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

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 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

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 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

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 1.3 BPA in tumor 3.8 Nitrogen and hydrogen dose 3.2 Photon 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 CONSTANT

Summary of the Results 22 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 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

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

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

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 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 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 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

1st FSNCT meeting Kiitos!

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

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.