DEVELOPMENTS IN ACCELERATOR BASED BORON

NEUTRON CAPTURE THERAPY

STUART GREEN

Department of Medical Physics, University Hospital Birmingham NHS Trust, Edgbaston,Birmingham B15 2TH, UK

AbstractÐThis paper will review the current status of Boron Neutron Capture Therapy (BNCT), frombasic physical mechanisms and clinical indications, to neutron beam development and dosimetry. Forin-hospital facilities, particle accelerators presently provide the favoured option, and this paper concen-trates on this approach to neutron beam production for BNCT. Various accelerator-based approacheswill be reviewed, but discussion will concentrate on the Birmingham programme, particularly the designof a suitable neutron beam delivery system and the experimental validation of Monte Carlo simulationson a mock-up neutron beam moderation system. The use of dose modifying factors to evaluate thelikely clinical utility of an epithermal neutron beam will also be discussed, with illustrations from theBirmingham programme. # 1998 Elsevier Science Ltd. All rights reserved

INTRODUCTION

There has been a resurgence of interest in BNCT inrecent years as a consequence of two separateevents. Firstly, the publication of promising clinical

results from BNCT treatments carried out in Japan(Hatanaka and Nakagawa, 1994) has encouragedclinicians that there might be some future in this

treatment modality. Secondly, a combination ofwork in neutron beam design and in characterisingthe various available compounds which can be used

to carry boronated drugs to the tumour site, hasencouraged scientists that a signi®cant doseenhancement can be achieved.

This paper provides a review of the signi®cantdevelopments in BNCT in recent years, and assessesthe opportunities for this treatment modality todevelop into mainstream radiotherapy practice. The

review will concentrate on future options which useparticle accelerators as the primary source of neu-trons, since these give greatest potential for in-hos-

pital facilities, and will draw speci®c data from thework on accelerator based BNCT in Birmingham.

OVERVIEW

Clinical indications for BNCT

BNCT may be a suitable treatment for a numberof tumour types. If the tumour is located such that

neutrons can be suitably delivered, and it is of atype which takes up a boronated drug, then treat-ment may be possible. In addition, in common with

all other radical radiotherapy treatments, local con-trol of the primary tumour should be the principalclinical problem. There are a number of tumoursfor which these factors apply, but the majority of

interest world-wide has focused on glioblastoma

multiforme and metastatic melanoma.

Glioblastoma multiforme

Two factors were mentioned above as being sig-

ni®cant in the recent resurgence of interest inBNCT. There is also an underlying third factorwhich is the very poor prognosis for the majority ofpatients with the tumour glioblastoma multiforme.

This is a grade IV astrocytoma, and is a tumour ofthe glial tissue which is the structural material ofthe brain. High grade (III or IV) astrocytomas are

around 1% of cancer diagnosis in the UK, andaround 2.5% of cancer deaths (James, 1996).Incidence increases with age with prognosis dete-

riorating with age and performance status. Patientstend to die as a result of uncontrolled local diseaserather than from the e�ects of metastasis. However,

there are a sub-group of the younger, ®tter patientsthat do receive substantial bene®t from convention-al therapy, both surgery and external beam photonradiotherapy. Hence great care must be exercised in

patient selection for BCNT trials which will almostcertainly be sub-therapeutic in their early stages.

BNCT physical mechanisms

BNCT is a form of binary radiotherapy andtherefore involves two key stages. The ®rst is thepreferential accumulation, in tumour cells, of an

isotope with a suitable a�nity for neutrons at a cer-tain energy. This must then be followed by anintense irradiation of these cells with neutrons at an

energy such that their probability for capture ismaximised. In BNCT, this means a preferential ac-cumulation of boron, followed by submerging thetumour and the surrounding healthy brain tissue in

Radiat. Phys. Chem. Vol. 51, No. 4-6, pp. 561±569, 1998# 1998 Elsevier Science Ltd. All rights reserved

Printed in Great Britain0969-806X/98 $19.00+0.00PII: S0969-806X(97)00203-X

561

a bath of thermal neutrons. These thermal neutrons

may either be incident directly onto the tissue, for

super®cial tumours or intra-operative treatment, or

may be produced locally by moderation of a higher

energy neutron source which is incident on to the

patient surface.

The interaction of thermal and epithermal neu-

trons is dominated by scattering. As a result, neu-

trons of these energies cannot be directed in a

beam-like manner. In order to achieve the required

thermal neutron ¯uence at the tumour, the whole

head (in the case of brain tumours) is given a sub-

therapeutic radiation dose, which is therapeutically

e�ective in the tumour cells because of the increased

dose from the boron capture reaction. However, for

the currently available boron carrier compounds,

the degree of selectivity in concentration between

tumour and healthy tissues is still so low that care-

ful treatment planning, combined with a detailed

understanding of the e�ects of the neutron ir-

radiation on the healthy brain, are essential prere-

quisites to a therapy programme.

