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REVIEW ON BORON NEUTRON CAPTURE THERAPY
1*
Sandhya M. J. Nair, 2Hima C. S.,
3Nisha V. T.,
4Aswany U. R. and
5Bismi S.
1,2,3,4
Assistant Professors, 5Student,
Department of Pharmaceutical Chemistry,
Ezhuthachan College of Pharmaceutical Sciences, Trivandrum, Kerala, India.
ABSTRACT
Boron neutron capture therapy (BNCT) is a non-invasive therapeutic
technique for treating invasive malignant tumours. It is based on the
nuclear reaction that occurs when boron-10 is irradiated with low
energy thermal neutrons or higher energy epithermal neutrons. BNCT
has been evaluated clinically as an alternative to conventional radiation
therapy for the treatment of high-grade gliomas, meningiomas, and
recurrent, locally advanced cancers of the head and neck region and
superficial cutaneous and extra cutaneous melanomas.this review
highlights the principle of BNCT, boron delivery agents, neutron
sources and accelerators are described.
KEYWORDS: Accelerator-based neutron sources, 10Boron, Linear
energy transfer, Massachusetts Institute of Technology Reactor,
Neutron capture therapy, Relative biological effectiveness.
I. INTRODUCTION
BNCT is based on the nuclear capture and fission reactions that occur when boron-10, a non-
radioactive constituent of natural elemental boron is irradiated with low-energy (0.025 eV)
thermal neutrons or alternatively higher-energy (10,000 eV) epithermal neutrons, which lose
energy as they penetrate tissues and become thermalized. This capture reaction results in the
production of high linear energy transfer (LET) alpha particles (4He) and recoiling lithium-7
(7Li) nuclei. In order to be successful a sufficient amount of 10B must be selectively
delivered to the tumor and a collimated beam of neutrons must be absorbed by the tumor to
sustain a lethal 10B (n, α) 7Li capture reaction. The destructive effects of the alpha particles
are limited to boron containing cells and since they have very short path lengths in tissues (5–
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 10, Issue 3, 356-372 Review Article ISSN 2278 – 4357
*Corresponding Author
Sandhya M. J. Nair
Assistant Professors,
Department of
Pharmaceutical Chemistry,
Ezhuthachan College of
Pharmaceutical Sciences,
Trivandrum, Kerala, India.
Article Received on
26 Dec. 2020,
Revised on 15 Jan. 2021,
Accepted on 04 Feb. 2021
DOI: https://doi.org/10.17605/OSF.IO/DZA4Y
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9 μm) in theory BNCT provides a way to selectively destroy malignant cells and spare
surrounding normal tissue making it an ideal type of radiation therapy.[1]
BNCT is a type of
cancer therapy that is based on the nuclear reaction that occurs when boron-10 is exposed to
radiation with low energy neutrons to yield α particles and recoiling lithium -7 nuclei.
10B + nth → [11B] → α + 7Li + 2.31 MeV
The theoretical advantage of BNCT is that it is a two component or binary system, consisting
of 10B and thermal neutrons which when combined together generate high LET radiation
capable of selectively destroying tumor cell without significant damage to normal tissues. In
order for BNCT to succeed a critical amount of 10B and a sufficient number of thermal
neutrons must be delivered to individual tumor cells. Advances in BNCT in the areas of
compound distribution and pharmacokinetics compare favorably with other emerging
modalities such as photon activation therapy photodynamic therapy and the use of
radiolabeled antibodies for cancer treatment in which physiological targeting is used.[2]
BNCT has more advantages than chemotherapy. The administration of chemotherapy drugs
results only in killing cancer cells that are actively dividing, whereas alpha particles have the
ability to damage tumor cells that are not dividing. These alpha particles have a very short
range only 9–14 µm, while the cell size is between 10 and 20µm. Therefore the radiation only
occurs within the tumor cells, and the normal cells surrounding the tumor site are
consequently relatively safe.[3]
Conventional radiation therapy involves the use of high-
energy X ray or electron beams. This form of radiation is termed "sparsely ionizing" and is
described as having a low linear energy transfer (LET) since the energy depositions in tissue
as ionizations are spatially infrequent. A higher absorbed dose to tumor relative to normal
tissue is achieved by precise geometric target localization, judicious computer-aided
treatment planning and accurate beam delivery systems. Radiotherapy also attempts to exploit
the subtle differences in the sensitivity to fractionation between tumor and normal tissues at
the biological level.[4]
