Glioblastoma multiforme
~ 7000 new cases/yr in the US.
Standard treatment: Surgery followed by radiation therapy.
Median survival is 10 to 12 months.
Boron Neutron Capture Therapy
• Glioblastoma: the invasive nature makes treatment difficult.
• BNCT has the potential to selectively target these infiltrating tumor cells.
The BNCT Reaction2.33 MeV of kinetic energy is released per neutron capture:initial LET 200-300 keV/µm
0.477 MeV Gamma (94%)
thermal neutron(<0.1 eV)
Li-7 recoil ion
Alpha particle
5 µ
8 µB-10
Thermal cross-section = 3837 barns (that’s very big…)
Boron Neutron Capture Therapy1. Selectively deliver 10B to the tumor.2. Irradiate the tumor region with low energy neutrons (nth).3. The short range of the 10B(n,α)7Li reaction products restricts most of the dose to the boron-loaded cells.
nthnth
nth
nth
BNCT Pre-History1932: Chadwick discovers the neutron
1935: Taylor and Goldhaber describe the 10B(n,α)7Li reaction
1936: Locher proposes BNCT as a cancer therapy
1951: Brookhaven Graphite Research Reactor
1951: W. Sweet, Chief of Neurosurgery at the MGH initiates BNCT clinical trial
Failure of the First BNCT Trials
• Poor penetration of thermal neutrons in tissue.
• Boron levels in blood higher than those in tumor.
• Viable tumor was found at depth following doses that exceeded the tolerance of normal surface tissues.
• BNL and MIT clinical trials were stopped in 1961.
Improved boron delivery agents
2-
2 Na+
= BH= B
BSHL-BPA
SH
B COOHHO
HO
NH2
(p-borono-L-phenylalanine)
(Na2B12H11SH)
Improvements in neutron beams
Thermal< 0.4 eV
Epithermal0.4 eV-10 keV
Improved penetration
Surface sparing
BNCT dose components
•Boron dose - from products of 10B(n,α)7Li reaction
• γ dose - from beam contamination and neutron capture reaction in hydrogen: 1H(n,γ)2H
• Nitrogen dose - from products of 14N(n,p)14C reaction
• Fast neutron dose – from recoil nuclei (mostly protons)
Thermal Neutron Cross Sections
Nuclide Cross section (barns)10B 383711B 0.00512C 0.00351H 0.3314N 1.7035Cl 43.623Na 0.534
157Gd 254,000153Gd 0.02
Photon-Equivalent DosesIAEA Workshop (6/99) recommends that BNCT doses be expressed as a weighted dose Dw , with the unit Gy, using the following convention:
Dw = wb.Db + wg.Dg + wn.Dn + wp.Dp
Currently:weighting factors termed RBE or CBE factors;BNCT doses expressed in Gy-Eq units.
Beam components: depth-dose profile
Depth (cm)0 2 4 6 8 10 12
Dos
e ra
te (c
Gy/
min
)
0.01
0.1
1
10total dose
∇ boron capture (13 µg 10B/g)gamma
fast neutrons◊ nitrogen capture
BMRR epithermal beam, 3 MW reactor power
The boron delivery agentBPA concentrates in tumor to levels 3.5 - 4 times higher than blood or brain.
L-BPA
B COOHHO
HO
NH2
(p-borono-L-phenylalanine)
18F PET study:adapted from Imahori et al.JNM, 39, 325, 1998.
Selective tumor ablation
500 µm
Normal brain Tumor scarHorseradish peroxidase perfusion
Rat 9L gliosarcoma:1 year post-BNCTMR images
Coderre et al., Int. J. Radiat. Oncol. Biol. Phys., 28, 1067, 1994.
Dose response: ED50 endpoint
x rays
thermal neutrons
thermal neutrons + BPA
Dose (Gy)0 5 10 15 20
Tong
ue fi
elds
exh
ibiti
ng u
lcer
atio
n (%
)
0
20
40
60
80
100
• Compare isoeffective doses (ED50)
Coderre et al., Radiat.Res., 152, 113, 1999
BNCT radiobiologyTissues studied: Weighting Factors Used
in Clinical Trial
• tumor 3.8• brain 1.3• spinal cord 1.3• skin 2.5• oral mucosa 2.5
10B biological effectiveness factors range from 1.3 to over 5.
