Boron Neutron Capture Therapy for Cancer
Treatments
by:
Junjie Huang
A dissertation submitted to the Department of Physics,
University of Surrey, in partial fulfillment of the degree of
Master of Radiation and Environmental Protection
Department of Physics
Faculty of Electronics & Physical Sciences
University of surrey
July 2009
© Junjie Huang 2009
1
Table of Contents
Glossary of Terms…………………………………………..P3-5
Abstract...……………………………..…...…………………..P6
1. Introduction………………………….………………..…P7-9
2. Three Major Factors of BNCT…………….……...…..P10-14
2.1 Boron 10-Delivery Agent……..…….….....………..…P10-12
2.2 Neutron Sources……………………..………………...P12-14
2.3 Dose Calculating and Treatment Planning by using Monte
Carlo....………..……..…..…………………………....P14
3. Clinical Studies for Cancer Treatments by BNCT…….P15-21
3.1 BNCT Trials for Brain Tumors…………………..…...P15-19
3.2 BNCT Trials for Other Tumors….……..……….…….P19-21
4. Recent Development of BNCT….…………..………...P22-23
5. Conclusion…...……………………………………..…P24-25
Bibliography………………………………………….… P26-27
References………...……………………………………...P28-37
2
Glossary of Terms
BBB: blood-brain barrier-is a separation of circulating blood and cerebrospinal fluid
(CSF) maintained by the choroid plexus in the central nervous system (CNS)
(Wikipedia 1, 2009).
BGRR: Brookhaven Graphite Research Reactor in BNL, USA
BMRR: The Brookhaven Medical Research Reactor, USA
BNCT: boron neutron capture therapy
BNL: Brookhaven National Laboratory, USA
BPA: 4-dihydroxy-borylphenylalanine-is considered to be the representative of the
first generation boron 10-delivery agent for BNCT
BSH: sulfahydryl borane-is considered to be the representative of the second
generation boron 10-delivery agent for BNCT
CT: computed tomography-a medical imaging method employing tomography created
by computer processing; digital geometry processing is used to generate a
three-dimensional image of the inside of an object from a large series of
two-dimensional X-ray images taken around a single axis of rotation (Wikipedia 2,
2009).
EORTCR: European Organisation for Research and Treatment of Cancer Reactor
FR: folate receptor
3
GBM: glioblasoma multiforme-a type of malignant brain tumors
HFR: High Flux Reactor in Petten, Holland
HTR: Hitachi Training Reactor in Japan
IMRT: intensity modulated radiation therapy
JAEA: Japan Atomic Energy Agency
JRR: Japan Atomic Energy Research Institute Reactor
KERMA: kinetic energy released in matter-is the sum of the initial kinetic energies of
all the charged particles liberated by uncharged ionizing radiation (i.e., indirectly
ionizing radiation such as photons and neutrons) in a sample of matter, divided by the
mass of the sample (Wikipedia 3, 2009).
KUR: Kyoto University Reactor in Japan
KURRI: Kyoto University Research Reactor Institute in Japan
LET: linear energy transfer-is a measure of the energy transferred to material as an
ionizing particle travels through it. Typically, this measure is used to quantify the
effects of ionizing radiation on biological specimens or electronic devices (Wikipedia
4, 2009).
MIT: Massachusetts Institute of Technology, USA
MITR: Massachusetts Institute of Technology Reactor in MIT, USA
4
MRI: magnetic resonance imaging-is primarily a medical imaging technique most
commonly used in radiology to visualize the internal structure and function of the
body (Wikipedia 5, 2009).
MuITR: Musashi Institute of Technology Reactor in Japan
NRI: Nuclear Research Institute in Rez, Czech Republic
5
Abstract
Boron neutron capture therapy (BNCT) is an ideal technique to kill cancer cells
selectively without harming healthy cells nearby, which is based on the reaction of
boron-10 nuclei capturing neutrons to yield high-LET alpha particles, recoiling
lithium-7 nuclei and gamma rays (Barth et al, 2006). BNCT was initially proposed to
treat the patients with GBMs. Although BNCT is reported to be at least equivalent or
more effective to treat GBM, when compare it with the other standard therapies. To
date, it has not revealed significant superiority to replace the others yet. However,
BNCT has started to shown its ability to treat other types of primary or recurrent
cancers such as melanomas, head and neck cancers, liver cancers and thyroid cancers
since the mid 1980s.
