03 Clinical results of Boron neutron capture therapy 2014/06/18 13:30-15:10 Parallel Clinical 1 (Pa C1) Pörssisali 03 Clinical results of Boron neutron capture therapy for the patients with malignant meningioma Shinji Kawabata (Japan), et al. Osaka Medical College, Department of Neurosurgery

Meningioma Meningiomas are a diverse set of tumors arising from the meninges, the membranous layers surrounding the whole central nervous system. These tumors are usually benign in nature; however, a small percentage are malignant. Meningiomas can usually be surgically resected (partially removed) and result in a permanent cure if the tumor is superficial on the dural surface and easily accessible.

Malignant Meningioma 1-2% of all meningiomas WHO grade 3 80 % of the cases recurs within 5 years Median TTP:２ years PFS for 5 years even after GTR:39% Uncontrollable tumors with modern treatment regimen. Kaplan Myer の出典 3

2014 Experiebce of BNCT in Osaka Medical College Osaka Medical College, Neurosurgery Experiebce of BNCT in Osaka Medical College Total number of patients : 148 (BNCT: 167) 2002 ~ 2014; OMC fresh N = 64 Meningioma N = 32 Female N = 75 Glioma N = 115 Male N = 73 recurrent N = 75

Our Challenge for MM with BNCT Our initial chgallenge for MM with BNCT were already published in JNS and Neurosurgery, 2006 and 2007. J Neurosurg 105:898-903, 2006 Neurosurgery 61:82-91, 2007 5

2014 Osaka Medical College, Neurosurgery Case Age/Sex PET (T/N) Prior to BNCT 1st BNCT Dose (Gy-Eq) Max　 　　Min BNCT (times) 1 Papillary 29 F 5.0 SRSx5, OPx3 93.9 39.7 3 2 Anaplastic 48 2.8 EBRT, SRS, OPx5 73.2 44.2 60 -　 SRS, OPx5 49.0 32.0 4 67 M EBRT, OPx2 71.8 22.1 5 77 4.5 SRSx4, OPx3 86.0 37.2 6 Atypical 72 2.0 SRS, OPx2 65.6 19.0 7 Sarcoma 57 2.7 SRSx2, OPx4 48.3 14.3 8 Rabdoid 26 - EBRT, OPx3 75.8 18.8 9 62 4.4 111.5 50.7 10 56 3.9 77.3 26.0 11 38 88.9 28.8 12 3.5 EBRT, OPx4 58.0 13 65 3.6 EBRT, SRSx2, OPx3 50.2 24.2 14 75 4.0 SRSx3, OPx1 72.9 42.3 15 79 3.7 SRT, OPx5 61.0 57.2 16 68 SRSx2, OPx2 67.0 52.0 17 49 SRS, OPx6 68.5 15.0 18 50 SRSx4, OP3 100.0 59.0 19 63 69.5 31.0 20 41 3.0 SRSx4, OPx5 80.2 21 anaplastic 69 6.3 SRSx2+1, OPx2 72.0 48.0 22 45 4.7 　78.4 30.0 23 SRSx1, OPx3 65.0　 50.0　 24 atypical 52 OPx2 62.0 25 66 2.4 SRSx2, OPx3 57.5 51.3 60.5 9.5 27 46 EBR, SRS, OPx3 37.0 28 SRS x 3, OP SRS x 1, SRT x 4, OPx2 84.7 67.1 30 2.9 SRS, SRS, OPx3 53.0 45.0 31 64 4.3 SRS, EBRT 91.0 40.0 We treated 20 MM including 4 cases of atypical meningiomas. All cases received multiple operations and iiradiations prior to BNCT.

Absorbed Dose by BNCT in Case 1 2014 Osaka Medical College, Neurosurgery Absorbed Dose by BNCT in Case 1 80 8 70 40 30 60 6 50 20 4 10 2 This is PC simulation of absorbed dose in case 1 for normal and tumor tissue, respectively. You can see almost 9 times higher dose could be applied for the tumor in comparison with normal brain, by PC simulation. Normal brain Tumor tissue 9 times higher dose could be applied for the tumor in comparison with normal brain 7

2014 Dose- volume histogram analysis of BNCT Osaka Medical College, Neurosurgery Dose- volume histogram analysis of BNCT (Case 1) Also you can see very good dose volume histogram for this case by BNCT. 8

Effect of BNCT in Case 1　　　　　 1 week prior To BNCT 65.6 cm3 2 weeks after BNCT 49.0 cm3 4 months after BNCT 25.4 cm3 This is effect of BNCT for case 1. This is 1 week prior to BNCT. The tumor volume became double for one month, waiting for BNCT This is 2 weeks after, and this is 4 month after BNCT. You can see the rapid shrincage of the mass. One week after BNCT, she could walk again. The tumor volume became double for one month, waiting for BNCT, which induced hemiparesis. One week after BNCT, she could walk again. 9

Typical Shrinkage of the Mass by BNCT 18F-BPA PET Treatment compound BPA is fluororide labelled and used as a tracer for PET imaging. Good accumulation of the tracer ensures the promising effects of BNCT, prior to neutron irradiaion. These are the typical shrinkage of the mass. Ave. L/N = 3.8 (n=31) 10

2014 Ave. tumor volume; 52.2 (+/-45.3) mL Tumor size after BNCT Osaka Medical College, Neurosurgery Tumor size after BNCT BNCT Ave. tumor volume; 52.2 (+/-45.3) mL Tumor volume (% of control) Each dot は何を示す？ Days after BNCT 11 11

