Radiation Research Society

The Radiation Biology of Boron Neutron Capture Therapy
Author(s): Jeffrey A. Coderre and Gerard M. Morris

Reviewed work(s):
Source: Radiation Research, Vol. 151, No. 1 (Jan., 1999), pp. 1-18
Published by: Radiation Research Society
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RADIATION RESEARCH151, 1-18 (1999)
0033-7587/99$5.00
? 1999byRadiation ResearchSociety.
in anyformreserved.
ofreproduction
All rights
REVIEW
The Radiation ofBoronNeutron
Biology Capture
Therapy
A. Coderrea
Jeffrey andGerardM. Morrisb
a
MedicalDepartment, NationalLaboratory,
Brookhaven NewYork11973;and
Upton,
b ResearchInstitute, Churchill
ofOxford,
University OX3 7L[, UnitedKingdom
Hospital,Oxford
It is basedon a straightforward conceptthatwas first pub-

Coderre,J. A. and Morris,G. M., The RadiationBiologyof
lishedby GordonLocherin 1936 (1). The minorstable
Boron NeutronCapture Therapy.Radiat. Res. 151, 1-18
isotopeofboron,1oB,hadbeenshowntointeract withlow-
(1999). energy(thermal)neutronsto producehighlyenergetic,
Boron neutroncapturetherapy(BNCT) is a targetedra-
diationtherapythatsignificantly short-range
increasesthetherapeutic ra- disintegration products(2). Locherreasoned
thatifthe1oBcouldbe localizedin tumor
tio relative to conventionalradiotherapeuticmodalities. tissue,theshort-
BNCT is a binaryapproach:A boron-10('OB)-labeledcom-rangedisintegration productswouldprovidean effective
and selectivetherapy.
thatdelivershighconcentrations ofI0B The conceptwas attractive in prin-
poundis administered
to the targettumorrelativeto surrounding ciple: The
normaltissues. neutron component of this therapy itself
by
wouldhavelittleeffect
This is followedby irradiationwiththermalneutronsor ep- on tumor ornormaltissue;thermal
ithermalneutronswhichbecomethermalized neutrons (<0.4 eV) haveinsufficient
at depthin tis- energy to damagetis-
sues. The shortrange (5-9 pim)of the a and 7Li particles
sue;thehigh-linear energy transfer (LET) radiationreleased
releasedfromthe'OB(n,a)7Li neutroncapturereactionmake
in thetumorcells by theinteraction of 1oBwiththermal
themicrodistribution of'IB ofcriticalimportance in therapy.
neutrons (IoB + In [11B]-* 7Li + 4He + 2.79 MeV)
The radiationfieldin tissuesduringBNCT consistsofa mix-
wouldbe sufficient to killor sterilize thosecells; and the
tureofcomponents withdifferingLET characteristics. Studies
shortrangeoftheparticles produced bytheneutron capture
have been carriedout in bothnormaland neoplastictissues
to characterizetherelativebiologicaleffectiveness reaction(<10
ofeach ra- should limit damageto cells con-
the
pIm)
IOB.Initialclinicalevaluation ofBNCT didnottake
diationcomponent.The distribution taining
patternsand radiobio-
logicalcharacteristicsofthetwoI0Bdelivery placeuntiltheearly1950s.Patients
agentsin current withmalignant gliomas
clinicaluse,theaminoacidp-boronophenylalanine wereirradiated
(BPA) and withthermalized reactor neutrons forBNCT
thesulfhydryl at Brookhaven
borane(BSH), have been evaluatedin a range NationalLaboratory (BNL) (1951-1961)
of normaltissuesand tumortypes.Consideredoverall,BSH-
and,starting later(1959-1961),at theMassachusetts Insti-
mediatedBNCT elicitsproportionately lessdamageto normal
tuteof Technology(3). The disappointing outcomesof
tissuethan does BNCT mediatedwithBPA. However,BPA to twoprimary factors:
thesetrialswereattributed (1) in-
exhibitssuperiorin vivo tumortargetingand has proven of theboroncompoundsem-
muchmoreeffective in thetreatment adequatetumorspecificity
ofbraintumorsin rats.
In termsof fractionation ployedand(2) insufficient
boron neutroncaptureir- penetration ofthermal neutrons.
effects,
Efforts
radiationmodalitiesare comparablewithotherhigh-LETra- to delivertherapeutic thermal neutron fluences to
diationmodalitiessuchas fast-neutron deep
therapy.Therewas no tumors resultedin excessive damage to thescalp(4).
The highboronconcentrations
appreciableadvantagein increasingthenumberofdailyfrac- in blood and braintissue
tionsof thermalneutronsbeyondtwowithregardto sparingduringirradiation resulted in extensive damageto thenor-
ofnormaltissuein theratspinalcordmodel.The experimen-
mal brain.Bothof theseBNCT clinicaltrialswerehalted
tal studiesdescribedin thisreviewconstitute theradiobiolog-
in 1961.However, BNCT ofbraintumors was resumed in
ical basis forthenewBNCT clinicaltrialsforglioblastoma in at
1968. A more selective boron was
BrookhavenNationalLaboratory,at theMassachusetts Japan Insti- delivery agent
employed butsurvivalwas notimproved
safely, relative to
tuteofTechnology, and at theHighFluxReactor,Petten,The
Netherlands.The radiobiologyof experimental conventional
and clinical treatment (5-7). Claimsthatsubgroups ofpa-
BNCTis discussed indetail. D 1999byRadiation tientstreated
Research
Society
withBNCT showincreasedmediansurvival
relativeto conventional treatment (5, 6) are difficult to
evaluatedue to a lackofinformation abouttheproportion
INTRODUCTION of lower-grade tumors includedin thesegroups.The clin-
Boronneutroncapturetherapy(BNCT) is a binarytreat- ical outcome for14 American glioblastoma patients treated
thatcan selectively
mentmodality target
neoplastictissue. withBNCT in Japanwas evaluatedby Laramore(8). The
1

2 CODERRE AND MORRIS
survivaltimesof thesepatientswereno betterthanfor 2
SH
thosereceiving conventional radiotherapy.
Recently, havebeenimprovements
there in borondeliv- HO 2Na+
ery agents and in low-energy neutron-beam technology. BB
COOH
Considerably moreis now knownabouttheradiation bi- HO
ology of BNCT. Several BNCT clinical trialshave recently NH2

beenstarted thattakeadvantage of theseimprovements: at O =B
Brookhaven NationalLaboratory in 1994forglioblastoma L-BPA BH
multiforme (9), at theMassachusetts Instituteof Technol- BSH
(p-borono-L-phenylalanine)
ogy (MIT) in 1994 for cutaneous melanoma (10) and in (Na2B12H,1SH)
1996 forintracerebral melanomaor glioblastoma, and in
1997forglioblastoma attheHighFluxReactor, The FIG. 1. The chemicalstructures
ofp-boronophenylalanine
(BPA) and
Petten,
Netherlands. the sulfhydryl
borane Na2B12H,,SH(BSH).
Reviewarticleshavebeenpublishedrelating to BNCT
in general,e.g. refs.(3, 11-13), to thechemistry ofboron
asideon accountof itspenetration oftheblood-brain bar-
compounds (14, 15), and to the of
development epithermal rieruntilMishimaet al., takingadvantageof itsstructural
neutron beams(16). The present articleis thefirst review
similaritytomelanin precursors, initiated a BNCT research
to focuson theradiobiology ofBNCT.The published data
program formelanoma (18). BPA was shown toaccumulate
relatingto the biological effects of the dose components of
selectivelyin B 16 melanoma cells both in vitroandinvivo.
themixedradiationfieldassociatedwithBNCT are dis- BNCT ofBPA-loadedtumors resulted in significantlevels
cussedin relationto normaland neoplastictissues.Since of tumorcontrol.Otherinvestigators have confirmed the
theshort pathlength oftheradiations produced bytheBNC effectiveness of BPA-basedBNCT forexperimental mela-
reactionmakethemicroscopic tissuelocalization ofthebo-
nomas(19-22). A clinicaltrialofBPA-mediated BNCT of
roncarrier ofcritical importance, thetwo boron compoundscutaneousmelanoma,usinga thermal neutron beam,has
in clinicaluse will be describedand comparedin some beenunderwayin Japanfora number of years(23-25).
detail.The different pharmacological properties of these The use of BPA in experimental braintumortherapy
twoagentsandtheresultant differences in theirtissuemi-
studiesfollowedthefirst reports of itsaccumulation in(26)
crodistributions provideinformative examplesforthisre- and effectiveness in controlling (27, 28) a non-melanotic
view. malignancy, the rat 9L gliosarcoma. BPA is transported
acrosstheblood-brain barrier intothenormal brain.Inboth
experimental animals and patients, averageconcentra-
the
BORON DELIVERY AGENTS
tionofboronin thenormalbrainis approximately equalto
Theinadequate tumor targeting of theboron compounds or slightlyless than that in the blood; but the averagecon-
used in theearlyBNCT clinicaltrialswas recognizedas centration ofboronintumor and
(glioma melanoma) is two
one of themajorfactorsin theunsuccessful outcomeof to fourtimeshigherthanin bloodandbrain(9, 22-24,26,
thosetrials.Searchesforbetter borondelivery agentswere 29-31). Thisdifference doesnotseemto correlate withthe
initiatedin the1960s.The aminoacidp-boronophenylala-mitotic activity. In ratliver that was after
regenerating par-
nine (BPA) and the sulfhydryl borane(Na2B12H,,SH,or tial hepatectomy, wherethemitoticindexwas similarto
BSH) weretwoofthecompounds evaluatedin thosestud- thatof the 9L tumor, the accumulation of BPA was the
ies. Development ofcompounds continues to be an active sameas in normalliverandthreeto fourtimeslowerthan
areaofBNCT research. However, giventhedegreeofchar- thatin thetumor(32). The biochemical rationaleforthe
acterization in
required, particular evaluation of toxicity preferential uptake of BPA in tumor is relatedto an ele-
andradiobiological studies, it would take severalyears for vated rate of amino acid transport at the tumor cell mem-
At
anynew compoundto entera clinicaltrial. thistime, brane. Analyses of kinetics in patients with either mela-
BPA and BSH are the only two boron compoundsin use noma or glioblastoma using18F-labeled BPA have shown
forclinical BNCT; hence much of thisreview will neces- thatthenetincorporation ratefortumorwas aboutfour
sarilyfocus on the radiobiologicalstudiesthathave been times that of normal brain (33-35). Intracellular boronwas
reportedforthesetwo agents.The approachesused to char- distributed uniformly across both and
cytoplasm nucleus,
acterizethesecompoundsshouldalso applyto neweragents as determined byionmicroscopy, afterexposureofcellsto
presentlyunderdevelopment. BPA in vitro(36-38) andin tissuefromratsinjectedwith
Figure1 showsthechemicalstructures ofBPA and BSH. BPA (39, 40). Boronwas detectedwithinthewalls of an
BPA was synthesizedin the late 1950s forpossible use in arteryat a concentration about1.7 timesthatin thesur-
BNCT (17). It was evaluated in the compoundscreening rounding normal brain (39). BPA also accumulates prefer-
effortsof the 1960s, butat thattimethefocuswas on com- entially in rat 9L tumor cells infiltrating thebrainaway
poundsthatwould accumulatein tumorsand not cross the fromthemaintumor mass,although theboronconcentra-
blood-brainbarrierinto the normalbrain. BPA was set tionin theisolatedclustersof tumorcells was onlyabout