An RBE of 3.2 is used for the high-LET beam components in all tissues.
Dog brain irradiations
Dose volume histogramsIsodose contours
Effective Dose (Gy-Eq)0 5 10 15 20 25
Frac
tion
of V
olum
e (%
)
0
5
10
15
20
25
30
Coderre et al., J. Neuro-Oncol., 48, 27, 2000.
Dog brain irradiations
Asymptomatic MRI changes Massive edema at 5 mos.
6 mos.post-BNCT
Coderre et al., J. Neuro-Oncol., 48, 27, 2000.
Dog brain irradiations• Average whole brain dose, single-field irradiation.
• 1 Gy = 1 joule/kg
• 2 Gy = conventional daily fraction for tumors (x 30d).
• 10 Gy whole body (brain) used in bone marrow transplant.
Ave
rage
Bra
in D
ose
(cG
y or
cG
y-Eq
)
0
200
400
600
800
1000
1200
1400fast neutrons nitrogen gamma boron
Dog 3746:No changesin 3 years
Dog 1655:Lethal necrosisin 5 months
cGy cGycGy-Eq cGy-Eq
The BNCT procedure
Time (hours)0 1 2 3 4 5 6
0
5
10
15
20
25
30
infusion10B
con
cent
ratio
n in
blo
od (µ
g/g)
250 mg BPA/kg (n=11)
BNCTSurgery 3-4 weeks prior to BNCT.
BNCT is given in a single session lasting less than 1 hr.
• 2-hr BPA infusion• BNCT starts ~ 45 min after end of infusion
Coderre, et al., J. Neuro-Oncol., 33, 141, 1997.
Brain Doses
Protocol
Ref
eren
ce D
ose
(Gy-
Eq)
6
8
10
12
14
16
18
2 3 4a 51 4b
n=1 n=10 n=4 n=11 n=17 n=6
BNL BNCT clinical trial.
Reference (peak) doses in brain (maximum dose to a 1 cm3 volume).
Doses escalated in 20% increments.
Chanana, et al., Neurosurg., 44, 1182, 1999.
Brain dose
Protocol
Dos
e (G
y-Eq
)
0
2
4
6
8
10
1 2 3 4a 54b
BNL BNCT clinical trial:
Whole-brain average doses.
CNS side effects observed in 2 pts in Protocol 4b and all pts in Protocol 5.
Brain: Dose Volume HistogramsDose-Volume Histogram
for the Normal Brain
Effective Dose (Gy-Eq)
0 5 10 15 20
Frac
tion
of V
olum
e (%
)
0
5
10
15
20
25
30
35
40
45
1-field
2-field dogs, MTD
3-field
• Escalation of the dose in humans.
• Comparison to the maximum tolerated dose in dogs.
