Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy
et al. (2017) Preliminary
dosimetric study on feasibility of multi-beam boron
neutron capture therapy in patients with diffuse
intrinsic pontine glioma without craniotomy. PLoS
ONE 12(6): e0180461. https://doi.org/10.1371/
Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy
Jia-Cheng Lee 0 1
Keh-Shih Chuang 1
Yi-Wei Chen 0 1
Fang-Yuh Hsu 1
Fong-In Chou 1
Sang-Hue Yen 0 1
Yuan-Hung Wu 0 1
0 Department Oncology, Taipei Veterans General Hospital , Taipei, Taiwan , 2 Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University , Hsinchu, Taiwan , 3 School of Medicine, National Yang-Ming University , Taipei, Taiwan , 4 Nuclear Science and Technology Development Center, National Tsing Hua University , Hsinchu, Taiwan , 5 Institue of Public Health, National Yang-Ming University , Taipei, Taiwan , 6 Department of Biomedical Imaging and Radiological Sciences, National Yang- Ming University , Taipei , Taiwan
1 Editor: Deric M. Park, National Cancer Institute , UNITED STATES
Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting.
Data Availability Statement: All relevant data are
within the paper.
Diffuse intrinsic pontine glioma (DIPG) is a very frustrating disease for patients, families, and
doctors. Because of the tumor's location in the brain stem, surgical removal is often impossible.
For radiotherapy, the dose constraint of the brain stem impedes dose escalation. Almost all
patients expire within 1 year of diagnosis despite radical treatment. Boron neutron capture
therapy (BNCT), a targeted radiotherapy, may have the potential to deliver an adequate
radiation dose to the tumor cells while sparing the normal brain stem.
and analysis, decision to publish, or preparation of
BNCT applies thermal neutrons to tumors that take up 10B selectively. Currently, there are
two 10B-containing drugs being used in human clinical trials for BNCT: BSH (disodium
mercaptoundecahydrododecaborate) and BPA (p-Boron-L-phenylalanine). Tumors tend to take
up these drugs preferentially, such that a higher 10B concentration can be achieved in tumors
than in normal tissue. The tumor/normal ratio (T/N ratio) is the ratio of the concentration of
the 10B-containing drug taken up by the tumor relative to that of normal tissue. The
neutroncapture reaction (10B(n,α)7Li) produces two high linear energy transfer (LET) particles with
approximately a 10-μm range that damage tumor cells while substantially sparing surrounding
normal tissues (Fig 1). With a high T/N ratio, targeted radiotherapy is thus made possible.
BNCT use has been limited by the advantage depth (AD), at which the dose to the tumor is
the same as the maximal dose to the normal tissue on the path of the neutron beam (Fig 2).
Using a 3.5 of ratio of BPA boron concentrations in tumor and normal tissue, it was found
that AD was 8.5 cm. Tumor tissue deeper than the AD would be without therapeutic benefit.
Attempts to treat DIPG with BNCT have been made in Japan [
], but all 6 patients treated in
that study expired. The failure in that study may be partially attributed to the invasiveness of
the treatment at that time and to the uncertainty of the true T/N ratio, making accurate dose
estimation difficult. Since the neutron source used in that study was a thermal neutron, which
has lower energy than the current standard epithermal neutron, the AD was thus inadequate
without craniotomy. The patients in that study were treated intra-operatively during
craniotomy. Moreover, positron emission tomography (PET) was not performed to estimate the
boron uptake for dosimetric estimation, which might have led to less accurate estimations
than does the current standard of performing PET as a part of dose calculation.
Fig 1. BNCT, as a targeted radiotherapy, may selectively damage cancer cells while sparing normal ones.
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Fig 2. Advantage depth. The advantage depth is the depth in the tissue at which the dose to the tumor equals the
maximum dose to the normal tissue along the beam. The AD of THOR is 8.5 cm, which is deeper than the deepest depth of
tumor tissue, providing therapeutic benefit.
Efforts to increase the energy of the neutron source have been made. Neutron sources with
higher energy, such as epithermal neutrons, have been used to perform BNCT as far back as
]. With better penetration, thus a deeper AD, it might be possible to treat DIPG with
BNCT without craniotomy. However, to the best of our knowledge, there has been no
published study treating DIPG with BNCT in the era of epithermal neutron sources.