6
1. Introduction
The most well-known radiation types applied to radiotherapy are gamma ray (γ) and
X-ray. They kill not only cancer cells but also normal cells. As appearance of gamma
knife, conformal radiation therapy and intensity modulated radiation therapy (IMRT)
(NCI, 2009), radiation dose can be increased to a higher level to the patients at the
same time as minimizing healthy tissue destruction, such as the treatment for
nasopharyngeal carcinoma (nose & throat cancer) and mastocarcinoma (breast cancer).
However, at present, many cancers such as malignant brain tumors can not be treated
effectively by conventional therapy (surgery, chemotherapy and radiotherapy). Boron
neutron capture therapy (BNCT) has been born to aim at these tricky cancers.
Chadwick who was from the Cavendish Lab of the University of Cambridge, United
Kingdom discovered the neutron in 1932. Three years later, in 1935, Taylor, Burcham
and Chadwick showed that boron-10 (10B) has the ability to capture slow neutron to
release lithium-7, alpha particles and gamma rays. That is called the boron-10
neutron-capture reaction. A year after, in 1936, the first person who proposed that this
reaction can be utilised to treat cancer was Locher. (Sweet, 1997) Boron neutron
capture therapy (BNCT) is an ideal treatment to kill cancer cells selectively without
harming healthy cells nearby. It is a targeted chemo-radiotherapy which utilises
boron-10 that is attached to a suitable tumor-seeking drug (Stable isotope - boron 10
is used because of its high neutron capture cross-section (approx 4000 barns) which
means that it is capable to capture slow neutron easily.) (Walker, 1998). First of all, a
boron 10-carrying drug is injected into the blood. Then, a tumor accumulates the drug
through the blood transportation system. Thereafter, the tumor is irradiated by a
thermal neutron (E ≈ 0.025eV)) or an epithermal neutron (1eV < E < 10keV) source
(At present, neutron beams are extracted from the uranium-235 fission reaction within
a nuclear reactor (Walker, 1998). Finally, the boron-10 atoms inside the tumor capture
the neutrons to produce highly energetic helium 4 (4He) nuclei (i.e., alpha (α) particles)
7
and recoiling Lithium 7 (7Li) ions to kill the tumor cells (Figure 1 illustrates the
sequence of nuclear events.) (MIT, 2008). Figure 2 shows the formula for the
reaction.
Figure 1: Schematic of Boron-10 Neutron Interaction (MIT, 2008)
Figure 2: Boron neutron capture reaction formula (Walker, 1998)
The range of the two particles - 4He and 7Li within a tumor cell are ~9μm and ~5μm
8
(approx the diameter of a tumor cell) respectively. They each have high linear energy
transfer (LET) values as well. Thus, all high energy is released in a tumor cell. As a
result, the reactions bring the tumor cells high lethal probability, while normal cells
outside the tumor survive. Figure 3 shows the schematic concept of BNCT. (MIT,
2008)
Figure 3: Schematic Depicting Concept of BNCT (MIT, 2008)
BNCT has been experimentally tested to treat malignant brain tumors called
glioblasoma multiforme (GBM) and other tumors. There are a number of reports of
successful trial examples, but these have not shown to be outstanding to other
conventional therapies yet. Thus, BNCT is still at trial stage. (Wikipedia, 2008)
9
2. Three Major Factors of BNCT
2.1 Boron 10-Delivery Agents
The primary factor for successful BNCT relies on the boron 10-delivery agents. These
are the types of tumor cell-finding boron 10-containing agent which are injected into
the human body, which then accumulates in the tumor through blood transportation
system within a period of time. There are seven aspects should be considered for a
useful boron 10-delivery agent: (1) the most important aspect is strong selectively
accumulative ability to achieve high ratios of (concentration of boron-10 in tumor
cells)/(concentration of boron-10 in normal cells) (the ratios should be greater than
3-4); (2) low or even none systemic toxicity; (3) to achieve at least ~20μg
10
B/g of
tumor boron-10; (4) rapid clearance from blood and normal tissues and persistence in
tumor during BNCT; (5) chemical stability; (6) water solubility; (7) lipophilicity
(Yamamoto et al., 2008; Barth et al., 2005). Failed to achieve high ratios will result in
unnecessary damage to the surrounding normal tissues. For example, use BNCT to
treat a patient with a brain tumor. The scalp is rich in capillaries. If the ratio is too low,
this means that the boron-10 concentration of the blood in the vessels is relatively
high. While irradiating the tumor with a dose of thermal neutron or epithermal
neutron beam, the scalp is receiving substantially unnecessary damage. As a result,
the neutrons have been wasted in damaging normal cells, and then less damage is
made to the tumor. Finally, the treatment is failed. However, there is no universal
agent. Various agents should be developed to aim different kinds of malignancies.
