A H I S T O R Y O F BORON NEUTRON C A P T U R E T H E R A P Y O F B R A I N T U M O U R S

POSTULATION O F A B R A I N R . 4 D I A T I O N D O S E T O L E R A N C E L I X I I T

Boron neutron capture therapy (BNCT) is ii form of radiation therapy incdiated by the shon-range ( l e s i than I O pin) energetic alpha ( 'He) and lithium-7 ( 'Li) ioniring particles that result from the prompt disintegration by \1o\v neutrons o f the stable (nonradioactive) nucleus boron- 10 ( ' " B ) . Rcccnt ad imccs in railiohicilogical and toxic0logic;il evaluation of tumour-affinitivc boron-containing drugs and in optimization 01' the cncrgics oI ncutroiis i n the incident beam have spurred interest in BNCT. Thih article presents :I Iiihtory o t RNCT that cmphasitcs studics in the USA. A ncw dosimetric analysis of the 1959- 1961 cl inical t r i i h 01' 13NCI' at RrocMiavcn National Laboratory is also prcxntcd. This analysis yields an acutc radiatiim dciw tolcrancc limit chiiniatc o f - I O Gy-Eq to the capillary cndothcliurn of human basal ganglia f r o n i 13NCT. tC;? -Eq: Gra~-cr lui \ ,a lcnt , o r relative biolosical clfcctivcncss of a radiatioii component iiiultiplicd hy thc pll!\l<:il J o c t i l ' [ l ie coniponcnt ( C y ) . \ummcd ovcr t he component kinds o l radiation.)

1 N T R 0 D U C T IO N

The cxistcncc ot'thc neutron. an electrically neutral atomic particle with a mass equal to ihat 01. the nucleus of hydrogen, the proton. was first postulated in Great Britain ( Ruihcrt.ord, 1920). Experimental verification of the concept originated from discovery ot' radiation with strange properties I O years later in Germany (Bothc and Bcckcr. I9300. / I ) . When alpha particles (eneryctic helium-4 nuclei) bonibardcd certain light clcmcnts (most effectively, beryllium), electrically neutral radiation wi th unprecedented pcnctrLrbiIity in lead was detected by 3 Geiger counter. This so-callcd 'beryllium radiation'. at first considered to be ultra high energy gamma radiation. W;IS found to eject protons with energies of up to 4 .5 million electron volts from hydrogen-containing iiiaicrials (Curie and Jol iot. 1932). J a m s Chadwick. Rutherford's student and colleague, t'inally explained the puzzling kinetics of the ejected protons when he suggested that thc beryllium radiation was ;I stream of neutrons (Chadwick. 1932. 1937). He held that ttic protons resulted from elastic collision of neutrons with hydrogen nuclei. Such collisions are coniparnble with those of billiard balls. A collision of a fast neutron with :I hydrogen nucleus imparts some (on the average, hal t ) o f the kinetic energy of the ncutron to the nucleus. which recoils as a proton. Enrico Fermi and his associates in Rome discovered that neutrons slowed by pa ige through paraffin or water arc more likel), to be absorbed by atomic nuclei than are fast neutrons. The capacities of boron

BOX No \

FOLDER

and lithium nuclei to absorb slow neutrons were greater than those of any other elemental nuclei examined (Fermi eral., 1934; Amaidi era/ . , 1935; Fermi, 1939; Stranathan, 1942).

The first observation of charged particles from slow-neutron irradiation of boron was made at Cambridge University on December 10, 1934 (Goldhaber, 1986). Charged particles, including protons, alpha particles and tritons (energetic tritium nuclei), are produced during bombardment of specific stable isotopes of boron, lithium and nitrogen with slow neutrons (Chadwick and Goldhaber, 1935; Taylor and Goldhaber. 1935: Burcham and Goldhaber. 1936).

'OB + In - 'Li + 'He 6Li + 'n - 'He + 'H 'JN f ' n - ''C + ' H

Nuclear reactions such as these were discovered in elegant experiments. Fast neutrons were produced at the rate of about 1 x 10"s when - 100 mg of radium, an alpha and garnnia emitter, was mixed with beryllium powder. The mixture was surrounded by lead plates that transmitted most of the fast neutrons so generated and attenuated gamma rays. The neutrons were slowed by multiple elastic collisions with the light nuclei (most effectively, with the hydrogen nuclei) in a layer of paraffin. The slow-neutron target was either a powder applied thinly to part of the inner wall of an ion detection chamber or a gas that filled the chamber. The electrodes of the chamber were connected to a n amplifier and an oscilloscope to detect pulses of ionization from reactions between slow neutrons and their targets. The energies of charged particles emanating from a solid target could be estimated by shielding the target with various layers of aluniinium and noting the suppression of pulse intensities.

When thc ncutron capturc nuclear reactions becarne known in the USA. i t w;is proposccl that they be applied to radiation therapy by the selective uptake of a suitablc isotopc into ;I paticnt's tumour. folluwcd by slow-neutron irradiation of the tumour-bearing tiswc (Lochcr. 1936). 01' ttic readily available nuclei that can react with slow neutron?, to produce short-range ionizing particles and that can be incorporated i n t o a varicly of ~ ~ ~ ~ i i o t ~ r - a t ~ l i n i t i v e drugs. the stable isotope boron- I O ("'B) is the ]nost likcly to rcact with a neutron in ;I slow-neutron irradiation ticld (Farr and Robertson. 197 I ) .

Tlic t ' i rh t radiobiological studies using the neutron-"'B reaction were pcrlornicd at thc Univcrhity ot Illinois in 1938 ( B . V . Hall, M. Goldhaber and P. G . Krugcr. citcd in Krugcr. 1940). Within the next few years. several articles described reduced viabilit) ot' iiiousc tumour transplants after their exposure to boric acid and irradiation by slo\t. neutrons i n vitro (Krugcr. 1940) and regression of mouse sarcomas infiltratcd with ;I

paste ol 'boric acid powder in sesame oil after their irradiation by slow neutrons in t ,i\ ,o (Zal i l c't li/.. 1940). I t was realized that thcrc would tic clinical advantages to irradiation with ncutrons of intcrmcdiate energies that could be slowed down further ('thermalized') in the brain, where the slower neutrons would be more likely to react with "'B (Zahl. 194 I ). Although the use of uranium-335 tor slow-neutron capture therapy was foreseen (Zahl and Cooper. 194I), a radiobiological study of the "-FU-tission reaction w;is not rcported u n t i l the late 1940s (Tobias et (11 . . 1948). It was also suggested thd t

a vital dye. appropriately labelled by '"B or "'U, might be useful in BNCT (Zahl and Cooper, 1941).

... . I . . . . . . . . . . . . . . ._- . . .

. . . . . . . . . - _ . . - . . . . . . . . . ....-...- .

. . . . . . . . . . . . . . . . . . . . . . . ._.,I .

I . . . . . . . . . . . .

B O R O N N E U T R O N C A P T U R E T H E R A P Y 161 1

L After World War 11, studies in radiobiology and medical physics were begun at institutes in the USA such as Brookhaven National Laboratory (BNL), which were established by the United States Atomic Energy Commission (AEC) primarily for nonmilitary nuclear physics research. In 1947, William Herbert Sweet, a neurosurgeon at the Massachusetts General Hospital (MGH) and professor at the Harvard Medical School, began collaborations with physicists at BNL and elsewhere to search for techniques to improve diagnosis and therapy of brain tumours. By 1949, these collaborations led to "P-labelled phosphate being used at the MGH as a radioactive tracer to localize brain tumours during neurosurgical operations. Working with the physicist Gordon Brownell, Sweet was among the first clinical investigators to image brain tumours with positron-emitting isotopes. However, no radiolabelled substance was known that would concentrate adequately in a brain tumour after its injection into a patient sb as to deliver therapeutic doses of radiation to the tumour while sufficiently sparing normal brain and radiation-sensitive haematopoietic and gastrointestinal tissues. Sweet's search for a proton beam to be used for human brain tumour therapy eventually led to the establishment of a proton radiation therapy unit at the Harvard University cyclotron, but most malignant cerebral gliomas were considered to be too large and their margins too irregularly dcmarcatcd for proton therapy. The f-irst clinical trial of fast-neutron therapy (radiation therapy mediated by fast recoiling protons in neutron-irradiated tumours), which had becn carricd out bctwcen 1938 and 1943 in California, was deemed to have Pdiled 10 years aftcr i t began (Stone, 1948). Thirteen patients with brain tumours were among those treated with fast neutrons, without much success. By the late 1940s circumstances in the USA were thus appropriate for a renewal of interest in neutron capturc therapy. Although thc potential irliportancc of BNCT was recognized by the British radiobiologist Douglas Lca in the 1940s (Lea. 1956). to my knowledge there were n o British studics o n BNCT publishcd un t i l the late 1970s (Constantine et lil., 1986. 1989; Mill P I 01.. 1080: Morgan c[ 01.. 1986).

Af'tcr 36 months undcr construction, the Brookhavcn Graphite Rcscarch Reactor (BCIIR) \viis conirnissioncd in August. 1950. Lee Edward Farr. a paediatric rcscarch pliyhician who w a s appointed chairman of the newly formed BNL ,VcdicaI Dcpartmcnt on Scptcmbcr I . 1949, became intcrcstcd in new applications of the BGRR to s lowneutroi i radiation therapy (L . E. Farr. personal communic;ition). Work o n BNCT hcgm at the BNL Mctlical Dcpartiiicnt i n the summer o f I950 (Brookhaven Nationd Laboratory. 195 I ) . Indcpcndcntly. 3 proposal by Sweet for BNCT of' brain tuniours a t the R G R R and tor later dcvelopmcnt of ;i major inrernicdiatc ('cpithcrnial') energy coiiiponcnt in ;I neutron beam for BNCT was submitted to the AEC in 1950 (Sweet. I9X6tr. / I ) and published. in part. ovcr I ycur later (Swcct. 1951: personal corn- niunication). Undcr thc aegis ot Donald Van Slykc. an cmincnt biochemist who w:i>

then BNL's Assistant Director for Biology and Medicine. A . Baird Hastings. ;I

dist inyishcd Harvard biochcniist and BNL trustee. and Shields Warren. 3 notccl pathologist who was thc Director of the Division of Biology and iMcdicinc in the AEC. plans by Swcct. Farr and others for BNCT of malignant gliomas at thc BGRR were coordinated and quickly brought to fruition (Brookhaven National Laboratory. 195 I ) . An irradiation facility with a 5 cniX IO cni rectanplar neutron pon in its stcelilcadlboron- shicldcd tloor was built at the top of the BCRR. surrounded by concrctc. The neutron port w;is at the apex o f a 3 '/z foot high conical air space in thc reactor shielding beneath

1612 D. S . S L A T K I N

the floor of the facility, with bismuth plates used as extra gamma shielding at the base of the cone. Preliminary experiments were performed at the MGH in which nontosic doses of borax ( - 70 mg/kg) were injected intravenously into volunteers with brain tumours (Javid et 01 . . 1952: Sweet and Javid, 1952). Beginning early in 1951. some patients with glioblastoma multiforme were referred from the MGH to Brookhaven ior BNCT at the irradiation facility of the BGRR.

