A phase I clinical trial was conducted to evaluate neutron capture therapy for brain tumors. 24 patients with glioblastoma or melanoma metastases to the brain received boronophenylalanine followed by neutron irradiation. Doses were escalated in cohorts from 8.8 to 14.2 RBE-Gy. The most common side effects were alopecia and temporary increased intracranial pressure. More serious adverse events included respiratory failure in two elderly patients and one treatment-related death. Two patients showed a complete response, and tumor volume decreased in most patients. The trial demonstrated neutron capture therapy can achieve a clinical response with acceptable toxicity.
2. 112
boron-carrier compound l-para-boronophenylalanine- Table 1. RBE values for radiation components in glioblastoma,
fructose (BPA-f). These trials demonstrated the fea- brain, and melanoma
sibility of NCT for intracranial tumors, specifically Tissue 10
B1 Fast Thermal Gamma3
glioblastoma multiforme and metastatic melanoma, at neutron neutron
an acceptable level of tolerance of the central nervous GBM2 3.8 3.2 3.2 0.5
system and other normal tissues, and demonstrated a Brain 1.3 3.2 3.2 0.5
favorable tumor response in some instances. The results Melanoma 4.0 3.2 3.2 0.5
of the Harvard-MIT phase I trial are presented and 1
RBE value for 10 B accounts for microdistribution in cells and is
include a complete description of all adverse reactions referred to as C-RBE. 2 GBM: Glioblastoma multiforme. 3 RBE
as well as observations of tumor response. The last sub- is adjusted to account for prolonged irradiation duration and two
ject was irradiated in 1999 and follow-up is complete. fractions.
was amended to allow two irradiations when neces-
Methods and clinical material sary. The 10 B carrier, BPA-f, was infused through a
central venous catheter at doses of 250 mg kg−1 over
A phase I clinical trial conducted at Harvard-MIT 1 h (10 subjects), 300 mg kg−1 over 1.5 h (two subjects),
was designed primarily to determine a maximum and 350 mg kg−1 over 1.5 h (10 subjects). Neutron irra-
tolerated dose (MTD) and secondarily to evaluate diation was scheduled to begin 45 min after the end of
tumor response following cranial NCT. The protocol the BPA-f infusion. The radiation dose is expressed in
and informed consent documents underwent critical photon equivalent RBE-Gy, which is the sum of the
review and were approved by the respective com- physical dose for each component in the beam weighted
mittees on clinical investigation at the Beth Israel by its RBE [7]. The RBE for 10 B is expressed as the
Deaconess Medical Center and MIT. Separate but sim- C-RBE, a value that also takes into account the distribu-
ilarly worded informed consent documents were used tion of the boron-carrier molecule in tissue at the micro-
to obtain consent for each institution. Patient eligi- scopic level. The RBE and C-RBE values that were
bility was restricted to a biopsy-proven diagnosis of used for the dose calculations are shown in Table 1. The
either glioblastoma multiforme or radiologic evidence dose was prescribed to the normal tissue Dmax , a 1-ml
of melanoma metastatic to the CNS, age greater than volume that was assigned the RBE and C-RBE values
18, a Karnofsky performance status of 70 or greater, of normal brain. The initial dose of 8.8 RBE-Gy was
no prior history of cranial irradiation, and a projected considered a conservative starting point. Escalation
life expectancy of at least 3 months. Subjects with a was carried out in a stepwise fashion and was increased
diagnosis of phenylketonuria (PKU) were excluded. by 10% every 3–5 subjects. The interval between the
Following an initial evaluation, subjects underwent a first subjects of any two dose cohorts was at least
CT and an MRI with and without contrast for treatment 3 months.
planning purposes. These also served as baseline stud- Vital signs, EKG tracing, and blood oxygenation
ies for follow-up. Each subject had an individualized were continuously monitored from the initiation of
treatment plan developed with MacNCTPlan [6,15–17] infusion of BPA-f to when subjects were transported
and computed using the MCNP 4B Monte Carlo radi- back to the hospital, where they continued to be moni-
ation transport code. This software system allows tored overnight. With rare exception, discharge was the
normal tissue and tumor volumes to be assigned, and following day. Follow-up was scheduled monthly with
generates two-dimensional isodose contours for nor- MRI scans whenever possible.
