Boron Neutron Capture Therapy (BNCT)
History
Pre-clinical Research
Clinical Trials
Glioblastoma multiforme
~ 7000 new cases/yr in
the US.
Standard treatment:
Surgery followed by
radiation therapy.
Median survival is 10 to
12 months.
Glioblastoma multiforme
Boron Neutron Capture Therapy
• Glioblastoma: the
invasive nature makes
treatment difficult.
• BNCT has the
potential to selectively
target these infiltrating
tumor cells.
The BNCT Reaction
2.33 MeV of kinetic energy is released per neutron capture:
initial LET 200-300 keV/µm
Li-7 recoil ion
5µ
0.477 MeV Gamma (94%)
thermal neutron
B-10
(<0.1 eV)
8µ
Alpha particle
Thermal cross-section = 3837 barns (that’s very big…)
Boron Neutron Capture Therapy
1. 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.
nth
nth
nth
nth
BNCT Pre-History
1932: 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
Brookhaven National Laboratory
BGRR
(1951-1968)
HFBR
(1968-1999)
BMRR
(1959-2000)
BNCT Clinical Trial: ~1953
BGRR Clinical Trial: 1951-1959
BNCT Clinical Trial: 1959-1961
Brookhaven Medical Research Reactor
Beam shutter
BMRR schematic
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
2SH
HO
COOH
B
2 Na+
HO
NH2
L-BPA
(p-borono-L-phenylalanine)
=B
= BH
BSH
(Na2B12H11SH)
Improvements in neutron beams
Thermal
< 0.4 eV
Epithermal
0.4 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
10B
11B
12C
1H
14N
35Cl
23Na
157Gd
153Gd
Cross section (barns)
3837
0.005
0.0035
0.33
1.70
43.6
0.534
254,000
0.02
Photon-Equivalent Doses
IAEA 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
BMRR epithermal beam,
3 MW reactor power
10
Dose rate (cGy/min)
z total dose
∇ boron capture
(13 µg 10B/g)
„ gamma
Πfast neutrons
◊ nitrogen capture
1
0.1
0.01
0
2
4
6
8
Depth (cm)
10
12
The boron delivery agent
BPA concentrates in tumor
to levels 3.5 - 4 times higher
than blood or brain.
HO
COOH
B
HO
NH2
L-BPA
(p-borono-L-phenylalanine)
18F
PET study:
adapted from
Imahori et al.
JNM, 39, 325, 1998.
Rat 9L gliosarcoma
BPA biodistribution
Coderre et al., Radiat. Res., 129, 290, 1992
BNCT
Selective tumor ablation
Horseradish peroxidase perfusion
Rat 9L gliosarcoma:
1 year post-BNCT
MR images
Normal brain
Tumor scar
500 µm
Coderre et al., Int. J. Radiat. Oncol. Biol. Phys., 28, 1067, 1994.
Dose response: ED50 endpoint
c thermal neutrons
z thermal neutrons
+ BPA
• Compare
isoeffective
doses (ED50)
Tongue fields exhibiting ulceration (%)
„ x rays
100
80
60
40
20
0
0
5
10
15
20
Dose (Gy)
Coderre et al., Radiat.Res., 152, 113, 1999
BNCT radiobiology
Tissues studied:
Weighting Factors Used
in Clinical Trial
• tumor
• brain
• spinal cord
• skin
• oral mucosa
10B
3.8
1.3
1.3
2.5
2.5
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 histograms
Isodose contours
30
Fraction of Volume (%)
25
20
15
10
5
0
0
5
10
15
20
25
Effective Dose (Gy-Eq)
Coderre et al., J. Neuro-Oncol., 48, 27, 2000.
Dog brain irradiations
Asymptomatic MRI changes
Massive edema at 5 mos.
6 mos.
postBNCT
Coderre et al., J. Neuro-Oncol., 48, 27, 2000.
Dog brain irradiations
brain dose, singlefield 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.
Average Brain Dose (cGy or cGy-Eq)
• Average whole
1400
1200
1000
fast neutrons
nitrogen
gamma
boron
800
600
400
200
0
cGy
Dog 3746:
No changes
in 3 years
cGy-Eq
cGy
cGy-Eq
Dog 1655:
Lethal necrosis
in 5 months
The BNCT procedure
• 2-hr BPA infusion
• BNCT starts ~ 45 min
after end of infusion
BNCT
B concentration in blood (µg/g)
BNCT is given in a
single session
lasting less than 1 hr.
30
25
20
15
10
5
infusion
10
Surgery 3-4 weeks
prior to BNCT.
0
0
1
250 mg BPA/kg (n=11)
2
3
4
Time (hours)
Coderre, et al., J. Neuro-Oncol., 33, 141, 1997.
5
6
Monte Carlo-based treatment planning
Tumor
Target volume
(tumor + 2 cm)
Brain
• One field versus two fields
• Peak dose, hemisphere dose, whole brain average dose
MITR-II showing current and new epithermal beam locations
Brain Doses
BNL BNCT clinical
trial.
Doses escalated in 20%
increments.
Reference Dose (Gy-Eq)
Reference (peak) doses
in brain (maximum dose
to a 1 cm3 volume).
18
16
14
12
10
8
6
n=1
n=10
n=4
1
2
3
n=11
4a
Protocol
Chanana, et al., Neurosurg., 44, 1182, 1999.
n=17
4b
n=6
5
Brain dose
BNL BNCT clinical trial:
CNS side effects
observed in 2 pts in
Protocol 4b and all pts in
Protocol 5.
