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RESEARCH ARTICLE
Enhancing Predicted Efficacy of Tumor
Treating Fields Therapy of Glioblastoma
Using Targeted Surgical Craniectomy: A
Computer Modeling Study
Anders Rosendal Korshoej
1
*, Guilherme Bicalho Saturnino
2,3
, Line
Kirkegaard Rasmussen
1
, Gorm von Oettingen
1
, Jens Christian Hedemann Sørensen
1
,
Axel Thielscher
2,3,4
1Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark, 2The Danish Research
Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark, 3Max
Planck Institute for Biological Cybernetics, Tu¨bingen, Germany, 4Biomedical Engineering, DTU Elektro,
Technical University of Denmark, Kongens Lyngby, Denmark
*andekors@rm.dk
Abstract
Objective
The present work proposes a new clinical approach to TTFields therapy of glioblastoma.
The approach combines targeted surgical skull removal (craniectomy) with TTFields ther-
apy 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 electri-
cal 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.
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 1 / 25
a11111
OPEN ACCESS
Citation: Korshoej AR, Saturnino GB, Rasmussen
LK, von Oettingen G, Sørensen JCH, Thielscher A
(2016) Enhancing Predicted Efficacy of Tumor
Treating Fields Therapy of Glioblastoma Using
Targeted Surgical Craniectomy: A Computer
Modeling Study. PLoS ONE 11(10): e0164051.
doi:10.1371/journal.pone.0164051
Editor: Waldemar Debinski, Wake Forest University
School of Medicine, UNITED STATES
Received: April 12, 2016
Accepted: September 18, 2016
Published: October 3, 2016
Copyright: ©2016 Korshoej et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper.
Funding: This work was supported by Eva og
Henry Frænkels Mindefond (PI: Anders R.
Korshoej), The Danish Council for Independent
Research, Medical Sciences, Lundbeckfonden (PI:
Axel Thielscher; Grant Nr. R118-A11308 and PI:
Hartwig Siebner; Grant Nr. R59 A5399, Grant of
Excellence “ContAct”), an Interdisciplinary Synergy
Grant “Basics” sponsored by NovoNordisk fonden
(recipients: Hartwig Siebner, Axel Thielscher & Lars
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.
Introduction
Glioblastoma Multiforme (GBM) is one of the most severe and debilitating types of brain can-
cer. The current standard of GBM therapy involves surgical tumor resection, radiotherapy,
and chemotherapy [1–7]. Within recent years, however, tumor treating fields (TTFields) has
become increasingly common as a supplementary treatment modality in several neuro-oncol-
ogy centers around the world. Results have been promising [8–17] with efficacy being compa-
rable to best choice physicians chemotherapy for recurrent GBM [9,10,13,18] and overall
survival time increased by approximately 5–7 months for newly diagnosed GBM [13,19].
Despite recent improvements, no treatment to date has been able to substantially increase the
chance of long-term survival for GBM patients and the disease remains a deadly condition.
In this study, we present a new clinical implementation of TTFields therapy, which has the
theoretical potential to significantly increase the clinical efficacy of TTFields therapy of intra-
cranial cancers. Standard TTFields therapy utilizes intermediate frequency (100–300 kHz)
alternating currents to disrupt cancer cell division and arrest tumor progression [20,21]. In
vitro studies have established that the effect of TTFields on tumor growth rate is positively cor-
related to the electrical fieldstrength induced by the treatment [20,22]. Although an equivalent
correlation between electrical field strength and clinical tumor control has not been firmly
established it is likely that this dose-response relationship extends to clinical settings. From a
clinical point of view, it is therefore desirable to apply TTFields therapy in a way which focally
increases the field strength in the tumor region while sparinghealthy regions of the brain. Here
we propose an intervention which achieves this objective for tumors in the cortical and subcor-
tical regions of the cerebral hemispheres. The approach combines TTFields therapy with
removal of selected parts of the skull (craniectomy) immediately over the tumor region in
order to create low resistance pathways for the current flow into the underlying tumor tissue.
We investigated the estimated efficacy of various sizes and configurations of craniectomy with
the objective to identify approaches which are effective, safe and feasible from a clinical per-
spective. In addition, we investigated the efficacy of the intervention for a deeply seated tumor
and addressed the potential limitations in the range of anatomical applicability. We used finite
element methods to calculate the electrical field distribution induced by TTFields, both in a
standard configuration (no craniectomy) and following a variety of virtual surgical craniec-
tomies located immediately above the tumor region. We quantified the expected field enhance-
ment induced by this approach to obtain a surrogate measure of the expected enhancement in
treatment efficacy [23]. To illustrate the most likely clinical scenarios we have investigated the
expected impact both before and after the resection of the superficialtumor. Based on the in
vitro dose-response relationship between field strength and decline in tumor growth rate
[20,22], the proposed implementation has the theoretical potential to considerably increase
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 2 / 25
K. Hansen, Grant Nr. 11413) and a Science Without
Borders Scholarship from the Brazilian Ministry of
Science and Technology (Recipient: Guilherme B.
Saturnino). The funders had no role in study
design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: Anders Rosendal Korshoej
has received funding from Novocure Ltd. to
support the clinical trial ’Enhancing Optune Therapy
with Targeted Craniotomy’ (clinicaltrials.gov
identifier NCT02893137). The remaining authors
have no competing interests.
TTFields efficacy for glioblastoma patients without compromising brain protection and patient
safety to an unacceptable extent. The potential benefit expectedlyapplies to a wide range of
tumor locations in the cerebral hemispheres, although only limited effect can be expected for
very deep tumors locatedin the thalamic regions and basal ganglia. Our results lay the grounds
for future pre-clinical and clinical studies to validate the concept.
Materials and Methods
The study protocol was submitted for approval by the Central Denmark Region Committee for
Health research Ethics. The study was accepted and full review was not required, as the study
was not considered to be a clinical research project. Use of clinical MRI scans for electrical field
modeling studieswas approved. The study was performed in accordance with the principles
expressed in the Declaration of Helsinki [24] and written consent to use MRI data for the study
was obtained from all included subjects.