THE RADIOBIOLOGY OF BNCT 3
50% ofthatobservedin themaintumor mass(39,40). The tributionof boronintotumorcellsinfiltrating intothenor-

ability of BPA to target tumor cells infiltratingthebrainis mal brainwerealso increased.Smithet al. havereported
a
presumablyconsequence ofits transport across theblood- in ratbraintumor models,however, that,evenwithdisrup-
brainbarrier. For highlyinfiltrative braintumorssuchas tionoftheblood-brain barrier,theboronconcentrations in
glioblastoma multiforme, theabilityoftheboroncarrier to clustersofinfiltratingtumorcellsarestillless thanthatof
crosstheblood-brain barrier may well be essential for ef- themaintumormass(40).
fectiveBNCT. Otherborondeliveryagentsare currently underevalu-
BSH was derivedfromthecompound testing efforts in ation.Mostprominent among these are the classes of li-
Bostonthatfollowedtheclosureof theU.S. clinicaltrials posomes and porphyrins. Compounds from both of these
in 1961(41). BSH was identified as a candidate forfurther classescan be loadedwithrelatively large amounts of bo-
preclinical evaluation in the U.S. and was chosen fora re- ron.The in vivouptakeofborondelivered to subcutaneous
newedclinicaltrialin Japan.BSH doesnotcrosstheintact EMT6 murinemammary tumors usinga unilamellar syn-
blood-brain barrier in thenormalbrain(42), butaccumu- theticliposomehasbeendemonstrated (53, 54). Theboron
latesin braintumors, due to thefactthatthebloodvessels concentration of =35 [Lgboron/g measuredin thetumor
in intracranial tumorslack a properly functioning blood- was encouraging. Potentially therapeutic levels of boron
brainbarrier. BSH has beenreported to be carriedin the havebeenreported in a rangeofmurine carcinomas using
bloodas a disulfide complexwithserumalbumin (43). Data severalboronated porphyrins (47, 55). However,theper-
fromanimaltumormodelshave shownthatthe tumor: formances ofthosecarriers in targeting gliomasandglioma
bloodboronconcentration ratiohas generally beenin the thenormalbrainhaveyetto be assessed.
cells infiltrating
range of 0.5:1 to 1:1 (44-47). In human glioblastoma, pub- An extensivereviewof the development of boroncom-
lishedvaluesfortumor-to-blood boronconcentration ratios is
pounds beyond scopethe of this paper.For recentre-
are somewhat higher. Hatanakaand Nakagawareported a viewson thissubjectsee refs.(14, 15).
tumor-to-blood ratioofabout2:1 at 17.5h aftertheendof The distributionpatterns ofBPA andBSH areverydif-
an intracarotid infusion of BSH in 39 patients treated by ferent,especiallyin the brain,wheretheblood-brain barrier
BNCT inJapan(6). Gabeletal. reported theresults ofBSH will keepBSH, butnotBPA, outof thenormalbrainpa-
biodistribution studiesfromfourcentersin Europe(48). renchyma. Thisdifference in biodistribution is reflectedin
The averagevaluesforthetumor-to-blood boronconcen- the biologicaleffectiveness factorsdescribedbelow.De-
tration ratiorangefrom1.3:1 to 2:1. Theserelatively low tailedstudyof thebiodistribution of new borondelivery
tumor-to-blood ratiossuggestthatpassivediffusion from agentsin tumor, andespecially in thenormaltissueswithin
bloodthrough an incomplete blood-brain barrier is thepri- theradiation field,willbe required priorto clinicaluse.
marymodeofaccumulation ofBSH in tumor. Finkeletal.
reported accumulation of BSH in thewalls of medium-
DOSIMETRICCHARACTERISTICS OF THE MIXED
sizedbloodvesselsin thebrainof a terminally ill patient
RADIATIONFIELD DURINGBNCT
withan anaplastic astrocytoma whohadbeeninfused with
BSH for24 hjustpriortodeath(49). BSH shouldnotcross Theneutron energiesinvolvedin BNCT aremuchlower
an intactblood-brain barrier.Ceberget al. reported, how- thanthosethathavebeenusedin fast-neutron therapy.The
ever,thatin theRG2 ratgliomamodel,BSH was takenup neutron capturereaction,
'0B(n,o)7Li,requires a neutron in
in distantmetastases. These authorspostulated thatBSH thethermal energyrange, i.e. <0.4 eV. Thermal neutron
entered thetumor the
through disrupted blood-brain barrier beamswereusedin theearlyBNCT trialsin theU.S. and
and diffused along the same white-matter tracts as the in- continueto be used clinicallyin Japan(6, 23). Thermal
tumor
filtrating cells (47). After exposure of cells in culture neutrons areattenuated
exponentially as a functionofdepth
to BSH, boronhas beendetectedin boththenucleusand in tissue,primarily in
by capture hydrogen. Thermalneu-
thecytoplasm. Zha et al. foundthenuclearboroncontent tronscatteringanddiffusionin tissuemakeitimpossible to
to be lowerthanthe cytoplasmic content(50), whereas collimate orlimitthebeamtothetumor region.One ofthe
Chandraet al. founda moreuniform distribution (38). In majorfactors totheclosureoftheearlyclinical
contributing
humanglioblastoma tissue,Otersenet al. reported boron trialsofBNCT in theU.S. was theinability ofthethermal
fromBSH tobe inboththecytoplasm andthenucleus(51) neutron beamsto delivertherapeutic neutron fluencesto
and to be firmly bound,whereasHaselsberger et al. re- deepbraintumors. As theseriousness ofthislimitation be-
portedtheboronfromBSH in humanglioblastoma tissue came morewidelyappreciated, higher-energy,"epither-
to be locatedonlyin thenucleus(52). mal" neutron beamsweredevelopedby moderation and
Disruption of theblood-brain barrier is reported to en- filtration
of thereactorfission-spectrum neutrons(16, 56,
hancethedelivery ofBPA andBSH to theF98 ratglioma 57). Whenepithermal neutrons penetratetissue,theyare
(45). By 2.5 h afterdisruption, theboronlevelsin thenor- slowedintothethermal energyrangeby collisionswith
mal brainhad declinedto thoseexpectedwithout disrup- atoms(primarily hydrogen) in tissueandarethencaptured
tion,buttheboronlevelsin thetumorremained elevated. morereadilybythe'IoBnucleus.Thus,compared to a ther-
Such an approachcouldproveusefulclinicallyif thedis- malneutron beam,an epithermal neutronbeameffectively