The biological response to ionizing radiation also depends on the type
of radiation and is characterized by its relative biological effectiveness (RBE) over the energy
range of therapeutically used X rays typically 100 kV to 25 MV approximately the same
physical dose needs to be delivered at different energies to reach a given biologic endpoint
resulting in similar RBEs. High LET radiations, however, result in biologic damage that is
generally larger per unit dose than for x rays resulting in an elevated RBE. Hence a lower
dose is required to achieve an equivalent effect.[4]
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II BORON DELIVERY AGENTS
General requirements
The most important requirements for a successful boron delivery agent are as follows: (a) low
systemic toxicity and normal tissue uptake with high tumor uptake and concomitantly high
tumor/brain and tumor/ blood concentration ratios (>3-4:1); (b) tumor concentrations of 20Ag
10B/g tumor; (c) rapid clearance from blood and normal tissues and persistence in tumor
during BNCT. However it should be noted that at this time no single boron delivery agent
fulfills all of these criteria. With the development of new chemical synthetic techniques and
increased knowledge of the biological and biochemical requirements needed for an effective
agent and their modes of delivery several promising new boron agents have emerged. The
major challenge in their development has been the requirement for selective tumor targeting
to achieve boron concentrations sufficient to deliver therapeutic doses of radiation to the
tumor with minimal normal tissue toxicity. The selective destruction of glioblastoma
multiform cells in the presence of normal cells represents an even greater challenge compared
with malignancies at other anatomic sites because high-grade gliomas are highly infiltrative
of normal brain histologically complex, and heterogeneous in their cellular composition.[6]
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First-generation and second-generation boron delivery agents
The clinical trials of BNCT in the 1950s and early 1960s used boric acid and some of its
derivatives as delivery agent but these simple chemical compounds were non selective had
poor tumor retention and attained low tumor/brain ratios. In the 1960s, two other boron
compounds emerged from investigations of hundreds of low molecular weight boron-
containing chemicals one [(L)-4-dihydroxy-boryl phenyl alanine] called BPA was based on
arylboronic acids and the other was based on a newly discovered polyhedral borane anion,
sodium mercaptoundecahydro-closo-dodecaborate, called BSH. These second-generation
compounds had low toxicity persisted longer in animal tumors compared with related
molecules and had tumor/ brain and tumor/blood boron ratios of >1.
Third-generation boron delivery agents
It consist of a stable boron group or cluster attached via a hydrolytically stable linkage to a
tumor targeting moiety such as low molecular weight biomolecules or monoclonal antibodies
(mAb). For example, the targeting of the epidermal growth factor (EGF) receptor (EGFR)
and its mutant isoform EGFRvIII, which are over expressed in gliomas as well as in
squamous cell carcinomas of the head and neck also has been one such approach. Usually the
low molecular weight biomolecules have been shown to have selective targeting properties
and many are at various stages of development for cancer chemotherapy, photodynamic
therapy, or antiviral therapy. The tumor cell nucleus and DNA are especially attractive targets
because the amount of boron required to produce a lethal effect may be substantially reduced
if it is localized within or near the nucleus. Other potential subcellular targets are
mitochondria, lysosomes, endoplasmic reticulum, and Golgi apparatus. Water solubility is an
important factor for a boron agent that is to be administered systemically, whereas
lipophilicity is necessary for it to cross the blood-brain barrier (BBB) and diffuse within the
brain and the tumor. Therefore amphiphilic compounds possessing a suitable balance
between hydrophilicity and lipophilicity have been of primary interest because they should
provide the most favorable differential boron concentrations between tumor and normal
brain, thereby enhancing tumor specificity. However for low molecular weight molecules that
target specific biological transport systems and/or are incorporated into a delivery vehicle,
such as liposomes, the amphiphilic character is not as crucial. The molecular weight of the
boron-containing delivery agent also is an important factor because it determines the rate of
diffusion within both the brain and the tumor.
