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Article ; Online: A review on tumor treating fields, a novel modality in cancer treatment

Nichal Gentilal / Pedro Cavaleiro Miranda

Annals of Medicine, Vol 53, Iss sup1, Pp S23-S

2021 Volume 23

Abstract: AbstractIntroduction Glioblastoma Multiforme (GBM) is one of the deadliest tumours that appears in the brain and it is characterised by its aggressiveness and by a very short overall survival (OS) [1]. Despite all the efforts that have been put into ... ...

Abstract	AbstractIntroduction Glioblastoma Multiforme (GBM) is one of the deadliest tumours that appears in the brain and it is characterised by its aggressiveness and by a very short overall survival (OS) [1]. Despite all the efforts that have been put into trying to improve treatment outcomes, GBM patients’ prognosis is still very poor. In the last couple of years, a new technique was developed to target tumoral cells. Tumour Treating Fields (TTFields) are intermediate-frequency (100–300 kHz) alternating electric fields (1–3 V/cm at the tumour bed) that can affect cells mitosis during metaphase and cytokinesis. Results from clinical trials [2,3] showed that this technique can lead to an increased OS both in newly diagnosed and recurrent patients. Our aim is to address the main findings regarding this therapy and discuss future challenges based on a literature review of the papers published since this technique was first reported in 2004 to the present date.Materials and methods This literature review was performed considering only publications made in journals with impact factor in the areas of interest (biomedical engineering and oncology). Appropriate keywords (TTFields, alternating electric field therapy, glioblastoma) were used to filter the results and select the relevant publications in Pubmed and Web of Science until May 2019. The total number of papers analysed was 29.Results Results from clinical trials showed that a minimum daily usage of 18 h can improve the OS, while other studies showed that switching the direction of the applied field between two perpendicular orientations alternately increases the number of cells that are affected by this technique. Up until now, only skin dermatitis was reported as a side-effect due to the usage of a hydrogel between the scalp and the electrodes. Computational studies allowed to predict the electric field in the brain during therapy and subsequent studies proved that the uncertainty regarding biological tissues parameters (e.g.: electrical conductivity) might have a ...
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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

Gentilal, Nichal / Miranda, Pedro Cavaleiro

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2020 Volume 2020, Page(s) 2283–2286

Abstract: 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 ...

Abstract	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.
MeSH term(s)	Body Temperature ; Gray Matter ; Head ; Hot Temperature ; Humans ; Temperature ; Thermal Conductivity ; Uncertainty
Language	English
Publishing date	2020-09-25
Publishing country	United States
Document type	Journal Article
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC44109.2020.9175372
Database	MEDical Literature Analysis and Retrieval System OnLINE

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

Gentilal, Nichal / Miranda, Pedro Cavaleiro

Computer methods and programs in biomedicine

2020 Volume 196, Page(s) 105706

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Brain ; Electric Stimulation Therapy ; Glioblastoma/therapy ; Hot Temperature ; Humans ; Temperature ; Uncertainty
Keywords	covid19
Language	English
Publishing date	2020-08-12
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	632564-6
ISSN	1872-7565 ; 0169-2607
ISSN (online)	1872-7565
ISSN	0169-2607
DOI	10.1016/j.cmpb.2020.105706
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Article ; Online: Tumor-treating fields dosimetry in glioblastoma: Insights into treatment planning, optimization, and dose-response relationships.

Mikic, Nikola / Gentilal, Nichal / Cao, Fang / Lok, Edwin / Wong, Eric T / Ballo, Matthew / Glas, Martin / Miranda, Pedro C / Thielscher, Axel / Korshoej, Anders R

Neuro-oncology advances

2024 Volume 6, Issue 1, Page(s) vdae032

Abstract: 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, ... ...

Abstract	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.
Language	English
Publishing date	2024-03-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	3009682-0
ISSN	2632-2498 ; 2632-2498
ISSN (online)	2632-2498
ISSN	2632-2498
DOI	10.1093/noajnl/vdae032
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Article ; Online: Temperature control in TTFields therapy of GBM: impact on the duty cycle and tissue temperature.

Gentilal, Nichal / Salvador, Ricardo / Miranda, Pedro Cavaleiro

Physics in medicine and biology

2019 Volume 64, Issue 22, Page(s) 225008

Abstract: In TTFields therapy, ... ...

Abstract	In TTFields therapy, Optune
MeSH term(s)	Brain/pathology ; Brain Neoplasms/pathology ; Brain Neoplasms/therapy ; Electric Stimulation Therapy/instrumentation ; Electric Stimulation Therapy/methods ; Glioblastoma/pathology ; Glioblastoma/therapy ; Humans ; Temperature ; Transducers
Language	English
Publishing date	2019-11-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ab5323
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Article: Heat transfer during TTFields treatment: Influence of the uncertainty of the electric and thermal parameters on the predicted temperature distribution

Gentilal, Nichal / Miranda, Pedro Cavaleiro

Comput Methods Programs Biomed

Abstract: 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. ...

Abstract	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.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #32818721
Database	COVID19

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

Gentilal, Nichal / Abend, Eyal / Naveh, Ariel / Marciano, Tal / Balin, Igal / Telepinsky, Yevgeniy / Miranda, Pedro Cavaleiro

Frontiers in human neuroscience

2022 Volume 16, Page(s) 931818

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2022-07-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2425477-0
ISSN	1662-5161
ISSN	1662-5161
DOI	10.3389/fnhum.2022.931818
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Article ; Online: 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.

Gentilal, Nichal / Naveh, Ariel / Marciano, Tal / Bomzon, Zeev / Telepinsky, Yevgeniy / Wasserman, Yoram / Miranda, Pedro Cavaleiro

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2021 Volume 2021, Page(s) 4192–4195

Abstract: 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 ...

Abstract	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.
MeSH term(s)	Brain Neoplasms/therapy ; Electric Stimulation Therapy ; Glioblastoma/therapy ; Humans ; Scalp ; Temperature
Language	English
Publishing date	2021-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC46164.2021.9630071
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A review on tumor treating fields, a novel modality in cancer treatment

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

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

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

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

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

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

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Article ; Online: 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.

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