At the beginning of BNCT usage, sodium borate and boric acid and its derivatives
were utilized in the 1950s, but boron concentrations in the tumor were not satisfactory
(Farr et al., 1954). Then, BPA (4-dihydroxy-borylphenylalanine) was made (Snyder et
al., 1958). The compound was shown to give much higher ratios of (concentration of
10
boron-10 in tumor cells)/(concentration of boron-10 in normal cells) than the other
compounds. In 1980s, it was reported to have a greater potential to treat melanomas
(Ichihashi et al., 1982). Later on, it was indicated to be applied in BNCT for
treatments of malignant brain tumors (Coderre et al., 1990). BPA can be considered to
be the representative of the first generation of boron 10-compound as a type of boron
10-delivery agent for BNCT.
Polyhedral boranes [B10H10]-2 and [Bl2H12]-2 were discovered with cage structures
which have very impressive properties of hydrolytic and chemical stabilities
(Hawthorne & Pitochelli, 1959). Later on, sodium decahydrodecaborate Na2Bl0H10
was indicated to be a promising boron 10-delivery agent (Soloway et al., 1961). It was
observed to show high ratios of (concentration of boron-10 in brain tumor
cells)/(concentration of boron-10 in normal cells). Unluckily, the drug was slightly
toxic to the human body. Finally, BSH (sulfahydryl borane, Na2B12H11SH) with lower
toxicity was developed (Soloway et al., 1967). Afterward, BSH had been applied to
most of the clinical trials in the USA, Europe and Japan, and then adequate results
were obtained. Therefore, BSH can be considered to be the representative of the
second generation of boron 10-compound as a type of boron 10-delivery agent for
BNCT.
The development of the third generation of the boron 10-delivery agents is the most
crucial factor to directly affect the destiny of BNCT. The third generation of delivery
agents has been developing due to unsatisfactory clinical results by using BPA or BSH
for BNCT. There is a major difference between the third generation agents and the
previous two. The third generation agents adopt third party agents to deliver boron-10
compounds. They mainly consist of a stable boron group or cluster attached via a
hydrolytically stable linkage to a tumor targeting moiety (Barth et al., 2005). There
are a few strategies for targeting the third generation agents to the tumor cells, such as
conjugating to recognition factors, entrapping in vesicles or incorporation in vital
compounds (Azab et al., 2006). So far, there are a number of third generation agents
11
have been investigated, such as monoclonal antibodies (Olsson et al., 1998),
biochemical precursors (Tjarks, 2001), polyamines (El-Zaria et al., 2002),
DNA-binding agents (Tietze et al., 2002), peptides (Ivanov et al., 2002), antisense
agents (Olejiniczak et al., 2002), polyhedral borane (Surewein et al., 2002),
porphyrins (Isaac & Kahl, 2003), carbohydrates (Tietze et al., 2003), amino acids
(Kabalka & Yao, 2003) and liposomes (Carlsson et al., 2003; Justus et al., 2007).
Organelles in the tumor cells such as golgi bodies, endoplasmic reticulums, lysosomes,
mitochondrion and nuclei are suitable for targeting; thereinto, nuclei are particularly
good for targeting, because less boron-10 nuclei will be needed to kill a tumor cell if
the boron-10 nuclei are located at/near the tumor cell centers (Cell nuclei are usually
at/near the centers of the cells.) (Gabel et al., 1987). A useful boron 10-delivery agent
must be soluble in water, which is to be systemically administered; also, lipophilicity
enables it to cross the blood-brain barrier (BBB) and diffuse into the tumor (Barth et
al., 2005).
2.2 Neutron Sources
The neutron beam source is another key to the success of BNCT. BNCT neutron
sources have been exclusive to nuclear reactors since the BNCT idea was proposed.
This is another reason why BNCT has not entered routine clinical application yet. As
BNCT technique is on the way to be mature, an attempt has been made to build an
advanced accelerator-based BNCT centre in a hospital to have a more flexible neutron
source than a research reactor (Matsumoto, 2007). Besides the accelerators, compact
medical research reactors are the other option, such as the operating one in Beijing,
China.
