International Journal of

Radiation Oncology
biology physics

www.redjournal.org

Head and Neck Cancers

Fractionated Boron Neutron Capture Therapy

in Locally Recurrent Head and Neck Cancer:
A Prospective Phase I/II Trial
Ling-Wei Wang, MD,*,y Yi-Wei Chen, MD, PhD,*,y Ching-Yin Ho, MD,y,z
Yen-Wan Hsueh Liu, PhD,x Fong-In Chou, PhD,x,k Yuan-Hao Liu, PhD,{
Hong-Ming Liu, PhD,k Jinn-Jer Peir, PhD,k Shiang-Huei Jiang, PhD,x
Chi-Wei Chang, PhD,y,# Ching-Sheng Liu, PhD,*,y Ko-Han Lin, MD,**
Shyh-Jen Wang, MD,y,# Pen-Yuan Chu, MD,y,z Wen-Liang Lo, DDS,y,yy
Shou-Yen Kao, DDS, DMSc,y,yy and Sang-Hue Yen, MD*,y
*Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; yNational Yang-Ming
University, Taiwan; zDepartment of Otolaryngology, Taipei Veterans General Hospital, Taiwan;
x
Institute of Nuclear Engineering and Science, National Tsing Hua University, Taiwan; kNuclear
Science and Technology Development Center, National Tsing Hua University, Taiwan; {Nuclear
Science and Engineering Department, Nanjing University of Aeronautics and Astronautics, Nanjing,
China; #Department of Nuclear Medicine, Taipei Veterans General Hospital, Taiwan; **Taoyuan
Veterans Hospital, Taiwan; and yyDepartment of Stomatology, Taipei Veterans General Hospital,
Taiwan

Received Nov 8, 2015, and in revised form Jan 2, 2016. Accepted for publication Feb 8, 2016.

Summary
To investigate the efficacy
and safety of boron neutron
capture therapy (BNCT), we
treated 17 patients with
recurrent head and neck
(H&N) cancer after photon
radiation therapy in a pro-
spective phase 1/2 trial star-
ted in 2010. Two-fraction
BNCT with intravenous
Purpose: To investigate the efficacy and safety of fractionated boron neutron capture the-
rapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy.
Methods and Materials: In this prospective phase 1/2 trial, 2-fraction BNCT with
intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a
28-day interval. Before each fraction, fluorine-18-labeled-BPAepositron emission to-
mography was conducted to determine the tumor/normal tissue ratio of an individual
tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover
80% of the gross tumor volume by using a dose volume histogram, while minimizing
the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects
were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the
Common Terminology Criteria for Adverse Events v3.0, respectively.

Reprint requests to: Ling-Wei Wang, MD, Department of Oncology,
Taipei Veterans General Hospital, No. 201, Sect. 2, Shih-Pai Rd, Taipei,
Taiwan 112. Tel: (þ886) 2-28757270; E-mail: lwwang@vghtpe.gov.tw
Presented in part at the 16th International Congress of Neutron Capture
Therapy, June 14-19, 2014, Helsinki, Finland.
Conflict of interest: none.
Supplementary material for this article can be found at
www.redjournal.org.
AcknowledgmentdThe authors thank Taiwan Biotech Co Ltd for help
in preparing the BPAefructose solution and performing pretreatment tests
for this trial.

Int J Radiation Oncol Biol Phys, Vol. 95, No. 1, pp. 396e403, 2016
0360-3016/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2016.02.028
Volume 95  Number 1  2016 BNCT in locally recurrent H&N cancer 397

L-boronophenylalanine at a
28-day interval was con-
ducted. The total response
rate was 71%, including 6
complete responses. Toxicity
was acceptable. Boron
neutron capture therapy may
be a treatment choice for
locally recurrent H&N
cancer.
Results: Seventeen patients with a previous cumulative radiation dose of 63-165 Gy
were enrolled. All but 2 participants received 2 fractions of BNCT. The median tu-
mor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas
the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively.
After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants ex-
hibited a complete response and 6 exhibited a partial response. Regarding acute
toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4
laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhib-
ited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40
Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locor-
egional control was 28%.
Conclusions: Our results suggested that 2-fraction BNCT with adaptive dose prescrip-
tion was effective and safe in locally recurrent H&N cancer. Modifications to our pro-
tocol may yield more satisfactory results in the future. Ó 2016 Elsevier Inc. All rights
reserved.

