The status of Tsukuba BNCT trial: BPA-based boron neutron capture therapy combined with X-ray irradiation.

Abstract

The phase II trial has been prepared to assess the effectiveness of BPA (250 mg/kg)-based NCT combined with X-ray irradiation and temozolomide (75 mg/m(2)) for the treatment of newly diagnosed GBM. BPA uptake is determined by (18)F-BPA-PET and/or (11)C-MET-PET, and a tumor with the lesion to normal ratio of 2 or more is indicated for BNCT. The maximum normal brain point dose prescribed was limited to 13.0 Gy or less. Primary end point is overall survival.

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1. Introduction
In the previous clinical trial, we evaluated the
effi cacy and safety of neutron capture therapy (NCT)
in 15 patients with newly diagnosed glioblastoma
(GBM). In that study, 7 patients received
intraoperative NCT (protocol-1) and 8 patients
received external beam NCT (protocol-2). Although
the results were favorable, the effectiveness of NCT
should be evaluated in larger number of patients
using more homogeneous and less complicated
treatment procedures. A new NCT trial is planned
to start in 2010 at the JRR-4 of Japan Atomic
Energy Agency (JAEA) to investigate the effi cacy
of boronophenylalanine (BPA)-mediated NCT in
combination with conventional chemoradiotherapy
(Stupp, 2005). However, the disorders at JRR-4
and the repair and improvement of the reactor core
delayed the initiation of the trial.
2. Trial design
The phase II trial has been prepared to assess
the effectiveness of BPA-based NCT combined
with X-ray irradiation for the treatment of newly
diagnosed GBM. The BNCT protocol was approved
by the Medical Ethics Committee of the University
of Tsukuba, and 20 participating patients will be
fully informed and provided their written informed
consent. This trial was also registered with the
Japanese Authority on clinical trial registration
(University Hospital Medical Information Network
Clinical Trial Registry: UMIN-CTR).
All patients will undergo maximal safe resection
of the tumor. The new NCT protocol uses 1 hour
injection of BPA (250mg/kg) followed by epithermal
neutron irradiation at JRR-4. Fractionated photon
irradiation and concomitant oral administration of
temozolomide (75mg/m2) are combined with the
BPA-based NCT. After a 4-weak break, patients are
to receive six cycles of adjuvant temozolomide at
a dose of 150 to 200 mg per square meter of body
surface area for 5 days during each 28-day cycle.
Eligibility criteria
- age between 15 and 80 at inclusion
- Karnofsky Performance Status (KPS) > 50
- supratentorial unilateral tumors located no
deeper than 7 cm from the brain surface
- maximal safe resection of main tumor mass
- pathological proof of GBM
- estimated lesion to normal ratio < 2
BPA uptake is determined by 18F-BPA-PET and/or
11C-methionine (MET)-PET. The maximum normal
brain point (5 x 5 x 5 mm voxel) dose prescribed
is limited to 13.0 Gy or less. For the various
prescribed doses, including the minimum tumor
dose at clinical target volume (CTV)-1, CTV-2
and CTV-3, the maximum normal brain dose, the
maximum skin dose, and the average brain dose are
calculated using the NCT dose simulation software,
JAEA Computational Dosimetry System (JCDS).
Survival and neurological status of the patients,
MRI and PET scans will be followed up every 3
months. Primary end point is overall survival.
Abstract
The phase II trial has been prepared to assess the effectiveness of BPA-based NCT combined with X-ray
irradiation and temozolomide (TMZ) for the treatment of newly diagnosed GBM. The new NCT protocol
includes 1 hour injection of BPA (250mg/kg) followed by epithermal neutron irradiation at JRR-4. Fractionated
photon irradiation and concomitant oral administration of TMZ (75mg/m2) are combined with the BPA-based
BNCT. BPA uptake is determined by 18F- BPA-PET and/or 11C-MET-PET, and a tumor with the lesion to normal
ratio of 2 or more is indicated for BNCT. The maximum normal brain point dose prescribed was limited to
13.0 Gy or less. The various prescribed doses are calculated using the BNCT dose simulation software JCDS.
Primary end point is overall survival.
Keywords: glioma, X-ray, chemotherapy, temozolomide, radiation
The status of Tsukuba BNCT Trial: BPA-Based Boron Neutron Capture
Therapy Combined with X-ray Irradiation
T. Yamamoto1,2, K. Nakai1, T. Nariai3, H. Kumada2, T. Okumura2, M. Mizumoto2, K. Tsuboi2, A. Zaboronok1,
E. Ishikawa1, H. Aiyama1, K. Endo1, T. Takada1, F. Yoshida1, Y. Shibata1, A. Matsumura1
1Department of Neurosurgery, 2Department of Radiation Oncology, Graduate School of Comprehensive
Human Science, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Japan
3Department of Neurosurgery, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, Japan