Thermal neutrons with energies of approximately 0.025eV are used in BNCT. They
are well below the threshold of ionizing tissue components (Zamenhof et al., 1994).
However, thermal neutron beam can not penetrate into deep tumors due to only 2.5cm
12
penetration range of them within the tissue’s surface (Sweet et al., 1960). Thus,
thermal neutrons are suitable for superficial tumor treatments, such as BNCT
treatment for melanoma which is a type of skin cancer (Mishima & Ichihashi et al.,
1989; Mishima & Honda et al., 1989). However, substantial amount Japanese patients
of malignant brain tumor have been treated with surgery of opening crania, followed
by BNCT (Nakagawa & Hatanaka, 1997). In order to effectively treat the tumors deep
inside the brain without opening crania, epithermal neutrons have been used to treat
these tumors instead of thermal neutrons. Epithermal neutron (1 – 10,000eV) beams
can deeply penetrate the tissue 3-6cm below the surface (Soloway et al., 1998). When
an epithermal neutron enters a human body, it decelerates to a thermal neutron
enabling easier boron neutron capture. In order to prevent the normal cells of patients
from being irradiated by too much unwanted background radiation such as gamma
rays and fast neutrons from the epithermal neutron beam port, patients must be
irradiated with enough efficient doses and positioned as close to the beam port as
possible within a period of time as short as possible (Walker, 1998). Hence, there are
some requirements for the quality and intensity of the epithermal neutron beams.
Within a shortening irradiation time, the degree of discomfort is also decreased. On
the other hand, errors made by subtle movements from the patients can also be
reduced with a shorter period of exposure. The quality of epithermal neutron beams
can be measured by an Epithermal Neutron Flux Rate (n/cm2/s) to Unwanted Back
Ground Radiation Flux Rate (n/cm2/s) ratio from the beam sources. The higher ratio it
is, the higher the quality of the neutron beam. The accuracy of beam direction is also
important. The patient’s head must be positioned flush against the beam port. The
more accurate the beam direction is, the less damage is made to the surrounding
normal tissues.
Although thermal neutron beams were used clinically in Japan, epithermal beams with
better abilities of penetration were used in the clinical trials in the United States and
Europe in 1990s (Diaz, 2003; Barth et al., 2005). There are a number of reactors
which produce beams that contain high percentages of neutrons with energies
13
between 1 and 10,000eV. For example, the beam at BMRR (The Brookhaven Medical
Research Reactor, USA) has been evaluated, and its purity and intensity have showed
that it is good enough for clinical use (Fairchild et al., 1989; Harling et al., 1990).
2.3 Dose Calculating and Treatment Planning by using Monte
Carlo
There are 4 main doses that contribute to BNCT: (1) the "boron dose"-dose from
boron neutron capture reaction, Db; (2) the proton dose from nitrogen capture reaction,
Dp; (3) the neutron dose, Dn; (4) the gamma dose, Dr (Chen, 2002).
There are 2 ways for calculating BNCT doses by using Monte Carlo. “(1) The patient
with low spatial resolution from MRI (Magnetic Resonance Imaging), CT (Computed
Tomography) or etc, typically with a mesh size of 5-10 mm resolution, and calculates
the neutron and gamma fluxes within these mesh regions. Thereafter, these fluxes are
converted to doses using flux-to-kerma (kinetic energy released in matter) rate
conversion factors. Assuming kerma is equal to absorbed dose to be true for the
gamma component, the mesh size should not be less than 5 mm in size. (2) The
patient with quite high spatial resolution from MRI (Magnetic Resonance Imaging),
CT (Computed Tomography) or etc. The Monte Carlo calculation based on such a
model directly tallies energy depositions within the various tissues from which dose is
then derived. This is usually a long time-consuming and direct calculation procedure
of a computer. The first way is applied to BNCT planning systems at Harvard-MIT
and BNL for BNCT clinical trials. Two computer codes have been applied to clinical
BNCT treatment planning, which are Harvard-MIT’s MacNCTPLAN and the Idaho
National Energy and Engineering Laboratory’s SERA.” (IAEA, 2001) Both systems
were designed specially for BNCT by using the Monte Carlo method.
14
3. Clinical Studies for Cancer Treatments by BNCT
3.1 BNCT Trials for Brain Tumors
The treatment for glioblastomas and anaplastic astrocytomas by standard therapy such
as conventional radiation therapy, surgery, and chemotherapy has had only few
successful cases and the median survival time of treated patients today is similar to 30
years ago (Barth, 2003). BNCT was initially proposed to deal with these brain cancers
such as glioblastoma multiforme (GBM).