In this study, we aimed to perform a preliminary dosimetric investigation on the feasibility
of BNCT without craniotomy in patients with DIPG and to compare the benefits of dose
distribution by increasing the field number from two to four.
Materials and methods
An epithermal neutron test beam of the Tsing-Hua open-pool reactor (THOR) was
constructed in 1998 for studying BNCT. A rebuilt epithermal beam port for BNCT at THOR was
finished in the summer of 2004. The first clinical trial of BNCT in THOR for recurrent head
and neck cancer was conducted between 2009 and 2013 [3, 4]. The AD of THOR is 8.5 cm [
In this study, simulation computerized tomography (CT) scans of 12 consecutive patients with
DIPG treated with external beam photon radiotherapy in Taipei Veterans General Hospital
(TVGH), Taipei, Taiwan, from 2008 to 2015 were used for dose calculation. The patients
ranged in age from 4 years to 53 years, with median age of 10 years. This study has been approved
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by Institutional Review Board, Taipei Veterans General Hospital (No. 2016-05-018CC). The
study has been conducted according to the principles expressed in the Declaration of Helsinki.
The data were analyzed anonymously.
The treatment planning systems
We used NCTPlan Ver. 1.1.44 [
], developed by the Harvard/MIT BNCT group, for
treatment planning. Because NCTPlan requires CT images in tagged image file format (TIFF) files,
we utilized ImageJ Ver. 1.48v [8±10] and in-house code to transform the CT images in Digital
Imaging and Communications in Medicine (DICOM) to TIFF format with 256 × 256 pixels,
125 slices, and a 2-mm slice thickness. The gray level of the CT images was set to 8 bits.
NCTPlan converted the input images into 21 × 21 × 25 voxels and 56 different materials,
which was defined in the International Commission on Radiation Units and Measurements 46
(ICRU-46) report  for calculations. The doses were calculated by F4 tally and kinetic
energy released in matter factors in Monte Carlo N-Particle Transport Code, Ver. 4C [
Dose-rate scaling factor (DRSF) is defined here as normalization factor derived individually
for each dose component in a BNCT in-phantom radiation field that provides the best
agreement between measured and computed data. The adjusted computed dose, Dadj (dose
component), at any position within the ellipsoidal head phantom was then given by Eqs (1)±(4).
The dose-rate scaling factor values derived from the measured and computed
depth-doserate distributions by least-squares criteria were 0.64, 1.39, 0.96, and 0.65, for thermal neutron,
fast neutron, photon, and B-10, respectively [
]. Although the T/N ratio between boron
concentrations in DIPG remains unknown, because most DIPGs are composed of glioblastoma,
we assumed a T/N ratio of 3.5 according to a previous glioblastoma study [
Based on the results of the Monte Carlo calculations, to compute the total biologically
weighted dose (RBE dose), we used the following parameters for our estimations: a relative
biological effectiveness (RBE) factor of 3.8 and 1.3 for BPA in the tumor cells and brain,
respectively. A RBE of 3.2 for THOR epithermal neutron beam high-LET components, such as
the products of thermal neutron capture in nitrogen and fast neutrons, and a RBE of 0.5 for
]. The default neutron power and flux were 1.2 MW and 1.28 × 109 (n cm-2 s-1),
respectively, for the conditions of THOR [
]. RBE dose was determined by Eq (5):
RBE dose RBE
B 10 Dadj
We measured the distance from the body surface to the deepest tumor depths on CT images
using the Eclipse version 13 treatment planning system (Varian Medical Systems, Palo Alto,
CA, USA). Dosimetry of multiple fields was calculated from two to four fields with 14
cmdiameter collimator. The directions used in the two-field (2F) plan were left (90Ê) and right
(270Ê). The directions used in the three-field (3F) plan were left anterior oblique (60Ê), right
anterior oblique (300Ê), and posterior (180Ê). The directions used in the four-field (4F) plan
were anterior (0Ê), left (90Ê), posterior (180Ê), and right (270Ê). The weightings of the multiple
fields from each direction were optimized manually until the difference of the maximal dose to
normal tissues of each direction was within 10%. The dose prescription was 20 Gy-Eq in 80%
of the clinical target volume (CTV), as prescribed in a clinical trial of BNCT for recurrent head
and neck cancer in our institution . We also calculated the estimated total beam-on time for
the 2F, 3F, and 4F plans.
