Boron Neutron Capture Therapy (BNCT)HistoryPre-clinical ResearchClinical 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 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

Brookhaven National Laboratory

BMRR(1959-2000)

HFBR(1968-1999)

BGRR(1951-1968)

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

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.

Rat 9L gliosarcoma

BNCTBPA biodistribution

Coderre et al., Radiat. Res., 129, 290, 1992

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.

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

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?

Dose Escalation in BNCT

• Increase boron concentration

• Increase neutron exposure

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

Clinical trial in Studsvik

6-hrBPA Infusion:900 mg/kg

WB ave dose3-6 Gy-Eq

JNO, 62, 135, 2003

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

Clinical Trials: New Directions

Retreatment: BNCT for recurrent GBM

CombinationsBPA + another boron compound

(GB-10, BSH, CuTCPH, BOPP)BPA + radiosensitizer

Gd-texaphyrinBPA + photons

whole brain photonsradiosurgery