mal tissue as well as tumor. Depending upon the loca-
tion and volume of disease, treatment plans varied from
one to three separate fields. Subjects were simulated in Results
the appropriate position for each beam entry position
and immobilized with commercially available systems. The first subject was entered in 1996 and the trial was
All irradiations were performed at the MIT Nuclear completed in 1999. Twenty-four subjects were entered
Reactor Laboratory with the M67 epithermal neutron and 22 were irradiated; 2 subjects were excluded due
beam [2]. The initial plan of the trial was to deliver to decline in performance status. The median age was
the irradiation for each subject in one fraction; how- 56 (range 24–78). Of the irradiated subjects, two had
ever, due to protracted irradiation times the protocol metastatic melanoma and the remainder glioblastoma
3. 113
multiforme. Surgery was performed on all subjects with
the exception of the two melanomas, including gross
total resection in four, subtotal resection in 12, and
biopsy only in four. The volume of tumor at the time
of NCT was variable and ranged from a small vol-
ume of enhancement on MRI (<10 cm3 ) to 121 cm3
of gross disease with central necrosis. Twelve subjects
received corticosteroids before, during, and after NCT
irradiation. Six dose cohorts were completed: 8.8, 9.7,
10.6, 11.7, 12.9, and 14.2 RBE-Gy. The number of
fields ranged from 1 to 3, and the orientations var-
ied over the course of the trial in order to optimize
dose to the tumor within the normal tissue dose con-
straints. An example of a typical normal tissue iso-
dose distribution from a two-field beam arrangement
is shown in Figure 1. In this arrangement, the dose
distribution is highly lateralized. The dose to normal
structures such as the eye, optic nerve, and optic chi-
asm were kept below 8 RBE-Gy (Figure 1A), a sin-
gle fraction dose shown to be within the tolerance of
these structures [18]. While the peak dose was esca-
lated in a systematic fashion, a second normal tissue
dose parameter, the volume average brain dose, varied
primarily as a function of the number of fields, and sec-
ondarily by tumor size and location and the prescribed
peak dose (Figure 2). The mean volume average brain
doses were 3.0, 4.5, and 6.5 RBE-Gy for 1–3 fields,
respectively.
10
B was delivered as BPA-f through an intravenous
infusion that lasted between 60 and 90 min. The amount
of BPA-f was increased during the trial from 250 to
350 mg kg−1 , and no untoward effects were observed
from the infusion (Figure 3). A detailed pharmacoki-
netic curve for blood was generated for each subject.
These demonstrated a peak infusion 10 B concentra-
tion of approximately 32 µg g−1 followed by a bipha-
sic washout due to redistribution and renal excretion
[19,20]. Because of the protracted irradiation times
with the M67 epithermal beam, it was necessary to fol-
low the blood 10 B concentration throughout the irradi-
ation so that the appropriate neutron fluence could be
delivered in order to reach the target dose for each field. Figure 1. (A) Normal tissue isodose distribution for a subject
The final dosimetry for each subject was determined with multiple ipsilateral unresected melanoma nodules. Dose is
through a retrospective analysis based upon the mea- expressed as RBE-Gy using normal brain RBE and C-RBE val-
sured blood 10 B concentration and the delivered fluence ues. (B) Tumor isodose distribution for the same subject. Dose is
for each field. expressed as RBE-Gy using tumor values for RBE and C-RBE.
All adverse events, irrespective of cause, were tab-
ulated and assigned severity scores between 1 and shown in Table 2. Overall, there were 16 grade 3 events,
5 according to the Common Toxicity Criteria of the 1 grade 4 events and 3 grade 5 events. Almost all
National Cancer Institute’s Cancer Therapy Evaluation subjects experienced alopecia within the area of skin
Program (NCI-CTEP CTC, v. 2.0). These data are exposed directly to the radiation. This was permanent
4. 114
and complete in all subjects. Additional dermal effects responded to medical management. A grade 4
included erythema that was self-limiting. One subject event related to increased ICP (decreased level
in the 14.2 RBE-Gy dose cohort was irradiated for a of consciousness/somnolence) occurred in a young
temporal lobe GBM and experienced moist desquama- woman with a large tumor (84 cm3 ) who was given
tion on the temporal area of the scalp six weeks fol- high-dose intravenous steroids starting 12 h before and
lowing NCT, which eventually completely healed. This during NCT. After the second fraction, she became
subject also experienced mucositis of the oral cavity increasingly somnolent and unresponsive and after sev-
and oropharynx two weeks after NCT. eral days developed the syndrome of inappropriate
Many adverse events, especially those of grade 3 anti-diuretic hormone secretion (SIADH). Aggressive
severity, were associated with a temporary increase medical management was successful and a debulk-
in intracranial pressure (ICP) following NCT and ing resection was performed. The resected tumor dis-
played extensive tumor cell cytoplasmic vacuolization,
fibrinoid vascular necrosis, and an extreme paucity
of mitotic figures, a histologic appearance very dif-
ferent from her initial surgery. One subject experi-
enced a treatment-related death 5 days after NCT. This
was a 58-year-old woman with a large central tumor
(121 cm3 ) who received only the first of two planned
fractions. After the first fraction, she experienced men-
tal status changes and had an increase in peritumoral
edema as seen on CT and MRI. A new ipsilateral
thalamic infarct was also found.