Introduction According to experience in photon therapy, adaptive

treatment planning during intensity modulated radiation
therapy has been used to counteract the effects of posi-
Head and neck (H&N) cancer, particularly oral cancer, is an
tioning errors and anatomic changes in H&N cancer (8, 9).
endemic disease in Taiwan. Despite the advances in sur-
Because the tumor/normal tissue (T/N) ratio of BPA uptake
gery, radiation therapy, and chemotherapy, locally recurrent
and tumor size may change before each fraction of BNCT,
H&N cancer after multidisciplinary treatment is not un-
we selected a similar adaptive approach for the second
common. It poses a therapeutic challenge because of high
complication and low success rates after reirradiation with fraction in this trial. It was approved by the institutional
review board of our hospital and the Ministry of Health in
a photon beam (1-3). Therefore, patients with locally
2009. We initiated this trial in August 2010 and terminated
recurrent H&N cancer require additional treatment options.
it in 2014. This article reports the results of 17 patients with
Boron neutron capture therapy (BNCT) is based on a nu-
recurrent H&N cancer treated with 2-fraction BNCT at our
clear capture reaction that occurs when the nonradioactive
research reactor.
boron (10B) is irradiated with thermal neutrons of energy
(V) <1 eV to yield high energy a-particles (4He2þ) and
lithium (7Li) nuclei (4). The effect of a-particles and 7Li Methods and Materials
nuclei is primarily limited to boron-containing cells
because their path lengths are approximately equal to 1 cell Study design and objectives
diameter (<10 mm). The preferential uptake of boron in
H&N cancer was achieved using boron carriers such as L-
This was a prospective, noncomparative, open-label, single-
boronophenylalanine (BPA), a phenylalanine derivative (5).
center phase 1/2 trial for recurrent H&N cancer. The pri-
Theoretically, only cancer cells with high 10B concentration
mary endpoints were treatment toxicity and tumor response
will be destroyed after neutron irradiation. Boron neutron
rates after 2 fractions of BNCT. The secondary objectives
capture therapy was used to treat recurrent H&N cancer of
were the time to tumor progression, progression-free
several series. High response rates (60%-83%) with an
survival, and overall survival.
acceptable toxicity have been observed in both the single-
fraction and 2-fraction designs (6, 7). For decades, the
most common neutron source for this treatment remains a Inclusion and exclusion criteria
nuclear reactor.
In our country, the National Tsing Hua University has a The inclusion criteria were (1) locoregionally recurrent
2 MW TRIGA CONV research reactor (General Atomics, and histologically proved malignancy of the head and
San Diego, CA), which is the only epithermal neutron neck; (2) previous receipt of conventional radiation ther-
source used for BNCT research. In 2008 a clinical trial apy for the disease (except melanoma); (3) a bidimen-
protocol with a 2-fraction design was drafted for recurrent sionally measurable disease evaluated using magnetic
H&N cancer at Taipei Veterans General Hospital. The 2- resonance imaging (MRI) and/or computed tomography
fraction design was hypothesized to be less toxic than a (CT), with the largest dimension being 12 cm; (4) age
single-fraction design and obtain equivalent or more satis- >18 years and <80 years and Eastern Cooperative
factory results. Oncology Group performance status 2; (5) white blood
398 Wang et al.
cell count >2.5  109/L, neutrophil count >1.0  109/L,
platelet count >75  109/L, and serum creatinine level
<1.25  upper limit of normal range; and (6) a T/N ratio
of BPA uptake >2.5 measured using fluorine-18-labeled-
BPAepositron emission tomography (18F-BPA-PET). The
exclusion criteria were (1) lymphoma or any other tumor
type that was expected to respond to cancer chemotherapy
or to a safe dose of conventional radiation therapy; (2)
availability of an effective standard treatment option; (3)
distant metastasis outside the H&N regions; (4) a life
expectancy <3 months; (5) receipt of the previous radi-
ation therapy <3 months before this trial; (6) receipt of a
concurrent systemic cancer treatment, including chemo-
therapy and target therapy; (7) pregnancy; (8) an inability
to lie or sit in a cast for 30-60 minutes; and (9) a cardiac
pacemaker or an unremovable metal implant present in
the H&N regions that would interfere with MRI-based
dose planning or tumor response evaluation.
Image studies
Before the screening procedure, each patient received