In 1951, the first clinical trial of BNCT for glioblastoma multiforme (GBM) patients
was started at Brookhaven Graphite Research Reactor (BGRR) from Brookhaven
National Laboratory (BNL) in the USA (Farr et al., 1954). From 1959 to 1961，a
group of patients with brain tumours were treated by BNCT at the Brookhaven
Medical Research Reactor (BMRR) (IAEA, 2001). During the same period, 18
malignant glioma patients were treated at the Massachusetts Institute of Technology
Reactor (MITR). The results from the BNL and MIT were unsatisfactory due to
insufficient penetration of the thermal neutron beams, inadequate accumulation of
boron-carrying drug in the tumour (poor tumour-to-blood concentration ratios of
boron-10 - less than 1) and excessive damage to healthy tissues including the scalp
and the brain vasculature (Farr et al., 1954; Asbury et al., 1972; Sweet, 1997; Diaz et
al., 2000; IAEA, 2001; Barth et al., 2005). As a result, all clinical trials in the USA
had been stopped before 1994.
Clinical trials of a group of 149 patients with various brain tumors were recovered by
Hatanaka at the Hitachi Training Reactor (HTR) in Japan from 1968 to 1985
following Sweet’s research by using craniotomy with BNCT. Thermal neutron beams
(whole-brain
average
equivalent
doses:
9.5-15.6Gy(w)
and
Sulfhydryl
15
borane-Na2B12H11SH (BSH) (dose: 30-50mg/Kg) were applied to the BNCT
processes within the trials. (Nakagawa & Hatanaka, 1997) (In 1967, the
chemist-Soloway developed BSH as a boron-carrying drug at the Massachusetts
General Hospital (Soloway et al., 1967). Hatanaka’s trial had 3 processes. First of all,
the tumor was removed as much as possible by surgery. Then, BSH was slowly
infused into the residual tumor. Half a day later, the residual tumor was finally
irradiated by a thermal neutron beam at a nuclear reactor. (Hatanaka, 1991; Hatanaka
& Nakagawa, 1994) Hatanaka and Nakagawa showed that 2 years survival rate was
11.4%, 5 years survival rate was 10.4%, and 10 years survival rate was 5.7% among
the treated grade-4 GBM patients, which was superior to the conventionaly treatment
(Nakagawa & Hatanaka, 1997; Nakagawa et al., 2003). As an adjuvant to surgery,
Hatanaka’s results were impressive. However, the results were indicated to be
exaggerated. Laramore et al. identified that Hatanaka had treated 14 USA GBM
patients from 1987 to 1994. But only 12 patients' data were available. They pointed
out that the median survival rate of the 12 patients was only 10.5 months, which there
were no difference in survival time compare with the conventionally treated patients.
(Laramore et al., 1994) Apart from this, from 1990 to 1996, a group of 44 grade-4
GBM patients were treated at the Kyoto University Reactor (KUR), 31 patients from
the group had 11 months median survival time which was similar to Laramore et al.’s
report (Kojo, 1997). From 1968 to 1997, Nakagawa et al. treated 130 grade-4 GBM
patients by using similar processes to Hatanaka at Musashi Institute of Technology
Reactor (MuITR) and Japan Atomic Energy Research Institute Reactor (JRR); they
reported the results of 21 months median survival time of patients after the treatment,
which was better than Hatanaka's results (Nakagawa & Hatanaka, 1997; Nakagawa et
al., 2003).
Although the early Japanese’s results seemed to be exaggerated, they still encouraged
the USA and Europe restarting efforts to the BNCT research. Also, in the late 1980s,
improvements in boron-carrying drug and neutron beams stimulated reconsideration
of BNCT. Because of these two reasons, in 1994, new clinical trial started at BNL and
16
MIT in the USA. The treatments were given to sealed cranias by replacing thermal
neutron beams to epithermal neutron beams. Epithermal neutron beams are capable to
penetrate deeper to get over the superficial tissues of the scalp and cranias to reach the
brain tumor without craniotomy (Diaz et al., 2000; IAEA, 2001). The beams can also
reach the deeper situated brain tumors than the thermal neutron beams. The
advantages of utilizing epithermal neutrons are outstanding. Because of these, they
have been applied to most BNCT clinical trials for brain tumors since 1990s.