4 CODERREAND MORRIS
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...........:..
ug Beam
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.;.............
:.
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i I....~.......
i i/
..... ................
...i..i
??i
.....a.....
............;...
I I
0.1 ??~i~r
0.01.
10-1 7 9
0 1 2 3 4 5 6 8
InTissue(cm)
Depth
FIG. 2. Variationof thethermal fluencewithtissuedepth
neutron
usinga thermalor epithermalneutron
beam.
0 1 2 3 4 5 6 7 8 g 10 1112
Depth(cm)
generates thermal neutrons at depthin tissueandprovides
a relativesparingof the skin fromdamage by the FIG. 3. The variouscomponents of theepithermal neutronbeamat
1oB(n,a)7Lireactionproducts(Fig. 2). Using epithermal theBrookhaven MedicalResearchReactor(BMRR)alongthebeamaxis
fluences as a functionofdepthin tissue.Theborondosewas calculated assuming
neutrons, it is nowpossibleto delivertherapeutic
13ppm'0Bintheblood,theaveragevalueobserved todateintheclinical
of thermalneutrons at considerable depthsin the brain BNCT irradiations at theBMRR. (0) Totaldose; (V) '0B dose;(0) total
without the
reflecting scalp and removing a portion of the y-raydose; (0) nitrogen dose; (A) fast-neutron
capture dose.
skullas is required withthermal neutron-based BNCT.Ep-
ithermal neutron beamsare generally contaminated with
higher-energy fast neutrons. The following classificationof penetration rangeoftheinducedy raysfromthe'H(n,y-)2H
neutronenergieshas been generallyacceptedin BNCT thermal neutron capture reaction, butalso dueto additional
medicalphysics:thermal neutrons, E, < 0.4 eV; epithermal (butminor) dose contributions from y raysin theepither-
neutrons, 0.4 eV < Eepi < 10 keV; fast neutrons, Efat > 10 mal beam and from activationof the collimation andshield-
keV. ing material around the patient port. The recoil proton dose
Linearenergy transfer is a measureofthedensity ofthe fromthe'H(n,n')pfast-neutron-proton collisionis highest
ionizations producedas radiation penetrates tissue.The ra- at thesurfaceand decreasesexponentially as thefastneu-
diationfieldproduced in tissueduring BNCT consistsofa tronsareattenuated. The dose components shown in Fig. 3
mixture of components withdiffering LET characteristics.are all physicaldoses (Gy). Each of thehigh-LETcom-
In addition to thehigh-LETproducts ofthe'0B(n,O)7Lire- ponentsmustbe multiplied by an experimentally deter-
action,theinteraction of theneutron beamwiththenuclei minedfactor forrelative biologicaleffectiveness toexpress
of elements in tissuewill deliveran unavoidable, nonspe- thetotaldosein photon-equivalent units.The derivation of
cificbackground dose,froma mixture of high-and low- thesefactorsis thesubjectof thenextsection.The treat-
LET radiation components, to bothtumorand normaltis- mentplanning software inuse forclinicalBNCT musttake
sue.Thermalneutron capture byhydrogen releasesa y ray into consideration these dose components, thevariation of
the
through 'H(n,y)2H reaction. The capture of thermal neu- each component as a function of depth, and the relevant
tronsbynitrogen intissue,the14N(n,p)14Creaction, releases biologicaleffectiveness factors (58, 59).
a high-LETprotonwithan energyof 590 keV.Contami-
natingfastneutrons (thosewithkineticenergies>10 keV) BIOLOGICALEFFECTIVENESSFACTORSFOR THE
in theepithermal neutron beamproducehigh-LETrecoil
HIGH-LETBNCTDOSE COMPONENTS
protons withsimilaraverageenergy through collisionswith
hydrogen nuclei['H(n,n')preaction] intissue.Thedosere- Dose components withdifferent LET characteristics will
sultingfrom fast neutrons is highest at the skin surface and have of
varyingdegrees biological effectiveness with re-
decreasesexponentially withdepth. gardto tumorandto thevariousnormaltissueswithin the
To illustrate thecomplexity ofBNCT dosimetry, Fig. 3 treatment volume,suchas theCNS andtheskin.To express
detailsthevariouscomponents of theepithermal neutron thetotalBNCT dosein a common, photon-equivalent unit,
beam at the BrookhavenMedical Research Reactor enablingcomparison withconventional photonirradiation,
(BMRR) alongthe beam axis as a function of depthin fortumorand foreach of thenormaltissuesat risk,each
tissue.The depth-dose characteristics ofthecurvesforthe ofthehigh-LETdose components (physicaldosein grays)
'oB(n,a)7Liand the'4N(n,p)14Creactions are similar, each is multiplied by an experimentally determined biological
beingdependent on thethermal neutron flux.The totaly- effectiveness factor.The totalphoton-equivalent BNCT
raydosehasa broader depth-dose profile duetothegreater dose can thenbe expressedas thesumof thebiological

THE RADIOBIOLOGY OF BNCT 5
physicalabsorbeddose compo-
effectiveness-corrected ly defining thebiologicaleffectiveness of the'OB(n,ct)4Li
nents,usinga unitdefined as thegray-equivalent (Gy-Eq). reaction.RBE is usuallydefined as theratioofdosesofa
A measureoftheRBE forthehigh-LETcomponents of reference radiation(generallyX rays)toa testradiation that
thebeam(the590 keV protons releasedfromthermal neu- willproducethesamebiologicalendpointin a givensys-
troncapturereactionsin nitrogen and therecoilprotons tem.Measuredin thisway,theRBE is solelya function of
resultingfromthecollisionof fastneutrons in thebeam thequality(LET) of thetestradiation. In BNCT radiobi-
withhydrogen atomsin tissue)can be obtainedin theab- ology,measuredbiologicaleffectiveness factorsforthe
senceof boronby comparing theneutron beamdose with component of thedose fromthe'0B(n,at)7Lireaction have
theX-raydose sufficienttoproducean isoeffect in a given insteadbeen termedcompoundfactor(65) or compound
biologicalsystem. Because theirenergies tend to be in the biologicaleffectiveness (CBE) factor(cf. 66). The term
samerange,theuniformly distributed ofthenitrogen
effects CBE factorwillbe usedthroughout thisreview.
captureprotonand thefast-neutron recoilprotonaremost Experimentally, the CBE factor
can be evaluatedbyfirst
convenientlymeasured as a combined "protondose". In comparing the effectof thebeam alone to theeffect of a
thisdiscussiontheendpointwillbe referred to as a 50% reference radiation X
(generally rays) to obtainan estimate
effectivedose(ED,,o).Theresultcanbe expressed as inEq. of thebeamRBE or of thehigh-LETcomponents of the
(1), whereED50ois thephysicalabsorbed dose which results beamas described abovein Eqs. (1) and(2). Thermal neu-
in a 50% incidenceofthebiologicalendpointundereval- tronirradiation, withboroncompound present,with total
a
uation,assuming thatthebeamdosecomprises a y-raydose dose producing thesameEDsoendpointis represented by
plus a combinedprotondose as describedaboveand that Eq. (3). SolvingEq. (3) fortheCBE factorproducesEq.
theRBE ofthey-raycomponent is 1. (4).
RBE] + [y-raydose]
["proton"ED5o]["proton" X-rayEDso
= X-rayED50o of EDo0][BeamRBE]
= [Beamcomponent
(1)
ofEDso][CBEfactor]
+ [IoB(n,a)7Li component
The RBE of thecombinedeffectof thehigh-LETbeam
components (protonsfromnitrogen capturereactionsand (3)
protonsfromfastneutron recoils)is determined by sub- CBE factor
tractionofthey-raycomponent attheED50from bothsides
of Eq. (1) andrearrangingas in Eq. (2). S{ [X-rayED50]- [Beamcomponent
of
ED50o
X-rayED50o
- y-raydose x [BeamRBE]}
protonRBE = (2) + [IoB(n,Co)7Licomponent
protonEDso ofED50] (4)
The effectiveness of BNCT is relatedprimarily to the Therehavebeenseveralexperimental measurements of
selectiveaccumulation of theboroncarrierin thetumor CBE factors forthe1oB(n,a)7Li reaction products in vitro.
relativeto thesurrounding normaltissues.Theremustalso CBE factorsof 3.7 forHeLa cells (67) and 3.3 forB16
be a sufficientlevel of '0B presentforthetumorcells to melanomacells (68) werereported: Bothusedboricacid
sustaina lethalradiationdosefromthe'0B(n,ca)7Lireaction. as the boron carrier.The shortpath lengthsof the
The minimum requirement foreffective BNCT has been 'OB(n,ac)7Li reactionproducts complicated theestimation of
estimatedto be - 109 10B atoms distributed uniformly thedosetocellsirradiated as monolayers attached toplastic
throughout a tumorcell (60). The shortrangesof thetwo culturedishes.A number of assumptions wererequired in
high-LETproducts of the reaction
1oB(n,ca)'Li (cL particle, theestimationof thedose to individual cells. Gabel et al.
1.47 MeV,range9 ptm,averageLET = 196 keV/Lm;Li irradiated
Chinesehamster V79 cells in suspension with
0.84
nucleus, Apm, MeV,range 5 average LET = 162 keV/ boricacid and calculateda CBE factor of 2.3 relative to
makethemicrodistribution oftheboronrelative tothe 250 kVp X rays(69). All threeof thesein vitrostudies
pxm)
targetcell nucleiof criticalradiobiological significance. usingboricacid assumeda uniform borondistribution be-
MonteCarlosimulations haveshownthatboronlocatedin tweenthemediumand thecells, and no selectiveaccu-
thenucleusis moreeffective thanborondistributed in the mulation of boronin thecells.A homogeneous borondis-
cytoplasm, whichis in turnmoreeffective thanboronat- tribution fromboricacid shouldproducea CBE factor that
tachedto thecell membrane (61-64). Thusboronmicro- is relatively freeoftheinfluences ofbiodistribution ofthe
localizationfactorsdetermine thebiologicaleffectiveness compound. In theabsenceofotherdata,thisCBE factor of
of the'0oB(n,a)7Lireaction. The dependence ofthebiolog- 2.3 was used by otherBNCT investigators forestimating
on variations
ical effect in themicrodistributionofdifferent thephoton-equivalent dose withotherboroncompounds
boroncompounds, and of the same boroncompoundin and in otherbiologicalsystems, in particular, in vivoirra-
differenttissues,makesthetermrelativebiologicaleffec- diationsofexperimental tumors, e.g. (20, 27). It was later
tiveness(RBE), as generally understood, inadequate forful- noted,however, thatwhentheCBE factors andRBE values

generally acceptedat thetime[2.3 for'0B(n,at)7Li,2.0 for overallbiologicaleffect.The modeof compoundadmin-