In describing the physical basis for BNCT, it is

necessary to use a number of terms which will be

familiar to clinicians and physicists alike. However,

in the case of BNCT, these terms may not carry

their normal inferences. For example, absorbed

dose is related to energy deposited by the radiation

®eld, and in clinical radiotherapy is directly corre-

lated with tumour control probability. In BNCT

the major dose component, that from the boron

capture reaction 10B(n,a)7Li, is deposited non-uni-

formly on the microscopic scale. The ranges of the

reaction products from this reaction are 5 and 9 mmfor the 7Li and a respectively which are comparable

with typical cellular dimensions of around 10 mm.

Hence, if the boron is located far from the radio-

sensitive structures with in cell nucleus, dose (i.e.

energy) will be deposited during the therapy with

negligible impact on tumour control. This is a cen-

tral problem to the whole of BNCT and has been

investigated by many authors (Gabel et al., 1987;

Kalend et al., 1995).

Since the tumour control is a�ected directly by

the location of the boron atoms within a cell, it will

be a�ected directly by the compound used to carry

boron to the cell. There is therefore a need to

characterise the biological e�ectiveness exhibited by

the boron distribution associated with a particular

compound. For this purpose the term Compound

Biological E�ectiveness (CBE) (Coderre et al., 1993)

has been developed. This is an empirical term which

has utility in characterising a treatment plan. It is

analogous to the conventional term Radio-

Biological E�ectiveness (RBE) since it is a simple

ratio:

CBE �dose of photons required to give a

certain surviving fraction

dose from the neutron capture reactionwhich gives the same surviving fraction

It has tended to be used as a multiplier for physi-cal dose (just as RBE is used) in order to providean overall characterisation of the e�ectiveness of a

particular treatment. However, by agreement of allparties at the recent Seventh Symposium onNeutron capture Therapy, Zurich, September 1996,

papers and patient treatment prescriptions inBNCT will carry full information on physical andbiologically equivalent dose, as well as on the con-version factors (RBE and CBE) which have been

used to derive equivalent doses from absorbed dosemeasurements and calculations.

Clinical BNCT programmes

Clinical experience and results from BNCT treat-ments is still patchy. Following early failures atBrookhaven National Laboratory (BNL) andMassachusetts Institute of Technology (MIT) using

extracted thermal neutron beams from reactors,BNCT was kept alive as a treatment modality bythe work of Hatanaka in Japan. This has resulted

in an extensive body of patient data from intra-op-erative irradiation of tumour residues post debulk-ing. The boronated compound used was BSH.

Hatanaka's work, and his use of BSH, has been avery signi®cant factor in the current European facil-ity at the High Flux Reactor (HFR) in Petten, the

Netherlands. However, this has yet to begin patienttrials. Hatanaka's work has attracted signi®cantcomment and criticism on a number of grounds re-lated to patient selection, tumour classi®cation and

the handling of the BSH compound (Dorn III,1994; Laramore and Spence, 1996). These criticismsnotwithstanding, it remains a very substantial con-

tribution to the ®eld on BNCT and provides sub-stantial encouragement for clinicians dealing withglioblastoma multiforme.

Experience with epithermal neutron beams isbeginning to mount with the on-going programmesat BNL and MIT. The BNL group have establishedthemselves as the focal point for western clinical

interest, and are undertaking a phase I/II clinicalstudy. This involves elements of dose escalation andnormal tissue toxicity, as well as paying obvious

attention to survival and quality of life. The resultscurrently being achieved show very similar meansurvival times to conventional X-ray therapy, with

hopes that further dose escalation may be possiblebefore the limit imposed by toxicity to healthy tis-sue is reached.

The published clinical experience has been sum-marised in Table 1. It should be noted that theongoing clinical studies mean that patient numbersare now increasing rapidly in some centres.

Stuart Green562

Potential agents for neutron capture therapy

Whilst the majority of attention world-wide has

focused on 10B as the neutron capture isotope,there are also signi®cant possibilities from other iso-topes which exhibit high neutron capture cross-sec-

tions for thermal neutrons. These are summarisedin Table 2, with the greatest potential beingattached to 157Gd. This isotope has the highest neu-

tron a�nity of any stable isotope (248 000 barns forthermal neutrons). Gadolinium is widely used toenhance images in MRI, and is therefore widely stu-died for toxicity and chemical manipulation, and it

also has limited potential for imaging. Imaging ofthe boron distribution prior to therapy is proble-matic, although substantial progress is now being

made. It is however commonly assumed that theuse of gadolinium instead of boron would provideexcellent opportunities for imaging on any local

MRI scanner. This is unfortunately untrue sinceconventional MRI images only protons, with gado-linium enhancement producing an e�ect on proton

spin relaxation. Hence, the MRI signal is basicallyrelated to proton concentration rather than gadoli-nium concentration, and will be e�ected by thelocal blood supply to the tumour. Whilst conven-

tional MRI would provide some information, thiswould not be of the quality required for dosimetricutility in radiotherapy.

Neutron sources

The neutron beam characteristics which arerequired for a useful BNCT facility are quite di�-cult to achieve. If we consider only BNCT based on

externally applied beams of epithermal neutrons,then we can consider the design criteria put forwardby the Petten group as a useful guide (Moss et al.,

1992). These criteria, along with the characteristicsof neutron beams in use at BNL, Petten, and thatprojected for Birmingham are shown in Table 3.