In the USA, from September 1994 to May 1999, 53 GBM patients were treated by
using epithermal neutron beams (whole-brain average equivalent doses: less than
5.5Gy(w) and BPA (4-Dihydroxyborylphenylalanine) (Snyder et al., 1958) (doses:
250-330mg/Kg) at BNL; they showed the results of 13.4 months median survival time
of patients after the treatment (Diaz, 2003). From 1996 to 1999, 20 GBM patients
were treated by using epithermal neutron beams (whole-brain average equivalent
doses: less than 5.5Gy(w) and BPA (doses: 250-330mg/Kg) at Harvard-MIT; the
results of 12 months median survival time of patients after the treatment were
reported (Diaz, 2003).
In 1997, the first European trial started in Holland. Since 1997, 26 GBM patients have
been treated by using BSH (dose: 100mg/Kg) and epithermal neutron beams
(whole-brain average equivalent doses: 8.6-11.4Gy(w) at the High Flux Reactor (HFR)
in Petten. The median survival time of 13.2 months for the group of 26 patients was
reported. So far, the trial is still continuing. (Surewein et al., 2002)
In Germany, from October 1997 to July 2002, 24 GBM patients were treated by using
epithermal neutron beams and BSH (doses: 100mg/Kg) at the European Organisation
for Research and Treatment of Cancer Reactor (EORTCR); except the methodology,
no other data was given (Vos et al., 2005).
In Japan, from 1998 to 2004, the Japan Atomic Energy Agency (JAEA) treated 7
17
GBM patients. They used BSH (dose: 100mg/Kg, 1 hour infusion) and epithermal
neutron beams (whole-brain average equivalent doses: 2.3-8.1Gy(w) for the
treatments at the Japan Atomic Energy Research Institute Reactor-4 (JRR-4). The
median survival time of 20.7 months for the group was reported (Yamamoto et al.,
2004). Since 2005, the same group has carried out new trials. 8 GBM patients have
been treated by using the combination of BPA (doses: 250mg/Kg, 1 hour infusion)
and BSH (doses: 100mg/Kg) as boron 10-carrying drugs and epithermal neutron
beams (whole-brain peak equivalent doses: approx. 13Gy(w). The trials are still
continuing. Therefore, the results have not been reported yet. (Yamamoto et al., 2008)
In Finland, from May 1999 to December 2001, 18 GBM patients were treated by
using epithermal neutron beams (whole-brain average equivalent doses: 3-6Gy(w)
and BPA (doses: 290-400mg/Kg) at Helsinki University Central Hospital and VTT
(Technical Research Center); 61% of the treated patients had 12 months survival time
(Joensuu et al., 2003).
In Japan, from October 1999 to July 2002, only 5 GBM patients were treated by using
a mixture of thermal and epithermal neutron beams and BSH (doses: 100mg/Kg); the
marvelous results of 23.2 months median survival time of patients after the treatment
were reported by Yamamoto et al. in 2004.
In Sweden, from March 2001 to March 2005, Swedish researchers carried out clinical
trials by using BPA (doses: 900mg/Kg, over 6 hours infusion) and epithermal neutron
beams (whole-brain average equivalent doses: 3-6Gy(w) to treat 52 GBM patients at
the Studsvik Medical AB Reactor; the median survival time of patients after the
treatment were 14.2 months (H-Stenstam et al., 2006).
In Rez, Czech Republic, since 2001, 5 GBM patients have been treated by using BSH
(doses: 100mg/Kg) and epithermal neutron beams (whole-brain average equivalent
doses: approx. 2Gy(w) at the Nuclear Research Institute (NRI) LVR-15 reactor. As
18
this series of trials are still being carried out, no results have been available yet.
(Surewein et al., 2002)
In Japan, since 2002, in Kyoto University Research Reactor Institute (KURRI), 27
GBM patients have been treated by using the combination of BPA (doses:
250-700mg/Kg, 1-6 hours infusion) and BSH (doses: 100mg/Kg, 1 hour infusion) as
boron 10-carrying drugs and epithermal neutron beams (whole-brain peak equivalent
doses: approx. 15Gy(w) at the Kyoto University Reactor (KUR). The results will be
reported by the research team. (Miyatake et al., 2005)
According to the cases shown above, BNCT seems to be at least equivalent or more
effective to treat GBM compare with the conventional standard photon irradiation
therapy. (The median survival time for the patients who have been treated by
conventional photon irradiation therapy is between 10 to 12 months.)
