BNCT Politics

BNCT Politics

BNCT Politics

Washington Post, 12/94

BNCT Politics

BNCT Politics

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

BNCT Patients



 

 



  

17

  





C 

 





BNCT at the BMRR, 1997

The MIT Research Reactor

MITR-II showing current and new epithermal beam locations

MIT BNCT Clinical Trial

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.

Boron microlocalization by SIMS

Tumor/normal brain boundary Boron concentration

50µm

D. Smith , Cornell University

Cancer Res., 56, 4302, 1996.

Boron microlocalization by SIMS

Tumor boundary

Infiltrating tumor cells

50µm

D. Smith , Cornell University

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.

Complete radiographic response following BNCT for a metastatic melanoma in the occipital lobe

MIT/Harvard clinical trial

Left: Pre-BNCT MRI

Middle: Increased enhancement at the site of original tumor one month following BNCT.

Right: Loss of enhanced signal and mass effect seven months following BNCT.

Busse, et al., JNO, 62, 111, 2003

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