Essentially one is looking to produce a beam withgood penetration, to ensure su�cient dose to thedistal edge of a target volume, with low fast neu-

tron and photon contamination, and of su�cient

intensity to allow a therapeutic dose to be delivered

in an acceptable time (less than 1 hour for

example).

The only external source of neutrons of su�cient

intensity for a practical BNCT treatment that is

currently available is that from a nuclear reactor.

While both boron enhanced fast neutron therapy,

and capture-based brachytherapy are possible,

neither currently available particle accelerators, or

radioisotope neutron sources can provide an exter-

nal beam suitable for BNCT. Nevertheless, the po-

tential utility of accelerators in a real hospital

environment provides such an attractive prop-

osition, that a number of groups around the world

are investing their research e�ort into this topic.

This e�ort gains impetus from the fairly certain

knowledge that new nuclear reactors are very unli-

kely to be located at hospital sites, and that the

potential income which could be generated from

a clinical BNCT programme is unlikely to be

su�cient to support the running costs of a nuclear

reactor.

The use of radioisotope neutron sources for

external `beam' BNCT has also been investigated

(Yanch et al., 1993). These investigations suggest

that a beam of su�cient intensity for a practical

treatment facility is unlikely to be realised by this

route. However, a number of centres are already

working clinically with neutron therapy based on

interstitial placement of neutron sources. The mod-

eration of these, usually ®ssion, neutrons within the

body, might produce a su�ciently high local ther-

mal ¯uence to mean that the introduction of a

boronated capture agent is clinically useful in cer-

tain circumstances (Allen and Ralston, 1996).

The potential for a dose enhancement in fast neu-

tron therapy has been considered at a number of

centres (Maughan et al., 1996). It is signi®cant here

to recall that tumour control probability is a very

strong function of applied dose, so the small poten-

tial for dose enhancement by using tumour speci®c

Table 1. Published BNCT clinical experience world-wide

Country/Lab Compound Condition Neutron beam No. of patients

Japan/Kagawa (Nakagawa et al., 1997) BSH Gliomas (all grades) Thermal 152Japan/JAERI (Matsumura et al., 1997) BSH Gliomas (III and IV) Thermal 4Japan/Kyoto (Ono et al., 1997) BSH/BPA Gliomas (III and IV) Thermal 44USA/BNL (Elowitz et al., 1997) BPA Glioblastoma Epithermal 10USA/MIT (MIT group, 1996) BPA Glioblastoma Epithermal 2USA/MIT (Busse et al., 1997) BPA Melanoma Epithermal 5

Table 2. Characteristics of di�erent isotopes for neutron capture therapy

Isotope Cross-section (barns)aNatural abundance

(%) Reaction Q (MeV) Products

10B 3800 19.6 2.79 a, 7Li, g157Gd 248 000 15.7 7.9 g, eÿ6Li 917 7.4 4.78 a, t235U 566 0.72 200 �, b, g, n

aValues taken from the JEF data library at 0.025 eV (JEF-2.2).

Boron Neutron Capture Therapy 563

capture agents in fast neutron therapy, could have

a signi®cant impact on overall cure-rates. Clinicalenthusiasm for such an approach is constrained bythe fact that the presently available capture agents,

combined with the low capture cross-sections of iso-topes such as 10B at high energy (10B(n,a) cross-sec-tion at 10 MeV is approximately 0.06 barns), means

that the potential for dose enhancement is thoughtto be around 5%. Hence this modality sees unlikelyto have a substantial clinical impact at present.Calculations suggest (Maughan et al., 1996) that

modi®cations to conventional fast neutron beamscould improve this ®gure to in excess of 10%, andthe development of capture agents with improved

speci®city would certainly have a dramatic impacthere.

Accelerator neutron sources

A particle accelerator suitable for BNCT is esti-mated to be of a similar cost to systems for high

energy neutron and proton therapy. That is ap-proximately three to four times the cost of a con-ventional high energy linear accelerator used

routinely in hospitals around the world. It is there-fore substantially cheaper than reactor technology,and would be acceptable for an in-hospital location.From the physics and neutronics point of view

there are also a number of advantages to accelera-tor systems. It is possible, by manipulating suchparameters as incident beam, energy, and modera-

tor thickness, to produce neutron beams of di�erentcharacteristics. There is also the option of usingdi�erent target materials and di�erent incident par-

ticle types but generally attention has focused onlow energy proton accelerators with the choice ofeither lithium or beryllium as the target material.Nevertheless, there are a number of alternative

accelerator con®gurations which also deserve someattention, including moderation of beams from highenergy proton accelerators, and designs for neutron

production at threshold for direct incidence ontothe patient without a moderator. These two alterna-tive approaches will be described ®rst, before con-

centrating on the application of moderated lowenergy proton accelerators as the principal route toaccelerator based BNCT.

High energy accelerators. The role of cyclotronsin the treatment of cancer is now well established.Their contribution to both fast neutron and protontherapy is substantial, and they are now an estab-

lished part of the armoury against cancer around

the world. It is also possible that high energy accel-

erators such as the one at PSI, Switzerland, will be

useful in producing a beam suitable for BNCT.