Two subjects experienced respiratory compromise
Figure 2. Volume average brain doses as a function of the number
of radiation fields; mean dose and standard deviation. and ultimately adult respiratory distress syndrome
(ARDS). Both were women in their mid-seventies who
required high-dose steroids for management of tumor-
associated edema, and both were irradiated with three
fields. The initial pattern of pulmonary infiltrate was
diffuse and not restricted to the lung apices as one
might expect if the infiltrate was related to a cranial
irradiation. A rapid clinical progression from dyspnea
and mild pulmonary infiltrates to ventilator dependency
and the clinical diagnosis of ARDS was observed.
A postmortem examination of one of these subjects
showed classic pulmonary changes associated with
ARDS, but no characteristic radiation changes to the
lung parenchyma. Later subjects who received irradia-
tions at a higher dose level and longer in duration did
not experience this adverse event.
Table 3 shows preliminary information on some
of the clinical factors that may be associated with
the development of grade 3 or above adverse events
thought to be related to increased ICP. Sixty-seven
percent of the subjects with gross disease exceeding
60 cm3 at the time of NCT and 50% of the subjects
irradiated on two successive days experienced some
Figure 3. 10 B concentration in blood during and after infusion form of CNS symptom that required medical interven-
of 250 mg kg−1 of BPA-f. Open symbols represent 10 B measure-
ments using PGNAA or ICP-AES; the line is the fit of a two-
tion. Subjects not on steroids at the time of entry onto
compartment pharmacokinetic model to the measurements. The the protocol, who typically had small tumor volumes
shaded area under the curve shows the irradiation time for a single and no edema, were irradiated without steroids. These
field. subjects had a low incidence of developing an acute
5. 115
Table 2. NCI CTEP common toxicity criteria: NCT, all dose groups
Category Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Alopecia 21 — — —
Radiation dermatitis 6 7 1
Headache 1 2 3
Nausea 7 — —
Vomiting 1 3 2
Mucositis 2 2
Dysphagia – pharyngeal 1 1
Dehydration 2
Xerostomia 1
Taste disturbance 1
Auditory – middle ear 2
Auditory – inner ear 2
Fatigue 1 3
Weight loss 2
↓ LOC1 /somnolence 3 1
Seizure — 1 1
Neurological – cranial n. 1
Neurological – motor n. 1
Neurological – sensory n. 1
New L thalamic infarct 1
Decreased LTM2 1
SIADH3 1
ARDS4 2
Singultus 1
Pulmonary – other 1 2
Renal calculus 1
FUO5 1 1
Pleuritic chest pain 1
1
LOC = Level of consciousness. 2 LTM = Long-term memory. 3 SIADH = Syndrome of inappropriate anti-
diuretic hormone secretion. 4 ARDS = Adult respiratory distress syndrome. 5 FUO = Fever of unknown origin.
Table 3. Treatment parameters and the development of grade 3 incomplete, as subjects in this study lived throughout
or above CNS adverse events related to increased ICP the US and Europe and often had difficulty in obtaining
Subject/treatment Percent of subjects MRI exams on a monthly schedule, or failed to com-
