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

Article (PDF Available)inApplied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 69(12):1817-8 · February 2011with106 Reads
DOI: 10.1016/j.apradiso.2011.02.013 · Source: PubMed
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.
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/m
2
) 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
18
F-BPA-PET and/or
11
C-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/m
2
) are combined with the BPA-based
BNCT. 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. 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. Yamamoto
1,2
, K. Nakai
1
, T. Nariai
3
, H. Kumada
2
, T. Okumura
2
, M. Mizumoto
2
, K. Tsuboi
2
, A. Zaboronok
1
,
E. Ishikawa
1
, H. Aiyama
1
, K. Endo
1
, T. Takada
1
, F. Yoshida
1
, Y. Shibata
1
, A. Matsumura
1
1
Department of Neurosurgery,
2
Department of Radiation Oncology, Graduate School of Comprehensive
Human Science, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Japan
3
Department of Neurosurgery, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, Japan
3. Discussion
T/N ratio estimated by
18
F-BPA-PET is the most
reliable factor to determine the candidates of
NCT because its effectiveness highly depends on
the degree of accumulation of
10
B in tumor cells.
However,
18
F-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
18
F-BPA-PET scan as
well as
11
C-MET-PET scan using a linear regression
between the T/N ratio of
11
C-MET-PET and that of
18
F-BPA-PET (Nariai, 2009). The PET amino acid
imaging, such as
18
F-BPA-PET and
11
C-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
10
B 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).
References
Diaz A, 2003, Assessment of the results from the
phase I/II boron neutron capture therapy trials
at the Brookhaven National Laboratory from a
clinician`s point of view. J Nurooncol 62: 101-
109.
Nariai T, Ishiwata K, Kimura Y, et al., 2009, PET
pharmacokinetic analysis to estimate boron
concentration in tumor and brain as a guide to
plan BNCT for malignant cerebral glioma. Appl
Radiat Isot 67: 348-350.
Stupp R, Mason WP, van den Bent MJ, et al., 2005,
Radiotherapy plus concomitant and adjuvant
temozolomide for glioblastoma. N Engl J Med
352: 987-996.
Yamamoto T, Nakai K, Kageji T, et al., 2009, Boron
neutron capture therapy for newly diagnosed
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    • "Kawabata, Miyatake and their co-workers plan to evaluate BNCT in combination with temozolomide in a multicenter Phase II Japanese clinical study (OSAKA-TRIBRAIN0902, NCT00974987). Finally, extensive studies also have been carried out by Matsumura and his clinical team at the University Hospital of Tsukuba108109110 using either BPA or BSH alone or in combination as the boron delivery agents (seeTable 3). In some cases BNCT was combined with a photon boost in combination with temozolomide in patients with either primary or recurrent GBMs. "
    [Show abstract] [Hide abstract] ABSTRACT: Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.
    Full-text · Article · Aug 2012
    • "For this purpose, a variety of methods including diffusion imaging, spectroscopy and prompt gamma imaging are under development. The success of BNCT also depends on developing new treatment schemes, such as combining BNCT with photon radiation therapy [10] [169] and on the development of new boron carrier drugs [21,170e173]. It also seems inevitable that in order incorporate BNCT treatment facilities into hospitals and thus to enable more extensive clinical use of BNCT in the future, development of efficient accelerator based neutron sources is required. "
    [Show abstract] [Hide abstract] ABSTRACT: Boron Neutron Capture Therapy (BNCT) is a binary radiotherapy method developed to treat patients with certain malignant tumours. To date, over 300 treatments have been carried out at the Finnish BNCT facility in various on-going and past clinical trials. In this technical review, we discuss our research work in the field of medical physics to form the groundwork for the Finnish BNCT patient treatments, as well as the possibilities to further develop and optimize the method in the future. Accordingly, the following aspects are described: neutron sources, beam dosimetry, treatment planning, boron imaging and determination, and finally the possibilities to detect the efficacy and effects of BNCT on patients.
    Full-text · Article · May 2012
    • "It theoretically allows a selective delivery of the radiation damage within an infiltrating cancer cell while preserving the surrounding healthy tissues. BNCT has been preferentially employed in clinical trials designed for the treatment of GBM (Henriksson et al., 2008; Yamamoto et al., 2008 Yamamoto et al., , 2011 van Rij et al., 2005). This high grade tumour of the central nervous system is highly malignant and extremely infiltrative, characterized by rapid tumour growth with a wide microscopic invasion of malignant cells within the normal parenchyma. "
    Full-text · Chapter · Sep 2011 · Physica Medica
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