Moderator design studies (Teichmann and Craw-

ford, 1996) have been undertaken which indicate

that a suitable epi-thermal beam can be produced

from this facility.

Unmoderated low energy accelerator systems. It

may also be possible to use a low energy accelerator

without a moderation system (Kononov, 1996) In

this case, the target material, usually lithium, is

bombarded with protons with an energy of around

1890 keV, i.e. only slightly above the threshold for

this reaction at 1881 keV. From kinematic consider-

ations, there will be neutron emission in a narrow

forward directed cone, with neutron energies in the

desired epithermal (around 10 keV) region. Since

the neutron production cross-section of the target

material will be changing very rapidly near

threshold, small ¯uctuations in incident particle

energy may lead to dramatic changes in all proper-

ties of the emergent neutron beam, i.e. in its energy,

angular distribution, and intensity. Hence, this

approach, while still requiring the production of

high proton beam currents and targets with high

power dissipation capabilities, also requires very

good voltage stability in the accelerator system.

One very interesting variant of the accelerator

option for BNCT, is that described by Song et al.

(1996) using a miniature accelerator tube, stereotac-

tically inserted into the centre of the tumour

through a bore-hole in the skull. This approach

could, in principle, provide a very substantial

increase in dose-rate around the tumour, but with

some cost in terms of the radiobiological character-

istics of the beam. Further technical work is necess-

ary to determine the heat removal capabilities of

such a miniature accelerator and target system.

Moderated low energy accelerator systems. Low

energy accelerators, generating neutrons up to

around 1.5 MeV, require quite small, compact, and

inexpensive beam moderation systems such as the

one shown in Fig. 1. This kind of accelerator sys-

tem for BNCT is favoured by many laboratories

around the world (Allen and Beynon, 1995; Yanch

et al., 1992; Chu et al., 1996) and appears to o�er

the best possibility for clinical use. The design of

these systems can be tuned to produce neutron

beams with di�erent characteristics, as illustrated in

Table 3. Neutron beam characteristics of a number of BNCT centres

Centre

Useful neutron¯uence-rate(cmÿ2 sÿ1)

Mean neutron kerma perunit neutron ¯uence

(Gn) (Gy cm2)

Mean photon kerma perunit neutron ¯uence

(Gp) (Gy cm2)

Petten Design (Moss et al., 1992) r1� 109 R8.1� 10ÿ13 R2.8� 10ÿ13

BNL I (Liu, 1996) 1.4� 109 4.5� 10ÿ13 1.5�10ÿ13

BNL II (Liu, et al., 1997) 0.84� 109 4.8� 10ÿ13 2.0�10ÿ13

Birmingham (Allen and Beynon, 1995)a 0.82� 109 7.4� 10ÿ13 0.8�10ÿ13

aFor a moderator depth of 20 cm and a proton beam of 5 mA at 2.8 MeV.

Stuart Green564

Fig. 2. Increased thermal components in the beam

(lower Gn in Fig. 2) would be useful for delivering

an enhanced boron-capture dose to more super®cial

region, while beam apertures, decreased moderation

and the use of thermal neutron absorbers such as

lithium in the moderation system, can be used toenhance the beam penetration. In this way it ispossible, in principle, to tune the delivered neutron

beam to suit a range of clinical situations. However,this process must be accompanied by detailed radio-biological studies to assess the impact of each beamadjustment on the response of normal tissues placed

in the beam.

Target cooling

The removal of heat from an accelerator target isone of the principal technological challenges to beovercome by all low energy accelerator systems.

The melting point of lithium metal is around1808C, which means that heat removal must behighly e�cient if the target is to remain solid. The

minimum beam power requirements for a moder-ated low energy accelerator system approximates toa proton beam current of 5 mA at an energy of

2.5 MeV. This is a beam power of 12.5 kW, depos-ited over a few square centimetres in a target layerwhich is only around 150 mm thick. The power den-

sity is therefore approximately 1 kW/cm2 for a uni-form 4 cm diameter beam and is near the limit thatcan be removed by water-based cooling mechanisms(see Table 4).

Fig. 1. The phase I beam moderator which has been experimentally validated in Birmingham.

Fig. 2. The variation in free beam parameters available byaltering the moderator depth in the Birmingham phase Imoderator design. Here Gn and Gp are the mean neutronand photon kermas per unit neutron ¯uence, the protonenergy is 2.8 MeV and the current is 10 mA (reproduced

with permission of IOP Publishing Ltd, Bristol, UK).

Boron Neutron Capture Therapy 565

Of the available options it appears that sub-

merged jet cooling is the only option worth pursu-ing. This involves placing the back surface of thetarget in contact with a ¯uid bath which containsa jet of the same ¯uid, injected via a nozzle onto

the centre of the target. In this way the jet ismaintained at a lower temperature than in forcedconvection cooling and in addition, localised boil-

ing is allowed on the target rear surface. Anyvapour bubbles are blown away by the impact ofthe jet which spreads out radially from the centre.