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Boron-containing amino acids and polyhedral boranes
Recognizing that BPA and BSH are not ideal boron delivery agents, considerable effort has
been directed toward the design and synthesis of thirdgeneration compounds based on boron
containing amino acids and functionalized polyhedral borane clusters. Examples include
various derivatives of BPA and other boron-containing amino acids, such as glycine, alanine,
aspartic acid, tyrosine, cysteine, and methionine, as well as non-naturally occurring amino
acids. The most recently reported delivery agents contain one or more boron clusters and
conco mitantly larger amounts of boron by weight compared with BPA. The advantages of
such compounds are that they potentially can deliver higher concentrations of boron to
tumors without increased toxicity. The polyhedral borane dianions closo-B10H10 2- and
closo-B12H12 2- and the icosahedral carboranes closo-C2B10H12 and nidoC2B9H12 - have
been the most attractive boron clusters for linkage to targeting moieties due to their ready
incorporation into organic molecules, high boron content, chemical and hydrolytic stability,
hydrophobic character, and in most cases their negative charge. The simple sodium salt of
closo-B10H10 2-has been shown to have tumor-targeting ability and low systemic toxicity in
animal models and has been considered as a candidate for clinical evaluation.[6]
III NEUTRON SOURCES FOR BORON CAPTURE THERAPY
Nuclear Reactors
At the present time only nuclear reactors are capable of generating such beams, although
accelerator-based neutron sources are being investigated as less expensive and more practical
for hospital environments. Approximately 35 research and test reactors with powers of ~1
MW now exist in the United States that potentially could produce beams of therapeutic
intensity. In particular the Brookhaven Medical Research Reactor the MIT Research Reactor
and the Georgia Institute of Technology Research Reactor have irradiation facilities that were
designed for medical and biological research. In addition extensive work has been done on
the design of a proposed clinical facility for NCT at the Power Burst Facility at the Idaho
National Engineering Laboratory. This reactor, with a steady state of power of 20 MW would
provide a beam of greater intensity than any other currently available. The patient irradiation
ports of all of these reactors have a geometry that reduces fast neutron and 7photon
contamination of the neutron beam thereby enhancing its clinical potential. Neutrons for
BNCT must not only be delivered with a high flow rate but also should have the right amount
of energy. The radiation beam which is directed into the tumor bed should have minimal
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contaminants. The neutron source for epithermal radiation is generated from Nuclear
Reactors and Accelerator-Based Neutron Sources.
Beam Types: Neutrons with an energy of ~1 MeV are "born” in the fission reaction within
the reactor core. Low energy or thermal beams (0.025 eV) epithermal beams (1-10,000 eV)
or fast neutron beams (> 10,000 keV) may be extracted from nuclear reactors for use in
radiation therapy by varying the amount of slowing down or "moderation" that occurs. Fast
neutrons can be obtained by extracting a beam of neutrons that has little or no moderation.
Scattering media such as light (H2O) or heavy (D2O) water or graphite can slow down or
"moderate" fast neutrons so that they lose energy and become thermalized. The latter
"thermal" or room temperature neutrons are the ones that are utilized in the l0B (n, α) 7Li
reaction. Thermal neutrons are rapidly attenuated by tissue with a half-value layer (distance
to reduce beam intensity by a factor of 2) of ~1.5 cm and consequently it is difficult to obtain
sufficient neutron fleece rates at increasing depth without heavily irradiating surface tissues.