About 15 vital dyes were screened in tumour-bearing mice at BNL for possible use. after their boronation. in BNCT (Brookhaven National Laboratory, 1951: Sines et ai.. 1953). Winton Steinfield, who joined the BNL group in February, 1952, announced his success in the boronation o f the vital dye Bismarck Brown after about 1 year's work. Unfortunately, Steinfield died accidentally in 1953 and his notebooks on the technique could not be deciphered (L. E. Farr. 1990, unpublished). Steinfield also performed a preliminary in vivo study relating to uranium neutron capture therapy (StGinfield. 1952). Coincidentally, the untimely death of another scientist, Leslie McKlintock. preventcd a rne t hod for preparation of uranium-bindi ng tumour-affini t ive anti bodies deve loped at ;I US Army laboratory (McClintock and Friedman, 1945) from being repeated (Knock. 1959). Such antibodies were thought to be potentially useful for uraniurn neutron c;1 p t u re t h e r;i p y .

About 70% of boron in the earth's crust is 'OB. The production of "'B-enriched boron did not begin in the USA un t i l 1943 when the first method for "'B-enrichment of boron. e q u i 1 i b r i u m c o u n t e r - c u r re n t d i s t i 1 I a t i o n o f ;I boron t r i fl u o r i d e d i a I k y I et h e rat e . was dcvclopcd at Columbia University in New York under the leadership of Harold Urcy. A dihtillation column I inch in diameter and 5 yards high could produce 500 ing of 95% "'B-enriched boron per day. Methods o f large scale production of "'B are now well known as. for example, in ;I factory conimissioncd in 1954 that was cap:ibIc of producing over I Ib of 95% "'B-enriched boron per day (Miller ct ~ 1 . . l958).

The lirat patient in Brookhavcn's initial 24-month. 10-patient BNCT atudy (Farr ( ' I (11.. I954i. h . (.: Gotlwin c l t (11.. 1955: Robertson ct u l . , 1962; Farr and Robertson. I971 1 w;is irradiated ;it thc B C R R on February 15. 195 1 . just 6 months after the BGRR \v:is

cerebral glioiii:~ and showed clinical evidence o f tumour recurrence. Eight o f the paticnts had rcccivctl conventional radiation therapy for their brain tumours. T h c x advanced inalignant cerebral gliomas werc irradiated by thermal neutrons (and by the inevitable concoinitant g;imiii;i. proton and fast-neutron radiations), after an aqeuous solution ot' 90% '"B-enriched borax was administered intravenously over a period of several minutcs. The paticnt was positioned horizontally with the tumour zone apposed to the ncutron port. Since there was then no irradiation shutter, the reactor pile w a s shut down during thc preirradiation infusion and aligntncnt procedure. which took about 10 inin. Critical reactivity of the pile was then reestablished and the reactor power was raihcd to 40 MMW I'or irradiations of 17-40 inin duration.

There \\'ere no serious side-effects of BNCT in the first 10 patients. although rhc large doses o f boras infused before irradiation. - 200 mgikg, were slightly toxic (Farr ct t i l . .

citcd in Sweet and Javid. 1951; Conn 01 d.> 1955: Locksley and Farr. 1955). A 20-ton armour steel irradiation shutter was installed below the BGRR treutmcnt port to allow a inore rapid r i x to full reactor power after the injection of borate without shutting

commissioncd. All the patients had underfone a neurosurgicril operation f o r mali, ~ ' n : I n I

B O R O N N E U T R O N C A P T U R E T H E R A P Y 1613

down the reactor (Brookhaven National Laboratory, 1953). The neutron port was enlarged to I O cmx 10 cm.

A second series. comprising 9 malignant glioma patients, was treated with a less toxic borate preparation, sodium pentaborate with D-glucose in the molar ratio 2: I (Easterday and Farr , 1961 ; Easterday and Hamel, 1963), but at a higher “B dose than in the first series: 32-50 nig ‘OB per kg body weight (median, 42 m g k g ) instead of 16-33 mg “B/kg (median, 26 mg/kg). Incident thermal neutron fluences were 2.34-3.84 X 10” per cm2 (median. 3.38 x 10” per cm’), higher than the previous fluences, which were 0.44- 1.93 X I O ” per cm‘ (median, 0.93 X 10” per cm’). A troublesome side-effect of BNCT in the second series was intractable radiation dermatitis of the scalp (Archambeau. 1970), sometimes with ulceration, despite later efforts to prevent i t b y application of tight head bandages during borate infusion. The median survival time after BNCT for the second series was 147 (range 93-337) days. which was longer than that for the first series (median 97, range 43- 185 days) (Farr ef ul. , 1958).

In the third series of patients treated by BNCT at the BGRR, in order to reduce the radiation dose to the scalp, the neurosurgeon H. J . Bagnall delivered the pentaborate (26-60 rng “’B/kg. median 50 mgikg) through a long warmed tube into the internal carotid artery o f the tumour-bearing hemisphere while the patient was positioned at the irradiation port. Neutron 11Liences were reduced to 0 .39- 1.5x I O ” per cni2 (median. 0.72 X I O ” per cm’). Survivals after BNCT in the 9 patients of the third group (median. 96 days. range 29- 158 days) were similar to those of the I O patients in the first ~ J O U ~

a n d to t h o x of. patients in the north-cast USA with similar cerebral tumours treated o n l y by conventional postoperative therapies during the 1950s (Slatkin P I ( I / . . 198610. N o n c o f the (1 dcvclopccl severe radiation dermatitis. a fortunate outcome that sustained prospects for furthcr clinical trials of BNCT at Brookhaven ( F a n et (11.. 1958: Farr. 1960).

SLvcct \vas involvd in the first two series of’ patients treated by BNCT at Brookhaven. Tticrcaftcr. hc turnod his attention to development of a brain tumour BNCT facility ;it thc Mahsachussctts Institute o f Technology (MIT) (Brownell and Sweet. 1958). To iclcntity a “’B-carrier that yielded more favourable tumour:brain boron concentration rat ioh than Lvcrc obtainable with boratcs. the MGH chemist Albert Soloway investigated ;i hcrics of monosubstituteti derivatives 01‘ phenylboronic x i d . Of 8 derivuti\.cs studiccl. t he m -c:i rba in i do. t h c m -ca rbox y and t h c p-ca rbox y derivatives y ic ldcd t u m o u r : bra i n ratios in the 7 .5 -9.0 range bctwecn I5 min and 3 h after their prompt intraperitoneal in.jcction in rnicc bcaring subcutaneous transplantcd gliomas (Solotvay. 1958). Nonc ol ‘ thc other 5 derivatives yicldcd ;i turnour:brain ratio grcater than 1 .6 . The p-carboxy dcrivativc of phenylboronic acid was selected as ;I “’B-carrier for I6 o f the 18 brain t u m o u r patients treated with BNCT by Sweet and his colleagues at thc MIT reactor during 1959- 1961. The outcomc of the MIT trial of BNCT was unsatisPictory (Asbury (’r (11.. 1972). with an avcragc post-BNCT survival time of 6 months (Hatanaka. 1986).

Whilc clinical trials of BNCT were in progress at the B G R R . a study i n niicc o f thc in vivo relative biological effectiveness (RBE) of heavy particles from the “’B(n.u)‘Li reaction was carried out at BNL (Bond e r 01.. 1956). Studies on BNCT of a mouse tumour were carried out by Farr and his laboratory assistant Tadcubz Konikowski during the 1950s and early 1960s at BNL. A methylcholanthrenc-induced glioma was

1614 D. N . S L A T K I N

transplanted intramuscuiarly into the mouse thigh. BNCT could cure the transplanted tumour almost predictably with no visible residual effects on the mouse (Table 1 ) (Farr and Konikowskl, 1967, 1976). The thigh tumour could also be eradicated by x-ray therapy, but this was only achieved with severe damage to the irradiated limb (Farr and Konikowski, 1964). These results were the first extensive experimental demonstration of the BNCT concept in vivo.

T A B L E I . B N L - 1 0 - 5 8 4 - 8 9 . S U L f M A R Y O F T U M O U R R E G R E S S I O N D A T A F R O M F A R R A N D K O N I K O W S K I ( 1 9 6 7 . 1 9 7 6 ) O N 1 5 8 7 M I C E W I T H A N O N M E T A S T A T I C G L I O M A

T R A N S P L A N T E D T O T H E T H I G H A N D T R E A T E D B Y B N C T U S I N G Y6 A T O M 7, " $ - E N R I C H E D S O D I U M P E N T A B O R A T E W I T H D - G L U C O S E ( M O L A R R A T I O 2 : I ) V I A P R ' b X I P T

I N T R A V E N O U S I N J E C T I O N

Injec.:iori-irrcidirrriori rime inrrn,al (inin) 7- 23 25 - 48 50- 72 74 - 92

A IY ru,qe hnrorr cor! cmrruriom (pg /,q)

Sarcoma 25 28 28 28 B I wd 34 26 21 18

E (84) I65 189) 2 (63) '!! (42) I37 I85 I25 95

R-9

14-15 1 ( 2 ) 3 (10) - 6 (7) 0 (0) 51 86 86 62

Surlacc Ilucncc 1.41 - 1.67X IO" riicrn': B M R R : 5 M W . 23 5

It was suggested that untoward complications of BNCT for human glioniiis might bc avoided i f adequate numbers of neutrons could be delivered to the tumour during thc few minutes when the tun1our:brain 'OB concentration ratio was considered most favourable. To achieve this, thermal neutrons would have to be generated at a much greater rate than was possible at any accccssible port o f the BGRR. Accordingly, plans were made to build a compact. high-tlux. broad-beam thermal neutron facility for BNCT at the BNL Medical Department (Robertson et al . , 1955). The 5-MW H,O-inodcr;lted Brookhaven Medical Research Reactor (BMRR) became operational in 1959 (Godel. 1960). I t was a great disappointment that BNCT of 17 cerebral tumours (all but 1 . malignant gliomas) carried out at the BMRR during 1959- 1961 was not nearly as useful as had been anticipated; the median post-BNCT survival was only 3 months (Table 7 ) . Failure to show substantial extensions of lifespan resulted in suspensions of both the B N L and the MIT clinical trials of BNCT. There has been no patient treated by BNCT in the United States since 196 I .

