sensitive to the parameters chosen. CONCLUSIONS: Better knowledge of the physical properties of tissues and materials and how they change with the temperature is needed to improve the accuracy of these predictions. This information would likely decrease the predicted temperature maxima in the brain and thus help ascertaining TTFields safety from a thermal point of view.

Temperature control in TTFields therapy of GBM: impact on the duty cycle and tissue temperature.

In TTFields therapy, Optune® is used to deliver the electric field to the tumor via 4 transducer arrays. This device monitors the temperature of the transducers and reduces the current whenever a transducer reaches 41 °C. Our aim is to quantify Optune's duty cycle and to predict the steady-state temperature distribution in the head during GBM treatment. We used a realistic head model and the finite element method to solve Pennes equation and to simulate how Optune operates considering that current reduces to zero when the thermal limit is reached. The thermal impact was evaluated considering the maximum temperature reached by each tissue and using the CEM 43 °C metric. We observed that Optune switches the current on and off intermittently. In our model, one transducer reached the temperature limit quicker than the others and consequently it was the one that controlled current injection. This led to different duty cycles for the anterior-posterior and left-right array pairs. The thermal analysis indicated that the highest temperature in the model, 41.7 °C, was reached on the scalp under a transducer. However, TTFields may lead to significant changes only at the brain level such as BBB permeability increase, cerebral blood flow variation and changes in the concentration of some neurotransmitters. The duty cycle may be increased, e.g. by controlling the current at the transducer level. These predictions should be validated by comparison with experimental data and reconciled with the lack of evidence of thermal impact in clinical trials.