Study subjects
Experiments were based on MRI data obtained from two patients: 1) A 36-year-old patient
(Subject 1) with a 50x35x51 mm hemispheric left fronto-parietal GBM (Fig 1A) centered at
approximately 20 mm depth relative to the cerebral cortex,and 2) a 22-year-old patient (Subject
2) with a deeply seated a 32x51x41 mm WHO grade III astrocytoma located in the right thala-
mus and surrounding basal ganglia and white matter tracts (Fig 2A). The choice of patients was
based on the objective to investigate the potential benefit, applicability and limitations of the
proposed skull remodeling procedure for both superficial hemispheric and deeply seated tumors
and further in order to illustrate the expected mechanism of action of the intervention. Subject 1
is representative of most GBM tumors in the sense that it is located in the hemispheric region
and has a representative size and radiologicalappearance. Studies of GBM volume distributions
in the brain have shown that approximately 97% of GBM tumors are located in the cerebral
hemispheres with significantproportions of the tumor volume located in the superficialparts of
the hemispheres [25]. Deep locations such as the basal ganglia or thalamic regions are very
uncommon. This observation is relevant for the present applications as our results demonstrate
that the intervention will arguably benefit most GBM tumors with significant volume propor-
tions located in the most superficial4–5 centimeters of the cerebral hemispheres (see Results
and Discussion). Contrary to the representative Subject 1, Subject 2 represents a rare case of
deeply located GBM. For these reasons detailed investigations of the impact and utility of cra-
niectomy were basedon data from Subject 1, whiledata from Subject 2 was mainly includedto
illustrate limitations in applicability of the skull remodeling procedure with regards to anatomi-
cal range of tumor location. With regards to Subject 2, it should be noted that anaplastic astrocy-
toma is not an approved indication for TTFieldstherapy. However, the disease bares significant
similarities to GBM, such as similar cellular origin, and it is considered a highly malignant
tumor with a poor prognosis. The chemo- and radiotherapy regimen for anaplastic astrocytoma
is most often the same as for GBM and in many cases anaplastic astrocytoma will dedifferentiate
to GBM. Furthermore, when viewed from a modeling perspective, the tumor may be considered
as equivalent to GBM, since the conductivity distributions of the two tumor types are known to
be highly comparable based on MRI based conductivity estimation and in vitro measurements
[26–30] and these findings were confirmed for the presented cases (see below).
Finite element head models
A finite element head model was generated for each patient based on T1 and T2 MRI data
using a custom version of the SimNIBS pipeline (www.simnibs.org) [31,32]. For statistical
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 3 / 25
purposes, we defined a peritumoral volume of interest, including all finite elements with cen-
ters closer than 1 cm to the tumor border, as exemplified in Fig 1B. For Subject 1 a realistic cra-
niotomy was outlined manually in the skull above the superficial part of the tumor (Fig 1C)
and modeled by assigning isotropic skin conductivity values (0.465 S/m, see below) to finite
elements belongingto the outlined bone flap. This was equivalent to virtually replacing the
bone flap with skin tissue. Using a similar approach, circular craniectomies with diameters
ranging from 10 to 100 mm (5 mm increments) were also introduced immediately above the
tumor to assess the importance of craniectomy size. Finally, a model with four 15 mm burr
Fig 1. MRI data from study Subject 1 and corresponding 3D head model. A. Coronal (left), axial (middle)
and sagittal (right) views of original Gadolinium enhanced T1 MRI patient data showing left parietal
glioblastoma (radiological orientation). B. Volume reconstruction of gray matter (gray), white matter (white),
tumor tissue (yellow), and a peritumoral region (blue). C. Surface reconstruction of patient skull rotated to
present the craniectomy boneflap outlined as a darkened area above the tumor (left). The rightmost image
shows the same view, but with the bone flap removed to display the underlying tumor and peritumoral region.
D. Surface reconstruction of the head model showing the optimized electrode layout used for simulation
(NovoTAL ™). Electrodes are paired orange with white and gray with blue.
doi:10.1371/journal.pone.0164051.g001
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 4 / 25
holes distributed across the tumor projection on the skull was created to investigate differences
in performance between two types of craniectomy with the same area but different configura-
tion. In order to investigate realistic treatment scenarios, gross total tumor resection was also
modeled for Subject 1 by assigning CSF conductivity values to all tumor elements, thereby cre-
ating a virtual resection cavity filled with CSF. This situation, in whichthe resection cavity is
filled with CSF, is representative of the majority of TTFields exposure time for patients who
Fig 2. MRI data from study Subject 2 and corresponding 3D head model. A. Coronal (left), axial
(middle) and sagittal (right) views of original T2 MRI patient data showing a deeply seated WHO III
astrocytoma (radiological orientation). The tumor was non-enhancing on T1 with Gadolinium enhancement.
B. Volume reconstruction of gray matter (gray), white matter (white), tumor tissue (yellow), and a peritumoral
region of interest (blue). C. Surface reconstruction of patient skull rotated to present the circular 50 mm
craniectomy boneflap outlined as a darkened area above the tumor on the right side. The rightmost image
shows the same view, but with the bone flap removed to display the underlying cortical surface. D. Surface
reconstruction of the head model showing the optimized electrode layout used for simulation (NovoTAL™).
Electrodes are paired orange with white and gray with blue.
doi:10.1371/journal.pone.0164051.g002
Enhancing TTFields Efficacy with Craniectomy
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have undergone surgical resection. This is dueto the fact that TTFields is always initiated at
least four weeks following surgery at which time blood and hemostatic compounds, which
have potentially been introduced in the resection cavity at the time of surgery, will have dis-
solved and become replaced by CSF.
For Subject 2, a circular craniectomy of 5 cm diameter was placed beneath the closest
TTFields generatingelectrode patch, which was located on the rightside of the head (Fig 2C).
This patient was not eligible for surgery and thus only the clinically relevant situation, in which
the tumor was present in situ and no resection was performed, was investigated.
Electrical field calculation and electrode design
Electric field calculations were performed using SimNIBS [31–34]. Finite element methods
were applied to obtaina numerical solution to Laplace’s Equation of the electrostaticpoten-
tial. The model was designed to represent a realistic treatment setting, i.e. electrode design
was equivalent to the Optune™ technology (private communication with Novocure™ Ltd.)
[31,35–39]. Calculations were based on a peak-to-peak current amplitude of 1.8 A in each
pair of electrode arrays and the estimated electrical field distributions thereby represented the
distribution of the maximum field intensity which occurs at one point during a duty-cycle
period (5 μs) when the alternating current reaches peak amplitude. It is thereby a repeating
snapshot of the field distribution, which occursrepeatedly every 5 μs (200 kHz) throughouta
patient’s continuous exposure to TTFields (>18 hours per day). The calculated field will
scale linearly with the current amplitude throughout the remainder of the duty cycle. Since
the distribution is determinedby the anatomy and electrical properties of the patient’s head,
in combination with the geometry, location and settings of the active electrodes,it can be
assumed that the estimated field distribution will remain representative of the treatment
throughout the periodof exposure as long as the radiological images used for simulation are
representative. Clearly, dynamic changes may occur in the region of pathology, such as pro-
gression or regression of the tumor, and such cases should be regarded as separate scenarios
for which separate field calculations should be performed to obtain the highest possible
accuracy.