MRI and whole-body 18F-fluorodeoxyglucose (FDG)-
PET/CT for evaluating the size and staging of the recur-
rent tumor. The PET/CT scanner at our hospital was the
GE VCT (GE Medical Systems, Milwaukee, WI). The
18
F-BPA-PET/CT scan procedure was repeated before
both the first and second fractions of BNCT to determine
T/N ratios. The injected dose of 18F-BPA was approxi-
mately 5 mCi. The uptake of 18F-BPA in the tumor was
measured by calculating the mean standard uptake value
of the gross tumor volume (GTV). The uptake of 18F-BPA
in the normal tissue was measured by calculating the
mean standard uptake value of a region in the subcu-
taneous connective tissue on the contralateral side of the
GTV, measured 60 minutes after 18F-BPA injection.
Before BNCT, a CT simulation was typically conducted in
a supine position with a slice thickness of 5 mm at our
department.
Treatment planning
For contouring the GTV (including the primary tumor and
adjacent lymphadenopathy), CT images from simulations
were coregistered with T1-weighted MRI and 18F-BPA-
PET images. Normal structures (including critical organs
and oral mucosa) were delineated. The CT images and
contours of all participants were subsequently sent to the
university for processing. In-house-designed treatment
planning software (10) was used for dose calculation, 3-
dimensional dose display on CT images, and generation
of dose volume histograms for tumors and normal struc-
tures. Tissue compositions as defined by the International
Commission on Radiation Units and Measurements were
used (11). The relative biological effectiveness was 1 for
g-ray and 3.2 for neutron. The compound biological
International Journal of Radiation Oncology  Biology  Physics
effectiveness factors for boron were 4.9 for the mucosa,
3.8 for the tumor, 2.5 for the skin, and 1.3 for other
normal tissues (12). Fluorine-18-labeled-BPA-PET, CT
simulation, and contouring were repeated before the sec-
ond fraction of BNCT.
During treatment planning, both the physical dose and
biologically equivalent dose were calculated. The equiva-
lent dose was defined as the sum of the physical dose
components multiplied by weighting factors (including
relative biological effectiveness and compound biological
effectiveness) of each dose component in a tissue. Princi-
ples of dose prescription included (1) delivering 20-25
Gy-Eq per fraction to 80% of the GTV (prescription dose,
D80); (2) limiting the volume of oral mucosa receiving
>10 Gy-Eq per fraction to the lowest possible level; and
(3) limiting the maximum dose available to the optic nerve
or chiasma to <8 Gy-Eq per fraction. The dose constraints
for the other critical organs were determined individually
according to the previous radiation dose. Because of the
potential change in the BPA T/N ratio after the first frac-
tion, the prescription dose for the second fraction may have
been different from the first. A single anterior, lateral, or
antero-oblique portal was used for each fraction.
Administration of BNCT
All participants were placed in a stable posture (lying or
sitting) during exposure to a horizontal radiation field by
using polyethylene extension collimators over the beam
aperture to facilitate the treatment position setup. An on-
site simulation at the research reactor was conducted to
verify the tumor location and irradiation volume (GTV
with a margin of at least 1 cm) through a beam’s-eye view
before L-BPA (from Hammercap, Stockholm, Sweden and
Taiwan Biotech Co Ltd) injection. To increase solubility,
L-BPA was complexed with fructose to form an L-BPA-F
solution (13), which was administered at a concentration
of 25 g/L and pH of 7.6 (14). Intravenous L-BPA-F
(400 mg/kg) was administered in 2 phases: the drug was
infused at the rate of 180 mg/kg/h for 2 hours before
neutron irradiation in the first phase, and at the rate of
1.5 mg/kg/min in the second phase, concurrent with irra-
diation and stopped when the beam was off. The blood
boron concentrations were measured using inductively
coupled plasma atomic emission spectrometry before in-
jection; 1 hour before, immediately before and after, and
30 minutes after neutron irradiation; and before leaving the
research reactor.
Follow-up
The participants were reviewed at the first and second week
and 1 month after each fraction of BNCT to record any
adverse effects. Each review included a physical exami-
nation, measurement of weight and vital signs, and
assessment of performance status, general well-being, and
Volume 95  Number 1  2016 BNCT in locally recurrent H&N cancer 399