Alternatively an "epithermal" neutron beam (1-10,000 eV) can be produced by using
moderators or filters that slow the fast neutrons into the intermediate or epithermal neutron
energy region. By filtering out residual thermal neutrons with absorbers such as boron or
cadmium a relatively pure epithermal beam can be produced. This beam produces ¹⁰B-
absorbing thermal neutrons, which are the ones that interact with ¹⁰B as it penetrates tissue
because of the moderating effects of hydrogen. Thermal neutrons generated in tissue by such
a beam actually "peak" at a 2-3 cm depth thereby circumventing problems associated with the
poor penetration of incident thermal beams. As an example the various beam components
from the epithermal beam at the BMRR. The thermal flux density generated by the
epithermal beam follows the curve for "30 ppm ¹⁰B" as the ¹⁰B (n, α) 7Li reaction is
produced by the thermal neutrons. If the incident beams were a thermal beam the fall off or
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attenuation of the thermal flux would be rapid and similar to the attenuation of the fast
neutron dose (H).[7]
Beam Requirements and Optimization: There is slightly increased penetration of tissues by
epithermal neutrons with increasing neutron energy so that the lowest energy fast neutrons or
the highest energy epithermal neutrons would be optimum. For example iron-filtered neutron
beams produce fairly pure 24-keV neutrons but both experimental determinations and
calculations have shown that the normal tissue dose produced by hydrogen recoils from 24-
keV neutrons is significant and produces ~3 times the normal tissue dose than that of an
optimal epithermal neutron beam. If, however neutrons with energies ≤ 1 keV are used this
harmful dose is reduced to negligible levels. The acceptable level of fast neutrons is generally
believed to be ~2 x 10~" cGy per epithermal neutron, i.e. that dose that would be delivered by
a monoenergetic 2-keV beam. Current research efforts are directed towards the production of
epithermal neutron beams which when filtered or moderated, have a preponderance of
neutrons in the 1-1000-eV range. Since the distribution of thermal neutrons generated at
depth is only moderately affected by the energy of the incident epithermal neutrons it would
be best to maximize intensity by using the entire epithermal energy region, rather than reduce
intensity via a filtered monoenergetic beam. When the whole reactor core is used as a source
of neutrons, suitable epithermal neutron beam intensities≥ l0ꝰ n/ cm2 sec'1 should be
available with reactor powers of 1-3 MW or more. Thus a single irradiation of 5 x 1012
nlh/cnr would take 80 min assuming that one thermal neutron was generated per epithermal
neutron. Fig 5.2: Nuclear reaction utilized in BNCT.
Approximately 35 ng/g of 10B/g of tumor would be necessary in order to raise the n,α tumor
dose to levels significantly above that delivered to normal tissues by the unavoidable n,p and
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n,ϒ reactions with nitrogen and hydrogen, respectively. With this "optimized" epithermal
neutron beam the therapeutic gain, or ratio of tumor dose to maximum normal tissue dose. It
is a tenet of radiation therapy that the tumor dose is limited by normal tissue tolerance. A
therapeutic effect could be achieved with an epithermal neutron beam delivering 5 x 10¹ꝰ
(peak) n,h cm~2. The reason for this is evident from calculated and measured dose
distributions generated in a phantom head, from "pure" epithermal neutrons. Approximately
900 cGy (rads x RBE) would be produced by gammas and protons from the ¹H (n,ϒ) 2H and
14N(n,pa)14C reactions. When this is added to 400 cGy (rads x RBE) from a hypothetical
present in normal tissue assuming one-tenth of the 35-1g 10B tumor, the normal tissue dose
would be ~1300 cGy, which approximates the normal tissue tolerance for single dose whole
brain irradiation. Current efforts directed towards the modification of existing reactors for
clinical trials in the United States include those at: BNL using the Al2O,-moderated
epithermal beam at the BMRR; MIT using a proposed aluminum-sulfur-moderated
epithermal beam; and PBF at Idaho National Engineering Laboratory using a proposed and
yet to be installed and tested aluminum-D2O-moderated beam. The MRR beam is the only
one the parameters of which have been measured and reported. The PBF at a power of 20
MW would theoretically be able to deliver therapy in a single dose in 6 min while ~45 min
would be needed for the BMRR. Calculated parameters for the MIT reactor are promising
and an experimental filter is currently being installed and tested. It is anticipated however that
because of radiobiological considerations such as selective repair of low LET damage in
normal tissues and redistribution of boron compounds in the tumor neutron irradiations will
be delivered in 4-6 fractions. Such fractionation would reduce the effective tissue dose
significantly due to repair of the low LET component. Tissues damaged by the 10B (n, α) 7Li
reaction should not repair due to the high LET character and the α and 7Li particles.