B O R O N N E U T R O N C A P T U R E T H E R A P Y 1615

T A B L E Z B N L - 1 2 - 2 3 - 8 9 C L I N I C A L P A R A M E T E R S A N D I N C I D E N T T H E R M A L N E U T R O N D O S E S F O R 17 P A T I E N T S W I T H M A L I G N A N T C E R E B R A L T U M O U R S T R E A T E D B Y B N C T A T T H E B h l R R D U R I N G T H E 1 9 5 9 - 1 9 6 1 S T U D Y T H E P A T I E N T S ' S E R I A L N U X I B E R S . A S S I G X E D

I N O R D E R O F I N C R E A S I N G N E U T R O N D O S E S . A R E NOT N E C E S S A R I L Y IS C H R O N O L O G IC A L 0 R D E R 0 F I R R A D I A T I 0 N

Serial

I 2 3 4 5 6 7 8 9

I O 1 1 12 13 14 15 16 17

Mcdian

110.

4' Su rr Yva 1 N I firsf a j e r jrsr

uperarion operarion @rs) idUKY)

58 148 38 I92 44 I81 61 488 35 I I28 33 68 65 - 220 57 144 43 313 56 I121 66 123 30 I750 51 425 35 636 32 50 66 36 50 312

50 yrs '-20 days

Sunivai a fer

BNCT (dU!S)

87 123 31 165 98 19

- 170 87 IS3 143 26 57

151 12 4 6 3

87 days

Prrviuus rudiorherupy

NO No Yes Yes Yes N O

NO N O

No Yes N O

Yes Yes Yes NO No Yes

-

No. of major cranruiutnies

I 1 2 2 2 I 2 1 I 2 I 2 1 3 I I I

-

/ncidenr rliennnl neulrnn j7irence X

Irenmienr urru ( X 10'" neurroris)

0.6 I .6 I .7 1.8

4.6 5.6 5.9 6.8 6.9 7.5 16.0 20.0 25.5 26.2 26.7 29.7

5 1.8

5.7 x IO" neutron5

I n the early clinical trials of BNCT, no technique was available that was fast enough to allow estimation of the patient's blood-'"B concentration in planning the duration of irradiation. In retrospect, this problem is seen to be important because radiation damage to thc cerebral vasculature turned out to be ;i complication of the early BNCT trials and because there was considerable variation from one patient to another in the concentration of "'B observed in the blood at a given time after administration of a standard dose of "'B-carrier. Recently, a gamma spectrometry facility has been constructed at BNL to measure 'OB quickly and accurately in less than a gram of blood o r tissue (Fairchild el u i . , 1986). In this so-called 'prompt-gamma' method, the sample is irradiated with slow neutrons. Gamma photons in the narrow energy range (-478 kcV) produced instantly by '"B-neutron capture reactions are counted. The amount of '"B in the sample is proportional to the net count. The '"B analysis of one blood or tissue sample at the prompt-gamma facility of the BMRR takes only several minutes.

Another important aspect of the initial clinical trials of BNCT was the unavailability of boron-containing compounds that would enter glioma tissues freely and not cross the blood-brain barrier. Such boron compounds were first synthesized in the 1960s from polyhedral boranes (Miller e r a l . , 1963; Knoth et uf.. 1964). The applicability of these compounds to BNCT was studied initially at the MGH (Soloway ef ai.. 1967). This led to the selection of sodium mercaptoundecahydrododecaborate (Na2B,,Hl ,SH) for a trial of BNCT of brain tumours in Japan. The first BNCT irradiation of a human brain tumour in Japan took place in August 1968 (Hatanaka c't u l . . 1 9 8 6 ~ : Hatanaka and Urano. 1986).

1616 D. N. S L A T K I N

It is instructive to estimate radiation doses to the normal cerebral capillary endothelium in patients who underwent BNCT at the BMRR 30 years ago, and to review those doses in relation to post-BNCT survival. The capillary endothelium of a tissue receives doses from BNCT that reflect 'OB concentrations in blood and tissue parenchyma weighted in the ratio of about 1:2. respectively (Kitao, 1975; Rydin el a l . , 1976; Slatkin et ( 1 . 2 1 . . 1988). Decreases of normal brain capillary endothelial cell radiation dose (see Appendix) with increasing penetration of neutrons are indicated in Table 3. As shown in the Appendix

T A B L E 3. B N L - I O - 1 7 5 - 8 Y . I R R A D I A T I O N P A R A 5 I E T E R S A N D E S T I h l A T E S OF C A P I L L . \ R \ I ' E N D O T H E L I A L D O S E F O R 17 P A T I E S T S W I T t L C E R E B R , \ L T U $ i O U R S T R E A T E Q B Y H S C T

A T T H E B $ l R K D U K I N ( ; 1'1S'I- 1961

. S < ~ I l d

1 1 0 .

I

1

4 5 h 1 X <I

111

I1 I? 13 I J

IS Ih 17

and in Tables 4 and 5 .

tll = ? ) 7 7

6 I1 6.J

h i h i

22.4 23 -1 2 1 0

'7 5 28 i 3s 5 35 3 44.7 5h (I 57.3 5 8 4 71 K

I1

IS

BNCT also involves radiations othcr than thosc from the "'B were neutron-I"B reaction that. in principle. cannot be limited to the tumour even i

limited exclusively to the tumour. These non-"'B-related radiations incrcasc in relative importance with increasing depth in the brain.

In retrospect. C u e 13 (Tables I -5 ) is of particular interest because BNCT apparently arrested the growth of his malignant cerebral tumour. An - 4 cm diameter carcinoma was removed from his anterior parietal region at a left temporoparietal craniotomy. Seven weeks later, a 6-week course of cobalt-60 gamma radiation thcrapy (51 Cy to the whole brain) was begun. Recurrence of neurological signs. including right hemiparesis, led the patient to undergo BNCT at the BMRR 6 months after the termination of cobalt-60 therapy. The patient developed right hemiplegia. acute incrcascd intracranial pressure and a slight drop in systemic blood pressure ( 150190 - 1 10/60 mmH2) about 10 h after BNCT. Following emergency treatment with intravenous urea. the patient slowly recovered and becamc ambulatory within I0 days. Before he left B N L 53 days

B O R O S N E U T R O N C A P T U R E T H E R A P Y 1617

T A B L E J B K L I 1 - 2 7 5 - 8 9 E S T I h i A T E S O F D O S E S T O C A P I L L , A R Y E R D O T H E L I A L C E L L S IK N O R X 1 A L B R A I N T I S S U E S F O R C A S E I 3

A T D E P T H D cm ( G l - E q l

Soirrce if rrrdicriioti

43 p g "B;g (RBE = 2.0)

Fait neutronc (RBE = 2.0)

22 mg I 4 y / g ( R B E = 2.0)

Intrinsic gsrnnia (RBE = 1.0)

Extrinsic gamma ( R B E = 1.0)

D 0 7 J

79 2 34 0 14.6

________

3.9 1.6 1.7

3.7 1.6 0 . 7

4.1 4.4 7.7

2.0 1.7 1.5

92.8 44 .3 21.2

6 8

6.3 2.7

1 I 0 .7

0.3 0.1

s

1.4 0 .7

1.3 1 . 1

Thc contrihutionh to t o ta l d o c s 1'rom neutron-induced proton radiation (iniainly Irom " 3 ) . l.roiii neutron-induced intrinsic g u n i i u radiation (mainly from hydrogcn). and l.roiii extrinsic rudiation\ (mainly rcaclor-peratcd fa..[ neutrons and gamma radi;itions, arc li>[cd Nuiiicricsl valuch ( 1 1 doses are given to the nearest 0. I Gy-Eq.

l 't\l~l.l< 5 U h ' L - I O - S X 3 - X Y . C O S t P O N E N T S O F T f l E M I X E D - F I E L I ) K A I ) I , \ l I O S D O S E S T O C A P I L L A R Y E N D O T H E L I A L C E L L S I N

N O K h l A L B K > \ l N T I S S U E S A T V A R I O U S D E P T H S I N C h l t D ) A S S O C l , \ ~ l ' l ~ l ) W I T H B N C T O F 17 C E R E B R A L T U M O U R S T R E A T E D 1 3 )

I 3 K C T Xr T H E B M K K D U R I N G 1 9 5 9 - 1961

Prripiir~iiiti 01 tomi Gy-Ey do;e ( % *XD) ~-

Siirrrc c 111 rcidiii~riiti /OB Giitrrnrtr (D L . I I I ) (RBE = 2.01 (RBE = 1.0)

0 85 .0+2 .0 5.6* I 0 2 76.2 * 2 . 0 12 2* 1.5

19.8 -t I . X 4 65.7 k 4 . 6 6 54.3 f 6.9 28.3 * 3 . 0 8 40.3 *8.9 40.7 h5.0

later. not only had the paresis largely disappeared but remarkable improvements in speech. ability to read, and vision were observed in comparison with the serious deficits in thcsc functions (right hemiparesis, complete expressive aphasia. complete right homonymous hemianopia) that developed before BNCT. The patient did not deteriorate neurolo_cically thereatier. but he died at BNL. severely jaundiced. 5 months after BNCT with widespread extracranial metastases. probably from a primary anaplastic carcinoma originating in the head of the pancreas (autopsy no. A-151-61: BNL). At necropsy. there was no evidence of viable brain tumour tissue or of brain oedema.

1618 D. N . S L A T K I N

Patients treated at the BMRR, many of whom had radiation therapy previously, were provided with meticulous care by the neurosurgeon Y. L. Yamamoto. Temporary skin flaps were reflected and shielded by sheets of 6Li before irradiation. Although this precaution avoided nohealing ulceration of the skin, it did not prevent radiation dermatitis altogether. Moreover, it was not always possible to prevent postoperative infections within the irradiation field. These responded favourably to drainage and antibiotic therapy. Postirradiation rises of intracranial pressure were treated by continuous drainage of CSF from the brain and by intravenous urea. Nevertheless, 4 of the 17 patients died within 2 weeks after irradiation (Table 2) with cerebral oedema and intractable shock. the explanation for which was not immediately apparent.