fastneutrons and2.0 forthe'4N(n,p)14Creaction] wereused istration, theborondistribution pattern withinthecell and
toplotsurvivalcurvesforB 16 melanoma cells,after either withinthetissue,thedose perfraction, and eventhesize
invitroirradiation orinvivoirradiation andcolony-formingofthenucleusinthetarget cellpopulation all mayinfluence
assay in vitro, as a function of photon-equivalent dose theexperimental determination ofa CBE factor.Itis critical
("Gy-Eq"), the curves could not be superimposed on the thatexperimental determinations of CBE factors be done
data forX rays,whichby definition they must (70, 71). under conditions that approximate the clinical situation as
Experimental measurements of CBE factors forboric acid, as
closely possible. The discussion in the section below on
BSH andBPA inrat9L gliosarcoma cellsirradiated invitro thecentral nervoussystem illustratesthedependence ofthe
or in vivowerereported using 250 X
kVp rays as the ref- measured CBE factor on experimental conditions.
erenceradiation (72). Comparison of theBNCT doses to
theX-raydosesthatproducedsurvivals of 10, 1 and0.1%
NORMALTISSUE RESPONSETO BORONNEUTRON
produced CBE factors in the range 3.4-2.8 forBSH and
CAPTUREIRRADIATION:SKIN
boricacid, butunrealistically highvaluesof 9.8-6.7 for
BPA (72). In theabsenceof accuratemethods to measure Dependinguponthedose, irradiated skinmayexhibit
intracellular
boronconcentrations at thetimeofirradiation, one or morecharacteristic radiation effects which,in order
equal distribution of BPA betweenthe mediumand the ofincreasing severity,includeerythema, drydesquamation,
cellswas assumedin thedose calculations, an assumption epilation, moistdesquamation and,finally, dermalnecrosis.
questioned at thetime.Subsequently, theintracellular con- Singledosesof 18 Gyproducemoistdesquamation, which
centration of BPA in rat9L gliosarcomacells has been is generally considered to indicatethetolerancelimitin
shownto be overthreetimesthatin thesurrounding me- clinicalradiotherapy (74). Singledosessubstantially larger
dium(73). Whenthisaccumulation effect is takenintocon- than18 Gy resultin criticaldamageto thevasculature in
sideration,therevisedCBE factorforBPA fallsintothe the underlying dermisresulting in dermalnecrosis.De-
samerangeobservedforboricacid andBSH (3.4-2.8). pendinguponthephotonenergy, themaximum tolerance
It is well established thatRBE will varyas a function dose forhumanskin(dermalnecrosisend point)aftera
of dose,withhighervaluesat lowerdoses.This apparent singleexposureis estimated torangefrom22.5 to 30.0Gy
increaseinRBE is related tothe"shoulder"onthesurvival (75).
curveforthelow-LETreference radiation and theability Thereare relatively few reportsof skintoleranceto
ofthelow-LETreference radiation torepairdamageatlow BNCT (Table 1). For thermal neutron beams(whichmay
doses.The samecan be expectedof CBE factors-avari- containcontaminating fastneutrons as well as y-raycom-
ationof the derivedvalue as a function of dose. In the ponents), RBE valuesin therangeof2.7 to 3.9 havebeen
experiment described above(72), therewas indeeda vari- determined (76, 77). Thesereports alsodescribed CBE fac-
ationoftheCBE factor withdose.Thecalculations ofCBE torsforsodiumpentaborate, thecompoundused mostin
weredoneusingdosesthatproduced10, 1 and 0.1% cell thefirst BNCT clinicaltrialsat BNL, of2.3 and 1.9 inpig
survival, whichcorrespond toX-raydosesofapproximately skinandrabbitskin,respectively. A CBE factor of2.4 was
10, 16 and 20 Gy in vitroand 8, 16 and 24 Gy in vivo. reported forBPA in hamster skin(78). The resultsof ir-
Thesesingle-fraction dosesarerelatively large,andthesur- radiations of dogswithepithermal neutrons at theBMRR
vivalcurvesforX raysarenearlylinearinthisregion. Thus indicatedan RBE (moistdesquamation as theend point)
thereis notas largea variation inthemeasured CBE factor forthecombinedhigh-LETcomponents of thebeam[fast
as wouldbe expectedifthecomparisons weremadeatlow- neutrons andtherecoilprotons fromthe'4N(n,p)14Creac-
erdoses.TheCBE factors at 10, 1 and0.1% survival[mea- tion]of 3.0 anda CBE factorforBSH of0.5 (79).
suredin vitroafterirradiation in vivo(72)] were4.0, 3.8 The responseof ratskinto BNCT usingBPA or BSH
and 3.6, respectively. The CBE factorforBPA in tumor has beenreported usingthethermal beamof theBMRR
tissueof3.8 thatis currently beingusedintheBNL clinical (66). Figure4 shows the data for the time-dependent
trialis theaverageof thethreevaluesmeasured in thein changesin skinobserved after increasing levelsofexposure
vivolinvitrosystem (72) described above.TheCBE factors to thethermal beamaloneor in combination withBPA or
were derivedunderconditionswhichare not dissimilar BSH. Notethebiphasicresponse;theacutereactions were
fromtheclinicalsituation, interms ofboronconcentrationscharacterized by erythema and moistdesquamation at the
in tumorandblood,andthemagnitude ofthesingledoses higherdoses. The onsetof the acuteskinreactionswas
employed. BecauseclinicalBNCT to dateis administered about11-21daysafter irradiation. Allskinfieldswerefully
in largesingledoses,thevariation ofRBE or CBE factors healedby 36 daysafterirradiation. The secondwave of
as a function of dose is nottakenintoaccount.If BNCT skinbreakdown (dermalnecrosis)was firstobserved24-
wereto be administered in a largenumberof smalldose 25 weekspostirradiation; thepercentage incidence was re-
fractions,thenthissituation wouldneedtobe reconsidered. latedto thedose. Healingat higherdose levelswas pro-
In summary, the way thatCBE factorsare measured tractedand was complete42-43 weeksafterirradiation.
meansthata numberof variableswill contribute to the Epilationwas observedin all skinfields.Thesedatahave

THE RADIOBIOLOGYOF BNCT 7
TABLE 1
Relative Effectiveness
Biological (RBE) and Compound Effectiveness
Biological (CBE) FactorsCalculated
for
Skin(In Vivo)afterSingle-Dose
Neutron CaptureIrradiation
Irradiation Tissue RBE CBE factor Reference
Thermalbeam Ratskin(MD)a 3.5 ? 0.2 - 66
Thermalbeam Rabbitskin(MD) 2.7 - 77
Thermalbeam Pig skin(MD) 3.9 - 123
SPb + thermal
beam Rabbitskin(MD) 1.9 77
SP + thermal
beam Pig skin(MD) 2.3 123
BPA + thermalbeam Ratskin(MD) - 3.7 ? 0.7 66
BPA + thermalbeam Ratskin(DN) - 0.73 ? 0.42 66
BPA + thermalbeam Hamster skin(MD) 2.4 78
BPA + thermalbeam Humanskin(MD) 2.5 24
BSH + thermalbeam Rat skin(MD) - 0.55 ? 0.06 66
BSH + thermalbeam Ratskin(DN) - 0.86 ? 0.08 66
BSH + epithermal
beam Dog skin(MD) 0.51 124
BSH + epithermal
beam Dog skin(DN) 0.52 124
aMD = moistdesquamation;
DN = dermalnecrosis.
b Sodiumpentaborate.
allowedcalculations of RBE and CBE factors(66). The whichcouldbe relatedto structural

differences
in thear-
CBE factors forBPA withmoistdesquamation anddermal chitecture
ofthevascularsupplybetweentheloose skinof
necrosisas theendpointswere3.7 ? 0.7 and0.73 ? 0.42, ratsandthefixedskinofhumans.
respectively.The CBE factors forBSH withmoistdesqua-
mationanddermalnecrosisas theendpointswere0.55 ?
0.06 and 0.86 ? 0.08, respectively. RESPONSEOF NORMALTISSUE TO BORON
Evidently,themicro-
distributionofthesetwocompounds NEUTRONCAPTUREIRRADIATION:THE
hada profound effect
on theCBE factors. The aminoacid BPA mayaccumulate CENTRALNERVOUSSYSTEM
inthebasalstemcellsoftheepidermis. Thiswouldaccount Giventhehistorical andpresent focusofBNCT ontreat-
fortheveryhighCBE factorformoistdesquamation ob- mentofbraintumors (primarily glioblastoma multiforme),
servedforBPA. Forthedermalnecrosisendpoint,where evaluations oftheeffects ofradiation onthecentral nervous
thevascularendothelial cellsrepresent thelikelytarget,the system (CNS) assumecentral importance. Thedevelopment
CBE factors forBPA andBSH werecomparable. Prelimi- of late changesin the CNS afterradiationexposurehas
naryobservations usingneutron autoradiography suggest traditionallybeendescribed in termsofdamageto specific
thatBPA andBSH havea similarmicrodistribution at the targetcell populations, theloss ofwhichis responsible for
levelofthedermis(Morris, unpublished). The clinicalim- specificfunctionaland histopathologically identifiable
plicationsofthesefindings arethat,perunitboronconcen- typesof injury.Conflicting theories considerthevascular
tration,BSH-mediated BNCT is less damaging to theepi- endothelial cell or elementsof theCNS parenchyma, or
dermisthanis BPA-mediated BNCT,and thatBNCT with both,to be thecriticaltarget cells(80-86). Morerecently,
thesetwocompounds is aboutequallydamaging totheder- radiationdamagetothevasculature during BNCT hasbeen
mis. showntobe theprobablecauseofnecrosisin theratspinal
The biologicaleffectof BPA-basedBNCT of human cord,suggesting thatthevascularendothelium is thepri-
malignant melanomausingthermal neutrons has produced marytarget of radiation in the CNS (87, 88).
important information on the effect of thistreatment on The shortrangesof the high-LETproductsof the
humanskin(24). Based on boronmeasurements in blood o1B(n,o)7Lireactionmakelocalizationof theboroncom-
and skin,theseinvestigators estimated theboronconcen- poundand thegeometry of blood vesselirradiation (i.e.
trationin theskinat thetimeof BNCT to be between1.3 microdosimetry) important. The smallestcapillaries in the
and 1.5 timestheconcurrent levelintheblood.Thethresh- brainhavean internal diameter of about8 pimand a wall
old formoistdesquamation in humanskinaftera single thickness of 0.1 to 0.3 The rangeof theparticles(5
dose ofphotonswas takento be 18 Gy.By comparing the pxm.
lim and 9 pimforthe7Li and ct particles, respectively)
calculateddosesto theskinandtheobservedincidence of releasedfromthe o1B(n,at)7Lireactionis suchthatsome
moistdesquamation, theseauthors wereabletoestimate the capture eventsinthevessellumenwilldeposittheirenergy
biologicaleffectiveness factorforthecombinedeffects of outsideof thevessel.Based solelyon geometry, Rydinet
thenitrogen reaction
capture andtheboronneutron capture al. showedthatthefraction of thedose receivedby the
reactionas approximately 2.3 to 2.5. This valueis some- vesselwall was one-third to one-fifth thatdelivered to an
whatlowerthantheCBE factorof 3.7 measured forBPA infinitepool of blood,depending on thediameter of the
withmoistdesquamation ofratskinas theendpoint(66), vessel(89). Theimplications ofthesestudieswerethat,for