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Boron neutron capture therapy is based on the nuclear capture and fission reactions that occur
when non-radioactive boron-10 a constituent of natural elemental boron, 80% of which is in
the isotopic form of 11B and 20% as 10B, is irradiated with low-energy (0.025 eV) thermal
neutrons or, alternatively higher energy (10,000 eV) epithermal neutrons. The latter become
thermalized as they penetrate tissues. The resulting 10B(n,α)7Li capture reaction yields high
linear energy transfer (LET) α particles (stripped down helium nuclei [4He]) and recoiling
lithium-7 (7Li) atoms. A sufficient amount of 10B must be delivered selectively to the tumor
(~ 20–50 μg/g or ~ 109 atoms/cell) in order for BNCT to be successful. A collimated beam of
either thermal or epithermal neutrons must be absorbed by the tumor cells to sustain a lethal
10B(n,α)7Li capture reaction. Since the α particles have very short path lengths in tissues (5–
9 μm) their destructive effects are limit to boron containing cells. In theory BNCT provides a
way to selectively destroy malignant cells and spare surrounding normal tissue if the required
amounts of 10B and neutrons are delivered to the tumor cells.[6]
Accelerators
Accelerators also can be used to produce epithermal neutrons and accelerator-based neutron
sources (ABNS). For ABNS, one of the more promising nuclear reactions involves
bombarding a 7Li target with 2.5 MeV protons. The average energy of the neutrons that are
produced is 0.4 MeV and the maximum energy is 0.8 MeV. Reactor-derived fission neutrons
have greater average and maximum energies than those resulting from the 7Li (p,n) 7Be
reaction. Consequently the thickness of the moderator material that is necessary to reduce the
energy of the neutrons from the fast to the epithermal range is less for an ABNS than it is for
a reactor. This is important because the probability that a neutron will be successfully
transported from the entrance of the moderator assembly to the treatment port decreases as
the moderator assembly thickness increases. Due to lower and less widely distributed neutron
source energies, ABNS potentially can produce neutron beams with an energy distribution
that is equal to or better than that of a reactor. However reactor derived neutrons can be well
collimated, while in contrast it may not be possible to achieve good collimation of ABNS
neutrons at reasonable proton beam currents. The necessity of good collimation for the
treatment of glioblastoma multiforme is an important and unresolved issue that may affect
usefulness of ABNS for BNCT. ABNS also are compact enough to be sited in hospitals
thereby allowing for more effective but technically more complicated procedures to carry out
BNCT. However to date no accelerator has been constructed with a beam quality comparable
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with that of the MITR, which can be sited in a hospital and that provides a current of
sufficient magnitude to treat patients in < 30 minutes.
IV FACTORS OPTIMIZING DELIVERY OF BORON CONTAINING AGENTS
General considerations
Delivery of boron agents to brain tumors is dependent on (a) The plasma concentration
profile of the drug, which depends on the amount and route of administration. (b) The ability
of the agent to traverse the BBB. (c) Blood flow within the tumor. (d) The lipophilicity of the
drug. In general, a high steady-state blood concentration will maximize brain uptake whereas
rapid clearance will reduce it except in intra-arterial drug administration. Although the i.v.
route currently is being used clinically to administer both BSH and BPA, this may not be
ideal and other strategies may be needed to improve their delivery. Delivery of boron-
containing drugs to extra cranial tumors such as head and neck and liver cancer presents a
different set of problems including nonspecific uptake and retention in adjacent normal
tissues. Intra-arterial administration with or without blood-brain barrier disruption: This has
been shown in the F98 rat glioma model where i.c. injection of either BPA or BSH doubled
the tumor boron uptake compared with that obtained by i.v. injection. This was increased 4-
fold by disrupting the BBB by infusing a hyperosmotic (25%) solution of mannitol via the
internal carotid artery. MSTs of animals that received either BPA or BSH i.c. with BBB-D
were increased 295% and 117%, respectively compared with irradiated controls. The best
survival data were obtained using both BPA and BSH in combination administered by i.c.
injection with BBB-D. The MST was 140 days with a cure rate of 25% compared with 41
days following i.v. injection with no long term surviving animals. Similar data have been
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obtained using a rat model for melanoma metastatic to the brain. BPA was administered i.c.
to nude rats bearing i.c. implants of the human MRA 27 melanoma with or without BBB-D.
