Tumor-treating fields (TTFields)
are a new and effective treatment against glioblastoma (GBM)
[
1‐
3]. The treatment
uses alternating fields (200 kHz for GBM) to inhibit cancer cell division
and tumor growth. TTFields are induced by two electrical sources, each connected to its own pair of 3×3 transducer arrays, which are placed on the patient’s body surface in the vicinity of the tumor [
4]. Recently, finite element (FE)
methods have been used to calculate the distribution of TTFields in realistic human head models in efforts to estimate the treatment dose of TTFields [
5‐
8]. This has provided important information about how the TTFields distribution is affected by human head morphology [
9], tumor position [
10,
11], tissue dielectric properties [
9,
10,
12,
13], and transducer array layout [
11,
14]. In addition, FE methods have been used to provide preclinical proof of concept for a new implementation of TTFields in which individual computational modeling is used to plan a surgical skull remodeling procedure that enhances the efficacy of TTFields by creating small holes in the skull at selected positions, facilitating current flow into the tumor [
15,
16]. However, state-of-the-art approaches only use the intensity of TTFields as a surrogate “dose” estimate. This is motivated by in vitro studies showing that increasing TTFields intensity decreases tumor growth rate [
17]. However, it is also known that the antitumor effects of TTFields depend on the treatment exposure time as well as the direction of the induced fields relative to the direction of cell division. Specifically, longer exposure time kills
more cancer cells [
18], and cells dividing along the direction of the active field are damaged to a greater extent than cells dividing perpendicularly to the field [
17,
19]. This observation is supported by the fact that two sequential fields induced by layouts placed in orthogonal directions on the scalp enhance the efficacy of the treatment in vivo by approximately 20% compared to a single field [
20]. This illustrates the notion that multidirectional TTFields are able inhibit a larger fraction of cells in a volume because the effect is distributed more uniformly across cells dividing in random directions [
20]. By a similar notion, TTFields are currently applied using two array pairs, which are activated in an even 50% duty cycle of 2-second duration (Optune®
, Novocure, Ltd.). The arrays are positioned so that the field intensity in the tumor is maximized, while the arrays are maintained in approximately orthogonal orientations [
4]. However, because of the complex conductivity distribution of the head and individual differences in anatomy and tumor morphology, the induced fields are not necessarily orthogonal throughout the exposed volume. This problem has not been addressed in TTFields modeling until now, which may give a biased or incomplete foundation for determining the actual efficacy
of TTFields. This chapter presents a new method, which potentially resolves this limitation by quantifying both the average field intensity and the amount of unwanted spatial correlation between the induced fields. The chapter is based on results published by Korshoej et al. [
21], and further elaborates on the underlying modeling methods. The new dosimetry approach is based on FE computations and principal component analysis (PCA)
. I will describe how significant field anisotropy can occur in GBM patients and how this potentially affects layout planning and clinical implementation. Finally, I will briefly discuss how unwanted field anisotropy can potentially be reduced using activation cycle optimization.