It was stated by the Amerian radiation oncologist Philip Rubin (1989, ynpublished) that large-field photon irradiation of the human brain with a single dose 6f 16 gray o r 20 gray carries with i t a 5 % or 95 % risk, respectively, of clinically unacceptable injury to the brain. Doses equivalent to these were apparently reached or exceeded in one hemisphere of the cerebrum during BNCT in Cases 6- 13 to a depth of about 2 cm and in Cases 12 and I3 to a depth of about 4 cm (Tables 2 and 3) with no dire consequences within 2 weeks after BNCT. Progressive deeper coma, cardiovascular collapse (shock) and death ensued within 2 weeks after BNCT only in Cases 14- 17. who also received the highest neutron doses in the series (Table 2). Dosimetric calculations for these patients, when contrasted with similar calculations for Cases I - 13, suggest that the acute (single fractic. q) BNCT tolerance dosc for endothelial cells in basal ganglia at depths of -6 cm is unlikely to be much greater than 10 Gy-Eq. Perhaps neuronal centres in the basal ganglia that were involved in cardiovascular homeostasis were secondarily compromised by doses to the endothelium of more than 10 Gy-Eq from BNCT and BNCT-associated reactor radiations in Cases 14- 17. I t is postulated tha t Case 13. who responded well to BNCT after a difficult postirradiation syndrome ot' acutc cerebral oedema and mild hypotension. received nearly the maximum acutely tolcrablc dosc of radiation to the capillary endothelium of his left cerebral heniisphcre. especially in his left basal ganglia.

An ongoing clinical trial o f BNCT for inalignant gliomas and other brain tumours has been led by the neurosurgeon Hiroshi Hatanaka in Japan since 1968. The agc distribution of patients treated for malignant glioma in Japan, the median age of incidcncc o t whom was approximately 40 y (Sano, 1981). seems to be quite different from the agc distribution o f patients with supratentorial malignant gliomas treated in Boston, whcrc the median age at tirst operation was 59 y between 1952 and 1981 (Slatkin (11.. 1986tr). Thus differences in age might contribute to differences in the survivals of groups 0 1 . patients with malignant glioma treated similarly in Japan and in the West sincc agc is an important prognostic o f postoperative survival among glioma patients. Moreover. i t is conceivable that some preparations of Na,B,,H, ,SH (monomer) may have developed variable amounts of the spontaneous oxidation products Na,B2,H2.S, (dirncr) and Na,B,,H,,S,O (dimer monoxide) by the time they were infused into patients (Hatanaka er d., 19860; Sweet et d.. 1986; Soloway, 1988). Consequently, inferences from the results of the Japanese trial of BNCT to date may not be unreservedly applicable elsewhere.

There have been reports of excellent clinical results in some malignant glioma patients treated with BNCT in Japan. For example. a man with glioblastoma muitiforme so treated

, B O R O N N E U T R O N C A P T U R E T H E R A P Y 1619

in 1972 at age 50 y was alive and neurologically stable in the spring of 1990 with no radiographic evidence of a brain neoplasm (Hatanaka, 1990, unpublished). Nine days after - 20 g of tumour was removed from a large glioblastoma in the posterior-inferior region of the left frontal lobe, 40 mg 'OBikg body weight of monomer was infused into the left carotid artery over 2 h. A 7 h irradiation that delivered a thermal neutron fluence o f 5 . 3 - 9 . 6 ~ 10"icm' to the residual tumour began 14 h after the end of the infusion. Half an hour before irradiation, a 3.5 cm diameter sterile ping-pong ball was inserted into the bed of the residual tumour, in a sample of which the 'OB concentration was 15.3 pgig. Half an hour after the beginning of irradiation, the blood-"B concentration was 27.5 pgig (Hatanaka et ai., 1984~). Post-BNCT instillation of 25 mg of methotrexate into the patient's tumour cavity over a 5-day period (Hatanaka et cil., 1986a), conceivably may have contributed to the long-term control of this tumour. Despite Hatanaka's successes with some patients, American and European oncologists are reluctant to endorse the Japanese BNCT technique in preference to alternative methods of postoperative brain tumour therapy. However, the astonishing energy and bold initiatives of the Japanese BNCT team are followed in the West with great interest because that team demonstrated for the first time that BNCT and BNCT-associated reactor radiations can be useful for some patients with brain tumours.

The microscopic distribution of boron in the brains of 2 Na,BlzH,,SH-infused patients with malignant glioma has been studied in joint BNL-MGH investigations (Finkel et u l . , 1989; Slatkin et NI., 1989u, b ) . One of these patients, who had a right temporal malignant glioma, demonstrated a continuum of concentrations of 'OB in tumour and in peritumour brain tissue by neutron-induced 'OB radiography (fig. I , right) of an air-dried. unfixed, unstained cryomicrotome section of a surgical specimen from the right temporal lobe (fig. I , left). The specimen was snap-frozen in isopentane cooled

FIG. I . BNL-1-130-88. Reflected-light (left upper frame) and alpha-track (right upper frame) images (Slatkin (21 ( I / . .

19x90. b ) of untixed. unstained. SO pm thick cryostat microtome sections from a right temporal lobe spccirnen removed Juring operation o n a patient wlth a malignant glioma. Thc small left and right lower frames are the corresponding rcllecled light and JI ha IrJcl, images of cross-sections of frozen brain hornogenates to which have been d d e d 30. 9 . 3 . 0.3 and 0 pg I t ' Big, respectively, ' ' as non-I'B-cnriched sodium tetraphcnylborate.

I670 D. X. S L X T K I N

with liquid nitrogen within 1 min after its excision by the MGH neurosurgeon Charles Poletti to preserve the microarchitecture of fluid-filled spaces in tumour and peritumour tissues in microscopic sections and to minimize loss of 'OB from the specimen. Fig. 2 shows intermediate-power views by light microscopy of haematoxylin and eosin-stained. 8 pm cryomicrotome sections from several areas of the temporal lobe specimen shown in fig. 1. Fig. 2~ is from a 2-3 pg 'OBig zone, heavily infiltrated by glioma cells. that is contiguous with the intermediate alpha track density zone near the left margin of the specimen (fig. I , right). Fig. 2~ is from a 1-2 pg ''Big, apparently tumour-free. slightly oedematous, low alpha track density zone just to the right of centre of the specimen. Fig. 2c, shown at the same magnification as figs. 2~ and B , is from a highly oedematous, high alpha track density zone further to the right of centre of lhe specimen. Only two isolated tumour cells are noted in this field, but alpha track densities in the alpha radiograph of that zone correspond to 4 - 6 p g 'OB/g of tissue. the highest seen in the specimen. I t is surmised that the relatively high extravascular 'OB concentration was due mainly to diffusion of protein-bound sulphydryl borane from the blood plasma through leaky capillary endothelium (Slatkin CY nl., 19890). The patient had received an intravenous infusion of 95% "B-enriched Na2BI2H,,SH to a total dose of 15 p g "'Big o f body weight over a 20 h period. The bpecimen was removed about 26 h after the end of infusion during a neurosurgical debulking. The total dose of Na,Bl2HIlSH infused into this patient was 2- to 5-fold less than the doses administered to BNCT patients in Japan (Hatanaka et u l . , 1 9 8 6 ~ ) . The uniform distribution o f boron tracks in thc peritumour oedema zone suggests that BNCT has the potential to deliver therapeutic doses of radiation to oedematous brain tissues that harbour tumour cells beyond the macroscopic limits of malignant gliomas.

I t was shown that Na4B24H22S2, one o f the spontaneous oxidation products of' Na,B,,H, ,SH, has more favourable properties as a carrier of boron to ;L.transplantablc moiise melanoma than does the parent monomer (Slatkin er r i l . , 19860). Other tlvourablc aspects of the dimer were recognized earlier (Hatanaka and Sano, 1973) and concurrently (Slatkin et d., 1 9 8 6 ~ ; Sweet et d., 1986). There is striking improvement in boron uptake and in tumour boron retention in rat gliosarcomas after delivery of boron 2s dimer as compared with delivery of boron as mononier (Joel et al . , 1989). Indeed. recent studies have shown a prolonged amelioration of neurological symptoms and ;I gcafly incrcascd median duration of survival in rats with otherwise rapidly lethal transplanted intracranial gliosarcomas treated with BNCT using "'B-enriched dimer as the boron transport agent (Joel el nl . , 1990). The estimated radiation dose to these tumours was 25.6 Gy-Eq. whereas the estimated dose to capillary endothelial cells of the normal cerebral parenchyma of these rats was 15.2 Gy-Eq, which is somewhat higher than the postulated tolerance dose limit ( - 10 Cy-Eq) to such cells in the human basal ganglia. The estimated dose to the normal rat brain parenchyma was only 6 .9 Gy-Eq, which corresponds to a tumour-to-brain radiation dose ratio of nearly 4 : 1 (Joel c'r a / . , 1990). As in the 1972 BNCT of one of Hatanaka's long-term surviving patients (cited above), '"B concen- trations in the rats' blood were higher than in the gliosarcomas during irradiation.

The spatial distributions of slow neutrons in BNCT patients at MIT during 1959 - I96 1 were different from those at BNL. At MIT, Sweet used an air-filled balloon to facilitate the transport of thermal neutrons to the deep margins of the tumour bed. This idea was adopted by Hatanaka for certain cases, including his outstanding case of 1972. Although

B O R O N N E U T R O N C A P T U R E T H E R A P Y

,

C I - . C I lobe \pccinicn containing 4 -6 pg "'Big (see rcrr and l ig I )

1621

FIG. 2 . A . BNL-6-342-X8. Photomicrograph 0 1 human cliorr1;i turntiur I ISWC in a temporal lobe hpccinicn containing 1 - 3 116 "'B/g o e c wsr and lig. I ). B . BNL-6-343-X8. Pli~i~oinicrocrnpti of \lightly cwxlcniauiuh hrain ti^^ in J t c ~ ~ i p ( ~ r ~ i I liibc \pccinicn containing 1-1 pg "'Bic (ircetexr and lig. I ) . (-. BKL-O-?JI-XX. Photomicrorranh ot h i r h l v ocdcnialouh hrain Iihwc in a tc'ninor:il

1622 D. N. S L A T K l N

the MIT BNCT trial failed, it is not clear that the usefulness of a gas-filled space in the tumour cavity during BNCT can be discounted. Not only might i t aid penetration of slow neutrons into the brain, but i t could also be used to mitigate postirradiation brain swelling and to apply postirradiation hyperthermia to the residual tumour. Conceivably, a semipermeable balloon could provide a steep concentration gradient of oxygen in tissue at the margin of the tumour cavity to enhance the radiotherapeutic efficacy of the concomitant gamma radiation. The catheter leading to the balloon might also serve as a conduit for delivery of chemotherapeutic agents directly to the residual tumour bed.