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3. Discussion
T/N ratio estimated by 18F-BPA-PET is the most
reliable factor to determine the candidates of
NCT because its effectiveness highly depends on
the degree of accumulation of 10B in tumor cells.
However, 18F-BPA is available only in a few PET
centers in Japan. Previous clinical PET study
showed that T/N ratio of boron concentration during
NCT can be estimated by 18F-BPA-PET scan as
well as 11C-MET-PET scan using a linear regression
between the T/N ratio of 11C-MET-PET and that of
18F-BPA-PET (Nariai, 2009). The PET amino acid
imaging, such as 18F-BPA-PET and 11C-MET-PET,
may be useful for selecting candidates, monitoring
the effect of NCT, and the differential diagnosis
between recurrent tumors and radiation necrosis.
Our previous trial suggested that NCT is effective
for prolonged survival of patients with newly-
diagnosed glioblastoma with acceptable adverse
effects (Yamamoto, 2009). In that trial, BSH (5g/
body) was administered intravenously. Additionally,
BPA (250mg/kg) was given in protocol-2. The
external beam NCT was combined with fractionated
X-ray irradiation. Salvage surgery (7 patients) and
chemotherapy (5 patients) were performed when
the tumor progression was evident. The median
overall survival and the time to tumor progression
(TTP) for all patients were 25.7 and 11.9 months
(M), respectively. There was no difference in TTP
between the protocol-1 (12.0 M) and protocol-2
(11.9 M). The 1- and 2-year survival rates were
80.0% and 53.3%, respectively.
The clinical records showed that the blood boron
concentration at the time of neutron irradiation was
17.4±2.4 μg/g for BPA in protocol 2. The maximum
normal brain dose for protocol 2 was 11.4±1.5Gy
(range, 8.4–14.1). The minimum tumor doses of
CTV-1, CTV-2 and CTV-3 averaged 29.8±9.9Gy,
15.1±5.4Gy and 12.4±2.9Gy, respectively. The
maximum brain dose, skin dose and average brain
dose were 11.4±1.5Gy, 9.5±1.5Gy and 3.9±1.8Gy,
respectively. The average brain dose was 3.1±0.4Gy.
The most common acute adverse event in protocol 2
was mild erythema (Grade 1), which was observed
in most patients. One patient suffered transient
orbital swelling accompanied by double vision
(Grade 2). No serious BSH- or BPA-related toxicity
was observed in the present series. In the previous
report of BNL trial, BPA precipitates in the urine
were found in patients receiving 330mg/kg BPA
in 2-hour injection. These fi ndings suggest that
acute toxicity of BPA-mediated NCT with 1-hour
injection of BPA (250mg/kg) is acceptable when the
prescribed dose for normal brain is limited to 13.0
Gy or less. The contribution of BSH in the minimum
tumor dose of CTV-1 (29.8 Gy) was estimated
at 31.7% (range, 18-54%). The dose simulation
assuming BPA-based NCT without BSH in the
protocol-2 cases suggests that the minimum tumor
boron dose can be adjusted to 26.0 Gy (range, 12.6-
37.4 Gy) after adjusting irradiation time and other
conditions. The combination of BPA and BSH was
incorporated into the previous protocol to minimize
the heterogeneous 10B distribution in glioma cells.
Therefore, this study may reveal the effectiveness
of the combination therapy, and defi ne whether the
additional temozolomide and X-ray fractionation
can compensate the dose contribution of BSH or
not.
Acknowledgments
This study was supported in part by a Grant-in-Aid
for Scientifi c Research (C) from the Ministry of
Education, Culture Sports, Science, and Technology
of Japan (22591604).
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