8 CODERREAND MORRIS
100o-
attenuation of the'0B(n,c)7Li dose in thebloodvessellu-
80 a men and the predominant exclusionofBSH fromtheCNS
parenchyma are the majorfactors resulting inthelow CBE
60 factor forBSH in theCNS described below.In thecase of
BPA, wheretheboronconcentrations in thebloodvessel
40 lumenand thesurrounding brainparenchyma are similar,
20 there is a contribution to the total dose received by the
endothelial cell nucleus from the boron within the endothe-
lial cell and fromthesurrounding parenchyma. This geo-
0 10 20 30 40 50
0 metrical sparing effectbasedonvesseldiameter shouldalso
"a
pertain tovesselsin anynormal tissue,butitis accentuated
S 100
o b in theCNS, wheretheintactblood-brain barrier can keep
(some) boron compounds out of the normal brain paren-
. soo
The
chyma. microdosimetry of BNCT is an active area of
o I
research; interested readersare directed to a recentreview
x Io
(90).
u, The ratspinalcordmodelhas beenusedto quantify the
l
20
biological effectiveness of BNCT in the normal CNS (91-
0 93). The late radiation-induced effects seen in thespinal
C)
0 10 20 30 40 50 cordaftera singlefraction of BNCT are similarto those
seenin thebrain(87, 94-96). The sensitivities of therat
100
brainand spinalcordto fractionated irradiation are also
comparable (97). The end point of limb paralysis(myelo-
paresis)fortheevaluation oflateradiation-induced damage
tothespinalcordis clearlydefined, whilehistopathological
and histomorphometric end pointsused to assess damage
40
to thebraincan be difficult to quantify.
The physicaldosecontributed to theCNS by1oBduring
BNCT is a function oftheneutron fluence andthe10B con-
centration inbloodandintheparenchymal tissuesurround-
0 10 20 30 40 50
ing the blood vessels. The dose contribution fromthe
TimeafterIrradiation (weeks) 'oB(n,ac)7Li reaction is routinely calculated based on the
FIG. 4. Time-related changesintheincidence ofratskinbreakdown blood 'oB concentration during the course of the irradiation.
afterirradiationwiththethermal neutronbeamalone,incombination with No directaccountis takenof theIoB content of theCNS
BSH, and in combination withBPA. Panel a: Thermalneutron beam parenchyma or the blood vessel endothelial cellsinthedose
alone:totaldosesof 10.8(A), 12.9(*), 15.1(e) and 17.2Gy(I). Panel calculations. Thisis due to thefactthatit is notpossible
b: Thermalneutron beamin combination withBSH: totaldosesof 51.5
atpresent toestimate CNS tissueconcentrations of'0B dur-
(0), 56.1 (0) and67.7 (A) Gy.Panelc: Thermalneutron beamin com-
bination withBPA: totaldosesof 12.5(0), 16.7(V), 20.9 (A) and24.3 ing the course of BNCT irradiation. Noninvasive imaging
(*) Gy.Reprinted fromref.(66) withpermission. techniques arecurrently underdevelopment to achievethis
objective(33-35, 98). The physicalabsorbeddose deliv-
eredtotheCNS is therefore described interms ofthephys-
equalboronconcentrations in tumor andblood,andno bo- ical dose deliveredto theblood,and the CBE factoris
ronin thenormalbrain,thebloodvesselsreceivesubstan- defined so as tobe themultiplicative factor thattransforms
tiallyless dose thanthe tumor.In BNCT, theionization theblooddose intothebiologically effective dose.Exper-
energyfromthe '0B(n,o)7Li reactionthatreachesthenu- imentally derivedCBE factorsmustnevertheless be used
cleus of thevascularendothelial cell is dependent on the withcautionin clinicaltreatment protocols. The biodistri-
distribution of theparticular boroncompound. The differ- butionprofile of a givenborondelivery agentneedsto be
ing distribution patterns of BPA and BSH have a profound characterized as as in
thoroughly possible therelevant an-
effecton theradiation response of the CNS. With BSH, imal models and in human In
patients. particular, vas-the
whichdoesnotcrosstheblood-brain barrieranddistribute cular:nonvascular 1oBpartition ratioin theanimalmodel
in theCNS parenchyma, damage to the endothelial cells used to derive the CBE factor must be similarto theratio
lining the walls of blood vessels comes primarily from the in patients atthetimeofirradiation. It mustbe emphasized
high-LETparticles producedby theneutron capturereac- thatcomparability ofbiodistributions ofloBis a prerequisite
tionsoccurring inthelumenofthevessel.Theparenchymal to translating a CBE factorderivedfroman animalmodel
tissueelements oftheCNS receivea relatively smalldose totheclinicalsituation. AtthelowdosesofBPA (250-290
ofradiation dueto thelimited range of theseparticles. The mgBPA/kg bodyweight)currently in use intheBNL clin-

TABLE2
Relative Effectiveness
Biological (RBE) and Compound Effectiveness
Biological (CBE) FactorsCalculated
for
theCentralNervous
Systemafter or
Single-Dose Fractionated
NeutronCaptureIrradiation
Irradiation Tissue RBE CBE factor Reference
Thermalbeamprotoncomponent (singledose) Ratspinalcord(myeloparesis) 1.80 - 91
beamproton
Epithermal component (singledose) Dog brain(brainnecrosis) 4.40 - 96
BSH + epithermal
beam(singledose) Dog brain(MRI changes) - 0.27-0.49 96
BSH + epithermal
beam(singledose) Dog brain(brainnecrosis) - 0.37-0.55 96
BPA + epithermal
beam(singledose) Dog brain(MRI changes/brainnecrosis) 1.10 96
Thermalbeam(singledose) Ratspinalcord(myeloparesis) 1.40 ? 0.04 - 91
BSH + thermalbeam(singledose) Ratspinalcord(myeloparesis) - 0.53 ? 0.03 113
BPA + thermalbeam(singledose) Ratspinalcord(myeloparesis) - 1.33 ? 0.16 91
BPA + thermalbeam(singledose) Ratspinalcord(myeloparesis) - 1.34 ? 0.13 93
Thermalbeam(2 fractions) Ratspinalcord(myeloparesis) 1.76 ? 0.03 - 93
BSH + thermalbeam(2 fractions) Ratspinalcord(myeloparesis) - 0.60 ? 0.04 113
BPA + thermalbeam(2 fractions) Ratspinalcord(myeloparesis) - 1.70 ? 0.20 93
Thermalbeam(4 fractions) Ratspinalcord 2.46 ? 0.10 - 93
BSH + thermalbeam(4 fractions) Ratspinalcord - 0.81 ? 0.06 113
BPA + thermalbeam(4 fractions) Ratspinalcord - 2.46 ? 0.29 93
Notes.Fractionated indicate? SE.
wereequalin size andspaced24 h apart.Errors
exposures
ical trial,thedistribution of IB in thehumanbrainis sim- thanthosein current use. Theseexperimental dataempha-