The MSTs were 104 to 115 days with 30% long-term survivors compared with a MST of 42
days following i.v. administration. A similar enhancement in tumor boron uptake and
survival was observed in F98 gliomabearing rats following i.c. infusion of the bradykinin
agonist, receptor-mediated permeabilizer-7 now called Cereport. In contrast to the increased
tumor uptake, normal brain boron values at 2.5 hours following i.c. injection were very
similar for the i.v. and i.c. routes with or without BBB-D. Because BNCT is a binary system,
normal brain boron levels only are of significance at the time of irradiation and high values at
earlier time points are inconsequential. These studies have shown that a significant
therapeutic gain can be achieved by optimizing boron drug delivery, and this should be
important for both ongoing and future clinical trials using BPA and/or BSH. Direct
intracranial delivery: Different strategies may be required for other low molecular weight
boron containing compounds whose uptake is cell cycle dependent, such as boron containing
nucleosides where continuous administration over a period of days may be required. We have
reported recently that direct i.t. injection or convection enhanced delivery of the boron
nucleoside N5-2OH were both effective in selectively delivering potentially therapeutic
amounts of boron to rats bearing i.c. implants of the F98 gloms. Direct i.t. injection or
convection enhanced delivery most likely will be necessary for a variety of high molecular
weight delivery agents such as boronated mAbs, and ligands, such as EGF as well as for low
molecular weight agents such as nucleosides and porphyrins. Recent studies have shown that
convection enhanced delivery of a boronated porphyrin derivative resulted in the highest
tumor boron values and tumor/brain and tumor/blood ratios that we have seen with any of the
boron agents that we have ever studied.[4]
V CLINICAL STUDIES OF BNCT
Clinical interest in BNCT has focused primarily on high grade gliomas and more recently on
patients with recurrent tumors of the head and neck (HN) region who have failed
conventional therapy. BNCT is a biologically rather than a physically targeted type of
radiation therapy and therefore it theoretically should be possible to selectively destroy tumor
cells dispersed in normal tissue providing that sufficient amounts of 10B and thermal
neutrons are delivered to the individual tumor cells. BNCT to treat patients with malignant
brain tumors the largest number of which had high grade gliomas. Challenges in treating
gliomas with BNCT: High grade gliomas are among the most difficult human malignancies
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to treat. This is hardly surprising since the single greatest advance in the treatment of patients
with high grade gliomas has been the combination of post-surgical photon irradiation with the
concomitant administration of temozolomide (TMZ) followed by repetitive cycles of TMZ
which resulted in a modest increase in median overall survival. Barring either some major
breakthrough in the development of new brain tumor-localizing boron delivery agents or a
large randomized clinical BNCT trial it probably will be difficult to obtain data that will
convince a broad audience of clinicians who treat patients with high grade gliomas that
BNCT has much to offer other than a type of salvage therapy for those patients with recurrent
tumors who have been treated to tolerance and have no other treatment options. Short of
developing new and more effective boron delivery agents for BNCT of brain tumors the best
hope for enhancing its clinical efficacy would be to improve the dosing paradigm by
increasing the dose of BPA and the infusion time use of novel physical methods to enhance
the delivery of BPA and BSH such as pulsed ultrasound (US). The use of pulsed US which
has been shown to transiently disrupt the blood–brain barrier (BBB) is one such approach that
could improve not only the uptake of BPA and BSH but also their micro distribution within
the tumor. Treatment of recurrent tumors of the head and neck region with BNCT: The
second largest group of patients who have been treated by BNCT are those with recurrent
tumors of the HN region who have had surgery followed by chemotherapy and photon
radiation with doses that have reached normal tissue tolerance levels and for whom there are
no other treatment options. Recurrent HN tumors all of whom had multi-modality standard
therapy received BNCT using BPA-F as the boron delivery agent with two administrations of
BNCT at 28-day intervals. Although the response rate was high (12 of 17 patients) and
toxicity was acceptable recurrence within or near the treatment site was common. The basic
problem resulting in recurrence following BNCT most likely has been due to
nonhomogeneous uptake of BPA-F with poor micro distribution in some regions of the
tumor. Short of the development of new boron delivery agents the best hope for improving
the response and cure rates would be to optimize the dosing paradigm and delivery of BPA,
either alone or in combination with BSH which has not as yet been evaluated. Here bio
distribution studies using 18F-BPA PET and pretreatment biopsies of different parts of the
recurrent tumor could be very useful, not only for treatment planning but also for improving
the therapeutic results.