Experimental evidence from Blackburn et al.(1996) suggests that submerged jet cooling iscapable of accommodating power densities up to

6 kW/cm2, which gives a factor of 6 safety marginover that required for a uniform beam power, andshould deal adequately with the non-uniform pro-ton beams which are likely to be encountered in

practice.

DOSIMETRY FOR BNCT BEAMS

The dosimetry of the neutron beams used in

BNCT is extremely complex. Neutron interactionsin boron-loaded and normal tissues give rise to arange of secondary particles which deposit the radi-ation dose. The very wide spread in LET of these

reaction products, and by implication the widerange of RBEs involved, means that these dosecomponents must be separately quanti®ed if an

accurate overall assessment of the radiation dose isto be made.Practical beam dosimetry in photon radiotherapy

is exclusively based on ion-chambers, with referenceto Primary standards which may either be based onionisation yield or on more direct measures ofenergy deposited such as calorimetry. Centres in

North America that already have active clinicalBNCT programmes have also chosen to use ion-chambers as their routine dosimetric tool (Rogus

et al., 1994) with reference to a Primary standardthrough a photon calibration of the dosimeters. InEurope, e�orts are in hand to develop an agreed

dosimetry protocol amongst the centres that arepursuing clinical BNCT facilities (Stechet-Rasmussen et al., 1996).

A number of authors have reported on the use ofthe microdosimetric technique for BNCT dosimetry(Wu et al., 1992; Maughan et al., 1992). InBirmingham, we are also attempting to further

understand the radiation absorbed dose depositionby making use of the microdosimetric technique

using specially designed proportional counters. Thefeasibility of this approach has been demonstratedat low ¯uence rates, but needs to be con®rmed in

the full therapy beam (Green et al., 1996).These techniques notwithstanding, macroscopic

dosimetry (i.e. determination of absorbed dose in

cm sized voxels) is not truly possible withoutsome information on the macroscopic distributionof boron in the tissues of the patient. It has

become routine practice in active BNCT centres,to rely on a pre-therapy bio-distribution study tomeasure the boron partitioning between tumour,blood and normal brain tissue, for a particular

infusion protocol. These relative partitions areassumed to be reproduced at the time of therapy,even when this follows a de-bulking procedure

(Chanana, 1996).Whilst these approximations are certainly appro-

priate for early trials, greater understanding of clini-

cal outcomes may be possible if the borondistribution can be measured at the time of thetherapy irradiation. Promising techniques in this

area are based on spectroscopic magnetic resonanceimaging (Flego et al., 1996) where the spin relax-ation of 11B is measured, and also on directmeasurement and possible imaging of the capture

gammas from the 10B capture reaction (Allen et al.,1996).

EXPERIENCE IN BIRMINGHAM

The dynamitron accelerator

The Birmingham BNCT programme is basedaround the 3 MV Dynamitron accelerator in the

School of Physics and Space Research at TheUniversity of Birmingham. In such an accelerator,the terminal voltage is maintained through a

series of Cockroft±Walton type voltage doublingstages, but unlike a conventional Cockroft Waltoncascade accelerator where power is delivered in

series through the chain of doubling stages, in theDynamitron, radio-frequency power is delivered inparallel from large cylindrical plates placed out-side the doubling chain, and coupled to it via cir-

cular metal strips. This coupling of the powerdelivery in parallel means that much higher char-ging rates are possible, giving the Dynamitron a

potential for stable production of high beampowers.In addition, the Dynamitron is built with an in-

ternal electrode geometry which is designed toreduce the path for scattered and divergent par-ticles, preventing them from reaching signi®cant

energies within the accelerator column. Hence theproduction of background X-rays and neutronswithin the accelerator column is minimised. In itspresent con®guration, the accelerator has produced

Table 4. Heat transfer coe�cients from a range of cooling mechan-isms (Blackburn et al., 1996)

Mechanism Coe�cient (W/m2 K)

Free Liquid Convection 50±1000Forced Liquid Convection 50±20 000Convection with a phase change 2500±105

Submerged jet with a phase change >6� 105

Stuart Green566

reliable beams of around 2 kW power (1 mAprotons at 2 MV).

The Birmingham programme is nearing the endof a second design stage. Work on the initial beammoderation system has now been completed. Thisincludes design (Allen and Beynon, 1995), measure-

ment validation (Tattam et al., 1996) and dosimetriccharacterisation (Green et al., 1996). Work isshortly to begin on two key areas, namely the

upgrade of the accelerator ion source to give thepotential for beams up to 10 mA, and constructionof a beam moderation system which will produce

a horizontal epithermal neutron beam from anincident vertical proton beam.

CHARACTERISATION OF THE BIRMINGHAMEPITHERMAL BEAM

Initial design studies for an accelerator basedneutron source for BNCT applications have been

performed using the radiation transport codeMCNP (Briesmeister, 1993). These have been fol-lowed by experimental validation based on the sys-

tem similar to that shown in Fig. 1, but without theouter D2O and Li shield. This is basically the Litarget and moderator system described by Tattam

et al. (1996).

Outline of the experimental programme

The experimental programme comprised the fol-

lowing elements.