3.2 BNCT Trials for Other Tumors
Monte Carlo simulation of depth-dose distributions for cancers of liver, lung,
pancreatic, prostate osteosarcoma etc. suggest that BNCT has the potential to be
applied for treating those cancers under certain conditions (Matsumoto, 2007).
A type of liver tumor that was recently treated by BNCT was metastasized
adenocarcinoma of the colon (Surewein et al., 2002). There were a substaintial
amount of patients who developed hepatic caner from colon adenocarcinoma. Here
were the processes for the trial. At the beginning, the patients was infused BPA
fructose (dose: 300mg/kg) for 2 hours. Then, hepatectomy was operated to the patient
(Surewein et al., 2002). Thereafter, the liver was irradiated by a thermal neutron beam
at the University of Pavia Laboratory Reactor. Finally, the treated liver was
re-implanted inside the patient’s body. 2 years after the treatment, no tumor recurrence
19
happened to the patient and the tumor cells were almost vanished (Pinelli, 2004).
Again, the trial showed that BNCT had the possibility to deracinate the root of an
organ tumor.
In September 2003, one patient with a recurrent papillary thyroid cancer who had
previously been treated by convention therapies was treated by BNCT in Japan. So far,
no recurrence and side effects have been observed to the patient who is still alive.
(Hiratsuka et al., 2006) The results show that BNCT has the potential to cure primary
or recurrent thyroid cancer.
Head and neck recurrent tumors were another group of cancers that were recently
treated by BNCT. Kato et al. reported that they have treated a group of 26 patients (1
had a 4 salivary gland carcinomas, 3 had sarcomas, and 19 had squamous cell
carcinomas) with BNCT since 2001 (Kato et al., 2009). The whole group of patients
had been treated by conventional therapy (chemotherapy, surgery and radiotherapy),
and then developed recurrent tumors. During the trials, all of them were irradiated by
epithermal neutron beams, and were injected with both BSH (doses: 5g) and BPA
(doses: 250mg/kg). All patients survived 1-72 months after the treatments. The mean
survival times were 13.6 months. Thereinto, 6 patients survived up to 6 years. (Kato et
al., 2009) The results indicated that BNCT had the potential to be applied to the
tumors which recurred after the treatments of conventional therapies, such as head
and neck recurrent cancers.
Besides GBMs, Cutaneous melanomas are another big cancer group which has been
treated by BNCT since 1980s. Mishima et al. treated animals with either
transplantable or primary melanomas by applying BPA as the boron-10 carrying drug
to the experiments (Hiratsuka et al., 1989; Mishima & Ichihashi et al., 1989).
Mishima’s experiments obviously initiated other investigators’ interests in BNCT
researches by using BPA as a boron-10 carrying drug. In 1985, Mishima treated his
first patient. He injected a total dose of 200mg BPA to the patient's tumor. About
20
45Gy(w) equivalent dose from the thermal neutron beam was given to the patient's
melanoma. The patient's melanoma cell was totally disappeared by 9 months time.
(Mishima & Ichihashi et al., 1989; Mishima & Honda et al., 1989) The success of the
case proved that BNCT had the protential to treat radio-resistant tumors. Thereafter,
more than 18 melanoma patients were treated by Mishima et al. (Larsson et al., 1997).
Busse et al. treated a few patients with either cerebral metastases or cutaneous of
melanoma by using a boron-10 carrying agent which was called BPA fructose
(Coderre et al., 2003; Busse et al., 1999). The most outstanding case is the treatment
of a patient who had an unresected cerebral metastasis in the occipital lobe (Barth et
al., 2005). The tumor on the patient was given an equivalent dose of 24Gy(w) thermal
neutron beam radiation. Magnetic Resonance Imaging (MRI) studies revealed that the
tumor was completely regressed by 4 months (Busse et al., 1999). All the results
showed that BNCT seemed to be more suitable to treat cerebral metastases or
cutaneous of melanoma rather than glioblastoma multiforme (GBM).
21
4. Recent Development of BNCT
It was recently found that BNCT with 'Bio-shuttled'-BPA and thermal neutrons was
effective to kill some radio-resistant carcinoma cells. 'Bio-shuttled'-BPA was infused
to radio-resistant HeLa-S cervix carcinoma cells, and then irradiated by a thermal
neutron beam, which resulting no carcinoma cells were alive after 3 days (Braun et al.,
2003).