Layouts of electrodes on the scalp (Figs 1D and 2D) were designed for the both patients using
the NovoTAL™ software [40], which is used for clinical treatment planning (courtesy of Novo-
Cure™). The setup consisted of two sequentially activated separate current sources connected to a
left-right (L/R) and anterior-posterior (A/P) electrode array pair, respectively. Anisotropic conduc-
tivity estimates of intracranial tissues were obtained from diffusion tensors measurements using a
direct mapping scheme [31,41–43]. The slope of the linear fit was optimized so that the mean
squared error between the estimated conductivities in gray and white matter of the unaffected
right hemispheres and the respective literature values of 0.275 S/m and 0.126 S/m were minimized.
For Subject 1 the resulting distributions had median (Q
2
) and interquartile range (IQR) values
of Qgm
2¼0:186 S=mðIQRgm ¼0:059 S=mÞand Qwm
2¼0:159 S=mðIQRwm ¼0:031 S=mÞ,
respectively, and were thus close to the corresponding literature values. The median
conductivity in the tumor was Qtumor
2¼0:244 S=mðIQRtumor ¼0:077 S=mÞ, which also corre-
sponds well to in vivo measurements of 0.10−0.43 S/mobtained at comparable frequencies
[26]. For Subject 2 the corresponding values were Qgm
2¼0:195 S=mðIQRgm ¼0:069 S=mÞ,
Qwm
2¼0:178 S=mðIQRwm ¼0:033 S=mÞ, and Qtumor
2¼0:220 S=mðIQRtumor ¼0:066 S=mÞ
and thus also within the expected range. Conductivities of CSF, skin, and bone were considered
isotropic and assigned corresponding in vivo estimates of 1.654 S/m, 0.465 S/m and 0.010 S/m
[26,44–47].
Enhancing TTFields Efficacy with Craniectomy
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Estimation of clinical efficacy
Expected clinical efficacy was assessed by calculating the therapeutic enhancement ratio (TER)
for each element in the tumor and peritumoral region. TER measuresthe change in tumor
growth rate caused by TTFields (GR
TTF
) relative to control tissue (GR
c
) and is defined as
TER = (GR
c
−GR
TTF
)/GR
c
[20,21]. TER >0 represents reduced growth rate of GBM tissue
exposed to T TFields and TER >1 implies tumor regression. TER was calculated from the elec-
trical field distribution using the relationship inferred from in vitro data obtained from human
glioma (U-118, U-87) and rat glioma (F-98, C-6, and RG2)cell lines exposed to TTFields at 200
kHz presented in Kirson et al. [21]. An equivalent relationship has not been investigated for gli-
oma cultures baseddirectly on patient specimens. Thedata was fitted using a third order poly-
nomial, p(x) = p
0
+p
1
x+p
2
x
2
+p
3
x
3
and the resulting linear parameters were p
0
= 4.0610
−7
,
p
1
= −1.7210
−4
,P
2
= 2.9610
−2
, and p
3
= −1.54. In order to ensure conservative assessment of
treatment efficacy, only values within the range covered by the measurements of Kirson et al.
[21] (110 V/m– 240 V/m) were interpolated using the above polynomial regression. Field values
below 110 V/mwere assigned a TER value of zero, while values above >240 V/mwere assigned
the value TER = 1.245 corresponding to the TER for 240 V/m. Percentages of tumor and peritu-
moral volumes in growth arrest or regression were calculated as P
225
= Prob(|E|225 V/m),
equivalent to Prob(TER 1). The percentage of pathological tissue in which the growth rate
was expectedly reduced by TTF was calculated as P
100
= Prob(|E|100 V/m), equivalent to
Prob(TER >0) [40].
Results
Effect of craniectomy without tumor resection
Initial analysis was performed on data from Subject 1 and based on a simple scenario in which
a realistic craniotomy bone flap was virtually removed and replaced by skin (will be referred to
as standard craniectomy). This type of craniectomy may be obtained by simply removing the
bone flap created in connection with primary surgical tumor removal. In the present case, the
craniectomy was approximately oval with principal diameters of 50 mm and 67 mm, respec-
tively, and a total surface area of 2902 mm
2
. The cumulative distributions of electrical field
strengths obtained before and after standard craniectomy are presented in Fig 3 for each tissue.
The topographical maps of the same estimates are presented in Fig 4A along with the topo-
graphical distribution of the paired difference between them (Fig 4B). The results generally
illustrate that craniectomy produced a marked and focal enhancement of treatment efficacy in
the regions of pathology underlying the craniectomy without inducing high electrical field
strengths in the surrounding healthy tissues.
In the tumor volume, craniectomy caused a paired median increase in field strength of 95
V/m (corresponding to 68%) for the L/A electrode array pair and 85 V/m (61%) for the
A/P pair, relative to the standard situation with no craniectomy. The absolute median
field strengths following craniectomy were 240 (IQR = 96) V/m for the L/R pair and 230
(IQR = 104) V/m for the A/P pair. Craniectomy increased the fieldstrength in nearly >95% of
the tumor volume, indicating that treatment efficacy was improved in nearly the entire region
of pathology. The percentage of tumor tissue in expectedgrowth arrest or regressionwas
increased from negligible values (P
225, tumor
<0.5%) before craniectomy to significant propor-
tions after craniectomy (P
225, tumor
= 59% for the L/R pair and P
225, tumor
= 52% for the A/P
pair). Following craniectomy, more than 99.5 percent were exposed to field strengths higher
than the minimum threshold value of 100 V/m and mean TER values were increased from ~
0.37 (L/R and A/P) to 1.13 for the L/R pair and 1.04 for the A/P pair. The latter observation
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 7 / 25
Fig 3. Effect of craniectomy without 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 increased the electrical field
strengths in tumor tissue and the peritumoral region compared to no craniectomy. The distributions of field strengths in
healthy tissues were largely unaffected.
doi:10.1371/journal.pone.0164051.g003
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 8 / 25
suggests that craniectomy may potentially convert a situation with considerable tumor progres-
sion despite TTFields therapy into a situation with average growth regression at a rate of 4–13%
of the normal glioblastoma growth rate. This marked increase in TTF efficacy highlights the
potential clinical impact of the procedure.
