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.

Th e BNC T Reaction

2.33 M e V o f k i ne ti c e n e r gy i s r e le ase d pe r ne utr o n c a ptur e : initial LET 200-300 k e V/ µ m

Li -7 r e coil i o n

5 µ

the r m a l ne utr o n B-10 (<0.1 e V) 8 µ

0.477 MeV G am m a (94 % )

Alpha par t i c le The r m a l c r o ss-se c t i o n = 3837 bar ns (t hat’s ver y bi g…)

Boron Neutron Capture Therapy

1. Selectively deliver 10 B to the tumor.

2. Irradiate the tumor region with low energy neutrons (n th ).

3. The short range of the 10 B(n,  ) 7 Li reaction products

restricts most of the dose to the boron-loaded cells.

n th

h

n th n th

n t

BNCT Pre-History

1932: Chadwick discovers the neutron

1935: Taylor and Goldhaber describe the 10 B(n,  ) 7 Li 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

HO

B C OOH

HO

NH 2

L- B P A

( p - b o r o n o - L- ph en y l al a n i n e)

2 N a +

2 -

SH

= B

= B H

BSH

(N a 2 B 12 H 11 SH )

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 10 B(n,  ) 7 Li reaction

  dose - from beam contamination and neutron capture reaction in hydrogen: 1 H(n,  ) 2 H

 Nitrogen dose - f rom products of 14 N(n,p) 14 C reaction

 Fast neutron dose – from recoil nuclei (mostly protons)

Thermal Neutron Cross Sections

Photon-Equivalent Doses

IAEA Workshop (6/99) recommends that BNCT doses be expressed as a weighted dose D w , with the unit Gy, using the following convention:

D w = w b .D b + w g .D g + w n .D n + w p .D p

Currently:

weighting factors termed RBE or CBE factors; BNCT doses expressed in Gy-Eq units.

Beam components: depth-dose profile

10

1

0.1

0.01

0

2

4

6

8

1 0

1 2

Dept h ( c m)

 total d ose

 boron capture (13 µg 10 B/g)

 gamma

 fast neutrons

 nitrogen capture

BMRR epithermal beam, 3 MW reactor power

The boron delivery agent

HO

B

C OOH

HO

NH 2

L- B P A

( p -b o r o n o- L- ph e n y l a l a n i n e )

BPA concentrates in tumor to levels 3.5 - 4 times higher than blood or brain.

18 F PET study: adapted from Imahori et al .

JNM, 39, 325, 1998.

Rat 9L gliosarcoma

BPA biodistribution

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

B NCT

Selective tumor ablation

Rat 9L gliosarcoma: 1 year post-BNCT MR images

Horseradish peroxidase perfusion Normal brain T umor scar

500 µm

Coderre et al., Int. J. Radiat. O ncol. Biol. Phys., 28, 1067, 1994.

Dose response: ED 50 endpoint

100

80

60

40

20

0

0

5

10

Dose (Gy)

15

20

 x rays

 thermal neutrons

 thermal neutrons

+ BPA

• Compare isoeffective doses (ED 50 )

Coderre et al., Radiat.Res., 152, 113, 1999

BNCT radiobiology

Tissues studied: Weighting Factors U sed

in Clinical Trial

10 B biological effectiveness factors range from 1.3 to over 5.

An RBE of 3.2 is use d for the high-LET beam components in all tissues.

Dog brain irradiations

Isodose contours

Dose volume histograms

Coderre et al., J. Ne uro-Oncol., 48, 27, 2000.

Dog brain irradiations

Asymptomatic MRI changes Massive edema at 5 mos.

6 mos. post- BNCT

Coderre et al., J. Ne uro-Oncol., 48, 27, 2000.

Dog brain irradiations

• Average whole brain dose, single- field irradiation.

• 1 Gy = 1 jou l e/k g

• 2 Gy = conventional daily fraction for tumors (x 30d).

• 10 Gy whole body (brain) used in bone marrow transplant.

The BNCT procedure

30

BNCT

25

20

15

10

5

inf u s i on

250 mg BPA/ kg (n= 11)

0

0

1

2

3

4

5

6

Ti me (hours)

Surgery 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. Ne uro-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

18

16

14

12

10

8

n=1 n =10 n =4 n=11 n= 17 n=6

6

1

2

3

4 a

4 b

5

Protocol

BNL BNCT clinical trial.

