REVIEW ON BORON NEUTRON CAPTURE THERAPY

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356

Nair et al. World Journal of Pharmacy and Pharmaceutical Sciences

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

https://en.wikipedia.org/wiki/Glioma

https://en.wikipedia.org/wiki/Head_and_neck_cancer


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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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