Current research on BNCT focuses on the pharmacological and radiobiological evaluation of new boron-transport agents (Barth el ai . , 1990). Besides that, a major accomplishment has been the design, construction and physical evaltation of an intermediate energy or ‘epithermal’ neutron beam at the BMRR suitable for clinical BNCT (Fairchild, 1965; Fairchild et a / . , 1990). An epithermal beam produced by a different neutron-moderation technique (G. Constantine, unpublished) is near completion at a nuclear reactor in The Netherlands under the sponsorship of the Commission of the European Communities (Gabel, 1990). Epithermal beams for clinical BNCT can be constructed at several nuclear reactors that are not far from centres of population in the USA (Fairchild et a) . , 1990; Brugger and Herleth, 1990), probably at modest cost. Whether the monomer Na2B,,H, ,SH, its dimer Na2JB2,H12SZ, a boronated porphyrin (Kahl et af., 1990), a boronated amino acid (Coderre ef al. , 1990), or some other boron carrier will be tested clinically for BNCT of malignant gliomas in the USA has not been determined. It is likely that the distributions of trace amounts of several boron carriers will be studied in volunteers before trials o f BNCT of human gliomas will resume in the USA, and that the new trials will use epithermal neutron beams. Thc use of ‘OB-microlocalization techniques such as neutron-induced alpha track registration in etchable plastic films (Becker and Johnson, 1970; A m m o and Sweet. 1973; Abc. 1982; Fairchild et af., 1986; Gabcl ct u l . , 1987; Finkcl C I u l . , 1989). as in fig. I . should facilitate such distribution studies.

A C K N 0 W L E D G E M E N T S

TliL aniclc IS dedicated to the late Mr Tadcusz Kunikowski in apprcciation’of his meticulous cxpcrirncnral work on neutron capture therapy. I thank Dr L c c Farr for his encouragement of the review of data from the BNL clinical trial o f BKCT at the BMRR. and Drs Victor Bond. Ralph Fairchild. Maurice Goldhabcr. laincs Robertson and William Swcct for their helpful comments. I am grateful to my collcaguc Dr Gsruld Finkcl lor his permission to publish the photomicrographs o f fig. 2 . Special thanks arc due to the nursinf staff o f t h c Hospital of the Medical Research Center for their extraordinary skills in thc cited BNCT 5tudich at BNL.

Many interesting contributions to ncutron capture therapy research have not k e n cited hcrc either bccausc of space limitations or because of my assessment of lhcir relevance to thib restricted review. This rcwarch was supported by the US Dcpartmcnt of Encrgy under Contract DE-AC02-76CH00016. Accordingly. thc US Government retains a noncxclusive. royalty-free liccncc to publish o r reproduce the published form of this contribution. o r al low others to do hu, for US Guvcrnmcnt purposcs.

B O R O N N E U T R O N C A P T U R E T H E R A P Y 1613

R E F E R E N C E S

A B E M (1982) 'OB compound distribution i n rat tissue of transplanted and ethylnitrosourea-induced brain tumors. F~rkuoka Acra Medicu, 73, 250-271 (in Japanese).

A h r A L D l E. D'AGOSTINO 0. FERMI E, PONTECORVO B, RASETTI F, SEGRE E (1935) Artificial radioactivity produced by neutron bombardment-11. Proceedings ofrhe Royal Soc ien o f b n d o t ~ . A . 149,522 - 5 5 8 .

A h l A N O K. SWEET WH (1973) Alpha autoradiography of 'OB compound distribution in tissue by use O f

superimposition technique. Nippoti Acra Radiologica, 33, 267 -272. A R C H A M B E A U JO (1970) The effect of increasing exposures of the i0B(n,cr)7Li reaction on the skin of man.

A S B U R Y A K . O J E M A N N RG. NiELsEN SL. SWEET WH (1972) Neuropathologic study of fourtcen cases of malignant brain tumor treated by boron-IO slow neutron capture radiation. Joiinlal ofNei tropar/~olo~!~ and Experitnenral Nertrology, 31, 278-303.

BAKTtI RF. SOLOWAY AH. F A I R C H I L D RG (1990) Boron neutron capture therapy ofcancer. Cuncer Research.

BECKER K. J O H N S O N DR ( 1970) Nonphotographic alpha autoradiography and neutron-induced autoradiography. Science, 167, 1370- 1372.

B O N D VP. EASTERDAY OD. STICKLEY EE. ROBERTSON JS (1956) The relative biological- effectiveness of thermal neutrons and of the heavy particles from the "B(n.u)'Li reaction for acute effects in the mouse. Rudiology. 67, 650-664.

B o i iir: W , BECKER H ( 1930(1) Eine Kern-y-Strahlung bei lcichten Elementen. Nurirnc,is.setiscliu~en. 18, 705. BO-IHE W. BECKER H (19300) Kunstliche Errcgung von Kern-y-Strahlen. Zcirsclrrifi Jir Pliysik, 66,

BROOKHAVEN N A T I O N A L L A H O K A T O R Y (195 L ) Annitri/ Reporr. Ju ly I . 1951. BNL 131 (AS-5) Upton. Ncw

R d i o l o g y . 94, 179- 187.

v

50. I061 - 1070.

289-306.

York: Brookhavcn National Laboratory. pp. 103 - 105.

York: Brookhavcn National Laboratory, pp. 52-54 . B K O W N E L L GL. SWEET W H (1958) Studies o n neutron capture therapy. I n : Procwrlinq.s o f r l r c , S w ) n t l

Utrirccl N~rrions lnrcrniiriorrcil Confcrcriw OII rlw PenccJitl Uses ofArottiic Enc,rsyy. Volume 26. Geneva: United Nations, pp. 444-450.

B R u ( ; ( ; r : R R M . HI:RL[~-I'H WH (1990) Intermediate energy neutron beams from the MURR. I n : Proc.cwliti,q.\ ( I J " ( 1 l~?trks/ fop ( ~ 1 1 ~ ( w r ~ i ~ i Bcw1n Design, Dcivkoptrictfr and Pcrfi,nnancr for Ncirfro,i Ce~prrm~ nic,rrip>'. March 30-April I . 1989. Editcd by 0. K. Hrrrling. J . A . Bernard and R. G . Zamcnhol'. New Yorl.: Plcnuni Press. pp. 153- 166.

B K O O K t I A V E N NA.TIONAI. LABORATORY (1953) A t f r ~ i r ~ l Repon. July I . 1953. BNL 246 (AS-7) Upton. N C W

BL:K( . I IAh i WE. GOLDHABER M (1936) The disintegration of nitrogen by slow neutrons. Proccwhngs of

C I I A I ) W I C K J (1932) The existence of a neutron. Procecclings of r / i e R o y d Socicrv o j L)ncIon, .1. 136.

CIIAI)WICK J (1937) The neutron and its propcrtics. In: L . s Prir Ntilxdcvi /935. Edilcd by M. C. G. Sanrcron.

C I I A I ) W I ( ~ K J . GOLIIHAUEK M (1935) Diiintcgration by slow neutrons. Nrrrirrc. f a t i d o n , 135, h5 COI)I!KKI; JA. GLASS JD. F A I R C I I I L D RG. MICCA PL. F A N D I . J O E L DD ( I 9 O ) Sclect ivc delivery of boron

by the niclrrnin precursor analogue I'-boronophcnylalanine to tumors other than melanoma. Cutic.c.r Rcscwrch. 50. 138 - 141.

CONN HL, ANTAL BB. FARR LE (1955) The effect of large intravenous doses of >odium borate on thc human myocardium as reflected i n the electrocardiogram. Circulurioti. 12, IO43 - 1016.

CONS.rANTINE G. B A K E R u. MOORE PGF. T A Y L O R NP (1986) The depth enhanced neutron intense source (DEN IS). In: Ncurron Cupriire n iempy: Proceedings ofr l ie Second ltrtenuiriorml Syrnposiion on Niwrriitr Ciiprirre 7?rcwpy. October 18 -20. 1985. Teikyo University, Tokyo. Editcd by H . Hatanaka. Niigaia. Japan: Nishimura. pp. 208-222.

CONS.I.ANTINE G. G I B S O N JAB. HARRISON KG. SCHOFIELD P (1989) Hawel l research o n beams for nculron capture thcrapy . Srrn/i/erir/ic~rc~p~e iord 011kologie . 165, 92 - 95.

C U R I E I. Jo i - iOT F (1932) Effct d'absorption de rayons y de [res haute frkquencc par projection de noyaux ICgcrs. Cotnprr.r Rcnclir. P(1ri.s. 194, 708-7 I I .

1/11, Cll/tf/?ridh'l' Plli/O.SO[?/liCU/ S(JCiely, 32, 632 -636.

h02 - 708.

Stockholm: Norstcdt and Siincr.

I624 D. N S L A T K I N

EASTERDAY O D , F A R R LE (196 1) Alteration of borate toxicity by D - ~ ~ U C O S C . Joiirtiul of Plicirtncicdox! und Epr in ienml 77iempeuric.s. 132, 392 -398.

EASTERDAY O D . HAhrEL H ( 1963) Acute intravenous and Intraperitoneal toxicity studies on hodiunl

pcntaboratc decahydrate and sodium tetraborate decahydrate. ,4rchii8rs //ircrtiNriorin/es dz Phcirt~icicori~,riattiie e! de 77ikrripie. 143, 143 - 163.

FAlKCHlLo RG 11965) 'Epithermal' neutron beam isodose charts in a phantom head. Radiolog!. 85, 555 -564.

F A I R C H I L D RG. ROBERTSON JS. LEVINE DA. GOoDhrAN LJ (1966) A tissue-equivalent ionization chamber for in-phantom dosimetry: comparison of measured values with calculated values. Hecilrli Pliysics.

F A L R C H I L D RG. CABEL D. LASTER BH, G R E E N B E R G D. KrszENrcK W. M I C C , ~ PL (1986) Microanalytical techniques for boron analysis using the '"B(n.a)'Li reaction. Medical Physics. 13, 50 -56.

F A I R C H I L D RG. S A R A F SK. KALEF-EZRA JA. LASTER BH (1990) Comparison of measured paramcters from a 24 keV and a broad spectrum epithermal neutron beam for neutron capture therqpy (NCT): an identification of consequential parameters. Medical Physics. 17, 1045 - 1052.

F A K R LE: (1960) Nuclear reactor radiology in clinical medicine. Nonliwesr Medicitie. 59, 1121 - 1133. F A R R LE. ROBERTSON JS. S-riCKLEY EE (195-10) Physics and physiology of neutron-capcure therapy.

Proceeditigs of rhe Nuriotiul Acciclettiy of Scioices of the USA, 40, 1087 - 1093. F A R K LE. SWEET WH. RoBwrso;.r JS, FOSTER CG. LOCKSLEY HB. SUTHERLAND DL ('1 (11. ( l954b) Neutron

capture therapy with horon in the treatment of glioblastoma multiforme. Aniericciti Joiinicil of

F A K K LE, SWEET W H . LOCKSLEY HB. RORERISON JS (1954~) Neutron capture therapy of gliomas using boron- I O . Trtitiscicriotis (jf rlie Attiericuri Ncitrolo,gicnl Associcirioti. 79, I I O - I 13.