1. Construction of a rectangular Perspex enclosedwater phantom. Following the computational

work of Gupta et al. (1993) we have chosen aphantom of dimensions 17 cm�14 cm�15 cm,which is the intermediate of the three phantoms

which they investigated.2. Measurements at four positions along the central

axis of this phantom of:

. fast neutron dose from a Tissue Equivalent(TE) microdosimetric detector

. photon dose from a TE microdosimetric detec-

tor. boron dose indirectly using thermal ¯uence®gures derived from gold foil activation

3. Comparison of absolute experimental results (interms of dose rate/mA of proton beam) with anabsolute MCNP simulation of the exact exper-imental con®guration.

4. Assessment of the clinical utility of this beamusing the CBE factors derived for BPA and thefast neutron RBE from the Brookhaven group

(Chanana, 1996). These are:

CBE, Tumour + BPA 3.8CBE Normal Brain + BPA 1.3RBE, photons 1.0RBE, neutrons 3.2Tumour 10B concentration 30 mg gÿ1

Normal Brain 10B concentration 10 mg gÿ1

Validation of the MCNP simulations

The comparisons between experimental andMCNP simulation results are represented in Table 4as ratios between the experimental and simulation

results at each depth. Hence good agreementbetween experiment and calculation would result ina value of 1.0. It is clear from Table 5 that the vali-dation is successful for fast neutron, photon, and

boron dose derived from gold foils.

Dosimetric data

In order to derive estimates of the likely biologi-cally equivalent dose which will be delivered by theBirmingham beam, and to further understand its

clinical utility, the factors listed above for concen-tration, CBE and RBE have been combined withthe physical dose measurements to give informationon the variation with depth of each dose com-

ponent to both tumour and normal tissue. Thesedata are represented in Table 6 which shows bothphysical (Gy) and Gy-equivalent dose data at 5 cm

deep in phantom.Hence, from Table 6, the total dose to normal

brain (in Gy-Eq) at 5 cm deep is only approxi-

mately 26% of the total dose to tumour at thisdepth, whereas the corresponding ®gure in terms ofphysical dose is 57%. It is therefore clear that by

using our understanding of the di�erent degrees ofcell damage that result from the di�erent dose com-ponents in BNCT, a signi®cantly increased relativedose to the tumour is predicted, being greater than

that derived from considerations of physical dosealone.

SUMMARY AND CONCLUSIONS

The ®eld of accelerator based BNCT is rapidlyexpanding, re¯ecting an increased clinical interest

Table 6. Relative doses at 5 cm deep in a water phantom exposedto an epithermal neutron beam

Physical dose (RBE or CBE)�dose

Component TumourNormalbrain Tumour

Normalbrain

10B 64.5 21.5 83.2 9.5Neutron 6.5 6.5 7.0 7.0Photon 29.0 29.0 9.8 9.8Total 100.0 57.0 100.0 26.3

Table 5. Ratio of experiment to MCNP simulation at di�erentdepths in a light water phantom

Depth (cm) Photon Neutron 10B (Au foils)

2.5 0.9920.09 0.9720.07 0.9820.065.0 0.9620.10 1.0020.07 0.9920.067.5 0.9920.10 0.9420.08 0.9120.0512.7 1.1820.13 0.8320.07 1.2320.07

Boron Neutron Capture Therapy 567

following positive results from work in Japan andNorth America. Data presented here indicate that

the enhanced toxicity of the boron capture reactionleads to a dose enhancement which appears favour-able for therapy. The ways in which particle accel-

erators may be used in BNCT are diverse, andcover a possible range of incident particle (almostexclusively proton) energies from around 2 to

600 MeV, with accelerators ranging in size fromthose which might be su�ciently small to allowdirect insertion into the tumour site, to spallation

sources which use synchrotron rings of many metresin diameter.This area has become very a very productive one

for radiation physicists throughout the world, who

function as part of multi-disciplinary teams broughttogether to struggle with the many scienti®c andtechnical challenges that BNCT involves. However,

this is not simply a subject for abstract research.Despite the best e�orts of modern medicine,patients diagnosed with the tumour glioblastoma

multiforme will be dead within 5 years of the initialdiagnosis, the vast majority dying within the ®rst 2years. BNCT o�ers some hope for these patients.

AcknowledgementsÐThis paper has relied heavily on visitsmade in 1996 to Brookhaven National Laboratory, MITand to the Seventh International Symposium on NeutronCapture Therapy, Zurich. Detailed discussion and datasupplied by the following people is gratefully acknowl-edged Jacek Capala, Je� Coderre, Ben Liu, LucianWielopolski and Dr Annan Chanana (all BNL) andRobert Zamenhof, Jacqualine Yanch and Prof. OttoHarling (all MIT). Thanks goes to the RadiologicalResearch Trust for funding for the trip to the Zurich con-ference. For their experimental microdosimetry atBirmingham, thanks also go to Richard Maughan andChandrasekar Kota of Harper Hospital, Detroit, and inaddition the assistance of the many members of theBirmingham group is gratefully acknowledged, particularlyDavid Tattam and Dennis Allen.

REFERENCES

Allen, D. A. and Beynon, T. D. (1995) A design study foran accelerator-based epithermal neutron beam forBNCT. Physics in Medicine & Biology 40, 807±821.