Reference (peak) doses in brain (maximum dose to a 1 cm 3 volume).

Doses escalated in 20% increments.

Chanana, et al., Ne urosurg., 44, 1182, 1999.

Brain dose

10

8

6

4

2

0

1

2

3

4 a

4b

5

Protocol

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 Histograms

• Escalation of the dose in humans.

• Comparison to the maximum tolerated dose in dogs.

Normal Brain Tolerance

A

100

80

60 2 fi el ds

40 3 fields

20

1 fi el d

0

0 2 4 6 8 10 12 14 16

Do se ( G y( W) )

Normal Brain Tolerance

B

100

80

BNL P a ti ents w i th Somnolence

60

40 2 f i el d s

20

0

0 2 4 6 8 10 12 14 16

Do se ( G y( W) )

Normal Brain Tolerance

C

100

2- fields

80

60

40

20

0

0 2 4 6 8 1 0 1 2 1 4

Do se (Gy(W))

Normal Brain Tolerance

18

BNL

BNL w i th somnolenc e

16 MI T

MI T w i th s o m nol enc e

14

12

10

8

6

1 2 3 4 5 6 7 8 9

Whole-Br ain Aver age Dose (Gy ( W))

Normal Brain Tolerance

100

80

60

40

20 A v erage B r ain D o se

P e ak Brain Dose

.... .... 95% confidence

0

0 5 10 15 20 25

Dose (G y ( w ) )

Patient survival data

90

80

70

60

50

40

30

20

X X X

X

X

X

10

X

X

X

X

X

X X X X X

X X X X

X

X X X

X X X X

X

X X X X

X

X X

X

0

1

2

3

4a

4b

5

BNCT Protocol number

 = alive

 = ali v e with

recurrence

X = deceased

1 - 4 a = single field 4b = two fields 5 = three fields

Approximate median survival with standard therapy

(Curran, JNCI, 85, 704, 1993)

Status as of 5/03

BNL BNCT Data - All Patien ts

1.0

0.8

0.6

0.4

0.2

0.0

0

2 0

4 0

6 0

8 0

1 0 0

Time post-diagnosis (m onths)

Patient survival data

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

80

70

60

50

40

30

20

10

n = 1 n = 1 0 n = 4 n=1 1 n= 17 n= 6

0

1

2

3

4 a

4 b

5

Protocol

Minimum dose to the contrast- enhancing tumor volume.

• Calculated Gy-Eq d oses are very high: 40, 50, 60 Gy-Eq i n 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 up take 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

0.40

GB M: 5 0 ppm BPA

0.35

0.30

0.25

0.20

9L: 50 pp m BPA

0.15

0.10

9L: 2 5 pp m BPA

0.05

0.00

0

5 0

1 00

150

2 00

250

3 00

Incubat i on Time (min)

• Cells in culture take hours to fully load with BPA

Wittig et al., Radiat. Res. 153, 173, 2000

BPA Dose Escalation

12 0

10 0

80

tumor

60

40

blood

20

br ain

(3 . 5 )

( 3 . 7)

(3. 1 )

( 3. 7)

0

0

1

2

3

4

5

6

7

Hours of continuous infusion

• Rat 9L gliosarcom a

• Infusion rate constant: 250 m g BPA/kg/hr

• Vary infusion time

• Sample tumor, blood 1 hr post-infusion

Joel et al., J. Neuro-On col., 41, 213, 1999.

Improve BPA delivery to tumor

3

2

1

0

0

5

10

15

20

25

30

Time of infusion (hrs)

• Rat 9L gliosarcoma

• Infiltrating tumor cells take hours to reach the same BPA level as the main tumor mass.

Ion microscop y at Cornell Univ.; D. Smith G . Morrison.

Smith et al., Cancer Res., 22, 8179, 2001

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

Studsvik: 6-hour BPA

infusion

1

0. 9

0. 8

0. 7

0. 6

H a r v ar d- M I T BN L

St u d s v ik

0. 5

JNO, 62, 135,

2003

0. 4

0. 3

0. 2

0. 1

0

0 5 10 15 20 25 30

T i m e af t e r D i agnos is (M ont hs )

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 m elanoma.

• 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