parameter developing CNS ply with the planned course of follow-up. However,
adverse event data on 17 subjects were sufficient for a quantitative
≥ grade 3 assessment of changes in the volume of disease fol-
Tumor volume <60 cm3 19 lowing NCT. Transverse images of the gadolinium-
Tumor volume >60 cm3 67 enhanced baseline MRI and all available follow-up
Dmax < 12 RBE-Gy 31
MRIs were scanned on a high-resolution scanner and
Dmax > 12 RBE-Gy 43
1 Fraction 20 the region of interest outlined. Tumor volume was then
2 Fractions 50 measured using software developed in our laboratory
1 Field 33 (G. Santa Cruz). These data are shown in Figure 4.
2 Fields 29 For each of the evaluable subjects, the volume of
3 Fields 33 gross (enhancing) disease is indicated at baseline (just
No steroids at evaluation 10 prior to NCT) and at successive time points during the
or during NCT
follow-up period. It can be seen that subjects in this
clinical trial presented with a range of tumor volumes,
increase in ICP. The number of fields does not appear from <10 to 120 cm3 . Two subjects with tumor vol-
to be related to CNS events. umes of 84 and 121 cm3 were not evaluable, as one
The tumor response following NCT was monitored expired and the other underwent post-NCT debulking
with serial MRI studies. These data are inherently surgery (subjects described above). A trend toward a
6. 116
Figure 4. Contrast-enhanced tumor volumes in evaluable sub- Figure 5. Contrast-enhanced tumor volumes normalized to the
jects at the time of NCT and in follow-up. initial tumor volume at the time of NCT.
reduction in volume post-NCT is evident, particularly was evident. This response was durable until the subject
in smaller tumors. developed widespread metastatic disease. No chronic
The response to NCT becomes clearer when the changes to the normal brain were observed at the site
tumor volumes are normalized to the initial tumor vol- of the original lesion.
ume, as shown in Figure 5. It can be seen that the
majority of subjects, 13 of 17 (76%), experienced a Discussion
sizable and progressive reduction in enhancing vol-
ume over the first several months, followed by a period These data represent a comprehensive analysis of the
of disease stability or regrowth (five subjects). When results of a phase I trial designed to evaluate the
tumor volumes are grouped by size, 6/7 with initial feasibility, safety, normal tissue tolerance, and tumor
volumes <10 cm3 , 4/4 with volumes between 10 and response following cranial NCT, a novel form of radi-
30 cm3 , and 3/6 with volumes >30 cm3 responded. Two ation therapy. An additional phase I trial for subjects
subjects experienced a complete radiographic response with melanoma of the extremities was open con-
(CR). One example of a complete response is shown currently. Preliminary evaluations of each have been
in Figure 6. This subject underwent NCT for an unre- reported [8,10,11,21]. These trials, along with similarly
sected occipital melanoma metastasis. Serial contrast- designed NCT phase I/II trials at BNL [12–14] served
enhanced MRI studies were obtained once a month and as clinical validation of a considerable amount of pre-
progressive volume reduction was noted, until a CR clinical work in NCT, from in vitro experiments to large
7. 117
Figure 6. Demonstration of a complete radiographic response following NCT for a metastatic melanoma in the occipital lobe. Images
are from enhanced MRI studies obtained monthly. A frontal craniotomy, evident in saggital views, is from a previously resected solitary
melanoma metastasis. (A) Pre-NCT MRI, saggital view. (B) Pre-NCT MRI, axial view. (C) Increased enhancement at the site of original
tumor one month following NCT, saggital view. (D) Increased enhancement at the site of original tumor one month following NCT, axial
view. (E) Loss of enhanced signal and mass effect 7 months following NCT, saggital view. (F) Loss of enhanced signal and mass effect
7 months following NCT, axial view.
8. 118
animal studies. Although much attention and hope for group of subjects, increased ICP was successfully
a quick clinical success has been placed in NCT, espe- treated with steroids and IV mannitol as indicated.
cially as a potential therapy for high grade astrocytic Non-neurological acute reactions were seen in the
tumors, the results presented here need to be interpreted parotid gland and the mucosal lining of the oral cav-
within the context of an exploratory, dose-seeking clin- ity and oropharynx. These were all self-limiting and
ical study of a nascent form of experimental radiation required only symptomatic intervention. One subject
therapy. at the highest dose level was irradiated for a tumor in
As originally designed, this trial sought to determine the anterior temporal lobe and experienced a dermal
an MTD for brain by systematic dose escalation using (moist desquamation) and mucosal reaction (confluent
parallel-opposed fields for all subjects. This is an opti- mucositis of the tongue and oropharynx) that required
mal field arrangement for a deep-seated midline tumor. close observation and management. It appears from
However, the limited penetration of epithermal neu- both clinical observation and studies in experimental
trons in tissue results in a steep dose gradient in the animal systems that BPA concentrates not only in tumor
brain and suboptimal tumor doses for lesions in loca- but also in the parotid gland and in rapidly dividing nor-
tions other than the midline when this arrangement is mal tissue such as the basal layer of the skin and mucosa
used. It was therefore decided early in the trial that of the oral cavity [22,23]. As with conventional radia-
treatment planning would be optimized for each sub- tion therapy, acute and painful normal tissue reactions
ject such that the highest possible dose would be given may be a potential dose-limiting factor to NCT.