Fig 4. Topographical effect of craniectomy without tumor resection. A. Field strength distributions with and without
craniectomy (coronal, axial, and sagittal sections from left to right, colorbar 0–300 V/m). B. Paired difference between
craniectomy and no craniectomy scenarios, i.e. Δ|E| = |E|
craniectomy
—|E|
no craniectomy
, for both electrode pairs. Leftmost panels
show a rotated surface view of the region of pathology. Craniectomy produced a marked and focal increase in electrical field
strength in the regions of pathology underlying the craniectomy, while healthy tissues were largely unaffected.
doi:10.1371/journal.pone.0164051.g004
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Compared to the tumor volume, similar beneficial tendencies of craniectomy were observed
in the peritumoral region although the absolute effect was slightly less pronounced. The
median increase in fieldstrength induced by the L/R pair was 85 V/m (63%), while the A/P
pair caused a 58 V/m (44%) increase. Equivalently P
225
was increased from 7% to 53% for the
L/R pair and from 0 to 23.5% for the A/P pair. Mean TER values increased from 0.39 to 1.03
for the L/R pair and from 0.31 to 0.81 for the A/P pair.
In healthy gray and white matter the distributions of field strengths were largely unaffected.
In addition, the median specific absorption rates (SAR = σ|E|
2
/ρ, σ: tissue conductivity, ρ: tissue
density) of skin tissue in the regions underlying the electrodes and overlying the craniectomy
were also unaffected by the intervention (SAR
pre
= 4–6 W/kg and SAR
post
= 5–7 W/kg). This
indicates that craniectomy would not cause unacceptable heating of healthy tissues in the pre-
sented case. Peak SAR values (99
th
percentiles) in the same regions were in the range 38–53 W/
kg before craniectomy and 54–83 W/kg following craniectomy and these results are all in the
range of previously reported median values obtained using FEM modeling with no craniectomy
[35]. Although this also supports acceptable safety of the procedure, the fact that craniectomy
did increase peak SAR values does indicate a higher risk of localized adverse skin effects follow-
ing craniectomy and this circumstance should be observed in clinical implementations.
It is noticeable that craniectomy produced a relatively focal enhancement of the electrical
field strength in the underlying region, as previously described for tDCS [23]. This resulted
from the fact that craniectomy created a corridor for high current flow into the underlying
intracranial tissue, as illustrated in Fig 5A. In addition, curre<nt density in the skin between
electrodes was reduced (Fig 5B) due to shunting through the hole in the skull. Craniectomy
thereby redistributedthe current flow to pass through the regionof pathology and thereby also
caused clear-cut changes in the topographical distribution of electrical field strength in this
region (Fig 4). The corresponding coefficients of determination between the pre- and post-
craniectomy scenarios were r
2tumor, L/R
= 0.53, r
2tumor, A/P
= 0.64, r
2peritumor, L/R
= 0.73, and
r
2peritumor, A/P
= 0.37. In light of themechanism of action indicatedabove, craniectomy should
be considered a method to focally intensify TTFields in the underlying region. Particularly, it
should be noted that the ability of a craniectomy to selectively enhance the field intensity in the
region of pathology in the presented case was attributed mainly to the fact that the skull defect
and electrodes were placed immediately over the tumor region.
Effect of craniectomy after tumor resection
Following resection of the tumor, standard craniectomy produced a qualitatively comparable
enhancement of treatment efficacy, although the absolute effect (Fig 6) and topographical field
distribution were significantly different from the preresection results (Fig 7).
The median paired change in peritumoral field strength caused by craniectomy was 83 V/
m (96%) for the L/R electrode array pair and 58 V/m (58%) for the A/P pair. Following cra-
niectomy the median field strength was 233 V/m (IQR = 98 V/m) for the L/R pair and 193
V/m (IQR = 56 V/m) for the A/P pair. P
100
was approximately doubled and >85% for both
pairs following craniectomy, while P
225
increased from 12% to 28% for the L/R pair and
from 4% to 32.5% for the A/P pair. Mean TER values were increasedfrom 0.23 to 0.58 for the
L/R pair and from 0.21 to 0.68 for the A/P pair. Considering the latter results, craniectomy
would thereby reduce cancer proliferation rate in the peritumoral tissue from approximately
80% to 30–40% of the normal glioblastoma growth rate. The topographical field distribution
was generally less affected by craniectomy in the post-resection scenario compared to the
pre-resection scenario, although some changes did occur (Fig 7, r
2peritumor, L/R
= 0.92 and
r
2peritumor, A/P
= 0.80).
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 10 / 25
Equivalent to the preresection scenario, craniectomy induceda focal enhancement of the
field strength in most of the peritumoral region, while not affecting surrounding healthy tissues
significantly. SAR values in the skin regions underlying the electrodes and overlying the cra-
niectomy were unaffected by the procedure.
Fig 5. Effect of craniectomy on current density. A. Current density distribution (color indication 0–180 A/m
2
) on the
brain surface with and without craniectomy (no resection). The skin surface (with placed electrodes) is shown for
orientation. Craniectomy significantly increases the current density in the region of pathology underlying the craniectomy
(black ellipse, Fig 1C). This in turn leads to increased field strength in the affected region. B. Topographical distribution of
the current density on the skin surface with and without craniectomy (range 0–250 A/m
2
). Craniectomy causes the
current to be shunted through the skull defect thereby lowering the current density in the skin region between the active
electrodes. The figure also shows how individual electrodes in the arrays contribute differently in the two situations.
doi:10.1371/journal.pone.0164051.g005
Enhancing TTFields Efficacy with Craniectomy
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Importance of craniectomy size
In order to assess the impact of craniectomy size we calculated the electrical field distribution
using circular craniectomies ranging from 10 to 100 mm (5 mm increments). All craniectomies
were centered at the same position immediately above the tumor region (Fig 8C). The range
of craniectomies spanned from small burr holes, which are clinically feasible to implement
Fig 6. 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.