toxicity. The participants were followed up every 3 months Statistical analysis

for the first 2 years and at least every 6 months for the next
3 years. The tumor response in each participant was eval-
uated at least 1 month after the last fraction of BNCT
by conducting a physical examination and MRI. Scanning
with 18F-FDG-PET/CT was conducted at least 3 months
after the last BNCT to confirm a complete response (CR)
and rule out distant metastases.
Criteria for evaluation of the response and toxicity
Tumor responses were assessed using the Response Eval-
uation Criteria in Solid Tumors v1.1, and adverse effects
were assessed using the Common Terminology Criteria for
Adverse Events (CTCAE) v3.0.
The efficacy analysis was based on the intent-to-treat
principle. All participants who received at least 1 fraction
of BNCT were included in the analysis. A Kaplan-Meier
estimate for overall survival was calculated from the date of
the first fraction of BNCT to the date of death. Participants
alive at the time of the analysis cutoff date (June 30, 2015)
were censored. Locoregional control was calculated from
the date of the first BNCT session to the date of locore-
gional progression in the head and neck area, whether it
was the BNCT treatment site or not. Participants who were
alive or dead without any evidence of locoregional pro-
gression were censored. The statistic software used was
Stata 12.0 (StataCorp, College Station, TX).

Results
Table 1 Patient and tumor characteristics
Characteristic n (%) Median (range)
Participant accrual and characteristics
Patient
Among the 25 patients with recurrent H&N cancer
Sex
Male 15 (88) screened during July 2010 and November 2013, 17 with 23
Female 2 (12) tumors were found to be eligible and were subsequently
Age (y) 56 (40-74) treated with BNCT. The most common primary site of the
Surgery before BNCT tumor was the oral cavity (41%). Most of the participants
Yes 15 (88) were heavily treated with photon radiation therapy in 1 or 2
No 2 (12) courses. Demographic data of all participants and tumor
Prior cumulative photon RT 107 (63-165) characteristics are listed in Table 1. All 17 participants
dose (Gy)
Period between prior photon 9 (4-58)
RT and BNCT (mo) Table 2 BNCT parameters
Tumor
Parameter Median (range)
Primary site
Oral cavity 7 (41) Interval between BNCT treatments (d) 28 (24-35)
Nose or paranasal sinus 4 (24) BPA T/N ratio by PET
Nasopharynx 3 (18) First fraction 3.4 (2.3-6.2)
Hypopharynx 2 (12) Second fraction 2.5 (1.2-4.4)
Parotid gland 1 (6) Irradiation time (min)
Pathology First fraction 23.4 (18.9-35.8)
SCC 11 (64) Second fraction 22.8 (18.5-31.2)
Other carcinoma* 5 (29) Gross tumor volume (mL)
Sarcoma 1 (6) First fraction 15.6 (0.5-130)
Diameter (cm) 5 (1-8.9) Second fraction 12.2 (0.2-105.5)
Recurrent T stage Minimal equivalent tumor dose (Gy-Eq)
rT0 1 (6) First fraction 13.0 (5.4-33)
rT1 2 (12) Second fraction 9.5 (2.0-22.6)
rT2 2 (12) Average equivalent tumor dose (Gy-Eq)
rT3 5 (29) First fraction 26.0 (8.1-40.1)
rT4 7 (41) Second fraction 17.0 (5.5-33.1)
Recurrent N stage Average tumor physical dose (Gy)
rN0 14 (82) First fraction 7.8 (2.5-11.2)
rN1 0 Second fraction 5.1 (1.7-9.8)
rN2 3 (18) Maximum mucosa physical dose (Gy)
rN3 0 First fraction 4.0 (1.3-5.6)
Abbreviations: BNCT Z boron neutron capture therapy; Second fraction 3.8 (1.4-5.4)
RT Z radiation therapy; SCC Z squamous cell carcinoma. Abbreviations: BPA Z L-boronophenylalanine; PET Z positron
* Other carcinomas include adenocarcinoma, sinonasal carcinoma, emission tomography; T/N Z tumor/normal tissue. Other abbreviation
and undifferentiated and nonkeratinizing carcinoma. as in Table 1.
400 Wang et al.
received 18F-BPA-PET/CT before the first fraction of
BNCT. The procedure was repeated in 14 participants
before the second fraction of BNCT.
Radiation dose delivered
The median average blood boron concentration was
28.8 parts per million (range, 21.3-38.8 parts per million)
during irradiation. The median neutron irradiation time was
23.0 minutes (range, 18.5-35.8 minutes). The D80 was
changed according to the changes in the T/N ratio within
the same participant to protect the oral mucosa and other
normal tissues. For the GTV, the median D80 was 19.8 Gy-
Eq (range, 6.7-37 Gy-Eq) and 14.6 Gy-Eq (range, 3.8-21.7
Gy-Eq) for the first and second fractions of BNCT,
respectively, whereas the corresponding median average