Allen, D. A., Beynon, T. D. and Perks, J. (1996) In-vivoon-line 10B(n,a) 3D dose measurements using binaryGabor zone plate encoded g-ray holography. ConferenceProceedings, 7th International Symposium on NeutronCapture Therapy. Vol. 1, 229±236.

Allen, B. J. and Ralston, A. (1996) Boron dose enhance-ment for 252Cf brachytherapy. Conference Proceedings,7th International Symposium on Neutron CaptureTherapy. Vol. 1, 271±274.

Blackburn, B. W., Klinkowstein, R. E., Yanch, J. C.,Song, H. and Howard, W. (1996) Development of ahigh-power, water-cooled beryllium target for the pro-duction of neutrons in a high-current tandem accelera-tor. 14th International Conference on the Applicationof Accelerators, Denton, Texas, Nov. 1995.

Briesmeister, J. F. (Ed) (1993) MCNP2ÐA generalMonte Carlo N-particle transport code, version 4A. LosAlamos 12625, M Manual UC705 & UC700.

Busse, P., Zamenhof, R., Madoc-Jones, H., Solares, G.,Kiger, S., Riley, K., Chuang, C., Rogers, G. and

Harling, O. (1997) Clinical follow-up of patients withmelanoma of the extremity treated in a phase I boronneutron capture therapy protocol. ConferenceProceedings, 7th International Symposium on NeutronCapture Therapy. Vol. 1, 60±64.

Chanana, A. D. (1996) Boron neutron-capture therapy ofglioblastoma multiforme at the Brookhaven MedicalResearch Reactor, Protocol #4.

Chu, W. T., Donahue, R. J., Gough, R. A., Kwan, J.,Leung, K.-N., Ludewigt, B. A., Phillips, T. L.,Reginato, L., Staples, J., Wells, R. and Yu, S. (1996)Design of a new BNCT facility based on ESQ accelera-tor. Conference Proceedings, 7th InternationalSymposium on Neutron Capture Therapy. Vol. 1, 533±537.

Coderre, J. A., Maker, M. S., Micca, P. L., Nawrocky, M.N., Liu, H. B., Joel, D. D., Slatkin, D. N. and Amols,H. I. (1993) Derivations of RBE for the high LET reac-ton produced during BNC irradiations of the 9L ratgliosarcoma in vitro and in vivo. Int. J. Radiat. Oncol.Biol. Phys. 27, 1121±1129.

Dorn, R. V. III (1994) Boron neutron capture therapy(BNCT): A radiation oncology perspective. Int.J. Radiat. Oncol. Biol. Phys. 28, 1189±1201.

Elowitz, E. H., Chadha, M., Coderre, J. A., Joel, D.,Slatkin, D. N. and Chanana, A. D. (1996) A phase I/IItrial of BNCT for glioblastoma multiforme using intra-venous boronophenylalanine±fructose complex andepithermal neutrons: Early clinical results. ConferenceProceedings, 7th International Symposium on NeutronCapture Therapy. Vol. 1, 56±59.

Flego, M., Nicolay, K. and Watkins, P. (1996) Three-dimensional back-projection reconstruction methods formagnetic resonance imaging (MRI) of nuclei with shortrelaxation times. Conference Proceedings, 7thInternational Symposium on Neutron Capture Therapy.Vol. 1, 289±293.

Gabel, D., Foster, S. and Fairchild, R. G. (1987) TheMonte Carlo simulation of the biological e�ect of the10B(n,a) 7Li reaction in cells and tissue and its impli-cation for boron neutron capture therapy. RadiationResearch 111, 14±25.

Green, S., Kota, C., James, N., Maughan, R., Tattam, D.A., Beddoe, A. H., Beynon, T. D. and Weaver, D. R.(1996) Dosimetric characteristics of an accelerator basedbeam for boron cancer therapyÐexperimental results.Conference Proceedings, 7th International Symposium onNeutron Capture Therapy. Vol. 1, 217±221.

Gupta, N., Niemkiewicz, J., Blue, T. E., Gahbauer, R. andQu, T. X. (1993) E�ect of head phantom size on 10Band 1H(n,g)2H dose distributions for a broad ®eld accel-erator epithermal neutron source for BNCT. Med. Phys.20, 395±404.

Hatanaka, H. and Nakagawa, Y. (1994) Clinical results oflong-surviving brain tumour patients who underwentboron neutron capture therapy. Int. J. Radiat. Oncol.Biol. Phys. 28, 1061±1066.

James, N. (1996) Presentation at the 1996 Meeting of theAssociation for Radiation Research, Birmingham, UK.

JEF-2.2. Joint Evaluated File version 2.2, Nuclear EnergyAgency Data Bank, 12, Bld des Iles, 92130 Issy-Les-Moulineaux, France.

Kalend, A. M., Bloomer, W. D. and Epperly, M. W.(1995) Dosimetric consequences of 10B(n,a)7Li reactionoccurring at the cellular membrane. Int. J. Radiat.Oncol. Biol. Phys. 31, 171±178.