doi:10.1371/journal.pone.0164051.g006
Enhancing TTFields Efficacy with Craniectomy
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without compromising brain protection, to very large craniectomies, which are highly danger-
ous to implement without external brain protection. Although only some of the investigated
craniectomiesare feasible from a clinical point of view, the wide range of diameters was chosen
to assess whether an optimum size may be determined for the individual patient. In order to
assess expected efficacy and safety at each diameter, we evaluated both the median and 99
th
percentile of field strengths in the regions of pathology. The median reflects the expectedper-
formance, whereas the 99
th
percentile reflects the risk of tissue heating. Ideally, one would aim
Fig 7. Topographical effect of craniectomy after tumor resection. A. Topographical maps of field strength
distributions (coronal, axial, and sagittal from left to right, colorbar 0–300 V/m) with and without craniectomy
and for both electrode pairs as indicated. B. Paired difference between craniectomy and no craniectomy
scenarios, i.e. Δ|E| = |E|
craniectomy
—|E|
no craniectomy
, for both electrode pairs. Leftmost panels show a rotated
surface view of the resection cavity and the surrounding region of pathology. Craniectomy produced a marked
and focal increase in electrical field strength in the peritumoral region underlying the craniectomy, while leaving
the healthy tissues largely unaffected.
doi:10.1371/journal.pone.0164051.g007
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 13 / 25
to obtain a uniform field distribution with high median values (i.e. 200–300 V/m) and low sta-
tistical dispersionin the tumor and peri-tumor regions and, importantly, a low spatial extent of
high field values beyond those regions.
Fig 8A shows the median and 99
th
percentile of fieldstrengths obtained in regions of pathol-
ogy at different (circular) craniectomy diameters before tumor resection. Regardless of diame-
ter, craniectomy did not affect field strength in healthy tissues to any significant extent and
median field values were between 85 and 100 V/m for all configurations. However, in tumor
Fig 8. Effect of craniectomy size and configuration on field distribution. A. Median and 99
th
percentile field strengths
(ordinate) in the tumor and peritumoral tissues at different craniectomy diameters (abscissa). Results are shown for both the L/R
(red line) and A/P (black line) array pairs. Asterisk symbols represent equivalent results obtained using a model with four 15 mm
burr holes located above the tumor region. The results are displayed at 30 mm craniectomy diameter as these configurations had
the same total area. B. Equivalent results as displayed in A but after resection of the tumor. C. Surface view of selected
craniectomies and the corresponding field distributions obtained before tumor resection. Color bar represent the range of field
strengths displayed.
doi:10.1371/journal.pone.0164051.g008
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 14 / 25
tissue, craniectomy significantly increased the median field strength by up to 100 V/m relative
to the baseline value with no craniectomy. Maximum field enhancement was obtained at a cra-
niectomy diameter of 50 mm at which the median field strength was ~250 V/m was induced
for the L/R pair. For the A/P pair, maximum enhancement was obtained at 70 mm diameter
with a median field strength of ~225 V/m. At larger diameters the field intensity was nearly sta-
ble and slightly below the induced maxima. The observed effects,particularly the saturation of
the field enhancement with increasing craniectomy size, were qualitatively comparable for
both the L/R and A/P pairs, although the L/R pair was more efficient at all diameters of cra-
niectomy. In the peritumoral region similar tendencies were observed, although the enhance-
ment of field strengths with increasing craniectomy diameter was observed throughout the
entire tested range for the A/P pair.
In the tumor tissue, peak field strength of ~650 V/m were obtained for the L/R pair for
small craniectomies of 15–20 mm diameters (Fig 8A, bottom row). This observationreflects
current funneling effects of the skull defects, which caused high current densities at the surface
of the underlying intracranial tissue. These results may support the use of larger craniectomy
diameters, since these distribute the current across a larger area and thus induce higher median
field values across a larger segment of the tumor and peri-tumoral region, and furthermore
result in lower peak field values. For the A/P pair, a similar pattern was observed, although the
maximum field strength (99
th
percentile) was considerably lower (~520 V/m) and occurred at
slightly higher diameters (55 mm). In the peritumoral tissue, peak field strengths appeared to
increase steadily with increasing craniectomy diameter reaching values up to 350–400 V/m
depending on the active electrode array pair.
Following resection, median field strengths estimated in the peritumoral region were highly
comparable to those observed before resection. Particularly, the field strength was enhanced by
craniectomy up to approximately 70 mm diameter after which it stabilized at approximately
240 V/m for the L/R pair and 225 V/m for the A/P pair (Fig 8B). Peak field strengths increased
up to approximately 600 V/m for the L/R pair and 450 V/m for the A/P pair both occurring at
diameters of 50 mm and higher. Contrary to the situation before tumor resection, high peak
field strengths were not observedat lower craniectomy diameters, likely becausethe high flux
of charges occurring within small burr holes was distributed throughout the CSF-filled resec-
tion cavity, thereby reducing the currentdensity and the boundary zonebetween CSF and the
peritumoral tissue.
Improving efficiency using multiple distributed burr holes
Since large craniectomies pose a considerable safety hazard for the patient due to impaired
brain protection, clinical feasibility of the concept is therefore likely limited to craniectomies
with relatively low diameters, e.g. <40 mm. Although craniectomies in this range expectedly
increase the field strength in the region of pathology their size is insufficient to obtain maxi-
mum expected benefit from the procedure in the given patient case (Subject 1). In order to
assess whether stronger field enhancement could be obtained using a safer skull remodeling
procedure than a large circular craniectomy we calculated the field distribution based on a
model with four burr holes of 15 mm diameter distributed evenly across the superficial tumor
bed or resection cavity (Fig 8C). This configuration arguably provides a better protection
against blunt trauma towards the region due to the presence of protective bone bridges between
the smaller burr holes. In the investigated situation with four burr holes, the total area of the
skull defect was 707 mm
2
, which is entirely equivalent to single craniectomy of 30 mm diame-
ter. The results are displayed in Fig 8A (asterisk symbols superimposed on the craniectomy
graphs).
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 15 / 25
Without resection of the tumor, the use of distributed burr holes increased the median field
strength in the tumor region from 211 V/m (30 mm craniectomy) to 230 V/m for the L/R pair
and from 171 V/m to 204 V/m for the A/P pair (Fig 8A, upper row), without inducing higher
peak field values compared to a 30 mm craniectomy (Fig 8A, bottom row). These results were
quantitatively comparable to those obtained with a 50 mm craniectomy and thus higher effi-
cacy was induced with a smaller area of skull defect. In the peritumoral region the burr hole
configuration induced a field enhancement of approximately 20 V/m for both pairs relative to
a 30 mm craniectomy. After tumor resection similar tendencies were observed with field
enhancements in therange of 10 to 20 V/m (Fig 8B, asterisk symbols). The same range of
enhancement was observed for the peak values. As observed for all other craniectomy configu-
rations, the effects of the burr hole configuration were focal and targeted at the region underly-
ing the skull defect. In the presented case, healthy tissues were unaffected.