dose was 26 and 17 Gy-Eq for the first and second fractions
of BNCT, respectively. The relationship between D80s and
BPA T/N ratios is shown in Figure E1 (available online at
www.redjournal.org). Two participants received only 1
fraction of BNCT. One of them had grade 3 scalp cellulitis
after the first fraction. Because the tumor was small
(0.5 mL), we omitted the second fraction to prevent
Fig. 1. Computed tomography and magnetic resonance images (upper) and photographs (lower) of recurrent ethmoid sinus
carcinoma before (left) and 4 years after boron neutron capture therapy (right). The arrow indicates the tumor, which dis-
appeared completely after therapy.
International Journal of Radiation Oncology  Biology  Physics
worsening of the toxicity. Another participant had 2 sepa-
rate lesions that could not to be covered within a single
portal. Because both lesions were relatively small (1 and
15.6 mL), we treated each lesion on different days. Treat-
ment parameters are listed in Table 2.
Efficacy
The median follow-up period was 19.7 months (range, 5.2-
52 months). All patients had the response evaluation
1 month after completion of BNCT (1 or 2 fractions), and 3
patients did not have the evaluation 2 months later because
of loss to follow-up or dropout. Six participants showed a
CR supported by PET 3 months after the last fraction of
BNCT. Imaging studies and photographs of 2 participants
before and after BNCT are shown in Figures 1 and 2. One
of them remained disease free for 4 years after BNCT. Six
participants exhibited no sign of locoregional progression at
their last follow-up. The median period for locoregional
tumor progression was 4.1 months after BNCT for the other
participants. Two-year locoregional control was 28% (95%
confidence interval 9%-52%; curve for locoregional
control in Fig. E2; available online at www.redjournal.org).
Volume 95  Number 1  2016
Two-year overall survival was 47% (95% confidence in-
terval 23%-68%; survival curve in Fig. E3; available online
at www.redjournal.org).
Toxicity
Acute and late toxicities after treatment are listed in
Tables 3 and 4. The most common grade 3 acute toxicity
was mucositis (29%). One participant showed acute grade 4
toxicity (laryngeal edema and carotid hemorrhage) within
3 months after BNCT and was salvaged with tracheostomy
and embolization of the common carotid artery. The most
common grade 3 late toxicity was cranial neuropathy in 2
participants. No grade 4 late toxicity was observed.
Discussion
Despite the advances in modern radiation therapy tech-
niques, reirradiation in locally advanced H&N cancer
carries a risk of severe complications. Boron neutron cap-
ture therapy, a type of target radiation therapy, can translate
Fig. 2. Fluorine-18-labeled fluorodeoxyglucose positron emission tomography/computed tomography images of a recur-
rent nasopharyngeal cancer before (left) and 3 months after boron neutron capture therapy (right). The arrows indicate the
tumor. Complete response was found.
BNCT in locally recurrent H&N cancer 401
differential boron uptake to a steep dose gradient between
tumors and surrounding critical structures via boroneneu-
tron reaction. Another advantage of BNCT is its conve-
nience; a large radiation dose can be delivered in 1 to 2
fractions that are smaller than those of photon radiosurgery.
Because H&N cancer sometimes recurs after photon radi-
ation therapy in Taiwan, we designed a prospective trial
utilizing 2-fraction BNCT at our research reactor.
The reasons for using 2 fractions of BNCT are listed as
follows: (1) A low dose per fraction can yield a low
toxicity; (2) The second fraction can suppress repopulation
of residual tumor cells after the first fraction, even after a
28-day interval; (3) Different beam angles can be used for
each fraction of treatment, thus improving the homogeneity
of the final dose distribution, particularly for relatively
deep-seated tumors; and (4) Adaptive planning for the
second fraction can be conducted by evaluating the updated
tumor size and T/N ratio. Most participants in the present
study exhibited a reduction in the tumor volume after the
first fraction (Table 2). A smaller collimator was selected
for 1 participant for the second fraction because of a dra-
matic reduction in the tumor volume.
402 Wang et al. International Journal of Radiation Oncology  Biology  Physics