Normal Brain Tolerance
Dose (Gy(W))
0 2 4 6 8 10 12 14 16
% B
rain
Vol
ume
0
20
40
60
80
100
1 field
2 fields
3 fields
A
Normal Brain Tolerance
Dose (Gy(W))
0 2 4 6 8 10 12 14 16
% B
rain
Vol
ume
0
20
40
60
80
100BNL Patientswith Somnolence
2 fields
B
Normal Brain Tolerance
Dose (Gy(W))
0 2 4 6 8 10 12 14
% B
rain
Vol
ume
0
20
40
60
80
100
2-fields
C
Normal Brain Tolerance
Whole-Brain Average Dose (Gy(W))
1 2 3 4 5 6 7 8 9
Peak
Dos
e (G
y(W
))
6
8
10
12
14
16
18BNLBNL with somnolenceMITMIT with somnolence
Normal Brain Tolerance
Dose (Gy(w))
0 5 10 15 20 25
som
nole
nce
prob
abili
ty (%
)
0
20
40
60
80
100
Average Brain Dose
Peak Brain Dose ........ 95% confidence
Patient survival data
1 2 4a 4b 53
BNCT Protocol number
Surv
ival
Pos
t-Dia
gnos
is (m
onth
s)
0
10
20
30
40
50
60
70
80
90
X XX
XXX
X
X
X
X
X
X
X
XXX
X
X
XX
X
XX
X XX X
XXX
XXXX
XX
XXX X
XXX
XX
X
1 2 4a 4b 53
= alive= alive with
recurrenceX = deceased
1 - 4a = single field4b = two fields5 = three fields
Approximate median survival with standard therapy
(Curran, JNCI, 85, 704, 1993)
Status as of 5/03
Patient survival dataBNL BNCT Data - All Patients
Time post-diagnosis (months)
0 20 40 60 80 100
Prob
abili
ty o
f Sur
viva
l
0.0
0.2
0.4
0.6
0.8
1.0
Clinical Trial Summary
• Escalation of neutron exposure may have reached CNS tolerance limits
• The BPA-F dose has only been marginally escalated so far.
• No tumor dose-response has been observed.
Tumor Doses
Protocol
Dos
e (G
y-Eq
)
0
10
20
30
40
50
60
70
80
2 3 4a 51 4b
n=1 n=10 n=4 n=11 n=17 n=6
Minimum dose to the contrast-enhancing tumor volume.
•Calculated Gy-Eq doses are very high: 40, 50, 60 Gy-Eq in a single-fraction.
• Tumor recurrence has been local in the majority of cases.
• Tumor necrosis has been documented histologically.
Tumor: Questions
• Does surgery affect BPA uptake in tumor?
• Do all tumor cells take up boron?
• Do infiltrating tumor cells accumulate boron as well as the main tumor mass?
BPA pharmacokinetics
Incubation Time (min)
0 50 100 150 200 250 300
Intr
acel
lula
r bor
on (µ
g 10
B/1
06 cel
ls)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40GBM: 50 ppm BPA
9L: 50 ppm BPA
9L: 25 ppm BPA
• Cells in culture take hours to fully load with BPA
Wittig et al., Radiat. Res. 153, 173, 2000
BPA Dose Escalation
Hours of continuous infusion0 1 2 3 4 5 6 7
10B
con
cent
ratio
n (µ
g/g)
0
20
40
60
80
100
120
tumor
blood
(3.5) (3.7) (3.1) (3.7)
brain
• Rat 9L gliosarcoma• Infusion rate constant: 250 mg BPA/kg/hr• Vary infusion time•Sample tumor, blood 1 hr post-infusion
Joel et al., J. Neuro-Oncol., 41, 213, 1999.
Improve BPA delivery to tumor
• Rat 9L gliosarcoma
•Infiltrating tumor cells take hours to reach the same BPA level as the main tumor mass.
Ion microscopy at Cornell Univ.; D. Smith G. Morrison.
Time of infusion (hrs)0 5 10 15 20 25 30
[10B
] MTM
/ [10
B] c
lust
ers
0
1
2
3
Smith et al., Cancer Res., 22, 8179, 2001
BNCT Patient Survival
0 5 10 15 20 25 300
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Time after Diagnosis (Months)
Pro
babi
lity
of S
urvi
val
Harvard-MITBNLStudsvikStudsvik:
6-hourBPA infusion
JNO, 62, 135, 2003
Currently…
• BNCT clinical trial for GBM in Sweden evaluating 6-hour BPA infusions.
• MIT clinical trials now open:• Two BNCT fractions on consecutive days• GBM or melanoma metastatic to the brain• Cutaneous melanoma.
• Other BNCT clinical trials underway in Finland, Japan, The Netherlands, Czech Republic.
Clinical Trials: New Directions
Other SitesHead and NeckBrain Metastases (multiple)Lung?
Criteriapoor local controlsensitive normal tissues limit dosecurrent therapies not effective