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Challenges relating to the use of BPA and BSH as boron delivery agents
The optimum dosing paradigm and delivery of BPA either alone or in combination with BSH
in patients with high grade gliomas has yet to be determined. Increasing the dose of BPA and
the duration of the infusion time would be a good starting point but improving tumor uptake
and micro distribution could require more than this. Again short of developing new and more
effective boron delivery agents better ways to enhance tumor uptake and the micro
distribution of BPA should be explored. One possible approach would be to use pulse-
focused US to enhance its delivery for patients with either gliomas or HN cancer. Two
experimental studies in mice specifically relevant to HN cancer have been reported. In the
first study the luciferase-positive HN cancer cell line SCC1 was implanted subcutaneously
into the flanks of nude mice. Micro bubbles triggered by localized US enhanced the delivery
of cetuximab labeled with a near infrared dye. Optical imaging and direct measurements
revealed that US resulted in a significant increase in cetuximab delivery and tumor size at 24
days following implantation was significantly less in treated mice versus untreated control
mice. More directly relevant to BNCT. Wu et al. have employed high-intensity focused ultra-
sound (HIFU) to enhance the uptake of BPA-F in nude mice bearing intra-oral xenografts of
a human squamous cell carcinoma cell line designated SASC03. In vivo PET imaging studies
using 18FBPA-F revealed enhanced tumor uptake with no concomitant increase in normal
tissue uptake. These two studies suggest that pulsed US should be evaluated clinically as a
possible way to enhance the uptake and micro distribution of BPA-F in patients with HN
cancer who are potential candidates for treatment by means of BNCT.
Treatment of cutaneous melanomas with BNCT
With cutaneous melanoma who ranged in age from 50 to 85 years at the time of treatment
were treated with BNCT using BPA-F as the boron delivery agent. The overall complete
regression (CR) rate was 78% (25/32) with 81% (22/27) for primary and 60% (3/5) for
metastatic lesions. Among the patients with primary lesions, the CR rates were 33% (1/3) for
nodular melanomas (NM) and 87.5% (21/24) for non-nodular melanomas. The complications
most frequently observed were edema and cutaneous erosion at the site of irradiation.
Favorable clinical responses were obtained for the treatment of primary cutaneous
melanomas with the exception of nodular melanomas. Since melanomas have a high
propensity to metastasize the possible combination of BNCT with new immunotherapeutic
approaches would provide a better rationale to treat melanomas in difficult anatomic regions
such as the vulva with BNCT.
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Treatment of genital cancers with BNCT
BPA-F was administered intravenously over 2 h and this was followed by neutron irradiation.
The minimum dose for tumor control was assumed to be either 20 GyEq for EMPD or 25 Gy-
Eq for the melanoma. There were striking clinical responses and all of the lesions regressed
completely within 6 months, and there were no recurrences in the radiation field during the
follow-up periods ranging from 1.6 to 6.9 years. Although both melanoma of the vulva and
EMPD of it and the penis are relatively rare malignancies, these tumors unfortunately are
very difficult to treat since the surgery can be very mutilating and the tumors are poorly
responsive to conventional photon irradiation. Clearly a larger number of patients need to be
treated before any definitive statements can be made but these results suggest that BNCT may
be a very promising treatment for these malignancies. Although the incidence of these tumors
is very low in a country such as China with a population in excess of 1.3 billion there could
be a very large number of patients who might be considered as candidates for treatment by
means of BNCT especially in the case of melanoma of the vulva when combined with
immunotherapy which recently has been shown to be very effective in treating patients with
metastatic melanoma who have failed all other treatments. BNCT for EMPD of the penis and
scrotum combined with antiPD1 immunotherapy, may represent a significant clinical advance
in the treatment of this malignancy.[3]
ADVANTAGES OF BNCT
It is a technique based on a targeted radiation approach, which represents and alternative
adjuvant therapy for malignant gliomas it has been used in patients with various types of
brain malignancies, including glioblastoma, anaplastic meningiomas, cerebral melanoma
metastases or tumor. It was postulated that the reduction of the blood brain barrier (BBB) in
the vicinity of tumor could be exploited to selectively increase the concentration of boron in
the brain tumor over normal brain. Initially sodium tetraborate (borax), was used as the
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vehicle for boron. Perhaps the early interest in applying BNCT to high-grade primary brain
tumors stemmed from the fact that this was a cancer with a very poor prognosis. This would
ensure that BNCT even if minimally successful would nevertheless appear superior to
ineffective conventional therapies.