Table 3 Acute toxicities Suzuki et al (16) demonstrated a CR rate of 28% with the
minimal GTV dose of 17.9 Gy-Eq (mostly administered in
None Grades Grade Grade
a single fraction). In the present study, we used D80 as the
Adverse effect (n) 1-2 (n) 3 (n) 4 (n)
prescription dose because it represents the minimal dose
Mucositis 2 10 5 0 received by most (80%) of the GTV and is located between
Radiation dermatitis 3 14 0 0 the mean and minimal doses delivered to the whole GTV.
Allopecia 5 12 0 0
Moreover, some correlations among this particular dose,
Dysphagia 10 6 1 0
Tumor pain 12 4 1 0
volume, and response were detected (Fig. E4; available at
Hemorrhage 15 0 1 1 www.redjournal.org). A high proportion (4 of 6 or 67%) of
Infection (soft tissue) 15 0 2 0 patients receiving total D80 > 40 Gy-Eq achieved a CR,
Pneumonia 15 1 1 0 without exceeding the dose constraint of the mucosa.
Edema (H&N) 15 1 1 0 Despite the initial positive response, the most common
Edema (laryngeal) 16 0 0 1 type of treatment failure observed in the present study was
Otitis 16 1 0 0 locoregional rerecurrence, which is consistent with the
Nausea or vomiting 16 1 0 0 findings observed in a Finnish study (15). Apart from the
Conjunctivitis 16 1 0 0 dosage effect on the GTV, other possible causes include (1)
Abbreviation: H&N Z head and neck. inhomogeneous BPA distribution in the tumor, particularly
Acute toxicities defined as those that developed within 3 months after
in large tumors with hypoxic areas; (2) an insufficient dose
the last fraction of boron neutron capture therapy.
or coverage of the clinical target volume, which extent was
difficult to define in a reirradiation situation; (3) impaired
Few studies have explored the relationship between the penetration of epithermal neutrons for deep-seated tumors;
dose and response of BNCT in H&N cancer. In a study and (4) epithelialemesenchymal transition that renders
comparing the treatment results of different administration tumors resistant to reirradiation and disposed to distant
routes of BPA, patients receiving BNCT via an intra- metastases (17). Combination of BNCT with other modal-
arterial route (median average dose, 45.0 Gy-Eq) exhibited ities of treatment, either systemically or locally, can be
a higher response rate (100%) than did those receiving the attempted in the future to improve results.
treatment via an intravenous route (median average dose, Interestingly, there were no obvious differences in the
16.4 Gy-Eq; response rate 33%) (6). Furthermore, the dose incidence of toxicities between the 6 patients receiving >40
description for BNCT varies among institutions. Both mean Gy-Eq and others. The possible reasons included (1) T/N
and minimal doses delivered to the GTV have been re- ratios of the former group were high (median 4.6 before