Delineation of target volume and normal tissue
The CTV and normal tissue were delineated by one radiation oncologist and verified by
another on NCTPlan according to the MRI images that were registered with the simulation
CT image on the Eclipse treatment planning system. The CTV contains the gross extent of the
malignant growth and subclinical microscopic malignant disease, as defined by ICRU 62 [
The dose distribution in the CTV in each plan was evaluated by the following parameters:
CTV minimal dose (CTVmin), CTV maximal dose (CTVmax), minimal dose to 95% of the CTV
volume (CTV95%), and homogeneity index (HI). HI was applied to evaluate the homogeneity
in CTV as defined by [
where D5 and D95 represent minimum dose in 5% and 95% of CTV, respectively.
The therapeutic gain, defined as the ratio of minimal dose to CTV and maximal dose to
normal tissue (CTVmin/NTmax), was calculated. The integral dose (ID) of radiation delivered
to the normal tissue was defined as ID
Gy Eq L D
Gy Eq V
L, where D
is the mean dose delivered to volume V(L,Liter)as noted by Aoyama et al. [
]. Avoidance to
organs at risk, including the normal brain (NB), optic nerve (ON), and circle of Willis (CW),
was evaluated by the following parameters: mean dose (Dmean), maximum dose (Dmax), and
ID of the NB, ON, and CW, respectively.
All statistical tests were performed using SPSS software (release 17.0, SPSS Inc., Chicago, IL,
USA). One-way analysis of variance was used to compare dosimetric differences of the 2F, 3F,
and 4F BNCT plans. Tests were two-sided. The differences were considered statistically
significant if P 0.05.
Maximal tumor depths and dose distribution
The maximal depth of tumors from body surfaces based on CT images with 0Ê, 60Ê, 90Ê, 180Ê,
270Ê, and 300Ê beam angles are shown in Table 1. This table shows that the mean maximal
tumor depths in six different beam directions were larger than the AD. Use of a single
Fig 3. Dose distribution of 2F (a), 3F (b) and 4F (c) irradiation. A lower dose to normal brain may be obtained with 4F.
direction for DIPG is without therapeutic benefit. The dose distributions and dose volume
histogram of 2F, 3F, and 4F irradiation are shown in Figs 3 and 4. With 4F irradiation, the dose
affecting normal tissue can be reduced.
Target dosimetric evaluation
The minimal, maximal, and mean dose to CTV and CTV95% are shown in Table 2.
There was no significant difference in CTVmin, CTVmax, CTVmean, and CTV95% among the
three settings. CTVmin/NTmax, HI, and beam-on time are shown in Table 3.
The CTVmin/NTmax of the 4F (P < 0.001) and 3F (P = 0.005) were better than that of 2F.
CTVmin/NTmax of 4F was slightly larger than that of 3F (P = 0.064). HI and beam-on time
were not significantly different among the three plans.
Radiation exposure of organs at risk
The volume, Dmean, Dmax, and ID of the NB, ON, and CW for 2F, 3F, and 4F plans are listed in
Fig 4. Dose volume histograms (DVHs) of 2F (a), 3F (b) and 4F (c) irradiation for one representative case.
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There was no significantly difference in Dmean and ID of NB among the three plans. Dmax
to NB was lowered with the 4F plan.
Dmean and Dmax to optic nerves were higher by 4F. Compared with the 2F plan, 4F yielded
significant increases in ID to the optic nerves.