Kononov, V. N., Regushevskiy, V. I., Soloviev, N. A. andLeipunskiy, A. I. (1996) Accelerator-based and intensedirected neutron source for BNCT. ConferenceProceedings, 7th International Symposium on NeutronCapture Therapy. Vol. 1, 528±532.

Laramore, G. E. and Spence, A. M. (1996) Boron neutroncapture therapy (BNCT) for high grade gliomas of the

Stuart Green568

brain: A cautionary note. Int. J. Radiat. Oncol. Biol.Phys. 36, 241±246.

Liu, H. B. (1996) Neutron capture therapy facilities at theBrookhaven Medical Research Reactor, private com-munication.

Liu, H. B., Capala, J., Joel, D. D., Brugger, R. M. andRover, D. C. (1997) NCT facilities at the BrookhavenMedical Research Reactor. Advances in Neutron CaptureTherapy. Vol. 1, 311±315, Eds. B. Larsson, J. Crawfordand R. Weinreich, Elsevier, Amsterdam.

Matsumura, A., Shibata, Y., Yamamoto, T., Yamada, T.,Fujimori, H., Nakai, K., Nakagawa, Y., Hayakawa, Y.,Isshiki, M. and Nose, T. (1996) The University ofTsukuba BNCT research group: ®rst clinical experiencesat JAERI. Conference Proceedings, 7th InternationalSymposium on Neutron Capture Therapy. Vol. 1, 46±50.

Maughan, R. L., Kota, C. and Forman, J. D. (1996)Feasibility of boron neutron capture enhancement offast neutron therapy using a superconducting cyclotron.Conference Proceedings, 7th International Symposium onNeutron Capture Therapy.

Maughan, R. L., Kota, C. and Yudelev, M. (1992) Amicrodosimetric study of the dose enhancement in a fastneutron beam due to boron neutron capture. Physics inMedicine & Biology 37, 1957±1961.

MIT group (1996) Oral contribution at 7th InternationalSymposium on Neutron Capture Therapy.

Moss, R. L., Stecher-Rasmussen, F., Ravensberg, K.,Constantine, G. and Watkins, P. (1992) Design con-struction and installation of an epithermal neutronbeam for BNCT at HFR Petten. Progress in NeutronCapture Therapy for Cancer, pp. 63±66. Ed. B. J. Allen,Plenum Press, New York.

Nakagawa, Y., Kyonnghon, P., Kitamura, K., Kageji, T.and Minobe, T. (1996) What were important factors inpatients treated with boron neutron capture therapy inJapan? Conference Proceedings, 7th InternationalSymposium on Neutron Capture Therapy. Vol. 1, 65±70.

Ono, K., Ueda, S., Oda, Y., Nakagawa, Y., Miyatake, S.,Takagaki, M., Osawa, M. and Kobayashi, T. (1996)Boron neutron capture therapy for malignant glioma at

Kyoto University reactor. Conference Proceedings, 7thInternational Symposium on Neutron Capture Therapy.Vol. 1, 39±45.

Rogus, R. D., Harling, O. K. and Yanch, J. C.(1994) Mixed ®eld dosimetry of epithermal neutronbeams for boron neutron capture therapy at the MITR-II research reactor. Med. Phys. 21, 1611±1625.

Song, H., Yanch, J. C. and Klinkowstein, R. E. (1996) Aninterstitial intracavity accelerator-based neutron sourcefor fast neutron brachytherapy. Conference Proceedings,7th International Symposium on Neutron CaptureTherapy. Vol. 1, 543±548.

Stecher-Rasmussen, F., Auterinen, I., Beddoe, A.,Goncalves, I., Jarvinen, H., Kosunen, A., Larsson, B.,Marek, M., Mijnheer, B., Raajmakers, C. P. J.,Savolainen, S., Voorbraak, W. P., Watkins, P. andZsolnay, E. (1996) A code of practice for the dosimetryof BNCT in Europe. Conference Proceedings, 7thInternational Symposium on Neutron Capture Therapy.Vol. 1, 237±240.

Tattam, D. A., Allen, D. A., Beynon, T. D., Constantine,G., Green, S., Scott, M. C. and Weaver, D. R. (1996)Preliminary neutron ¯uence measurements in theBirmingham BCT beam. Conference Proceedings, 7thInternational Symposium on Neutron Capture Therapy.Vol. 1, 472±476.

Teichmann, S. and Crawford, J. F. (1996) Theoreticalstudy of a spallation neutron source for BNCT.Conference Proceedings, 7th International Symposium onNeutron Capture Therapy. Vol. 1.

Wu, C. S., Amols, H. I., Kliauga, P., Reinstein, L. E. andSaraf, S. (1992) Microdosimetry for boron neutron cap-ture therapy. Radiation Research 130, 355±359.

Yanch, J. C., Kim, J. K. and Wilson, M. J. (1993) Designof a californium-based epithermal neutron beam forneutron capture therapy. Physics in Medicine & Biology38, 1145±1155.

Yanch, J. C., Zhou, X.-L., Shefer, R. E. andKlinkowstein, R. E. (1992) Accelerator-based epithermalneutron beam design for neutron capture therapy. Med.Phys. 19, 709±721.

Boron Neutron Capture Therapy 569