8
Dose (Gy-Eq)
Whole-brain average
doses.
10
6
4
2
0
1
2
3
4a
Protocol
4b
5
Brain: Dose Volume Histograms
Dose-Volume Histogram
for the Normal Brain
45
• Escalation of the dose
• Comparison to the
maximum tolerated dose
in dogs.
Fraction of Volume (%)
in humans.
40
1-field
35
30
25
2-field
dogs, MTD
3-field
20
15
10
5
0
0
5
10
15
Effective Dose (Gy-Eq)
20
Normal Brain Tolerance
A
100
% Brain Volume
80
2 fields
60
3 fields
40
20
1 field
0
0
2
4
6
8
10
Dose (Gy(W))
12
14
16
Normal Brain Tolerance
B
100
BNL Patients
with Somnolence
% Brain Volume
80
60
2 fields
40
20
0
0
2
4
6
8
10
Dose (Gy(W))
12
14
16
Normal Brain Tolerance
C
100
2-fields
% Brain Volume
80
60
40
20
0
0
2
4
6
8
Dose (Gy(W))
10
12
14
Normal Brain Tolerance
18
BNL
BNL with somnolence
MIT
MIT with somnolence
Peak Dose (Gy(W))
16
14
12
10
8
6
1
2
3
4
5
6
7
Whole-Brain Average Dose (Gy(W))
8
9
Normal Brain Tolerance
somnolence probability (%)
100
80
60
40
Average Brain Dose
20
........
0
0
5
10
15
Dose (Gy(w))
Peak Brain Dose
95% confidence
20
25
Patient survival data
1 - 4a = single field
4b = two fields
5 = three fields
Approximate median survival
with standard therapy
(Curran, JNCI, 85, 704, 1993)
Status as of 5/03
90
Survival Post-Diagnosis (months)
{ = alive
z = alive with
recurrence
X = deceased
80
70
60
50
40
30
X
X
X
X
X
X
X
X
X
20
X
10
0
X
1
1
2
X
X
X
XX
X
X
X
X
X
X
X
X
XXX
XXX
XX
XX
XX
X
XXX
X
XX
X
3
4a
4b
5
2
3
4a
4b
5
BNCT Protocol number
Patient survival data
BNL BNCT Data - All Patients
Probability of Survival
1.0
0.8
0.6
0.4
0.2
0.0
0
20
40
60
Time post-diagnosis (months)
80
100
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
Minimum dose to the contrastenhancing tumor volume.
80
•Calculated Gy-Eq doses are
•
Tumor recurrence has been
local in the majority of cases.
•
Tumor necrosis has been
documented histologically.
60
Dose (Gy-Eq)
very high: 40, 50, 60 Gy-Eq in a
single-fraction.
70
50
40
30
20
10
0
n=1
n=10
n=4
1
2
3
n=11
4a
Protocol
n=17
n=6
4b
5
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?
Dose Escalation in BNCT
• Increase boron concentration
• Increase neutron exposure
BPA pharmacokinetics
• Cells in culture
take hours to fully
load with BPA
Intracellular boron (µg 10B/106 cells)
0.40
GBM: 50 ppm BPA
0.35
0.30
0.25
0.20
0.15
0.10
9L: 25 ppm BPA
0.05
0.00
Wittig et al., Radiat. Res. 153, 173, 2000
9L: 50 ppm BPA
0
50
100
150
200
Incubation Time (min)
250
300
BPA Dose Escalation
• Rat 9L gliosarcoma
• Infusion rate constant:
250 mg BPA/kg/hr
• Vary infusion time
•Sample tumor, blood 1 hr
post-infusion
10B concentration (µg/g)
120
100
tumor
80
60
40
blood
20
brain
(3.5)
0
Joel et al., J. Neuro-Oncol., 41, 213, 1999.
0
1
(3.7)
(3.1)
2
3
(3.7)
4
5
6
Hours of continuous infusion
7
Improve BPA delivery to tumor
• Rat 9L gliosarcoma
take hours to reach the
same BPA level as the
main tumor mass.
[10B] MTM / [10B] clusters
•Infiltrating tumor cells
3
2
1
Ion microscopy at Cornell Univ.; D.
Smith G. Morrison.
0
0
5
10
15
20
Time of infusion (hrs)
Smith et al., Cancer Res., 22, 8179, 2001
25
30
Clinical trial in Studsvik
6-hr
BPA
Infusion:
900 mg/kg
WB ave
dose
3-6 Gy-Eq
JNO, 62, 135, 2003
BNCT Patient Survival
Harvard-MIT
BNL
Studsvik
1
JNO, 62, 135,
2003
0.9
Probability of Survival
Studsvik:
6-hour
BPA
infusion
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
5
10
15
20
Time after Diagnosis (Months)
25
30
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 Sites
Head and Neck
Brain Metastases (multiple)
Lung?
Criteria
poor local control
sensitive normal tissues limit dose
current therapies not effective
Clinical Trials: New Directions
Retreatment: BNCT for recurrent GBM
Combinations
BPA + another boron compound
(GB-10, BSH, CuTCPH, BOPP)
BPA + radiosensitizer
Gd-texaphyrin
BPA + photons
whole brain photons
radiosurgery