ilarto thatmeasuredduringradiobiological studiesin the size the importance of thorough preclinicaland clinical
rator dog fromwhichtheclinicalCBE factors wereesti- biodistribution studiesin protocols involving escalationof
mated(9, 30). thedose of a boroncompoundor an alteration in thein-
The CBE factorsthathave beenmeasuredexperimen- fusionschedule. In addition,
thedependence ofCBE factors
tally(Table2) reflect thedifferent biodistributions of the on experimental conditions makesitcritical thatstudiesin-
boroncompounds andthegeometric attenuation effects in tendedto provideCBE factors forclinicaluse be designed
thebloodvessels,as discussedabove.In thecase ofBSH, to approximate theclinicalsituation as closelyas possible.
usingmyeloparesis in the rat as the end point, the CBE The RBE of the thermal-beam component of thetotal
factorwas calculatedat 0.53 ? 0.10 (91). This value is radiation dose mustbe takenintoconsideration in thecal-
approximately threetimes lower than thatfor BPA (1.34 ? culation of the CBE factor (see Eq. 4). Studies withthe
0.13) at a comparable blood 1oB concentration of -20 pLg BMRR thermal beam using therat spinal cord model in-
'0B/g, as would be predicted from the different biodistri- dicatedan RBE value of 1.4, the"fulleffect" (91). In other
butioncharacteristics of thesetwocompounds. In theder- words,the"fulleffect" RBE was derived usingthethermal
ivationof CBE factors forpotential use in clinicalproto- beamas theonlycomponent oftheradiation dose,i.e. with
cols, it is advisableto use a widerangeof bloodIoBcon- no boronpresent.Withboronpresent, thethermal-beam
centrations. Such studiescarriedoutusingBSH indicated component of thedose requiredto producetheparalysis
thattheCBE factorremained constant at about0.5, with endpointis reduced.This"fulleffect"thermal beamRBE
blood'oB levelsin therangeof20 to 120[pg/g (99). How- value has beenused to represent thebiologicaleffective-
ever,progressive escalationof thedose of BPA to deliver nessofthe"partialeffect"ofthethermal-beam component
blood '0B concentrations in therangeof 20 to 90 Vag/g ofBNCT irradiation modalities.The "partialeffect"refers
resulted in CBE factors thatvariedfrom0.66 to 1.34(92). to thethermal-beam component ofthedosewhenboronis
Spinalcordirradiations tookplace 1 h after theadministra- present. The partialeffect, by involvesconsid-
definition,
tionoftheBPA. Atthistime,majordifferences werefound erablysmallerdoses thanthefulleffect.However, it has
in therelativedistribution ofIoBin thebloodandtheCNS beenestablished thattheRBE ofhigh-LETradiation, such
parenchyma, such that at the highest blood I'B concentra- as fast
neutrons, increasesas thedose per fraction decreas-
tion(90 pRg/g), ratiosof thelevelsof IB in thebloodand es, comparedwith250 kVp X rays,forthesame "partial
CNS parenchyma werea factorof 3.5 higherthanat the effect".This phenomenon has beenwell documented for
lowestblood IoB concentration (20 pg 'OB/g). This major fastneutrons (100-102) and the BMRR thermal neutron
changein thepartition ratioof'0B was responsible forthe beam(92) usingtheratspinalcordmodel.CBE factors for
observedvariations in thecalculatedCBE factors at differ- BPA andBSH haverecently beenrecalculated taking into
entconcentrations of '0B in theblood(92). In theclinical accountthechangingRBE of thethermal neutron beam
situation, BPA is administered moreslowly(2 h i.v. infu- withtheuse ofsmallerdosesperfraction (92). In all cases,
sion),and as a resultit is unlikely thattherewouldbe a therecalculated CBE factors arelowerthanthosepublished
pronounced change in the '0B concentration ratio between previously (91, 99). However,froma clinicalperspective,
thebloodand theCNS parenchyma at higherBPA doses itis inadvisable tousetherevisedCBE factors indose(Gy-

10 CODERREAND MORRIS
factorsare in agreementwiththevaluesderivedindepen-
dentlyfrom the ratbraintumor(72) and spinalcord(91)
70 models.
BORONNEUTRONCAPTURETHERAPYOF
EXPERIMENTAL TUMORS
6Q Experimental
in a variety
studiesusingBNCT havebeencarriedout
of animaltumormodels.Mouse sarcomasim-
.....
.,. plantedsubcutaneously
dictableregularity
thethermal
on thethighwerecuredwithpre-
usingBNCT withsodiumpentaborate
beamof theBMRR (106). BPA-basedBNCT
at
has been shownto inhibitthegrowthof melanomawith

highcureratesin mice,hamsters and pigs (18, 20). BPA
hasalso proveneffective inBNCT studieson hamster mel-
anomaxenografts in therabbiteye (107). The firstsuc-
FIG. 5. Isodosecontoursforirradiation
of thedog brainin theepi- cessfultreatments of an experimental braintumor(rat9L
thermalbeamusinga 5-cmx 10-cmfieldcentered overthelefthemi- gliosarcoma) were carried out by Joel et al. in the late
Note
sphere. theattenuation
of thefluence
as a functionof in
depth tissue, 1980s (108) using the dimeric form of BSH incombination
andthelateralspreadof thebeamdue to scattering. withthermal neutrons at theBMRR. Thiswas followedin
1992 by another studyinvolving thefirsttreatment of the
rat9L gliosarcoma withBPA-mediated BNCT (27). These
Eq) calculations. This is becauseat presentthereare no experiments wererepeated in 1994usinga vastlyimproved
accurately determined values forRBEs of epithermal neu- BPA deliverysystem with long-term survivallevels ap-
tronbeamsovera widerangeofdose levels. proaching 100% (28). Additional work bySarisetal. (109)
Studiesof thetolerance of thedog brainto single-frac- usingthemurine GL 261 gliomaandbyMatalkaetal. (22)
tionBNCT havebeencarriedoutusingepithermal neutron usingcellsof a humanmelanomacell line(MRA 27) im-
beamsat theBMRR andattheHighFluxReactoratPetten plantedin thebrainof nuderatsalso demonstrated theef-
using either BPA or BSH infused prior to irradiation (96, ficacy of BPA-mediated BNCT. More the
recently, prefer-
103, 104). Fike et al. reported an ED50o forbrainchanges entialuptakeof BPA andBSH by theratF98 gliomahas
detectable by computedtomography of 12.8 Gy and an been enhancedconsiderably by disruption of theblood-
for of
ED50 lethalbrainnecrosis 14.9Gy in dogsafteruni- brainbarrier withintracarotid injectionof mannitol (110,
formirradiation of one hemisphere with4 MeV X rays 111). Dramaticimprovements in inhibition of growthof
(105). Theattenuation oftheepithermal neutrons as a func- F98 tumorswereobservedin subsequent BNCT studies,
tionof depthproduceda nonuniform dose acrossthedog usingeitherBPA or BSH, whencombinedwithdisruption
brain(Fig.5). TheBNCT dosesusedforcomparison tothe of theblood-brain barrier(45).
published dataforX raysweredefined as theaveragephys- WhiletheCBE factorsin theCNS forbothBPA and
ical dose(Gy) in thevolumeofthedogbrainthatreceived BSH are fairlywell defined, the CBE factorsforuse in
between90 and 100% of themaximum braindose. This estimating thedose to tumorare muchless certain.With
corresponds to a volumeofabout30 cm3, orabout20% of BPA, a CBE factor of 3.8 (range3.6-4.0 forsurvivalfrac-
thebrainvolumeof a dog. Thereare differences in the tionsof 10, 1 and 0.1%, respectively) was derivedin the
volumesand dose distributions betweenthe X-rayand 9L ratgliosarcoma modelusingan in vivo/lin vitroclono-
BNCT experiments, but the volumesreceivingthe pre- genicassay whereintracranial tumorswereirradiated in
scribeddosesarerelatively large,andpotential volumeef- situ,surgically removedimmediately afterirradiation,and
fectson theED50can be excluded.Two end pointswere plated forcolony-forming assay (72). A CBE factorin the
scoredas a function of theincreasing BNCT dose: abnor- 9L gliosarcomaof 1.2 forBSH is based primarilyon the
malitiesnotedonMRI scansandsevereneurological deficit published value for the oxidized dimeric form of BSH
requiring euthanasia. The RBEs and CBE factorsof the (BSSB). The CBE factorsdeterminedfor both BSH and
varioushigh-LETdose components of BNCT weredeter- BSSB in vitrowere the same (72). Additionalexperiments
minedbycomparing effects on thenormal braintothepub- (Coderre, unpublished)with BSH indicatedthat the cell
lisheddataforhemispheric irradiation with4 MeV X rays survivaldeterminedin the in vivolinvitrocolony-forming
(105). The RBE valueforthehigh-LETcomponents ofthe assay was indistinguishablefromthat of BSSB. BSSB-
beams[fastneutrons andthe'4N(n,p)14Creaction] was3.3. based BNCT producedapproximately50% long-termtu-
The CBE factorsderivedfromthedog experiments were morcontrolafteronlyabout3 logs of cell killing(i.e. by
thesame forbothend pointsand were 1.1 forBPA and reducingthe numberof clonogenictumorcells to 0.1% of
0.3-0.5 forBSH (96, 103, 104). These RBEs and CBE thatmeasuredin controls)as measuredin the in vivolin

40
vitrocolony-forming assay.It is postulated
thattumor con-
trolwithBSSB mightbe due to vasculardamagerather
thandirectkillingoftumor cells(72). Ifthisis correct,
and 30 -
ifthisalsopertainstoBSH-basedBNCT,thequestion arises
as to theapplicabilityof a CBE factorderivedin an assay
of tumorcell killingif thein vivotargetis primarily the
20
tumorvasculature and tumorcontrolis an indirect effect.
Ideally,CBE factors forBPA and BSH shouldbe derived
using survivaldata, thishas beendifficult
but withthe9L
gliosarcoma due to thenormal tissuecomplications result-
ing from the largesingle fractions of X rays needed to
controlthistumor. 10
1 2 3 4
FRACTIONATION Numberof Fractions