to the tumor while not exceeding the normal tissue and Chronic effects were also tabulated and are pre-
dose escalation constraints of the protocol. A mini- sented in Table 2; however, a limitation of these data
mum dose to the tumor was not formally specified, a is the variability in the length and quality of follow-up.
distinction between this study and the BNL trials. As The geographic dispersion of the study population
a result, subjects received 1, 2, or 3 fields depending and the understandable tendency of subjects to pur-
upon the size and location of the tumor. This resulted sue additional forms of therapy or to stop obtaining
in a greater degree of variation in the volume average scans once disease progression had become obvious
brain dose (Figure 2), as opposed to a uniform, step- make the long-term data variable in quality and quan-
wise increase with each dose cohort. This normal tissue tity. However, all follow-up radiographic studies were
dose parameter may have important clinical implica- reviewed and examined for evidence of MRI changes.
tions. It is well-recognized in clinical radiation therapy One of the primary radiographic endpoints for toxi-
that the volume of irradiated tissue, in this case CNS, city in this trial was the development of white mat-
is directly related to the development of side effects. ter changes following irradiation; this effect preceded
This relationship most likely holds true for NCT as the manifestation of clinically apparent neurological
well as for conventional radiation. Preliminary evi- changes and was typically seen 6 months following
dence for this comes from a comparison of the inci- NCT in dogs [24,25]. Within the scope of this study,
dence of grade 3 somnolence in this series (4/20) with any MRI changes following NCT have been attribut-
the incidence seen in the last group of subjects irradi- able to disease progression (as seen in one subject with
ated at BNL (Protocol #5) [14]. In BNL Protocol #5 multifocal metastatic melanoma) and not to injury to
the average brain dose was increased to 9 RBE-Gy, and the brain parenchyma.
7/7 subjects experienced somnolence. The threshold The data presented on the type and severity of
for its development may reside in an average brain dose observed adverse events are not atypical for a diverse
between 7 and 9 RBE-Gy. The somnolence observed population of patients undergoing combined modality
in both NCT experiences is a known CNS reaction fol- therapy for glioblastoma multiforme or intracranial
lowing cranial irradiation and was similar to that expe- metastatic melanoma. The majority of the reactions
rienced by many patients treated with standard external were acute, self-limiting, and related to a temporal
beam photon therapy. increase in ICP, and responded to standard measures
A number of anticipated and unanticipated acute such as dexamethasone, anticonvulsants, antiemetics,
effects have been noted following NCT. Acute effects and occasionally intravenous mannitol. An increase
secondary to increased ICP such as severe headache, in ICP is often multifactorial; however, in this trial it
nausea, vomiting, change in consciousness, and appears to be related to enhancing tumor volume at
seizures were seen during hospitalization and occa- the time of NCT irradiation. A comparison of the fre-
sionally reached grade 3 in terms of severity. In this quency with which increased ICP was seen and tumor
9. 119
volume shows that tumors with volumes >60 cm3 were Some of the smaller enhancing volumes (<10 cm3 ) in
associated with a 67% incidence of developing grade 3 subjects who have undergone resection may represent
or higher symptoms, while tumors <60 cm3 had a post-operative changes to the brain, and the data from
19% incidence. In addition, the two subjects with the this group must be interpreted with caution; neverthe-
most severe CNS adverse events, grades 4 and 5, had less, as an aggregate these responses are very encour-
volumes of 84 cm3 and 121 cm3 , respectively. aging, particularly at such an early stage in the NCT
The 10 B carrier chosen for this study was BPA-f. clinical trials. The median survival for the subjects
Experimental and early clinical work in Japan showed in this series was 13 months, a duration not unlike
BPA to have promise [26] as a therapy for melanoma. that seen with resection and standard radiation. An
Human tumor biodistribution studies on GBM demon- important caveat however is, some subjects underwent
strated a sufficient intracellular concentration of BPA-f second surgeries as well as reirradiation for recurrent
could be achieved to allow the delivery of a clinically disease so 13 months is not a survival value for NCT
meaningful dose of NCT [27,28]. The limitation of sol- alone. It does indicate that no untoward reaction was
ubility of BPA-f to approximately 30 mg ml−1 at phys- experienced by the group as a whole that led to a reduc-
iological pH at room temperature meant that infused tion in median survival.