ported in previous studies. Kankaanranta et al (15) showed BNCT); (2) some of them were small in size; (3) the tumor
that administering a total mean GTV dose of 45 Gy (W) location had some distance from critical organs or previous
divided in 2 fractions resulted in a high CR rate of 45%. high dose areas; and (4) some tumors received only 1 rather
than 2 courses of RT before BNCT. Mostly, the toxicity
profile was acceptable for participants heavily treated
Table 4 Late toxicities before. However, despite adaptive planning, we still found
None Grades Grade Grade 1 patient with severe (grade 4) toxicity of laryngeal edema
Adverse effect (n) 1-2 (n) 3 (n) 4 (n) and carotid hemorrhage. This patient had 2 courses of ra-
Dysphagia 10 7 0 0 diation therapy before enrollment in this trial and a short
Fatigue 11 5 1 0 interval (5 months) between photon treatment and BNCT.
Xerostomia 11 6 0 0 For recurrent tumors surrounding or adjacent to carotid
Trismus 11 6 0 0 artery after high-dose radiation, we suggest that a preven-
Allopecia 11 6 0 0 tive measure such as stent placement be performed before
Cranial neuropathy 12 3 2 0 BNCT.
Soft tissue necrosis 13 3 1 0 The limitations of the present study are as listed follows:
Pain 13 3 1 0
(1) The number of participants was small and heterogeneity
Impaired hearing 13 4 0 0
Dysgeusia 13 4 0 0
of tumors was high, which make analysis of prognostic
Otitis 14 3 0 0 factors difficult; (2) The follow-up period was not
Osteoradionecrosis 14 3 0 0 adequately long; (3) The dosimetry for BNCT carries more
Dry eyes 14 3 0 0 complexity and uncertainty than that for photon beam
Smell loss 15 2 0 0 treatment planning (16, 18); and (4) We assumed that the
Edema (H&N) 15 2 0 0 BPA concentration in the blood was equal to that in the
Keratitis 16 0 1 0 normal connective tissue; however, this assumption was
Infection (soft tissue) 16 0 1 0 found to be untrue in several animal studies (19, 20) and
Abbreviation as in Table 3. might have led to inaccurate tumor dose calculations.
Late toxicities defined as those that developed beyond 3 months after
In conclusion, treatment of locally recurrent H&N
the last fraction of boron neutron capture therapy.
cancer after photon irradiation remained a therapeutic
Volume 95  Number 1  2016
challenge, even with target radiation therapy like BNCT.
Generally, our fractionated regimen was effective and
safe. Adaptive planning according to changes in the 18F-
BPA T/N ratio and tumor size was feasible. With ongoing
clinical trials on accelerator-based BNCT, which can be
installed in hospitals, the role and application of this
special radiation therapy in H&N cancer can be broadened
in the future.
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