Carborane nucleotides were found to be a boron-10 delivery agent for BNCT which
might be suitable for treatment of prostate tumor. It was showed that similar
nucleoside bases may have different tissue-favorable characteristics, which could be
selected as a BNCT boron-10 delivery agent for treatment of different kinds of cancer.
5-o-Carboranyluracil was recently discovered to be the most suitable boron
10-carrying drug for future investigations of prostate cancer treatment (Schinazi et al.,
2004).
Animal trial was carried out for lung cancer treatment by using BNCT. The folate
receptor (FR) targeted liposomes were selected as indirect boron-10 delivery agent for
Na3B20H17NH3 for the treatment of murine lung carcinoma in mice by using BNCT.
The results showed that FR targeting was not significantly superior to the others in
terms of tumor localization, but changing the boron 10-carrying drug may improve
the outcome. (Pan et al., 2002)
BNCT was considered to treat oral cancers. Because they could be easily exposed to
the neutron beams. BNCT studies for oral cancer of hamsters were carried out.
Human oral mucosa tumors were transplanted in the hamsters. BPA was proven to be
a. effective boron-carrying agent for oral cancer (Kreimann & Dagrosa et al., 2001).
The animals were treated by using thermal neutron beams and BPA. Complete
regression with 78% of the tumor was observed 15 days after the treatment, and there
22
was no damage to the healthy oral tissue (Kreimann & Longhino et al, 2001).
The possibility of applying BNCT to treat liver tumors was investigated by using
normal liver cells in mice. BNCT with the use of boron-lipiodol was evaluated to
have the potential to treat VX2 liver tumor. Some time after infusing boron-lipiodol
into the liver, the researchers determined that the ratio of boron concentrations of the
tumor to the healthy liver tissue was around 8. (Lin et al., 2002; Suzuki et al., 2004)
According to the investigations shown above, BNCT still has the potential to be
expanded for other cancer treatments.
23
5. Conclusion
The elegant BNCT concept is based on the Boron-10 Neutron Capture Reaction to
release alpha particles, recoiling lithium-7 nuclei and gamma rays with high linear
energy transfer (LET) to kill tumor cell without the influence of the surrounding
normal tissues. But there are a few critical problems that have to be solved for BNCT
becoming another type of standard therapy in the future. Successful BNCT mainly
rely on boron-10 delivery agents, neutron beams, dosimetry and experts in each
related areas. Developing more effective and selective boron-10 delivery agents is the
primary issue of BNCT. The agents should be able to deliver adequate amounts of
boron-10 to the tumor cells, in order to achieve high ratio of (concentration of
boron-10 in tumor cells)/(concentration of boron-10 in normal cells). Second, Up to
date, only few clinical trials on BNCT have been carried out all over the world, one
major reason is the limitation to the neutron sources from which are expensive nuclear
reactors. These reactors are commonly located distant from the BNCT research
centers of the cities/towns, because they are unwelcomed by the public due to safety
issues. Therefore, there is a need for advanced accelerators and compact medical
research reactors such as the operating one in the capital of China-Beijing. Apart from
this, high quality neutron beam sources should be developed and applied to BNCT.
Third, dosimetry of BNCT mainly includes two parts, which are boron-10 uptake
(boron-10 dose) and neutron irradiation (neutron dose). It is necessary to find a way
for real-time determination and monitoring for both doses, in order to optimize dose
distributions
around
the
tumor.
So
far,
there
are
not
any
existing
common/international standards for BNCT dosimetry. Finally, BNCT refers to a wide
range of disciplines. Thus, it requires a wide range of experts in all BNCT related
areas including administrators.
The future of BNCT is promising. It has got the high potential to fill the gap of the
treatment for the tough recurrent or primary malignancies before the coming age of
24
tissue regeneration, gene-modification, clone, nano robot or even 'matrix'. BNCT was
initially proposed for malignant brain tumor such as glioblastoma multiforme (GBM).
Although BNCT has been reported to be at least equivalent or more effective to treat
GBM compare with the other conventional standard therapies. Up till now, it has not
shown significant superiority to replace the others yet. Nevertheless, since the mid
1980s, BNCT has started to shown its great potential to treat other types of primary or
recurrent cancers such as a kind of malignant skin cancers which are called
melanomas, head and neck cancers, liver cancers and thyroid cancers. I believe that
the BNCT will have a bright future if the researchers focus on studying and
developing better tumor cell-seeking agents (boron-10 delivery agents).
25
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