volumes were hypertonic and frequently approached or A true MTD for CNS tolerance was not reached
exceeded 1 liter. These factors, along with an increase in this study. There were a number of adverse events
of the BPA-f dose, led to the use of a central venous observed but not with a consistent pattern or clear
catheter for drug delivery and an increase in the dura- etiology. One reason is the heterogeneity of the patient
tion of the infusion from 60 to 90 min. The blood population and the finding that acute tolerance may
pharmacokinetic profiles are characteristic and repro- be more related to gross residual intracranial dis-
ducible and have allowed the development of a highly ease than to normal tissue brain dose. Another factor
predictive model [19,20]. is that the irradiation times became increasingly long
While the primary endpoint of a phase I trial is with the M67 epithermal beam and further dose esca-
normal tissue tolerance, evidence of tumor response lation became impractical. The M67 beam was also
is not without interest. The two subjects who expe- scheduled to be replaced by a new medical neutron
rienced a CR following NCT, one with a small vol- source, the fission converter beam (FCB) [29–31], for
ume residual GBM and the other with an unresected which additional phase I studies were planned. These
melanoma nodule, were dramatic examples of a ther- trials using the FCB, a phase I/II for GBM and intracra-
apeutic potential for NCT in two disease settings that nial melanoma and a phase II for peripheral melanoma,
have limited success with conventional radiation ther- have been funded by the NIH and are in progress. While
apy. In order to evaluate response or intervals of dis- the FCB will allow an irradiation to be completed in
ease stability in the subjects who experienced less a matter of minutes with a higher therapeutic ratio,
than a CR, a program was developed in our labora- that alone may not be sufficient for NCT to realize its
tory where regions of interest could be identified on full utility. Newer compounds demonstrating a higher
axial MRI images for measurement of tumor volume. tumor uptake of 10 B and prolonged retention or a more
All available baseline and post-NCT imaging studies rapid normal tissue washout could hold potential, as
were evaluated and tumor volumes quantified. Once could novel methods for selective delivery of already
normalized to the tumor volume at the time of NCT, available 10 B-containing compounds [32,33].
13 of 17 subjects displayed strikingly similar degrees
and rates of tumor volume reduction for the first sev-
eral months, after which the disease either stabilized or Acknowledgements
grew, sometimes rapidly. Larger tumor volumes were
less likely to show a measurable reduction in volume; The authors would like to thank Dr. John Bernard and
these subjects either had stable disease or significant the MIT Nuclear Reactor Laboratory for reactor time
side effects such as an increase in peritumoral edema, and support provided by the reactor-sharing program.
which is suggestive of a high dose to the tumor. This This work was supported by a grant from the United
trend in response is consistent with response following States Department of Energy: DE-FG02-96ER62193.
conventional radiation therapy, i.e., the likelihood or Human subject transportation was provided by
magnitude of a clinical response is inversely related to American Medical Response and the Fallon
the amount of disease present at the time of treatment. Ambulance Service.
10. 120
References 12. Chanana A, Capala J, Chadha M, Coderre JA, Diaz A,
Elowitz E, Iwai J, Joel D, Liu H, Ma R, Pendzick N, Peress N,
1. Harling OK, Bernard JA, Zamenhof RG: Neutron beam Shady M, Slatkin D, Tyson G, Wielopolski L: Boron neutron
design, development, and performance for neutron capture capture therapy for glioblastoma multiforme: interim results
therapy. In: Bernard JA, Harling OK, Zamenhof RG (eds) from the phase I/II dose-escalation studies. Neurosurgery
Neutron Beam Design, Development, and Performance for 44: 1182–1192, 1999
13. Diaz AZ, Chanana AD, Capala J, Chadha M, Coderre JA,
Neutron Capture Therapy. Plenum Press, New York and
Elowitz EH, Iwai J, Joel DD, Liu HB, Ma R, Shady M,
London, pp, 1990
Slatkin DN, Tyson GW, Wielopolski L: Safety and efficacy
2. Rogus RD, Harling OK, Yanch JC: Mixed field dosimetry of
of BNCT for glioblastoma multiforme: results from the ini-
epithermal neutron beams for boron neutron capture therapy
tial dose escalation studies. In: Hawthorn FM, Shelly K,
at the MITR-II research reactor. Med Phys 21: 1611–1625,
Wiersema RJ (eds) Frontiers in Neutron Capture Therapy.