Standard photonradiation therapy forglioblastoma mul- FIG. 6. Log-logplotoftheED,,oformyelopathy as a function
ofthe
tiforme is usuallydelivered indailyfractions number of fractionsof X rays(U), thermal
neutrons
alone(A), thermal
(5 days/week)
neutronsinthepresence ofBPA (*), orthermalneutrons inthepresence
of 1.8 to 2.0 Gyto a cumulative doseof55-60 Gy.BNCT, of BSH (0). Adaptedfromref.(93). The dataforX raysaretakenfrom
on theotherhand,has generally beendelivered in a single refs.(125, 126). Errorbarsrepresent thestandarderrorof themean
fraction. Some of theconsiderations thatjustifyfraction- (?SE). Errorbarsnotshownarecontained within
thesymbol.
ationof conventional therapy are clearlynotapplicableto
BNCT Givenboronconcentrations in therangeof 20-30
jig '0B/g, 85 to 90% of the totalGy-Eqdose to thetumor notbe entirelyapplicabletoglioblastoma multiforme. Thus
willbe fromhigh-LETradiations. Tumorhypoxiaand tu- thestudyin ratsdoes notnegatetherationale fortesting
morcell cycle-dependent radiation sensitivityare of rela-
fractionatedBNCT clinically. To date,clinicalBNCT for
tively minor importance in BNCT-mediated tumor control. or
glioblastoma malignant melanoma hasusuallybeengiv-
In thetumor, theissueof repairbetweeneach fraction of
en in a singlesession.Therecould be disadvantages to
radiation is largelycircumvented. In an epithermal neutron
repeated administrations
of BPA-F (or ofanother boron de-
beamat depthin thenormalbrain,they-raycomponent of
liveryagent)formultiple-fraction BNCT suchas reduced
thetotaldose can be as highas 40-50%, dueprimarily to
uptakeby tumorcells aftereach BNCT session,thepos-
thecaptureof thermal neutrons by hydrogen in tissueand
sibilityofincreaseduptakeofBPA bythenormal braindue
thereleaseof a y rayfromthe 'H(n,y-)2H reaction. Frac-
to radiation-inducedinflammation ortoperturbed endothe-
tionation wouldbe expectedto be of benefit in allowing and retargeting
lial integrity, to othernormaltissuessuch
fortherepairof photon-induced sublethal damageas well as mucosaor glandular tissues.Therecouldalso be risks
as allowingforrepopulation ofrapidly growing normaltis-
associatedwithsingle-fraction BNCT.Deliveryofa tumor
sues in thetreatment fieldsuchas mucosaor skin.Retar- control doseina singlefraction could,inprinciple, produce
getingof boronto a new subsetof tumorcells duringa tumornecrosisand thereby brainedemaandincreased in-
fractionated BNCT regimen couldbe usefuldueto thede- tracranial Forthisreason,surgicaldebulking
pressure. sev-
pendence of the dose distribution fromtheo1B(n,ot)7Li re-
eral weeksbeforeBNCT has been a requirement of the
actionon thedistribution oftheparticular boroncompound BNCT clinicalprotocols thatbeganin theU.S. in 1994.
at thecellularand subcellular level.Tumorvasculature is The effectsof fractionatingBPA-orBSH-basedBNCT,
dynamic, with variousvascular networks opening and clos-
orfractionatedexposure to the BMRR thermal beamalone,
ingasynchronously invivo(112). Areasofnecrosis inglio-
havebeenevaluatedin theratspinalcordmodel(93, 113).
blastoma multiformeare characteristic,the proliferative Afterirradiation withthermal neutrons in thepresenceof
fractionmay be low, and quiescentcells may be presentin no
BPA-F, significant change(P < 0.1, Student's t test)in
werea major theED,,owas observedwhenthenumber
areas of poor vascularperfusion.If retargeting of fractions was
factorin BNCT, thena fractionated courseof BNCT would increasedfromone to four(Fig. 6). Increasing thenumber
be expectedto be moreeffectiveagainstthetumor.Studies of thermal neutron fractionsin thepresenceof BSH from
usingtheintracerebral rat9L gliosarcomahave shownthat a singledose to twoequal fractions had a relatively minor
dividingthe BNCT treatment into two or threefractions, effecton theED,,oformyeloparesis, whichincreasedby
each separatedby 48 h, did notimprovetumorcontrolcom- about17%. No further increasein EDso was observedin
pared to a single BNCT session (93). In the rat 9L glio- movingfromtwotofourequalfractions (113). Itcanthere-
sarcoma,most if not all cells are activelyproliferating.
In forebe concludedfromthestudiesof theratspinalcord
glioblastomamultiforme, different cohortsof tumorcells thatfractionationofBNCT yieldsonlya minortissue-spar-
may enterthe proliferative phase at different times. The ingbenefit. The proportion of low-LETradiation inherent
resultsof studiesin the rat 9L gliosarcomatherefore may in theirradiation of theratspinalcordwiththermal neu-

tronsin thepresenceof BSH (-10%) or BPA (-20%) is CLINICALAPPLICATIONOF BNCTRADIOBIOLOGY

considerably lower than that likely to be encountered at
The software currently availableforclinicalBNCT treat-
depthin thebrainduring clinicalBNCT (9). It couldthere-
forebe arguedthatthe findings fromthisexperimental mentplanning makesit possibleto calculatetotalbiologi-
studyare likelyto underestimate thevalue of dose frac- callyequivalentBNCT doses to thenormalbrainand to
tionation in clinicalBNCT. However,conditions thatare thetumor(58, 59, 115). The expression of Gy-Eqdoses
morerepresentative oftheclinicalsituation havebeensim- delivered to tumor and to normal tissues in BNCT requires
ulatedin theratspinalcordusingthermal irra- estimates of three basic parameters: (1) the boronconcen-
beam-only trationsin tumor and normal the CBE factors
diations(93). Heretheradiation mixwas -53% highLET tissues, (2)
for thatparticular boron compound in tumor and in all nor-
and -47% low LET, whichis close to thatwhichis likely
mal tissueswithin the treatment field,and (3) the RBE of
to occurat depthsof >5 cm in thehumanbrainduring
thehigh-LETcomponents ofthebeamitselffortumor and
BNCT. At the EDso level of effectforradiation-induced InitialBNCT clinicaltrials
forthenormaltissuesinvolved.
myeloparesis, a relativelysmallsparing effect (---14%)was
usingepithermal neutrons are primarily safetyand dose-
seen whena single-dose exposurewas comparedto four trials.In these trials, a BNCT dose to a specific
equal fractions (93). The effectwas mostpronounced in ranging
volumeor critical region of the normal brain is prescribed.
comparing single-andtwo-fraction exposures (Fig.6). The Measurement of theboronconcentration in theblood of
degreeof sparingobservedwas less thanwouldbe ex- individual is used to adjusttheexposuretimeto
of the dose had been patients
pectedif thelow-LET component the normal brain up to theprescribed dose.Forboth
fullyrepaired. Overall,theseexperimental studiesindicate bring
BPA andBSH, theCBE factors areinplaceto allowfairly
thattherewouldprobablybe no practicaladvantage, in reliabledosecalculations dose delivery
and,
termsofnormalCNS sparing, in movingfroma two-frac- to thenormalbrain.With consequently,
BSH, thereis moreuncertainty
tionto a four-fraction BNCT protocol. in theestimation ofthedose to thetumordue to thevari-
Gavinandcolleagueshavereported similarresults from
abilityin thepublished dataforbiodistribution of BSH in
split-dose irradiations orfour-fractionirradiations ofnormal and humantumors, and thelack of experi-
experimental
dog brainwithBSH and epithermal neutrons fromeither mentaldataon theCBE factorforBSH in tumors.
the BMRR or the HFR at Petten,The Netherlands (96, ForBPA, a method fortheestimation oftheboroncon-
114). There was no appreciable sparing of the normal brain centration in tumorbased on measuredbloodboroncon-
in eitherthesplit-dose orfour-fraction groupscompared to centrations has beenreported (31). A morphometric index
thesingle-dose group. Even though the numbers of dogs in of thedensity of viable-appearing tumorcellsin histolog-
thesestudiesweresmall(fourfractions, n = 12; twofrac- ical sectionsobtainedfrom
samplesadjacentto,and mac-
=
tions,n 8), anyamountofsignificant repairshouldhave roscopically similarto,thetumorsamplesused forboron
beendetected. The skinreactions in thefour-fraction group analysiscorrelated withtheboronconcentrations.
linearly
attheBMRR wereworsethanthoseobservedinthesingle- Fromthatcorrelation itis estimated that'0Bconcentrations
fractiongroup.Thiswas attributed to increased boroncon- in tumorcells wereoverfourtimesgreater
glioblastoma
centrations in theskinduringlaterfractions as a resultof thanconcurrent blood'0B concentrations. Thus,inthedose
acutereactionsfromtheearlierfractions. Thesefraction- rangeof98 to 290 theaccumulation ofboron
mgBPA/kg,
ationstudieswithBSH in the dog brainagreewiththe in tumorcells is a linearfunction of BPA dose,and the
studiesin theratspinalcord(93): The degreeof normal variations observedin boronconcentrations of surgically
tissuesparingis muchless thanthatpredicted basedupon obtainedtumorspecimens arelargelydueto differences in
completerepairof thelow-LET component of thedose. theproportion ofnontumor tissue(i.e. necrotic tissue, nor-
Theseauthors offered possibleexplanations forthelackof malbrain)present inthesamplessubmitted forboronanal-
sparingof normaltissuein the dog brainexperiments ysis.The tumor:blood '0B concentration ratioderivedfrom
(114): (1) The low doserateofthey-raycomponent ofthe thisanalysisprovides a rationale forestimating thefraction
dose ( 0.05 Gy/min) mayallowrepairof thedamagein- of theradiation dose to viabletumorcells resulting from
ducedby thelow-LETradiation duringtheirradiation. (2) theboronneutron capturereaction.Thismethodis based
Therecouldbe interactions betweenthelow-LETandthe on measured boronconcentrations in thebloodat thetime
high-LETcomponents ofthedosethatinhibit repairofthe of BNCT without theneedforanalysisof tumorsamples
damageinducedbythelow-LETradiation. Thisbasiclack fromindividual patients.
ofrepairin theCNS hasbeenreported intwoexperimental ClinicalBNCT studiesrecently initiated at Brookhaven
systems:thedog brain(96, 114) and theratspinalcord NationalLaboratoryand the Massachusetts Institute of
(93). These resultsindicatethatreasonsforfractionatingTechnology in theU.S. involvetheuse oftheborondeliv-
BNCT shouldnotfocuson sparingof normaltissuefrom eryagentBPA andepithermal neutron beams.The trialin
thelow-LETcomponent ofthedose.Retargeting ofboron Europeusesepithermal neutrons fromthereactor atPetten,
through repeatadministration during a fractionated regimen The Netherlands, andBSH. The Europeanstudyuses four
ofBNCT remains a viableareaforBNCT experimentation.fractions administered on sequential days.All ofthesetrials