Collectively, these results suggest, that it is possible to design a patterned distribution of
small burr holes for the individual patient, which is both constrained to an acceptable total area
and able to induce considerable enhancement of the field strength in the relevant regions.
Despite the potential of this approach, a more detailedinvestigation of the procedure, including
planning of optimal burr hole placement, is beyond the scope of the present study.
Effect of craniectomy on deeply located tumors
In order to evaluate the potential impact of craniectomy on tumors located deeply in the brain,
analyses were performed on the model based on Subject 2 (see Finite element head models)
who had an anaplastic astrocytoma located in the right thalamus and the surrounding regions.
Deeply seated gliomas are interesting from the point of view that they are often inoperable and
associated with a poor prognosis, thereby making TTFields a potentially attractive supplement
to the standard regimenof radio- and chemotherapy. In this respect, it is of course also inter-
esting to clarify whether craniectomy may potentially benefit such patients. However, as previ-
ously mentioned, craniectomy exerts its field enhancing effect by creating a corridor for
enhanced current flowinto the region underlying the skull defect (Fig 5) and it is questionable
whether the enhancing effect will be able to reach the deeper areas. In support of this notion,
results from Subject 2 indeed show that the field enhancement caused by craniectomy occurred
in the healthy brain tissue underlying the craniectomy but not in the deep tumor tissue (Fig 9).
Craniectomy only marginally increased the fieldintensity in the tumor region from 81
(IQR = 47) V/m to 91 (IQR = 19) V/m for the L/Rpair while no enhancement was observed
for the A/P pair with field strengths 118 (IQR = 26) V/m before craniectomy and 118
(IQR = 23) V/m after craniectomy. For the peritumoral region the results were comparable
with craniectomy slightly increasing the field strength from 108 (IQR = 47) V/m to 118
(IQR = 56) V/m for the L/R pair, while no change occurred for the A/P pair with median field
strength 113 (IQR = 26) V/m in both cases). As evident from Figs 4and 9, the field enhance-
ment induced by craniectomy was located to the region underlying the craniectomy for both
Subjects 1 (tumor) and 2 (healthy brain tissue). In both cases, field enhancement occurred
throughout most of the hemispheric region immediately underlying the craniectomy, albeit the
most significant enhancement was obser ved in the cortical and subcortical structures down to
a depth of approximately 4–5 cm.
On an additional note, it is also noticeable that the field induced in the deeply seated tumor
(Subject 2) by standard TTFields therapy without craniectomy was considerably lower com-
pared to the more superficial tumor (Subject 1). In the tumor region the median field intensity
was 81 V/m compared to 140 V/m, respectivelyfor the LR pair. For the A/P pair, the equivalent
values were 118 V/m and 139 V/m, respectively. Similar results were obtained for the
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 16 / 25
peritumoral region, although less pronounced. These results indicate, that TTFields is arguably
less effective for deeply seated tumors. They also indicate, that the A/P pair contributes consid-
erably more than the L/R pair for deep tumors, which is contrary to the superficial tumors for
which the L/R and A/P pairs contributed equally. This effect likely resulted from the fact that
Fig 9. Topographical effect of craniectomy for a deeply seatedtumor. A. Field strength distributions with and without
craniectomy (coronal, axial, and sagittal sections from left to right, colorbar 0–300 V/m). B. Paired difference between craniectomy
and no craniectomy scenarios, i.e. Δ|E| = |E|
craniectomy
—|E|
no craniectomy
, for both electrode pairs. Leftmost panels show a surface
view of the region of pathology. Craniectomy caused no considerable changes in electrical field strength in the regions of
pathology, but rather induced a significant increase in field strength in the healthy tissues immediately underlying the skull defect.
doi:10.1371/journal.pone.0164051.g009
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 17 / 25
current was effectively shunted through the lateral ventricles towards the deep tumor during
activation of the A/P pair.
Discussion
In the present work, we have evaluated the potential impact of targetedcraniectomy on the
estimated field distributions and efficacy of TTFields therapy. We have focused our analysis
mainly on a representative case of cortical/subcorticalhemispheric GBM and compared electri-
cal field distributions calculated without craniectomy with distributions obtained following 1)
removal of a realisticcraniotomy bone flap, 2) introduction of a wide range of circular craniec-
tomies of varying size all located immediately above the superficial part of the tumor, and 3)
introduction of four 15 mm burr holes above the tumor. In addition, we have assessed these
effects both before and after gross total resection of the tumor in order to address the impact of
the approach in the most realistic clinical situations. To illustrate the potential limitations in
applicability of the intervention, we have also assessed the expected efficacy on a patient with a
very deeply seated tumor located in the thalamic region. All calculations were based on realistic
head models constructed from structural and diffusion MRI.
Overall efficacy of craniectomy combined with TTFields
Our results provide preliminary but strong evidence that surgical craniectomy placed in close
vicinity to superficialtumors may provide a substantial and highlyfocal enhancement of the
field strength inducedby TTFields in the tumor tissue. In the present case of superficial fronto-
parietal GBM, standard craniectomy, i.e. removal of a realistic bone flap as could be created in
connection with primary surgical tumor resection, increased in the electrical field strengths in
the regions of pathology by 50–70% while leaving healthy tissues largely unaffected. In addi-
tion, standard craniectomy increased the percentage of pathological tumor tissue in expected
growth arrest or regression from negligiblevalues to more than 50% both before and following
resection. When no resection was performed, craniectomy changed the expected average can-
cer growth pattern from considerable tumor growth to regression at a rate of ~10% of the nor-
mal glioblastoma growth rate. This illustrates the clinical potential of the proposed procedure
and even suggests that significant disease regression might potentially be possible. Similar
results were obtained with 50 mm circular craniectomy centered above the tumor center. The
enhancing effect of craniectomy increased almost linearly with craniectomy diameters in the
range 0–50 mm after which the effect appeared to stabilize.
Following resectionof the superficial tumor the effect of standard craniectomy was qualita-
tively similar, although slightly less pronounced, compared to the preresection scenario. It was
not possible to obtain average estimated regression of neoplastic tissue in the peritumoral
region, however, craniectomy did produce a considerable (2- to 3-fold) estimated reduction of
residual tumor growth rate. Again, the median field strength increased almost linearly with cra-
niectomy diameter, in this case up to 70 mm for the L/R pair and throughout the entire range
for the A/P pair.