F A K K LE. ROHEKTSON JS. S I I C K L E Y EE. BAGNALL HJ. EASTERDAY OD. K A H L E W (1958) Rcccnt advance!, in neutron capture therapy. I n : Proccediti~q.s of rlie Scrnrid Urii!erl Nuriom /t//crriti!iotiu/ Cottji,rctil,c, o t i r l i r Pctict$il Uw.s of Atomic Eriergjf. Volurnc 76. Gcncva: United Nations. pp. 45 1 -456.

F A K K LE. K O N I K O W S K I T (1964) The effect of regional thermal-neutron exposure upon the growth and transplancability of a ni;ilignanf tumor in Ihc inouse. In: Procceditigs t / l / ie sytripo.Yiutti of1 Bio/ocqicw/ E f f i ~ l . ~ ~ ~ N C I I I N J ~ /rrudi(iiiotis. Brookhaven National Laboratory. Upton. New York. October 7 - I I . 1963. Volume 2. Vienna: IAEA, pp. 157- 172.

F A K K LE. K O N I K O W S K I T ( 1967) Transplantable mouse ncopla>m control by neutron caprurc therapy. " & ~ i ~ t - t , ~

FAKK LE. R O I ~ E K T S O N JS ( 197 I ) Ncurron capture therapy. In: b f o ~ t d h i i c ~ l i dcr Mtdi;irii.\t./ic /?eic/io/o,yic Hcidclbcrg: Springer. pp. 68 -97.

FAKK LE. K U N I K O W S K I T (1976) Long rangc effects of neutron capture therapy of canccr in iiiicc-I. l t i! t , t - t i [ i f iot i ( i l Joirrricil o/ Niie/cwr Mctlicitir ririti Bio/o,qy. 3 . I - 8.

I'bKhii E (1939) Artificial rgdioactivity produced by ncutron bonibardinent. In: k s Prir /Vo/ic/ ('ti /939. Edited by M . A. Holmberg. Stockholm: Norstcdt and Stjncr.

f : t ; K M l 1;. Ahl,\i.nI E. D'Acos-riNo 0. RASETTI F. SE(;K<: E (193-1) Artificial radioaclivil)' produced hy ncu~ron honibardmcnt. Proc~c,cclitig.s of rlrc Ro!u/ SocYer!, of L~tidon, A . 146, 48.7 -500.

f-ixI;i.i. C C . Poi.r:.r.iy CE. FAIRC.I{II.D RG. SixrKIN DN. SwmT WH (1989) Distribution of "'B al ter inlusion of Na,,"'B,,H,,SH into a patient with inalifnant astrocytoma: implications for boron ncutron capturc iherapy. Nciiro.siir,y~~n.. 24, 6- 1 I .

GAI)I:I. D. HOI.STI:,IN H. LAKSSON B. C3ti.t.E L, EKrc-soN C. S A C K E R D. Soh1 P. FAIHCII I I .D RG (19x71 Quantitative neutron capture radiography for studying the biodistribution of [uiiior-sxking boron- conlairiing compounds. Git icrr Rcserirch. 47, S45 I -5354.

G A H E L . G (1990) The Europcm collaboration o n boron neutron capture therapy. In : Forinli Jtipritr-,.lii.srrci/i[i

/ t i r cn i t i r i o t i t i l Workshop OII 77ie,rrntii Neulroti Coprurt, 77ic.rup? for Mci l i , y t i r i t~~ M c / ~ i t ~ o t t i ~ i . Kohc. Japlrn. Fchruclry 13 - 16. 1990. The Japanese Ministry of Education. Rcpon SINCT-REP-3. p . 39.

Gorxi . J B ( 1960) Description of facilities and mechanical components: Medical Research Rcactor 1 &IRK). Rcpon BNL 6W (T- 173). Upton, NY: Brookhaven National Laboratory.

Gonn,iw JT. F A K K LE. SWEET WH. ROHEKTSON JS (1955) Pathological h t u d y of eight paticnth with glioblastoma multilornic treated by neutron capture therapy using boron IO. C(itic.c8r. 8 , 001 -0l.S.

12, 787-792.

R ~ ~ e t ~ ~ ~ ~ t ~ r i o l o ~ ~ . ? ~ . 71, 779 -793.

Lr)t i t lot i . 215, 550-552.

B O R O N Y E U T R O N C , A P T U R E T H E R A P Y 16-75

GOLDHABEK M 1986) Introductory remarks. In: Procecdiri,qs nfn Workshop O ~ I IVfwrmi Cripritrc 71rc,r(t0>. Repons BNL-51994. Edited by R . G . Fairchild and V . P. Bond. Upton. NY: Brookhaven S;itional Laboratory, pp 1-2 .

H A T A N A K ~ H (1986) Introduction. In: Borori-f~'cicrrori Ccipritrc 77ierapyfiir Tie/r1or5. Edited by H . Haranaha Niigara. Japan: Nishimura. pp. 1-28,

HArmr\Kt t H. S A N O K (1973) A revised boron-neutron capture therapy for rnalignant brain tumors: I . Experience on tcmminally i l l patients aftcr Co-60 radiotherapy. Zti i .sc/mJfi ir- !Veitm/ogic. 2 0 4 , 309 -332.

Hxr.AvAliA H. KAhlANO s. AhlANO K . HOJO s. SANO K. ECAUVA s. YAsuKocIil H (1986ct) Clinical experience of boron-neutron capture therapy for gliomas -a comparison w i t h conventional chcrno- immuno-radiotherapy . In: Borori-Neicirori Coprirre nicmpyfor Tirrtiors. Edited by H. Hatanaka. Xiigata. Japan: Nishiniura. pp. 349-379.

H A I . A N A K A H. AhiANo K. K A N E S I I T S U H. I K C U C H I I . Y O S H I Z A K I T (19860) Boron upt?kc by h u m a n brain tiiinors and quality control of boron compounds. In: Bororz-Neiirrmi Giprrtrc nTicrcip? for Tirrrior.~. Edited by H . Hatanaka. Niizata. Japan: Nishiinura. pp. 77- 106.

H A I A S A K A H. URANO Y (1986) Eighteen autopsy cascs of malignant brain tumors treated by boron-neutron capture therapy betwcen 1968 and 1985. In: Bn/-ori-Nciirrori Cnprirre 7 7 i c r u p ~ j b r Tirrrior.7. Editcd b) H. Hatanaka. Niigata. Japan: Nishimura. p p . 381 -416.

J A V I D IM. B R O W N E L L GL. SWEET W H (1952) The possible use o f neutron-capturing isotopes such ;I\

boron"' in the trcatmcnt of ncoplasms. 11. Computation o f rhc radiation energies and c'stiziiate\ o f effects in normal and neoplastic brain. JoierficJ/ of' C/iri ica/ / / i ~ , f ~ . s f ; ~ ~ c i i ; o j r i , 31, 601 -610.

J o i : ~ D . S L A I . K I N D. F A I K C I ~ I L D R. Mice,\ P. NAWKOCKY M (1989) Pharmacokinetics and tissuc distribution of the \ulfhydryl boranes (monomer and dimer) in glioma-bearing rats. Srrci/ilcri/lic,ntpic, i r / i r i Oriko/o.qie,. 165. 167 - 170.

JOEI. DD. F#t!Kcifii.n RG. L A ~ S S U E JA. SAKAF- SK. K A L E F - E Z R A JA. S;I.,imiv DN (1990) Bi)ron neutron caprurc thcrapy of intraccrcbral rat gl iosarcomih. Procec,diri,q.v od'rlic N e t r i o r i ( t / Ac.err/c./try oj'Sc.ic~,rc e'\

K A I I I . SR. JOI..L DD. NALVKOCKY M M . MICCA PL. T R A N KP. F I N K E L GC. SL.AIKIN Dh' (1990) Uptahc of :I ,rtc/i,-carboranylpo~hyrin by h u m a n glioma xenografts in athyrnic nude inicc and by \yngcncic i)v:iri:iii carcinomas in iiiiiii~noeonipetcnt micc. Proccw/iri,qs of//ic h'uriorirrl , . i u / d ( ~ r i ~ r , jS( . ic / ic . t , . \ I ) /

l l i l , iJS/i, 87, 7265-7269. K I I 40 K (1075) A incrhi)d for calculating the absorbed dose ncar interface from "'B(n.cu)'Li rcactio~i.

Ro/o/i~lfiorl R(,.vcwrc./l, 61, 304 - 3 15. KSO(.K FE ( 1059) Pcrl'uhion of uraniuni-antibody cornplcxes for the neutron capture [herap! o f iuii icir\ .

. ' j r / rqc,r : ) , , Gyri~c.rn/o,~~~~ c i r i r l Oh.src,/ric.c. 109, 445 -449. K N O I I I WH. S A U E K J C . EN(;I .ANI) DC. HERTLEK WR. M U E ~ . T E K T I E S E L (1964) Chcmihtry of boronh.

X I X . Dcrivativc chcmktry o f Bi i lHl , , - ! and B, ,H, , -!. Joitrticil of'rhc Arrrc-ric.ciri C / i m t ~ ~ c t / Srx.rci\. 86. 3973-3YX3.

K ~ W I K O \ ~ T K I T. F A K K LE (1965) Determination o f microgram quantities o f inorganic hori)n i n nianiiii~i1i;in

>pcciiiicnh. Cliriit~il C/ic,rni.\iry, 11. 378 -385. K K I J G I . K PG ( 1940) Sonic biological ctfccts o f nuclear disintegration products o n neoplastic tissuc.

LI.A DE i l9S6j ,+I(.iioti,x of Rrrc/itrtioir.s 011 Lii,irig Ccl/.\. Second edition. Cainbridgc: C~lmbridgc Univcr~iry

LOCIII -K GL (1936) Biological effects and therapeutic possibilities of neutrons. ,+ucri(nri Joirrrw/ (4'

LOCKSL.EY HB. F A K R L E (1955) The tolerance of large doses of sodium boratc intravcnouhly by patient\ rcccivrng neutron capture rherapy . Jo/r~-n(i/ 14 P/icirrriric.,,/o,~? rrrirl Erp',rirtit,rifci/ Tlic~/-ct/~c~riric..s. I 14. 484 -489.

MCCI. IN IOCK L A . FHIEDhlAN MM (1945) Utilization of ;intibody for the localiration o f iiicta1\ and d y c h i n the tihwcs: preliminary rcport. .Atticrre.ciri Joitrrirrl od' R ~ ~ ~ ~ / i i , ~ ~ " i ~ ~ / ~ ~ g ~ ~ , 54, 704 - 706.