1994
Kluwer Academic / Plenum Publishers, New York, 2001,
3. Riley KJ, Harling OK: An improved prompt gamma
pp 61–72
neutron activation analysis facility using a focused dif-
14. Diaz AZ, Chanana AD, Coderre JA, Ma R: Retrospective
fracted neutron beam. Nucl Instru Meth Phys Res B 143:
review of the clinical BNCT trial at Brookhaven National
414–421, 1998
Laboratory. Ninth International Symposium on ‘Neutron
4. Solares GR, Zamenhof RG: A novel approach to the
Capture Therapy for Cancer’, Osaka, Japan, 2000, pp 13–14
microdosimetry of neutron capture therapy. Part 1. High-
15. Palmer MR, Goorley JT, Kiger III WS, Busse PM, Riley KJ,
resolution quantitative autoradiography applied to micro-
Harling OK, Zamenhof RG: Treatment planning and
dosimetry in neutron capture therapy. Radiat Res 144:
dosimetry for the Harvard-MIT phase-I clinical trial of cra-
50–58, 1995
nial neutron capture therapy. Int J Radiat Oncol Biol Phys
5. Soloway AH, Tjarks W, Barnum BA, Rong F-G, Barth RF, 53: 1361–1379, 2002
Codogni IM, Wilson JG: The chemistry of neutron capture 16. Zamenhof RG, Solares GR, Kiger III WS, Redmond EL,
therapy. Chem Rev 98: 1515–1562, 1998 Busse PM, Yam CS: MacNCTPLAN: an improved
6. Zamenhof R, Redmond E, Solares G, Katz D, Riley K, Macintosh-based treatment planning program for boron
Kiger S, Harling O: Monte Carlo-based treatment planning neutron capture therapy. In: Larsson B, Crawford J,
for boron neutron capture therapy using custom designed Weinreich R (eds) Advances in Neutron Capture Therapy.
models automatically generated from CT data. Int J Radiat Elsevier, Amsterdam, 1997, pp 100–105
Oncol Biol Phys 35: 383–397, 1996 17. Zamenhof RG, Solares GR, Kiger III WS, Riley KJ,
7. Coderre JA, Morris GM: The radiation biology of boron Busse PM, Fischer E, Norregaard T, Harling OH: Clinical
neutron capture therapy. Radiat Res 151: 1–18, 1999 treatment planning of subjects undergoing boron neutron
8. Busse PM, Zamenhof RG, Madoc-Jones H, Solares G, capture therapy. In: Larsson B, Crawford J, Weinreich R
Kiger III WS, Riley KJ, Chuang CF, Rogers G, Harling OK: (eds) Advances in Neutron Capture Therapy. Elsevier,
Clinical follow-up of patients with melanoma of the extrem- Amsterdam, 1997, pp 614–620
ity treated in a phase I boron neutron capture therapy proto- 18. Tishler RB, Loeffler JS, Lunsford LD, Duma C,
col. In: Larsson B, Crawford J, Weinreich R (eds) Advances Alexander III E, Kooy HM, Flickinger JC: Tolerance of
in Neutron Capture Therapy. Elsevier, Amsterdam, 1997, cranial nerves of the cavernous sinus to radiosurgery. Int J
pp 60–64 Radiat Oncol Biol Phys 27: 215–221, 1993
9. Busse PM, Zamenhof RG, Harling OK, Kaplan I, Kaplan J, 19. Kiger III WS, Palmer MR, Riley KJ, Zamenhof RG,
Chuang CF, Goorley JT, Kiger III WS, Riley KJ, Tang L, Busse PM: A pharmacokinetic model for the concentration
Solares GR, Palmer MR: The Harvard-MIT BNCT program: of boron-10 in blood after boronophenylalanine-fructose
overview of the clinical trials and translational research. administration in humans. Radiat Res 155: 611–618, 2001
In: Hawthorn FM, Shelly K, Wiersema RJ (eds) Frontiers 20. Kiger III WS, Palmer MR, Riley KJ, Zamenhof RG,
in Neutron Capture Therapy. Kluwer Academic / Plenum Busse PM: Pharamacokinetic modeling for
Publishers, New York, 2001, pp 37–60 boronophenylalanine-fructose mediated neutron capture
10. Busse PM, Zamenhof RG, Harling OK, Kaplan I, therapy: 10 B concentration predictions and dosimetric con-
Kaplan J, Chuang C, Goorley J, Kiger III WS, sequences. J Neuro-Oncol 62: 171–186, 2003
Riley K, Tang L, Solares GR, Palmer M: The Harvard- 21. Madoc-Jones H, Zamenhof R, Solares G, Harling OK,
MIT BNCT Program: overview of the clinical tri- Yam C-S, Riley K, Kiger III S, Wazer D, Rogers G,