Mechanism of action
Craniectomy had a significant impact on the topographical distribution of the electrical field.
As a general observation,the procedure induceda highly focal enhancement of theelectrical
field strength in the tissue lying immediately below the craniectomy (Figs 4and 9). This effect
reflected the procedure’s generic mechanism of action, namely that craniectomy created a
low resistance pathway and thereby caused current to be funneled through the skull defect and
into the underlying tissue (Fig 6). A high focality of field enhancement was observed for all
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 18 / 25
craniectomy configurations, although less so for large diameters exceeding the superficial
boundaries of the tumor region. It was obser ved both when no resection was performed and
following gross total resection of the tumor, which indicates that the approach is likely applica-
ble to most clinically relevant scenarios of superficial tumors.
In the case of a deeply seated tumor, craniectomy only caused a slight enhancement of the
field induced by the L/R electrode pair, while no enhancement was observed for the A/P pair.
This selective alteration of L/R efficiencylikely resulted from the fact that the L/R electrode
pair was located immediatelyabove the skull defect and that the induced field and current vec-
tors were perpendicularto the craniectomy plane. This caused current to flow directly into the
underlying tissue. On the contrary, the A/P pair was located far from the skull defect and
induced field and current vectors parallel to the hole, which therefore did not facilitate current
flow into the intracranial space.
Despite the fact that craniectomy was unable to cause notable enhancement of the field in
the deeply seated tumor tissue, it did indeed significantly increase the field intensity in the
healthy GM and WM tissue immediatelyunderlying the skull defect during activation of the L/
R pair. This supports the notion that the intervention induces field enhancement by facilitating
current flow into the underlying region. The effects of craniectomy on TTFields are therefore
not related to a selective interaction with tumor tissue, but rather the location of the skull defect
and electrodes relative to the tumor. In conclusion, craniectomy will expectedly be beneficial if
it can be placed on the path of current flow between the active electrode and the tumor, such
that currents are funneled towards the region of pathology, as illustrated in Fig 6.
Clinical applicability
As evident from Figs 4B and 9B, the enhancing effect of craniectomy occurred down to approx-
imately 4–5 centimeters in depth for both the superficial and deep tumor case. In addition, the
anatomical range of applicability may further be extended in some situations by creating high-
conductivity CSF pathways, e.g. in connection with partial or total surgical resection, such that
current may be funneled from the craniectomy to deeper tumor regions. This concept is illus-
trated in Fig 7, which shows how gross total resection extends the topographical range of the
treatment (compare to Fig 4) and increases the electrical field in deeper regions of the brain rel-
ative to the field direction. Collectively, this suggests that the intervention may potentially be
beneficial for most cases of hemispheric tumors. As evident from a recent study, most GBM
tumors (97%) are located in the frontal, parietal, temporal and occipital lobes of the cerebral
hemispheres [25]. Only very few are located solely in deeper regions, such as the brainstem,
thalami and basal ganglia. The study also showed that on average a significant proportion of
the GBM tumor volume was located in the superficial most 5 cm of the cerebralhemispheres,
in which the proposed intervention is expectedly beneficial. Specifically, it was shown that the
median tumor volume was approximately 45 cm
3
(median radius 22 mm) and that the
median tumor centroid was located approximately 50 mm from the center of the third ventri-
cle. Both findingsare highly comparable to case ofSubject 1 (volume 46 cm
3
and centroid 58
mm from middle of third ventricle).Given the generic mechanism of action, the craniectomy
procedure will therefore expectedly work for a wide range of tumors located in both the frontal,
parietal, temporal and occipital lobes. The concept will generally apply when 1) a significant
portion of the tumor volume is located in the outermost 5 cm of the cerebral hemispheres, 2) a
craniectomy can be placed in close vicinity to the region of pathology and 3) one patch in each
electrode pair can be placed in close vicinity to the craniectomy. The intervention is unsuited
for tumors located deeply in the thalamic regions and basal ganglia.
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 19 / 25
Balancing safety and efficacy
For the described concept to be clinically feasible,it is necessary to carefully consider safety/
efficacy profile ingeneral terms and for each individualpatient. In this regard, two major safety
considerationsneed to be addressed: 1) What is the riskof damage to healthy tissues due to
unacceptable heating, and 2) can craniectomy be planned to maintain adequate brain
protection.
With regards to the first consideration, our results have confirmed the general expectation
that the field enhancement caused by craniectomy was relatively focal and to a significant
extent determined by the geometry and location of the craniectomy together with the position
of electrodes. In the investigated cases, the most significant field enhancement was restricted to
the area immediately underlyingthe craniectomy. In the presented case of a tumor located
superficially beneath the craniectomy, no notable changes were observed in the surrounding
healthy tissues. The median and peak electrical field strengths in healthy brain tissues were
unaffected by craniectomy, regardless of configuration or size, as was the median SAR values
in skin regions underlyingthe electrodes and overlying the hole in the skull (pre- and post
resection of the tumor). Peak SAR values were increased by craniectomy but still within the
range of median SAR values reported in previous modeling studies. Therefore the treatment
would not impose additional risk of over heating or damage of healthy tissues and craniectomy
would expectedly not imply safety concerns in this regard. However, single small craniectomies
(15–20 mm) did appear to cause very high field strengths in the underlying tumor tissue in the
pre-resection scenario. This questions the feasibility of this approach, although the affected tis-
sue was pathological in this caseand heating therefore not necessarilya critical issue. In the
case of tumor resection, high peak field strengths were not obser ved for any craniectomy diam-
eters, including small diameters, which indicates that craniectomy above a resected region will
likely not induce heat toxicity. The mechanism behind this observation is likely that that cur-
rent was dispersedmore uniformly in the underlying CSF (resectioncavity) which thereby
reduced the current density at the tissue boundaries. Finally, it should be considered that the
modeled scenarios reflect the clinical situation at a given point in time during the course of
treatment. It is possible, that dynamic changes in tumor morphology and tissue properties,
such as disease progression or regression, will occur during the continuous treatment with
TTFields. One aspect to consider in the respect is that tumor regression, as potentially induced
by TTFields or other treatment, may reduce the tumor burden in the area of maximum field
intensity, such that such that generated heat could instead be deposited in the surrounding
healthy tissues. For this reason, additional modeling should be performed to ensure sufficient
safety if radiological changes indicate that healthy tissues could be at risk. This consideration
holds for TTFields in general but particularly if the treatment is to be combined with craniect-
omy, as the induced field strengths in intracranial tissues are significantly enhanced by this
procedure.