Current boron compounds at the required concentrations are non-toxic.
The time interval between drug administration and neutron irradiation can be chosen to
maximize the concentration differential between tumor and normal tissue.
Only the tissues located around the tumor volume are exposed to significant neutron
activated boron damage.
DISADVANTAGES OF BNCT
It includes unacceptable scalp reactions brain capillary necrosis in isolated cases and
persistent disease attributed to insufficient beam penetration.
A major difficulty facing BNCT is the lack of successful drug development. BNCT is a
complex therapy in which interdisciplinary interaction amongst many professionals in
indispensable.
The boron dose that is the tumor-selective component the remaining radiation components
in the beam should be kept at a minimum. This constitutes an important challenge in beam
design. The beam should also be sufficiently intense to ensure that treatment times remain
within reasonable limits. This facilitates the procedure for the patient and reduces the
problem of patient motion during treatment. It should be realized that whereas conventional
radiotherapy fractions are administered within a period of about 10 minutes, current clinical
BNCT treatments often extend to a few hours per fraction.
Clinical irradiations could be shortened from the current 3–3 1/2 hours to approximately 5–
10 minutes per field. It should be noted that a number of fields may be required in one day to
complete a treatment. In addition to facilitating patient setup and increasing patient comfort
during BNCT irradiations, the much higher beam quality of this facility compared to the
existing epithermal beam should increase the ratio of tumor to tissue dose by a factor of
two.[9]
VI CONCLUSION
Cancer treatment is an important and global human health issue and breakthroughs in
effective treatment are urgently required. By the joint efforts of various experts the prospects
of BNCT implementation has gradually been revealed. The delivery systems for 10B the
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optimization of the neutron beams to be used careful dosimetry based on pharmacokinetic
and tissue analytic studies and the design of neutron sources that takes into account all of the
advances that have been made in neutron physics and nuclear engineering. We have
summarized the current clinical experience using BNCT to treat patients with brain tumors
recurrent tumors of the head and neck region and cutaneous and extra cutaneous melanomas
and EMPD. BNCT represents a joining together of nuclear technology, chemistry, biology,
and medicine to treat malignant gliomas and recurrent head and neck cancers. Sadly the lack
of progress in developing more effective treatments for these tumors has been part of the
driving force that continues to propel research in this field. BNCT may be best suited as an
adjunctive treatment used in combination with other modalities, including surgery,
chemotherapy and external beam radiation therapy for those malignancies, whether primary
or recurrent, for which there are no effective therapies. Clinical studies have demonstrated the
safety of BNCT. Boron delivery agents must not only have tumor selectivity but also deliver
amounts far in excess of that required for radiopharmaceuticals to detect tumors by radio
diagnostic modalities such as single photon emission computerized tomography and PET. In
contrast to radiopharmaceuticals these agents must deliver enough 10B, presumptively to all
tumor cells, in amounts sufficient to sustain a lethal 10B (n,α) Li capture reaction.
BNCT still remains an attractive twenty first century treatment option for hard to treat types
of human cancers but the problems associated with this modality including the lack of new
and better boron delivery agents the uncertainty regarding accelerator neutron sources and
imprecise radiation dosimetry must be surmounted if it ever will become anything more than
a seductively attractive but unrealistic therapeutic modality.
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