als and translational research. Eleventh International Atkins M: A phase-I dose escalation trial of boron neutron
Congress of Radiation Research. Dublin, Ireland, 1999, capture therapy for subjects with metastatic subcutaneous
pp 702–705 melanoma of the extremities. In: Mishima Y (ed) Cancer
11. Busse PM, Harling OK, Palmer MR, Kaplan I, Neutron Capture Therapy. Plenum Press, New York, 1996,
Newton TH Jr, Kaplan J, Chuang CF, Kiger III WS, p 707
Riley KJ, Goorley JT, Zamenhof RG: A phase I clinical 22. Kiger III WS, Micca PL, Morris GM, Coderre JA: Boron
trial for cranial BNCT at Harvard-MIT. Ninth International microquantification in oral muscosa and skin following
Symposium on ‘Neutron Capture Therapy for Cancer’, administration of a neutron capture therapy agent. Radiat
Osaka, Japan, 2000, pp 27–28 Protection Dosimetry 99: 409–412, 2002
11. 121
23. Morris GM, Smith DR, Patel H, Chandra S, Morrison GH, Ostrovsky Y, Stahle P, Binns P, Kiger III W, Busse P:
Hopewell JW, Rezvani M, Micca PL, Coderre JA: Boron The fission converter based epithermal neutron irradiation
microlocalization in oral mucosal tissue: implications for facility at the MIT reactor. Nucl Sci Eng 140: 223–240,
boron neutron capture therapy. Br J Cancer 82: 1764–1771, 2002
2000 30. Kiger III WS, Sakamoto S, Harling OK: Neutronic design
24. Gavin PR, Kraft SL, DeHaan CE, Swartz CD, of a fission converter-based epithermal neutron beam for
Griebenow ML: Large animal normal tissue tolerance with neutron capture therapy. Nucl Sci Eng 131: 1–22, 1999
boron neutron capture. Int J Radiat Oncol Biol Phys 28: 31. Sakamoto S, Kiger III WS, Harling OK: Sensitivity stud-
1099–1106, 1994 ies of beam directionality, beam size and neutron spectrum
25. Gavin PR, Kraft SL, Huiskamp R, Coderre JA: A review: for a fission converter-based epithermal neutron beam for
CNS effects and normal tissue tolerance in dogs. boron neutron capture therapy. Med Phys 26: 1979–1988,
J Neuro-Oncol 33: 71–80, 1997 1999
26. Mishima Y, Honda C, Ichihashi M, Obara H, Hiratsuka J, 32. Barth RF, Yang W, Rotaru JH, Moeschberger ML, Joel DD,
Fukada H, Karashima H, Kobayashi T, Kanda K, Yoshino K: Newrocky MM, Goodman JH, Soloway AH: Boron neu-
Treatment of malignant melanoma by single thermal neutron tron capture therapy of brain tumors: enhanced survival fol-
capture therapy with melanoma-seeking 10 B-compound. lowing intracarotid injection of either sodium borocaptate
The Lancet August 12: 388–389, 1989 or boronophenylalanine with or without blood–brain barrier
27. Coderre JA, Chanana AD, Joel DD, Elowitz EH, Micca PL, disruption. Cancer Res 57: 1129–1136, 1997
Nawrocky MM, Chadha M, Gebbers JO, Shady M, 33. Barth RF, Yang W, Bartus RT, Rotaru JH, Ferketich AK,
Peress NS, Slatkin DN: Biodistribution of boronophenylala- Moeschberger ML, Nawrocky MM, Coderre JA,
nine in patients with glioblastoma multiforme: boron con- Rofstad EK: Neutron capture therapy of intracerebral
centration correlates with tumor cellularity. Radiat Res 149: melanoma: enhanced survival and cure after blood–brain
163–170, 1998 barrier opening to improve delivery of boronophenylala-
28. Elowitz EH, Bergland RM, Coderre JA, Joel DD, Chadha M, nine. Int J Radiat Oncol Biol Phys 52: 858–868, 2002
Chanana AD: Biodistribution of p-boronophenylalanine
(BPA) in patients with glioblastoma multiforme for use in
boron neutron capture therapy. Neurosurgery 42: 463–469, Address for offprints: Paul M. Busse, Department of Radiation
1998 Oncology, Beth Israel Deaconess Medical Center, 330 Brookline
29. Harling O, Riley K, Newton T, Wilson B, Bernard J, Hu L-W, Avenue, Boston, MA 02215, USA; Tel.: 617-667-2345; Fax:
Fonteneau E, Menadier P, Ali S, Sutharshan B, Kohse G, 617-667-4990; E-mail: pbusse@caregroup.harvard.edu