The second major safety concern is that craniectomy will compromise the local protection
of the brain and therefore may increase the risk of traumatic brain injury. The aim is therefore
to determine the smallest possible craniectomy, which provides the desired enhancement of
the field strength, such that an appropriate balance between safety and efficacy is obtained.
Our results suggest, that the median field strength in the region of pathology was largest for
craniectomies around 50–70 mm in diameter, which is regarded as unsafe to implement with-
out additional external skull protection. Increasing the size of the craniectomy to values larger
than 50–70 mm did not appear to provide additional benefit, although this conclusion is only
valid for the case investigated here and likely depends on the size and location of the tumor in
question.
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 20 / 25
Despite variations between subjects, our results do imply that some craniectomies may be
both safe and efficient in connection with TTFields. Even relatively small craniectomies of
30–40 mm diameter can significantly increase the field strength induced in the underlying
tumor tissue and such craniectomies may be clinically safe and feasible in many cases. In
addition, our results also show that even stronger field strength enhancement may be
obtained be distributing the skull defect area across multiple smaller burr holes placed in the
immediate vicinity of the tumor. The latter approach would likely provide better protection
against blunt trauma injuries compared to single craniectomies with equivalent total area.
Furthermore, the burr holes could be placed such that they could be covered directly by the
ceramic transducer discs of the TTFields delivering device, thereby allowing direct current
flow from the electrodes through the hole, while also providing mechanical protection over
the defects.
Limitations and future perspectives
Despite the generic mechanism of action and arguable generalizability of the results, future
investigations are required to thoroughly characterize the impact of tumor location and tissue
morphology/compositionon the efficacy of craniectomy. Ideally, however, individualizedsim-
ulations should be performed to establish the potential benefit of skull remodeling surgery for
every patient before such procedures are performed. Furthermore, it would be beneficial to
develop and refine the current modeling techniques for better accuracy and applicability,
including estimation and validation of electrical properties for a variety of surgical products
used in glioma surgery. For instance, methods that would allow for accurate modeling of the
most common bone fixation implants and hemostatic products would be highly valuable in
order to reproduce the field distribution in the tumor region in greater detail. Such investiga-
tions would be highly relevant for future work with TTFields modeling in general, including
modeling of the treatment in its standard implementation.
It should also be noted, that the promising potential for improved disease control presented
in this manuscript was based on in vitro evidence for a direct correlation between increased
field strength and reduced tumor growth rate (therapeutic enhancement ratio) [21]. Although
this relationship was established on immortalized human glioma cell lines, it may not accu-
rately represent the interaction between T TFields and glioma cells for individual patients. It is
most likely that the relationship extends to the clinical setting, however a direct correlation
between the individual estimated field distribution and clinical tumor control remains to be
validated. Similarly, it would be valuable to establish and quantify the correlation between field
strength and TER on a case basis using cultured tumor specimens from the individual patients.
Such information would potentially allow for individualized prognostication and assessment of
the expected clinical benefit of TTFields for each patient.
Although many aspects of TTFields remain elusive, we do conclude that craniectomy causes
a considerable enhancement of the TTFields intensity in the underlying region and that this in
turn likely represents a significant enhancement of the clinical efficacy. As previously men-
tioned, however, it is important to consider that craniectomy is an invasive and potentially
dangerous and may put the patient at additional risk. Preliminary phase 1 studies are therefore
needed to characterize the clinical safety profile of the intervention and determine if the
expected benefit will justify clinical implementation. Such a study is currently being planned by
the Authors and the trial will expectedly initiate in late 2016. Finally, it is imperative to conduct
a careful assessment of the potential risks and benefitsfor each individual patient before skull
remodeling surgery is considered. Most importantly, such assessment should include the
impact of the procedure on quality of life and subsequent treatment options. Ideally,
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 21 / 25
individualized field modeling should also be performed to plan the procedure and ensure suffi-
cient field enhancement.
Conclusions
Our results provide preliminary but strong evidence that craniectomy located immediately
above superficial intracranial tumors significantly increases the efficacy of TTFields therapy of
glioblastoma by up to 100%. The concept is based on the fact that craniectomy creates a path-
way of low resistance through the skull and thereby effectively guides the current towards the
region of pathology. Even smaller craniectomies (30–40 mm diameter) or use of multiple burr
holes (four 15 mm burr holes) may provide significant benefit while preserving acceptable
brain protection and patient safety. The concept theoretically applies to a wide range of tumors
and resection may extend the anatomical range of applicability. Three main criteria should be
fulfilled to apply the concept: 1) a large part of the tumor should be located relatively close to
the surface (4–5 cm), 2) it should be feasible to place a craniectomy immediately above the
region of pathology, and 3) it should be feasibleto place the TTFields electrodesin close vicin-
ity to the craniectomy. The procedure is unsuited for deeply located tumors, such as tumors
located in the brainstem, thalami and basal ganglia.
The proposed procedure may potentially provide a considerable leap forward in the treat-
ment of one of themost serious and debilitatingcancer diseases of all. Future clinical investiga-
tions are required to validate the clinical safety and efficacy of the approach.
Acknowledgments
The Authors acknowledge Novocure™ for extending the courtesy of providing technical specifi-
cation about the Optune™ technology and NovoTAL™ electrode layouts based for analysis and
publication.
Author Contributions
Conceptualization:ARK GvO AT JCHS.
Data curation: ARK GBS LKR GvO JCHS AT.
Formal analysis: ARK GBS AT.
Funding acquisition: ARK JCHS AT GBS.
Investigation: ARK GBS LKR GvO JCHS AT.
Methodology: ARK GBS AT.
Project administration: ARK JCHS AT.
Resources: ARK GBS LKR GvO JCHS AT.
Software: ARK GBS AT.
Supervision: ARK JCHS AT.
Validation: ARK GBS AT.
Visualization: ARK GBS LKR GvO JCHS AT.
Writing – original draft: ARK.
Writing – review & editing: ARK GBS LKR GvO JCHS AT.
Enhancing TTFields Efficacy with Craniectomy
PLOS ONE | DOI:10.1371/journal.pone.0164051 October 3, 2016 22 / 25
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