Boron Neutron Capture Therapy in the treatment of brain tumours - The Swedish experience - L. Pellettieri Md. Ph. D. Professor emeritus Gothenburg University SWEDEN XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours From: S.I. Miyatake, et al. J. Neurosurg. 103: , 2005 Early reduction of tumour enhancement after BNCT ABCABC Primary GBM treated by BNCT Images obtained just prior to BNCT. A.Images demonstrating the initial effect of therapy estimated within 1 week. B.Images revealing the most improvement, obtained during the follow-up.

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours BNCT: neutron- 10 B reaction Boron neutron capture reaction 10 B + 1 n = 7 Li + 4 He (  ) MeV 7 Li ion and  particle: range in tissue, 5 and 9  m, respectively

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours hours3 hours6 hours24 hours Studsvik BNL Infusion time Boron concentration in spread cells vs infusion time Data from: Smith DR, Chandra S, Barth RF, Yang W, Joel DD, and Coderre JA. Quantitative Imaging and Microlocalization of Boron-10 in Brain Tumors and Infiltrating Tumor Cells by SIMS Ion Microscopy: Relevance to Neutron Capture Therapy. Cancer Res 2001;61:8179–8187.

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours 52 patients treated from March 2001 to March primary glioblastoma multiforme (GBM) 16 recurrent GBM 2 meningeal tumors Synthesis route for cGMP L-BPA developed and large scale production established. New boron substance (Borace) in preclinical phase. BNCT at Studsvik, Sweden

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours DAY 1_______________________ CT scan with fiducial markers Treatment planning DAY 2_______________________ BPA infusion Positioning Irradiation DAY 3_______________________ MRI scan Release from the hospital Typical BNCT treatment schedule

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Efficacy of prolonged infusion of BPA-f BNL Phase I/II study with 2 hour infusion versus Studsvik Phase II study with 6 hour infusion Skold.K.et al 2010 Acta neurol.scand.vol.122:58-62

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Kaplan-Meier plots for overall survival

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours ParameterBNL phase I/IIStudsvik phase II PFS from BNCT [months]4.9 (95% CI: 4.2 – 5.8) 5.8 (95% CI: 5.2 – 8.7) MST from diagnosis [months] All patients Two field treatment 12.8 (95% CI: ) 12.6 (95% CI: ) 17.7 (95% CI: 13.6 – 19.9) 17.7 (95% CI: 13.6 – 19.9) Adverse events (WHO grade 3-4) Number of patients (%) Events (events per patient) 7 (13) 12 (0.22) 4 (14) 9 (0.31) Summary of clinical results

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Postmortem neuropathological examinations Studsvik a  No GBM tumor at primary site in any of the 7 cases analyzed  No GBM tumor anywhere in the brain in 5 of the 7 cases BNL b  Local recurrence found in all 13 cases analyzed b c,d H-Stenstam B, Pellettieri L, Sköld K, Rezaei A, Brun A. Neuropathological postmortem evaluation of BNCT for GBM. Acta Neurol Scand 2007;116: b Aziz T, Peress NS, Diaz A, Capala J, Chanana A. Postmortem neuropathological features secondary to boron neutron capture therapy for glioblastoma multiforme. J Neuropathol Exp Neurol 2000;59:62-73.

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours BNCT compared with standard treatment (Radiotherapy plus temozolomide ) Studsvik phase II BNCT study versus Stupp et al. phase III study Skold.k.et al.2010 British J. Radiology vol. 83:

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours ParameterRTRT/TMZBNCT Number of patients Age, median (range) [y]57 (23-71)56 (19-70)53 (28-69) Tumor volume, median (range) [cc]--45 (11-306) Initial surgery [%] Gross total Subtotal Biopsy only RPA class (%) Average RPA class III (14), IV (52), V (34) 3.8 III (15), IV (53), V (32) 3.7 III (14), IV (21), V (65) 4.5 Salvage chemotherapy [%] Temozolomide Other Salvage surgery [%]23 7 Baseline characteristics and salvage treatment Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Survival in the two arms of the Stupp study (red) and in the Studsvik study (blue), all RPA classes BNCT vs RT (based on the time from surgery) BNCT vs RT/TMZ (based on the time from surgery)

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Survival in the two arms of the Stupp study (red) and in the Studsvik study (blue) for RPA class V BNCT vs RT in RPA class V (based on the time from surgery) BNCT vs RT/TMZ in RPA class V (based on the time from surgery)

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours ParameterRTRT/TMZBNCT PFS [months]5.0 (95% CI: ) 6.9 (95% CI: ) 5.8 (95% CI: 5.2 – 8.7) MST from surgery [months] All patients RPA class V patients 12.9 (95% CI: ) 10.1 (95% CI: ) 15.5 (95% CI: ) 12.0 (95% CI: ) 17.7 (95% CI: 13.6 – 19.9) 13.3 (95% CI: 10.3 – 18.2) 1-year survival [%] All patients RPA class V patients 57.5 (95% CI: ) 42.8 (95% CI: ) 66.1 (95% CI: ) 49.5 (95% CI: ) 78.7 (95% CI: ) 66.9 (95% CI: ) Adverse events (WHO grade 3-4) Number of patients (%) Events (events per patient) 42 (15) 111 (0.39) 137 (47) 318 (1.11) 4 (14) 9 (0.31) Summary of clinical results

