1. Biokinetic analysis of tissue 10B concentrations of glioma patients treated with BNCT in Finland
H. 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 Hospital
2VTT 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

2. 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 ( 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

3. 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

4. 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

5. 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

6. 3-Compartment Pharmacokinetic Model
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)
18F-BPA in plasma K1
18F-BPA
in tissue endoplasm
18F-BPA binding
in cell nucleus k3
Blood brain barrier k4 k2
k3 is anabolic and k4 reverse process rate constant
Tissue
(Imahori et al 1998) K1
(ml g-1 min-1) k2
(min-1) k3 k4
GBM (n=11)
0.04
0.034
0.018
0.011
Normal brain (n=21)
0.025
0.033
0.009

7. Patients Neutron irradiation durations
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 min after the end of BPA-F infusion
Neutron irradiation durations
1st field min
2nd field 9-24 min
Limiting factor: normal brain peak or average dose

8. 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 calculation
Boron dose
BPA in brain
BPA in tumor
Nitrogen and hydrogen dose 3.2
Photon dose 1

9. 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 CONSTANT

10. Summary of the Results 22 patients
Effective 10B concentration during the treatment increased along the BPA-F infusion dose
Blood ppm (average 15)
Brain ppm (average 21)
Tumor 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

11. Modeled 10B Concentration Curves Example: BPA-F 290 mg/kg
Brain doses, Gy (W)
Originally
Max 8
Ave 3
Recalculated
Max 9 (+9%)
Ave 4 (+8%)
Tumor doses, Gy (W)
Min 24
Ave 38
Min 15 (-36%)
Ave 25 (-36%)
1st irradiation 53 min after end of BPA infusion
Tumor/blood 10B ratio 2.1
1st irradiation 1.9
2nd irradiation 2.4

12. Modeled 10B Concentration Curves Example: BPA-F 350 mg/kg
Brain doses, Gy (W)
Originally
Max 8.1
Ave 3.0
Recalculated
Max 9.6 (+18%)
Ave 3.5 (+16%)
Tumor doses, Gy (W)
Min 30
Ave 46
Min 21 (-30%)
Ave 32 (-30%)
1st irradiation at 71 min after end of BPA infusion
Effective 10B concentration
Blood 15 ppm
Brain 21 ppm
Tumor 35 ppm
Tumor/blood 10B ratio 2.6
1st irradiation 2.4
2nd irradiation 2.9

13. Modeled 10B Concentration Curves BPA-F 450 mg/kg
Brain doses, Gy (W)
Originally
Max 8.0
Ave 2.9
Recalculated
Max 10.8 (+36%)
Ave 3.8 (+31%)
Tumor doses, Gy (W)
Min 22
Ave 44
Min 17 (-22%)
Ave 34 (-23%)
1st irradiation 98 min after end of BPA infusion
Effective 10B concentration
Blood 22 ppm
Brain 35 ppm
Tumor 58 ppm
Tumor/blood 10B ratio 2.6
1st irradiation 2.5
2nd irradiation 2.9

14. Plasma 10B Concentrations as Input Function in the 3-Compartment Model patient 02-P03
Whole blood
Tumor/blood 10B ratio 2.1
1st irradiation 1.9
2nd irradiation 2.4
Effective 10B concentration
Brain 16 ppm
Tumor 29 ppm
Plasma
Tumor/blood 10B ratio 2.5
1st irradiation 2.3
2nd irradiation 2.7
Effective 10B concentration
Brain 19 ppm
Tumor 34 ppm
Plasma-to-blood 10B ratio
No significant difference in T/N ratios
Plasma measurements indicate 14-22% higher normal brain and tumor concentrations during irradiations

15. Conclusion
According to 3-compartment model and the rate constant applied here
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
Also 10B concentration in normal brain tissue, and consequently brain dose, increases similarly
40-60 minutes after end of BPA-infusion N/B ≈ 1  agreement with previously determined brain doses
If the irradiation starts later than 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

16. 1st FSNCT meeting
Kiitos!

17. Modeled 10B Concentration Curves BPA-F 400 mg/kg
Brain doses, Gy (W)
Originally
Max 8.0
Ave 3.8
Recalculated
Max 9.3 (+16%)
Ave 4.4 (+14%)
Tumor doses, Gy (W)
Min 19
Ave 34
Min 13 (-30%)
Ave 23 (-31%)
1st irradiation 99 min after end of BPA infusion
Effective 10B concentration
Blood 17 ppm
Brain 23 ppm
Tumor 39 ppm
Tumor/blood 10B ratio 2.4
1st irradiation 2.2
2nd irradiation 2.6

18. 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.