M,\ISLhlolo T. A!%Aw,\ 0. X ~ L A R I T. SAKI T (1986) Musahtii lnhtitutc ofTechnolocy Rcactor as a nicdical faciliry-with reference to dosimetry and iri . r i r i t boron conccntration rneasureiiients. In: B~,r /~/ / - rVc. i r f r -~ f r~ Cctpf/tr-e 77icrcipy j i ) r Tiirtior-.v. Edited by H . Hatanaka. Niigat;i. Japan: Nishiniura. p p 235 -24 I

o / ' r / w USA, 87, 9808-9812.

P/-oc.c,c,c/i/i,q.v (4 ! / I C /Vti/iotiei/ , 4 c ~ i r l c t 1 1 ~ (4 SC~O/ICC.S (d' / / I C U S A , 26, I8 I - 197.

Prchh. pp. 19-21.

Ro)c, r l r~c ' r l , ' /o ,q~ ' . 36, I - 13.

1626 D. N . S L A T K I N

M I L L AJ, DURRANT KR, HOPEWELL J W (1986) Dose distribution and rationale for BNCT with filtercd beams. In: Neutron Captiire Therapy: Proceedings of the Second lnrernatintiul Ssrriposiilrn oii Neiirrorr Cnprltre 77zerupy. October 18-20, 1985. Tcikyo University, Tokyo. Japan. Edited by H . Hatanaka. Niigata. Japan: Nishimura. pp. 12.5 - 126.

MILLER GT. KRALIK RJ. BELbioRE EA. DRURY JS (1958) Production of boron-10. In: Proceetlitigs of the Second Uriired Nutions Cut$ererice on Peacefit1 Uses of Arotriic Giergja. Geneva: United Nations. pp. 585-594.

MILLER HC, MILLER NE, ,MUETTERTIES EL (1963) Synthesis of polyhedral boranes. Jortrtini ofrhe Atnericutr Clierriicnl Society. 85, 3885 -3886.

MORGAN GR. ROBERTS CJ , MILL AJ. CONSTANTINE G. HOLT P D (1986) Survival and cytogenetic analysis of Chinese hamster. V7914 ( A H ] ) and human. HcLa cells irradiated with 24 keV neutrons. I n : N e w m i Cupriire Therapy: Procredirrgs of the Second hrcrnnrionu/ S?.rnposiriin on Neurroti Cuplitre 77ierap!.. Octobcr 18-20, 1985. Teikyo University. Tokyo. Japan. Edited by H. Hatanaka. Qiigata. Japan: Nishimura. pp. 117- 124.

ROBERTSON JS. STICKLEY E. BOND VP, FARR L E (1955) The proposed Brookhaven Medical Research Reactor. Nucleonics. 13, No. 12. 64-68.

ROHERTSON JS. STICKLEY EE. FARR LE (1962) Uses of a nuclear reactor in medical and biological research. In: Prcq,Jrurrirriitig atid Uii/izoriori of Resecircli Rcwcrors. Proceedings o f a Symposium. Vienna. Octobcr 16-21. 1961. Volume 3. New York: Academic Press. pp. 451-461.

ROI3ER.rsON 1s. L E V I N E DA. FARR LE (1967) A method of calculating intracranial thermal neutron isodose curves. Merhods of lt~j?rrtriuri~iti in Mcdicitic, 6 , 19 -83.

RUTHEHFOHD E ( 1920) Nuclear constitution of atoms. Procccditigs of rhe Ro>al Socirrx of Lmlori. .i, 97, 374-400.

R Y D I N RA. DEurscrr OL. M U R R A Y BW (1976) The effect o f geometry on capillary wall dohc for boron neutron capture thcrapy. P/iysic.s ;ti Medicitic, u / d Biology. 21, 134- 138.

SANO K [ 1981) In: Bruiti Eitnors. Second cdition. Tokyo: Igaku-Shoin. p. 92. S 1 ~ f . x F L I . FAHR LE. RoeERTsoN J S (19.53) Dye carricrs of boron for neutron capture therapy. In: Qiur~r*r /~ .

ProSrcss Rcporr, April I -June 30, 1953. Upton. NY: Brookhaven National Laboratory. BNL 243

SI.,\ I K I N DN. ,McCtiEsNEY DD. WALLACE DW (1986fi) A rctrospcctive study of457 ncuromrgicsl paticnts with ccrcbral malignant glioma at the Massachusctts General Hospital, 1952- 1981: implications f i x q u c n t i a l trial5 of postoperative therapy. I n : Neitrr,itr Ccipritrc, 77lerup.v: Procccrlitigs ( $ r / i c . k c , o t r t /

/ i i cc*n ic i r io t r~ i / Sytriponiiuti o t i Netirrori Cuptirrc 77rerupy. Octobcr 18 -20. 1985. Tcikyo Univcrsir): . Tokyo. Japan. Editcd by H . Hatanaka. Niigata. Japan: Nishimura. pp. 434-446.

SI .AI K I N D. MICCA P. FORMAN A . GABEI. D. WIELOPOLSKI L. F A I R C H I L D RG (19x611) Boron upt;ihc in mclsnoma. ccrchrum and blood from Na,B12H, ,SH and Na,B,,H21S2 adniinihtcrcd to niicc. B i o c . l r r , t t i i c . r i / Plirrr /~ir icolo,~~. 35, I77 I - 1776.

SI.A I K I N DN. IMIC'CA PL, LASTEH BH. FAIRCtI1t.D RG ( 1 9 8 6 ~ ) Distribution of sulfhydryl horsnch in mice

and r3t.j. in: IVorkshop o i i Ncittro/i Cuprttrc nicrupy. Rcports BNL-S1994. Edited by R . G . Fair~~tiiltl and V . P. Bond. Upton. N Y : Brookhavcn National Laboratory. pp. 173- 177.

radia~ion \yndrornc in mice from prcfcrcntial "'B(n.u)'Li irradiation o f brain vasculaturc. P r o c . c ~ l i t ~ , i ' . \

( S I X ) . p. 49.

S I . , \ I K I K DN. S l O N l < H RD. K O S A N D E K K M . K A L E F - E Z R A JA. LAISSUE JA (1988) Ccnrral ncrvouh >y\ lCI11

(Ij ' l l tc. / v ~ l l i o t l c i ~ Au1o/r,rtty or/ SCiC~llC~C'.S r h r , USA. 85. 4020 -4024. S l . h l K l N Dh'. JOEL DD. FAIRCt1II .D RG. MICCA PL. NAWHOCKY MM. LASTER B H , CODERRI: JA. FI

GC. Por.ci--ri CE . SWfiET W H (1989~0 Distributions of sulfhydryl boranc monomer and dimer in rwlcnts and monomcr i n humans: boron neutron caprurc thcrapy of mclanonia and flioina in horonstcd rodenrs. In: Clitiicrrl A.spc,cr.s of Noirirorr Cuprrtrc 77ierup.v. Edited by R. G. Fairchild. V . P. Bond and A . D. Woodhcad. New York and London: Plcnuni Press. pp . 179- 191.

S L A I . K I N DN. F I N K E L GC. MICCA PL, LASI-EK BH. POLEITI CE. SWEET W H ( 1 9 8 9 h ) Dihtribution of boron in two (B, ,H, ,SH) "-infuxd paticnts with malignant gliomas. Srrc,/iloi//ic,rci/,ic t i t i t i Otiho/o,ycc..

SOLOWAY AH ( 19.58) Correlation o f drug pcncrration of brain and chemical structure. St.ic,iir~,. 128. 165, 243 -246.

1572-1.57-1.

B O R O N N E U T R O N C A P T U R E T H E R A P Y 1627

SOLOWAY AH ( 1988) Summary of workshop. In: Procedir igs ofn Workshop ot i Eorori Cornporrr~ois Ibr Neitrrori Cupritre nierapyfor rhe Treurrtierzr of Cuticer. Radiation Research Program. Division of Cancer Treatment. Bethesda. MD: National Cancer Institute. pp. 1 - IO .

SOI.OWAY AH. H A T A N A K A H. D A V I S ,MA (1967) Penetration of brain and brain tumor. VII. Tumor-bindin: sulfhydryl boron compounds. Jourtiul of Medicitid Clierri isrn. 10. 714-717.

STEINFIELD W ( 1952) Preparation of uranium arsphenamine. a possible capture compound. In: Qrtcir!e!lx Progress Reporr. October I -December 31. 1952. Upton. NY: Brookhaven National Laboratory.

STICKLEY EE. F A R R LE (1960) Design and performance of field-defining apenures for neutron capturc

S.1 ONE RS ( 1948) Neutron therapy and specific ionization. htiericciji Joirniril (f Rorrirgoi,,lo,s?. 59.

S T R A N A I H A N JD (19.12) n i e 'Pnrricles' of Modprri Physics. New ' fork: Blakiston. p: 386-402. S W E E T WH ( I 9 5 I ) The uses of nuclear disintegration in the diagnosis and treatment of brain tumor. ,Vci~.

Etrglarid Joitrriul of Meclicirie. 245, 875 - 878. SWEET WH ( 1986n) Preface. In: Neirrrori Cqmtrc nicr(zpy: Proccediqx of rhc. . k o , i r / // i((,r/ ioriori(i/

sy!tipo.siit/ti oli N(,tirrori Cuprure T/ierapy. Octobcr I8 - 20. 1985. Teikyo University. Tohyo. Japan. Edilcd by H. Hatanaka. Niigata. Japan: Nishimura.

S W E E T WH ( 19866) Medical aspects of boron-slow neutron capture therapy. I n : Workshop o r 1 Ncitrrori CqmtrLp 77rcrcip.v. January 22-23. 1986. BNL-51994. Edited by R. C. Fairchild and V . P. Bond. Upton. New York: Brookhavcn National Laboratory, pp . 3 -21 .

Swt; .~-r WH. J A V I D M (1951) The possible use of s l o w neutrons plus boron"' in therapy of intracranial tumors. Trcrrr.strciio,r.s ofrlic A/ticricwi Neitro/o,qiccil Associririori. 76th Annual Mccting. pp. 60 -63 T WH. J A V I r ) M (1952) Thc poasiblc use of ncutron-capturing isotopcs such as boron"' in the

trcalmcnt of ncoplasms: I . Intracranial tuniors. Joirnicil of Neitrositr,qcn, 9, 700 -709. 'I WH. Mr:ssri~ JR. H A I - A N A K A H (1086) Suppleriicntary pharmacological a tudy hctwccn 1977 and 1977 on puri ficd incrcaptoundccahydrcidodccahorate. In: Oon,ii-rVf,trrro/i Gipritrc, 77icrfrp),jiir f io/ior.\. Edited hy H. Hatanaka. Niigata. Japan: Niahiniura. pp , 59 -76 .

