Biokinetic analysis of tissue 10B concentrations

of glioma patients treated with BNCT in

FinlandH. Koivunoro1, E. Hippelänen1, I. Auterinen2, L.

Kankaanranta3, M. Kulvik4, H. Revitzer5, J. Laakso6, T. Seppälä3, S. Savolainen1 and H. Joensuu3

1HUS Helsinki Medical Imaging Center, Helsinki University Central Hospital2VTT Technical Research Centre of Finland, Espoo,

3Department of Oncology, Helsinki University Central Hospital, 4Department of Neurology, Helsinki University Central Hospital,

5Aalto University School of Science and Technology, 6Finnish Safety and Chemicals Agency (Tukes),

Finland

Glioma BNCT in Finland 98 glioma patients treated from year 1999 to 2011

Newly diagnosed glioblastoma (n=39) Malignant glioma recurrence after surgery (n=59)

L-BPA-F dose escalation (290-500 mg/kg) Administered as a 2-hour intravenous infusion

Peripheral venous blood samples collected periodically for 10B concentrations analysis (ICP-AES) 10B concentrations in tumor and normal brain, and radiobiological weighting factors for radiation dose calculation applied according to Brookhaven clinical trials (Coderre et al. Rad Res 149, 1998) A correlation between the calculated tumor doses and treatment response not found

Might suggest an incorrect estimation of the tumor dose

10B Concentrations of Tissues

Commonly constant tissue-to-blood 10B concentration ratios applied based on study by Coderre et al. (Rad Res 149, 1998)

Tumor-to-whole blood boron concentration ratio, T/B = 3.5

Normal brain tissue-to-whole blood concentration ratio, N/B = 1

T/N = 3.5 In this study the 10B concentrations in the

tumor and brain are obtained with a segmental convolution method using the rate constants from study by Imahori et al (1998) defined with closed 3-compartment pharmacokinetic model

Recurrent gliomas patients who have received BNCT in Finland

The patient doses are recalculated based on the modeled 10B concentration in tumor and brain at the time of neutron irradiation

3-Compartment Pharmacokinetic Model

Defined from dynamic 18F-BPA-F PET studies

of glioma patients

(Imahori et al Clin Cancer Res 4,

1998) Normal brain and tumor 18F activity measured

continuously with PET

18F activity of plasma measured from arterial

blood samples

Model requires plasma data as input

Whole blood to plasma concentration

ratio ≈ 1.3

3-Compartment Pharmacokinetic Model

Verification

Model verified with slow (20 min and 60 min) 18F-

BPA-F infusion and tumor resection after PET study

Imahori et al 1998

3-Compartment Pharmacokinetic Model

18F-BPA in plasma18F-BPA

in tissue endoplasm18F-BPA bindingin cell nucleus

Blood brain barrier

K1

k2

k3

k4

k3 is anabolic and k4 reverse process rate constant

Rate constants K1, k2 , k3, and k4 define transport between the central compartment (plasma), tissue compartment 1 (tissue endoplasm), and a deeper tissue compartment 2 (binding in cell nucleus)

Tissue

(Imahori et al 1998)

K1 (ml g-1 min-

1)

k2(min-1)

k3(min-1)

k4(min-1)

GBM (n=11) 0.04 0.034 0.018 0.011

Normal brain (n=21) 0.011 0.025 0.033 0.009

22 patients with recurrent glioma (20 glioblastoma, 2 anaplastic astrocytoma), treated within a clinical trial “P03” (Kankaanranta et al. 2011)

BPA-F dose escalation (2-hour intravenous infusion) 290 mg/kg (n=10) 350 mg/kg (n=3) 400 mg/kg (n=3) 450 mg/kg (n=6)

The 10B concentration of whole blood measured with ICP-AES Two neutron fields applied in all cases

Irradiation initiated 46-144 min after the end of BPA-F infusion

Neutron irradiation durations 1st field 26-51 min 2nd field 9-24 min

Limiting factor: normal brain peak or average dose

Patients

Dose calculation

The 3-compartmental model requires plasma 10B concentrations as input function

Since only whole blood 10B concentration measured, constant plasma-to-blood concentration ratio of 1.3 was assumed as suggested by Imahori et al (1998) Measured plasma 10B concentration available for one of the analyzed cases

Average 10B concentration in normal brain and tumor tissue were calculated with segmental convolution method for the irradiation times and used for the recalculation of doses

Radiobiological weighting factors in dose calculationBoron dose

BPA in brain 1.3BPA in tumor 3.8

Nitrogen and hydrogen dose 3.2Photon dose 1

Summary of the Results:T/N and T/B ratios

The 3-compartment model predicts differing pharmacokinetics for the brain tissue and blood, which results in distinct T/N and T/B concentration ratio curves than previously assumed

NOT CONSTANTTumor-to-normal brain ratio

0.0

0.5

1.0

1.5

2.0

2.5

120 140 160 180 200 220 240 260 280 300 320 340 360 380Time from start of BPA-F infusion (min)

T/N

rati

o

Tumor-to-blood ratio

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

120 140 160 180 200 220 240 260 280 300 320 340 360 380Time from start of BPA-F infusion (min)

T/B

rati

o

Summary of the Results22 patients

Effective 10B concentration during the treatment increased along the BPA-F infusion

dose

Blood 11-22 ppm (average 15)

Brain 14-35 ppm (average 21)

Tumor 24-58 ppm (average 36)

Based on 3-compartment model

Brain max dose increases 0-41% (average 19%)

Tumor dose reduces 16-44% (average 30%)

If the irradiation was initiated later, higher increase in brain dose and less reduced tumor dose