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There was no significant difference in ID to CW among the three settings. The Dmax to CW
by the 4F plan was higher than that of the 2F plan. The dose constraints may be fulfilled by all
In this study, we reviewed the simulation CT scans of 12 consecutive patients treated by
conventional radiotherapy in our institution. We found that, without craniotomy, the prescribed
NB: normal brain, L-ON: left optic nerve, R-ON: right optic nerve, CW: circle of Willis, Dmean: mean dose, Dmax: maximum dose, ID: integral dose.
a in Gy-Eq.
b in cGy-Eq-L
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therapeutic dose to the CTV may be fulfilled while complying with the dose constraints to the
NB, ON, and CW. Specifically, a therapeutic benefit may be achieved by applying multi-field
BNCT to treat DIPG without craniotomy, while the therapeutic gain, defined by CTVmin/
NTmax, was greatest in 3F and 4F plans. To the best of our knowledge, the current study is the
first to show that, dosimetrically, treatment of DIPG by BNCT without craniotomy may be
Besides the normal tissue constraints referred to in Table 4, Harvard-MIT and the
Brookhaven National Laboratory Phase I and Phase I/II clinical trials found that the doses associated
with a 50% incidence for somnolence (ED50 ± SE) were 6.2 ± 1.0 Gy-Eq for the average
wholebrain dose and 14.1 ± 1.8 Gy-Eq for the peak brain dose [
]. In the present study, we found
that when multi-field BNCT was applied, the mean and maximal doses to the brain were
below the aforementioned ED50 levels.
The Harvard-MIT trial data also suggested that the increased number of radiation fields
may be the major reason for increased average whole-brain dose. However, in the present
study, we found that when we applied a four-field plan, the average whole-brain dose
decreased. The reason for this discrepancy is likely due to the fact that that in the previous trial,
the clinicians increased radiation fields for dose escalation. Instead, in the present study, the
prescribed dose remained the same, while the number of radiation fields was increased.
For a disease of involving predominantly children, the duration of treatment is crucial. In
this study, we found that the average beam-on time was within 1 hour, which should be
feasible for treatment of pediatric patients.
The outcome of BNCT in treating glioblastoma has been shown to be comparable with
conventional radiotherapy with concurrent temozolomide, with a much shorter treatment
]. The present findings suggest that treatment of DIPGs with multi-beam BNCT may
have a therapeutic benefit dosimetrically. Given that most DIPGs are glioblastomas, a similar
outcome may be expected. A clinical trial is warranted for this grave disease.
The actual T/N ratio of DIPG is unknown. The normal tissue tolerance of pediatric patients
may be different from that of adults. To further reduce the dose to normal tissues, blockers
should be applied in future studies.
Although the beam-on time in two, three, and four port irradiation was almost the same, if
we consider the interval time for set-up of the patient, the treatment time in four-port
irradiation may be much longer compared with two-port irradiation.
Therapeutic benefits may be achieved using multi-field BNCT in patients with DIPG. The
maximal dose to normal brain would be minimal and the prescription dose to tumor would be
higher by four fields. To initiate a clinical trial on this devastating disease might be
We would like to thanks all BCNT staff members of the radiation oncology at VGHTPE
(Taipei Veterans General Hospital) and Institute of Nuclear Engineering and Science at NTHU
(National Tsing-Hua University). The authors are grateful for the financial support from
grants of Taipei Veterans General Hospital (No: V105A-046, V105A-013, V106A-007, and
V106A-016) and Taipei Veterans General Hospital-National Yang Ming University Excellent
Physician Scientists Cultivation Program, No. 105-V-B-107. Part of this manuscript was
presented at the 17th International Congress on Neutron Capture Therapy, Columbia, Missouri,
USA, October, 2016.
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Conceptualization: J-CL K-SC Y-WC F-YH S-HY Y-HW.
Data curation: J-CL K-SC Y-WC F-YH S-HY Y-HW F-IC.
Formal analysis: J-CL Y-HW.
Funding acquisition: J-CL Y-HW.
Investigation: J-CL K-SC Y-WC Y-HW.
Methodology: J-CL K-SC Y-WC Y-HW.
Project administration: J-CL K-SC Y-WC Y-HW.
Resources: J-CL Y-WC F-YH F-IC Y-HW.
Supervision: K-SC Y-WC F-YH F-IC S-HY Y-HW.
Validation: K-SC Y-WC F-YH F-IC S-HY Y-HW.
Visualization: J-CL K-SC Y-WC F-YH F-IC S-HY Y-HW.
Writing ± original draft: J-CL Y-HW.
Writing ± review & editing: K-SC Y-WC F-YH F-IC S-HY.
10 / 11
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