T A Y I O K JH. GoI . ! ) i1AI%t ; .K h.1 (1Y35) Dctection ofnuclcar disintcgralion in a photographic ciiiulsion. ~ V ~ i r i t / - c ,

Lnrt/orr. 135, 14 I . Toiii,\s Ci\. b ' f : Y h i o u 1.11 PP. W,\ssriKh!,\N L.R. S I A P I . I : I ~ N GE ( 1938) Sonic hiological cl.l'ccts due IO riuclc:ir

Visaion. .Scicrrr.c,. 107, I I S - I I X. ZAI{I. PA (1041) In: R t i i / ; o / o ~ y ~ , 37, 680. ZAIII PA. COOIT.K FS. I ~ C I N N I N G J R ( 1940) Sonic in v i v o ct'li'cts o l local izcd iiuclcar disinic:ra~ion protluc.is

on ;I r r an~p lan~ab lc niousc urcoriia. Procwr/i/i,q.\ (d'rlic, iVtrrio/rti/ ,4ctrcl1wr? i f . S c / c * / i c . c , r i d r h c , U.S.,I, 2 6 . 5x!,-5vx.

Z A I I I . P A . COOPI:K FS ( I94 I ) Phyhical and hioIogic;il ~~~)n\ idcr : t t ions in [tic usc o t \lo\\ neutron\ l.or c:~iic.c'r [herap.. R(irlio/i),~x. 37. 073 -6X7.

ZIWhl I RI: ( l').?O) Ratliohiological additt\ 11. 0 1 \':irtotia iunt/.iii: radialioiih. . 4 r , i c . i - r c . o , 1 j o i t r . i i i i / , I /

BNL 719 (S-16). p. 51.

therapy. Radiology. 75, 602-607.

771 -785.

R o c ~ , i r , c i , , r r ~ / i ~ , ~ ~ , 63, 170- 17s.

( R ~ c . o / ~ ~ c * c / O r ~ o h c , ~ . I I . I Y Y O . : I ( . c . i , / ~ l ~ / ,V i ) \ . c+ / i i / )c , / - 16, / Y Y O I

1628 D N S L A T K I N

concentrationh in t issues by a modif ied quinal irarin method (Koni'io\bski and Farr. 1965) The I i r n L ' curyes tor "'B concentralions in blood. 6(t). and brain C( t ) , arc related by a l l rst-order differentia1 equal lon '

dC(t)/dt = 0 .012 [B( t ) -C l t ) l I l l

where coricentrationh are e x p r o d in p g I g tissue or blood. and time (1) i s expressed in ni in. The \anic equat ion d c s c r i h . with less precihion. the inouie blood-brain boron concentration relationship when the i . v . dose \va\ rcduccd to 35 "'BIg body weight. the dose which wab given in rhe 17-paricnt seriei at the B M R R . BIowI and brain bori)n concenrr;ition\ (measured by thc prompt-ganlmr! rechnique) afrer 3 \ingle i .p . injection into mice o t boric J C I ~ at a dohe of 125 rig boronig body w i g h t (Slatkin ('I nl.. 1988) can be correlated by the same k ind of equation with a slightly greater rate constant:

dC(t)/dt = O.OIS[B( t ) -C( t ) ] 12 I r

T h e e equations are analogous IO the cxpreshion of Fick's lirsr law of diffusion. whereby the rare of difru\ion of a \ubstancc 3cro\s a boundary hein ccn two compartnlents i s proportional to the concenlralion gradicnt bctuccn the compannicnis. Since t i h u e constitucnti and their microicopic dimensions in human and rnou.\c brain\ arc similar. Equation [ I I , which contains no tcrni t ha t i s an explicir nlcasurc of ;1 macroscopic brain diniension or ol a iiiacr:,scopic hrain boron concentration. can be used IO estimate [he average concentration of boron i n nonoedematous zones 01' the human cerebrum alter I . V . injection of pentaborate. The net rate of entry of pentaborate into ocdcnutou\ zone., of the radiarion-tlariia@cd human brain most probably exceeds [he raw of entry into the nonwdcniatoub brain. 50 that concentrations h o dcrivcd l o r brain tuniour pa[icnts Iron1 Equation [ I I arc low chtiniates. Upper estimatci arc reasonably cquarcd with blood concentrations. The uppcr curve of fig. 4 lollows "'6 concentrations i n 4 of the series of 17 paricnts with cerebral turnours (Tables 1-5) trcatcd at the B M R R who had the loweit measured b lood conccntrat ion~ a l ic r a htandard S-min i .v. inlu.\ion ol 35.1 +0.9 (SD) p g "'E/g body weight ( ranre: 32.4-36.9 pg 'OB/g) as \odium pentab~iratc cli.cahyJralc:D-rrluco\e i n the niolar ratio 2: I (Ho\pital o l the Medical Research Center. B N L . unpublished medical record\. 19SY - I Y O l ) . This standard inlusion ended about 30 i i i in belore thc \tart of irradiarion :I[ Ihc Bh4RR. B l o ~ d conccntrations iiicasurcd i n orhcr patients of Ihc same series wcre abour one-l i f th t o one-rhird greater rhan rhohc ( 1 1 the 4 patient\ indicated i n l ig. 4. T h e do\cs. l iming and other conditions of adminisIration o f pcn1:lborale. as well ;I\

the in lus ion- i r r l l~ ia t i [ )n t i i i ic intervals ( - 30-35 i i i in) . were alinosr identical in the 17 paticnr.s. T h u \ lo r the purpo\c 0 1 Ihcsc compararivc dosiinctric calculation\, the hlood arid riorrrial brain conccn~rations 01 "'B Juring irradiation\ arc ehtiii i i itcd lo hc 60 + I O p g i 9 and 35 r5 jig/g. rcspccriwly

Rxli:itiori tIo\c\ f rom the "E-neutron capture therapy rcx- t ion ro capillary cndothclial c e l l \ i n the hruin ;ire dcri\.cd

F I G . 3 . E N L - 9 - 1 0 0 - X Y . Conccntr:itionh o f "ID i n iiiousc blood (cro\sch) and brain Icirclcs) a l t e r prompt i . v injection o f I(X) pg "'B/g hod! wcicht a h Oh atoni "r "'U-enriched h t )d iu i i i

pcntaboratc with [>-gluct)\c. iiioI;ir ratio 7: I (T. K o n i h w \ h i and D. N. Slatkin. unpubli \hcd datal

'L 'I,

B O R O N N E U T R O N C A P T U R E T H E R A P Y 1629

130 t

FIG. 4. BNL-9-1 I 1-89. Concentralions of 'OB in patients after a 5 rnin I . V . infusion of 35 pg ' "Big body h c i g h t as 96 aloin '2 If'B-enriched sodium pcnraborare w i th D-glucosc. molar rat io 2: I measured in the blood (circles) and calculatcd in the bmin ( lower curve) for the 1959- 1961 B.MRR B N C T study. Estimated rnininiuiii concentrations durinr the irradiations corrcspond to thc intcrsccrions ( 1 1 the vcn ica l bar w i th the two curvc'i (T . K o n i k o \ \ \ k l . unpublished data: D. N. SI-ithin. Appendix) Ti i n c ( in i 11 )

in part lroin "'B in h lmd and from "'E in brain parenchyma in the relative proponion of approximately I :2 (set [ c r i I . Th;it I \ , the c l l c c t i v c "'B concentration l o r irradiation 01 normal brain capil lary endothelial cells in the 1959- 1961 U L I K K \tudy w a s ahout 1.'3 ( 6 0 ) + 7 / 3 (35). o r 43.3 wg "'W~ Similarly. m c c the i rcnchymal hrain '"N concentration is ahuut I9 ingig and the h l t x d IJN conccn[ration is about 38 i i ig/g, the effective "N conccntration for brain cndothclial irr:di:ition l.rorn Ihc ncutron-"N reaction was approxiniatcly 1!3 ( 2 8 ) + 2 / 3 (19). or 22 nig "Nlg. Ahsumins that the cllC.ctivc thcrrnal ricutron capture cross-scctions lor the ncutron-"'B and ncutron-I'N reactions arc 3.40 x I O - ' ' cni' and I . M X 10 - " em2. respectively (Slatkin c l d . . 1988). the doses to endothelial ccIl\~ f r om thcsc rcaciions arc h 0 5 1 x I O - I ' [b G y - E q lroni ")B and 0.31 I X I O - ' ' [b Cy-Eq l ron i IAN. whcrc 4> i s the thcrrnal neutron llucricc in ncutri ins pcr ciii'. Thcsc lormulac arc based on an assumed RUE o12.0. which is appropriatc lo r acutc cllccrs i n nornial iii:iiiiiii;ili;in hrxi i i capil lary cndothcliuin of rhc shon-rangc ioniring parriclcs produced by the ncutron-"'B ;ind ncutron-"N reaction\ ISIJtkii i ('1 ill.. 1988). I t is calculatcd I r o m puhlihhcd data (Matsumoto ( ' I d.. 19x6) that the half- arrcnuarion d c p h . l)i!2 cni. lo r thcrrnal neutrons in the hurnnn head i \ approximately 0 .32 In A . whcrc A is the surl'acc rlrc:i cxpo\cd I O !tic t h c r n u l ncutrim hcaiii. in ci i i ' .

1 1 i s .\urnii\cd (Fairchild CI (I/.. 1906) [hat dur ing 1959- 1961. last neutrons ( R B E = 2 ) I r o m the BSlRR delivered r a t l u t i o i i d( i \c\ [ ( I \hull \url'acc\ 010 GO30 Gy-Eqis per hlW reactor power. I t is also w r m i d (Fairchi ld P I i t / . . 1966) th:it the cxtr i i i \ ic gaiiiiiia tJciw r:irc t R H E = I ) 31 zkull surI:iccs was 0.0030 G y i per SlW rcactor power. and that the i n i t i i i \ i c g;iiiiiii;i do\c ;]I shul l \urI:icc\ NU 0.070-1 Cy/ IO' ncutron/cm' maximum w r l x c Ilucncc.'cni' o f sur(;lcc cxpc i \c~ I I ( I rhc Ihcrnl;il neutron l i c ld . The relative :itrcnu:ition :I\ a lunction o Idcp th ( i t penetration in thc head o l each c o l ~ i p ~ ~ i i c i i i rypc ( 1 1 ' r;idiation I \ g ivc i i hy the lolloN*ing ch:lrt. \vhich wd\ inl'crrcd l r ( m puhl i4 ied s t u d ~ c s of thc r i iu l i ic t i t ro i i hc:iiii\ (S t i ih lcv ;ind 1::irr. IOO(1: Fa i rch i ld c r (I/.. 1906: Rohcrr\on v r ( I / . . 1967. M: i l \ i i t i i o t i i 1.1 c t l . . IOX6)-