Modeled 10B Concentration Curves Example: BPA-F 290 mg/kg

Tumor/blood 10B ratio 2.1 1st irradiation 1.92nd irradiation 2.4

Brain doses, Gy (W)Originally

Max 8 Ave 3

Recalculated Max 9 (+9%) Ave 4 (+8%)

Tumor doses, Gy (W)Originally

Min 24 Ave 38

Recalculated Min 15 (-36%) Ave 25 (-36%)

1st irradiation 53 min after end of BPA infusion

Patient 05-P03, BPA dose 290 mg/kg

0

5

10

15

20

25

30

35

0 20 40 60 80 100120140160180200220240260280Time from start of BPA-infusion (min)

10 B

con

cen

trati

on

(p

pm

) TumorBloodBrain

Modeled 10B Concentration Curves

Example: BPA-F 350 mg/kg

Effective 10B concentration

Blood 15 ppm Brain 21 ppm Tumor 35 ppm

Brain doses, Gy (W)

Originally Max 8.1 Ave 3.0

Recalculated Max 9.6 (+18%)

Ave 3.5 (+16%)

Tumor doses, Gy (W)

Originally Min 30 Ave 46

Recalculated Min 21 (-

30%) Ave 32 (-

30%)

1st irradiation at 71 min after end of BPA infusion

0

5

10

15

20

25

30

35

40

0 20 40 60 80 100120140160180200220240260280

Time from start of BPA-infusion (min)

10 B

con

cen

trati

on

TumorBloodBrain

Patient 12-P03, BPA dose 350 mg/kg

Tumor/blood 10B ratio 2.61st irradiation 2.42nd irradiation 2.9

Modeled 10B Concentration Curves

BPA-F 450 mg/kgBrain doses, Gy (W)Originally

Max 8.0 Ave 2.9

Recalculated Max 10.8 (+36%) Ave 3.8 (+31%)

Tumor doses, Gy (W)Originally

Min 22 Ave 44

Recalculated Min 17 (-22%) Ave 34 (-23%)

1st irradiation 98 min after end of BPA infusion

Tumor/blood 10B ratio 2.61st irradiation 2.52nd irradiation 2.9

Effective 10B concentration Blood 22 ppm Brain 35 ppm Tumor 58 ppm

Patient 22-P03, BPA dose 450 mg/kg

0

10

20

30

40

50

60

70

0 20 40 60 80 100120140160180200220240260280300320Time from start of BPA-infusion (min)

10 B

con

cen

trati

on

TumorBloodBrain

Plasma 10B Concentrations as Input Function in the 3-

Compartment Model patient 02-P03

Patient 02-P03, BPA dose 290 mg/kg

0

5

10

15

20

25

30

35

40

45

50

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280

Time from start of L-BPA-F infusion (min)

10B

con

cen

trati

on

Tumor BloodBrain PlasmaTumor, plasma-based Brain plasma-based

PlasmaTumor/blood 10B

ratio 2.51st irradiation

2.32nd irradiation

2.7

Effective 10B concentration

Brain 19 ppm Tumor 34 ppm

Whole bloodTumor/blood 10B ratio 2.1

1st irradiation 1.92nd irradiation 2.4

Effective 10B concentration Brain 16 ppm Tumor 29 ppm

• Plasma-to-blood 10B ratio 1.2-1.4 • No significant difference in T/N ratios• Plasma measurements indicate 14-22% higher normal brain and tumor concentrations during irradiations

Conclusion

According to 3-compartment model and the rate constant applied here

1. The highest 10B concentration in tumor, and

consequently tumor dose, will not be achieved earlier than >170 minutes after the end of BPA-F infusion

No blood samples available for later moments

2. Also 10B concentration in normal brain tissue, and consequently brain dose, increases similarly

3. 40-60 minutes after end of BPA-infusion N/B ≈ 1 agreement with previously determined brain doses

4. If the irradiation starts later than 40-60 minutes after, the normal brain dose increases from previous predictions

Model needs to be verified for BPA infusion doses >290 mg/kg

Correlation between clinical response and the doses presented here will be evaluated

Kiitos! Kiitos!

1st FSNCT meeting

Modeled 10B Concentration Curves

BPA-F 400 mg/kgBrain doses, Gy (W)Originally

Max 8.0 Ave 3.8

Recalculated Max 9.3 (+16%) Ave 4.4 (+14%)

Tumor doses, Gy (W)Originally

Min 19 Ave 34

Recalculated Min 13 (-30%) Ave 23 (-31%)

1st irradiation 99 min after end of BPA infusion

0

5

10

15

20

25

30

35

40

45

0 20 40 60 80 100120140160180200220240260280300320

Time from start of BPA-infusion (min)

10 B

con

cen

trati

on

(p

pm

)

TumorBloodBrain

Patient 14-P03, BPA dose 400 mg/kg

Tumor/blood 10B ratio 2.41st irradiation 2.22nd irradiation 2.6

Effective 10B concentration Blood 17 ppm Brain 23 ppm Tumor 39 ppm

Discussion

As the vascular endothelium may be the main target of BNCT damage, instead of examining the T/N ratio, the ratio of tumor-to-combination of 1/3 blood + 2/3 the normal brain tissue has been proposed to be examined (Kiger et al 2000)

Suggests that brain doses determined according to 10B concentration of brain tissue might be overestimated

The highest tumor-to-combination of 1/3 blood + 2/3 the normal brain tissue ratio of 1.8 to 2.0 was observed 70 to 130 minutes after end of the L-BPA F-infusions, which was the time range within which all patients received neutron

irradiation.