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours ( Hegi et al., N ENGL J MED 352;10 MARCH 2005) Hypothesis With conventional radiotherapy methylation of the MGMT promoter gene, particularly in the presence of TMZ, is believed to prolong patient survival by to the inhibition of repair of DNA damage. Repair is considerable after conventional radiation but DNA damage is not repairable after BNCT and thus the MGMT methylation status will not be an influencing factor. MST [m] versus MGMT Promoter Methylation Status

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours BNCT for recurrent GBM at Studsvik: Kaplan-Meier plots of survivals Pellettieri et al.2008 Acta Neurol. Scand. Vol. 117:

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours GBM Liver cancer Breast cancer Synovial Sarcoma  g B / g protein BORCAP (L-BPA) BORACE ® 0,0 0,2 0,4 0,6 0, Time (hours)  g B / cell pellet BORCAP (L-BPA) BORACE ®  times more boron in tumor  Lower neutron doses needed  Applicable to tumors at any depth  Enables whole brain irradiation.  Applicable to multifocal brain metastases.  Potential efficacy for many cancer types. BORACE®: 10 B uptake in vitro BORACE®: 10 B cellular retention BORACE® a new promising boron drug

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours  BNCT involving a 6 hour infusion of BPA (900 mg/kg) is an effective targeted treatment for GBM.  BNCT is as least as effective if not more effective than conventional radiotherapy (RT) and is associated with fewer severe adverse events than RT/TMZ.  BNCT induced damage to DNA is not repairable and is thus unlikely to be influenced by mechanisms influencing DNA repair i.e. the MGMT promotor gene methylation status.  BNCT possibly has a clinically relevant advantage over RT/TMZ for patients with unmethylated MGMT promotor gene (HR 0.68).  A randomized clinical trial (phase II, stratified) to compare BNCT with RT/TMZ in unmethylated patients is proposed. Conclusions

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Baseline characteristics and salvage treatments ParameterBNL phase I/IIStudsvik phase II Number of patients5329 Age, median (range) [y]56 (22-81)53 (28-69) Tumor volume, median (range) [cc]25 (2-98)45 (11-306) Initial surgery [%] Gross total Subtotal Biopsy only RPA class (%) Average RPA class III (8), IV (30), V (62) 4.5 III (14), IV (21), V (65) 4.5 Salvage chemotherapy [%] Temozolomide Nitrosurea-based Other Salvage surgery [%]517 Salvage radiotherapy [%]257

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours SUMMARY Comparison of the BNL study and the Studsvik study indicates that prolonged infusion of BPA-f is highly beneficial

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Kaplan-Meier plots of survival of patient (based on time from initial surgery) BNCT vs RT/TMZ (MGMT unmethylated) Patient survival (%) BNCT vs RT/TMZ (MGMT methylated)

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours ParameterRT/TMZ (MGMT methylate) RT/TMZ (MGMT unmethylate) BNCT MST from surgery [months] All patients24.7 (95% CI: 19.3 – 34.1) 13.4 (95% CI: ) 17.7 (95% CI: 13.6 – 19.9) 1-year survival [%] All patients80.0 (95% CI: ) 66.7 (95% CI: ) 78.7 (95% CI: ) Summary of clinical results from Kaplan-Meier analysis

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours BNCT for GBM, recurring after surgery and standard fractionated photon therapy. Explorative study including 12 patients: 6h infusion of BPA- 900 mg per kilo body weight 6 patients treated with two fields of irradiation 6 patients treated with one field of irradiation BNCT for recurrent GBM

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours 26 Cox proportional hazard ratios for BNCT versus either RT/TMZ for bothe MGMT methylated and unmethylated subgroups of patients. Hazard ratio (unadjusted) (adjusted*) BNCT versus RT/TMZ (MGMT unmethylated) All patients (95% CI: ) (95% CI: ) BNCT versus RT/TMZ (MGMT methylated) All patients (95% CI: ) (95% CI: ) Adjusted by extent of surgery, age and WHO preformance status. NOTE: Overall numbers of patients was too low to allow stratification by RPA class and thus the excess of poor prognosis cases (RPA class V) in the BNCT cohort is not adjusted for.

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Parameter Number of patients12 Age, median (range) [y]58 (26-65) Tumor volume, median (range) [cc]70 (8-173) WHO status, grade (%)I (8), II (17), III (75) Temozolomide (%)92 Surgery at relapse (%)67 BNCT for recurrent GBM at Studsvik: patient characteristics Data from:Pellettieri L, H-Stenstam B, Rezaei A, Giusti V, Sköld K. An investigation of Boron Neutron Capture Therapy for recurrent glioblastoma multiforme. Acta Neurol Scand, 2008;117:

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours BNCT for recurrent GBM at Studsvik: dose levels for 1 field (right) and for 2 fields (left)

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours BNCT for recurrent GBM at Studsvik: survival times from initial diagnosis

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours BNCT for meningeal tumors

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Case reports for 2 patients 1 case of malignant meningioma 1 case of mesenchymal chondrosarcoma Uptake similar to that for GBM, also for one case of meningioma of lower malignancy grade. BNCT for meningeal tumors

XIX Symposium Neuroradiologicum Bologna, October 4-9, 2010 BNCT for treatment of brain tumours Case 1: Malignant meningioma 7 operations and XRT prior to BNCT Time span between reoperations down to months Life expectancy 2-4 months at time of BNCT Survival time after BNCT 32 months Good QoL for 22 months after BNCT Case 2: Mesenchymal chondrosarcoma 6 operations and XRT prior to BNCT Time span between reoperations down to 2 months Life expectancy 2-4 months at time of BNCT Survival time after BNCT 27 months Good QoL for 6 months after BNCT BNCT for meningeal tumors