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.