TABLE 3 (9, 117). A morerelevantconsideration is theestimated

FactorsUsed in Calculating
BiologicalEffectiveness dose delivered totumor cellsinvading thebrainadjacentto
PhotonEquivalentDoses duringBNCT at the themaintumormass.Thisregionhas beendefined as the
BrookhavenMedical ResearchReactor
"targetvolume" and relatesto a 2-cm-thick margin brain
of
Dose component Biologicaleffectiveness factor(CBE or RBE) tissuesurrounding theMRI-enhanced zone of thetumor.
Tumor(9L ratgliosarcoma)a = 3.8 The calculatedminimum dose to individual infiltratingtu-
n
(BPA-fructose) CNS (ratspinalcord)b= 1.3 morcellswithinthetarget volume(i.e. to thedeepestpart
Humanskin(moistdesquamation)c = 2.5 of thetarget volume)in thefirst10 BNCT patients was in
Tumor(9L ratgliosarcoma)a = 3.2
therange8-16 Gy-Eq.The dosesdelivered in thestarting
a14 14p ns Dog braind= 3.3 dosegroupoftheBNL clinicaltrialwerewelltolerated
'4N(n,p)4Cand Dog skin
Dog skine== 3.0 (9,
XH(n,n')p 117); themediansurvivaltimefromdiagnosisforthefirst
a
Determined fromtheresultsof in vivo/lin
vitroclonogenic assaysof 10 patients was 13.5months (117). Thistrialis nowinthe
therat9L gliosarcoma (72).
b Determined fromdose-response studiesof theirradiated ratspinal dose escalation phase.
cordwithan endpointof limbparalysis within7 months (91, 93). The single-fraction BNCT dosesestimated fortumor and
cDetermined fromthermal neutron-based BNCT of cutaneousmela- braincanbe putintosomeperspective with
bycomparison
nomain patients (24). dosesusedin conventional treatment Stereotactic
d Determined in normaldogs in theBMRR epithermal neutron beam
regimens.
usingMRI to detectdamageto theblood-brain barrier(96, 103).
radiosurgery delivering15-35-Gy(20 Gymean)boostto
a
e Determined in dog skinusingtheBMRR epithermal neutron beam the tumor after 54-60 Gyofconventional fractionated pho-
(79). ton has
therapy proven to be locallyeffective intumor con-
trolin thecentralportionof thetreatment volume(118).
To be comparedto the single-fraction BNCT doses,the
are dose escalationstudiesinvolvingsurgicalremovalof fractionated courseofphotontherapy andthe20-Gyradio-
thetumorfollowedby BNCT,wherethesafetyof thead- surgery boostmusteachbe converted intothecorrespond-
ministered dosetothenormaltissuesis ofprimary concern ingbiologically equivalent dose usingthelinear-quadratic
and effectiveness againstthe tumoris a secondaryend formalism (119):
point.Table3 liststhebiologicaleffectiveness factors [RBE
of thebeamprotons, CBE factorforthe'0B(n,a)7Lireac- E/t = nd[1 + d/(al/)], (5)
tion]thathavebeenchosenforuse in theclinicalBNCT
trialat Brookhaven NationalLaboratory as an exampleof whereE/a is thebiologically effective dose,d is thedose
theclinicalapproach(9). The preclinical databehindthese per fraction, n is the number of fractions, and at/ois as-
valuesarethesubjectofthisreview.Thephoton-equivalent sumed to be 2 Gy for brain and 10 Gy for tumor(120).
dose (Gy-Eq) to thenormalbrainis estimated fromthe Consider a course of fractionated photontherapy thatde-
measuredboronconcentration in thebloodat thetimeof livers60 Gy in 30 fractions to the tumor and to a large
BNCT usinga CBE factorof 1.3 (91). The dose to the margin of brain around the tumor followed a
by singlefrac-
scalpis basedon themeasured boronconcentration in the tion of stereotactic radiosurgery of 20 Gy to the tumor.
bloodat thetimeof BNCT,assuminga blood:scalpboron SolvingEq. (5) for d (121) indicatesthat,in brain,the
concentration ratioof 1.5:1(9, 24, 116) anda CBE factor treatment with60 Gy in 30 fractions corresponds to a sin-
forBPA in skinof2.5 (24). The doseto tumor is basedon gle-doseequivalentof 14.5 Gy. The starting dose in the
themeasured boronconcentration in thebloodat thetime BNL clinicaltrialdelivered10.5 Gy-Eqto 1 cm3ofbrain.
of BNCT,theassumption thatthetumor:blood boroncon- Fortumor, thebiologically effective dose forthe60 Gyin
centration ratiois 3.5:1 (31), anda CBE factor forBPA in 30 fractions is 72 Gy; thebiologically effective dose for
tumorof 3.8 (72). An RBE of 3.2 is used forthebeam thesingle20-Gyboostis 60 Gy.Thesingle-dose equivalent
protons in all tissues. to thetumor fortheentiretreatment is obtained byadding
The attenuation of epithermal neutrons as a function of thebiologically effective doses and solvingEq. (5) ford
depthproducesa peakdoseat a depthofabout2-3 cmand (121), whereEla = 132 Gy (the sum of theindividual
a continuous falloff in dose at greater depths(see Fig. 2). biologically effective doses),n = 1, and a/p fortumoris
For theinitialdose groupin theBNL trial,theprescribed 10 Gy.Thisconformal photontreatment afterfractionated
dosetothenormalbraindelivered a peakdose(toa volume photontherapy resultsin a single-dose equivalentto the
of 1 cm3) of 10.5 Gy-Eq(9, 117), whichcorresponds to tumorof 31.7 Gy.One objectiveoftheclinicaltrialunder
an averagewholebraindose of approximately 2.8 Gy-Eq. wayatBNL is toescalatetheminimum target volumedose
Because of the dose gradients as a function of depthin into the rangeof 30-40 Gy-Eq. This would bringthe
BNCT,it is veryusefulto use dose-volume histograms to BNCT doses to peripherally infiltrating tumorcells (as-
comparedoses deliveredto tumorand normaltissues(9, sumedto containthesame amountof boronas themain
117). The maximum tumordosesin theinitialdosegroup tumormass)intotherangeused forthemaintumormass
of theBNL clinicaltrialwereestimated to rangefrom48 in conformal photontherapy. Infiltrating tumorcells that
to 64 Gy-Eq.The minimum tumor dose was 20-32 Gy-Eq contained less boronthanthemaintumormasswouldre-

14 CODERREANDMORRIS
lessdose,whichwouldhavetobe tak-
ceiveproportionally compound, and on thebiologicalend pointstudied.BPA
in dose-escalating
en intoconsideration clinicaltrials. and BSH haveverydifferent CBE factors in thetumor, in
theskinand in thecentralnervoussystemwhichare di-
OPTIMIZATIONOF CLINICALBNCT rectlyrelatedto theverydifferent biochemical properties
ofthesetwocompounds. It is therefore imperative that,for
Maximizing thedeliveryof boronto tumoris themost anynewboroncompounds, theCBE factors mustbe mea-
effectiveway to optimizeBNCT. Increasing theneutron suredinnormal tissues, underclinically relevant conditions,
exposure will increase thenonspecific background dose to prior to initiation of clinical trialsof BNCT to estimate dose
thenormaltissuesand produceno netgainin thethera- tolerance limits.It is also advantageous to estimateCBE
peuticratio.A boroncompound witha highdegreeoftu- factorsfortumortissues,although suchknowledge is not
morspecificity, long retentionin the tumor, and complete absolutely in a
required safety-oriented Phase I clinicaltrial.
clearancefrombloodandnormaltissueswouldbe optimal
forBNCT,producing verysubstantialtherapeutic ratios.In ACKNOWLEDGMENTS
reality,
compounds like BPA thatare of
capable producing A. Z. Diaz usefuldiscussions and valuableadvice.D. N.
tumor-to-normal tissueboronconcentration ratiosof be- SlatkinandR. provided constructivecriticism
on earlydrafts
Huiskamp provided
tween3:1 and4:1 maybe sufficient to provetheprinciple ofthismanuscript. GM is supported by theUK CancerResearchCam-
ofBNCT.Anybiochemical manipulations thatcanimprove paign.JC is supported by theOfficeof Biologicaland Environmental
thetumor-to-normal tissueboronconcentration ratioswill Research,U.S. Department ofEnergy, undercontractnumber DE-AC02-
Even if thetu- 98CH10886.
improvethetherapeutic gainsignificantly.
mor:blood boronconcentration ratioremains fixed, thether-
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The Radiation Biology of Boron Neutron Capture Therapy

Author(s): Jeffrey A. Coderre and Gerard M. Morris

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It is basedon a straightforward conceptthatwas first pub-

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survivaltimesof thesepatientswereno betterthanfor 2

Considerably moreis now knownabouttheradiation bi- HO

ology of BNCT. Several BNCT clinical trialshave recently NH2

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50% ofthatobservedin themaintumor mass(39,40). The tributionof boronintotumorcellsinfiltrating intothenor-

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generally acceptedat thetime[2.3 for'0B(n,at)7Li,2.0 for overallbiologicaleffect.The modeof compoundadmin-

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allowedcalculations of RBE and CBE factors(66). The whichcouldbe relatedto structural

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ical trial,thedistribution of IB in thehumanbrainis sim- thanthosein current use. Theseexperimental dataempha-

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has been shownto inhibitthegrowthof melanomawith

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FRACTIONATION Numberof Fractions

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tronsin thepresenceof BSH (-10%) or BPA (-20%) is CLINICALAPPLICATIONOF BNCTRADIOBIOLOGY

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TABLE 3 (9, 117). A morerelevantconsideration is theestimated

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112. R. K. Jain,Physiological barriersto deliveryof monoclonal anti- Stereotacticradiosurgeryforglioblastoma: a finalreportof 31 pa-

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