Case 17 : Anaplastic meningioma Pre-BNCT This is case 17, anaplastic meningioma. The upper is pre-BNCT and the lower shows 10 M after BNCT. White arrows show the good tumor control. １０M after BNCT 12

Case 7: anaplastic meningioma with sarcomatous transform Prior to BNCT ７M after BNCT This is case 7, sarcoma transformed from anaplastic meninigioma. This is pre-BNCT and this is 7 month after BNCT. Red arrows show the drastic effects of BNCT. But we lost the case by sysltemic metastasis in lung and lever. ７M after BNCT Left :Chest XP Rt.: abd CT Systemic metastasis to lung and lever 13

Case 8: Rhabdoid meningioma 3 wks prior to BNCT 1 M after BNCT 2 M after BNCT 4 M after BNCT This is case 8 rhabdoid meninigioma. These are Pre BNCT, 1 M after BNCT, 2 M after BNCT These changes are pseudoprogression. White arrow shows equivocal CE. Simultaneously cytology showed malignant cells in CSF. We lost the case by CSF dissemination. CSF dissemination Pseudoprogression (enlargement on contrasted MRI) 14

Case 14: Atypical meningioma Pre-BNCT This is case 14 atypical meningioma. These are PRE BNCT and 6M after BNCT. Irradiated massed responded well, however, you can see the new lesion out of field of neutron irradiaion. ６M after BNCT Recurrence at the Out-of-the field of BNCT 15

2014 Survival analysis (Kaplan-Meyer) Median survival 59.6 months Osaka Medical College, Neurosurgery Survival analysis (Kaplan-Meyer) Median survival 59.6 months (95%CI: 42.8 – 113.4) (after diagnosis) <2-y 100, 3-y 79.2, 5-y 48.6> Median survival 24.6 months (95%CI: 12.9 – 44.0) (after BNCT) <1-y 78.5, 2-y 45.8> after BNCT after diagnosis Survival rate Months after BNCT / diagnosis (m) 2014.5.30

2014 Osaka Medical College, Neurosurgery Case Age/Sex PET (T/N) Depth (mm) 　Longivity (M) from diag BNCT Remarks 1 Papillary 29 F 5.0 39 44.2 22.4 metastasis 2 Anaplastic 48 2.8 59 43.2 14.1 3 60 - 49 32.4 12.9 Gastric Ca meta 4 67 M 70 70.7 13.1 Local 5 77 4.5 45.7 24.6 senility 6 Atypical 72 2.0 69 64.3 6.4 RN 7 Sarcoma 57 2.7 92 113.4 8.6 8 Rabdoid 26 3.1 66 30.4 7.3 dissemination 9 62 4.4 36.8 9.4 10 56 3.9 74 47.5 44.0 alive 11 38 68 28.3 12.4 12 3.5 54 56.8 55.6 13 65 3.6 64 59.6 40.4 14 75 4.0 12.3 16.1 15 79 3.7 12.8 8.3 16 45 69.1 15.0 17 22.1 15.6 Out of field 18 50 52 68.6 10.7 19 63 76 10.4 20 41 3.0 30.1 21 anaplastic 6.3 33.3 2.5 22 4.7 30.7 15.7 23 17.6 15.3 24 atypical 33 24.1 10.5 25 2.4 34 35 16.0 85 23.6 11.7 27 46 25.8 8.8 28 17.7 10.3 40 27.9 30 2.9 2.2 31 4.3 193.8 1.0 We lost one case by local tumor progression. 4 cases by systemic metastasis, 3 cases by CSF disseminarion and 1 case by recurrence at out of field irradiaation. Local; Local recurrence, RN; radiation necrosis 17

45F, anaplastic meningioma, WHO G3 (two-field irradiation) 700mglkg (200mg/kg/h x 2 + 100mg/kg/h x 3) 　　Malignant meningioma 　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 Irrad 30+31 m BPA (pre) 33.6 Ave.1, 2 34, 39 skin 6.0 brain 12.2 Optic N >7.0 Tumor 70.0 4.0cm 51.0 11/ 8/2012 BNCT T/N=4.7

45F, anaplastic meningioma, WHO G3 (two-field irradiation) 700mglkg (200mg/kg/h x 2 + 100mg/kg/h x 3) 　　Malignant meningioma 　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 Irrad 30+31 m BPA (pre) 33.6 Ave.1, 2 34, 39 skin 6.0 brain 12.2 Optic N >7.0 Tumor 70.0 4.0cm 51.0 11/ 5/2012 12/20/2012 11/ 8/2012 BNCT Marked decrease in BPA uptake within 2months after BNCT T/N=4.7

2014 Conclusion Malignant meningioma is good candidate for BNCT. Osaka Medical College, Neurosurgery Conclusion Malignant meningioma is good candidate for BNCT. BNCT can reduce the tumor size and control MM locally, but not for systemic metastasis or recurrence from Out-of the field region. Major causes of death are Systemic metastasis CSF dissemination Recurrence at out of field of BNCT

Thank you Clinical results of Boron neutron capture therapy for the patients with malignant meningioma S. Kawabata1, S-I. Miyatake1, G. Futamura1, R. Hiramatsu1, Y. Matsushita1, M. Furuse1, Y. Tamura1, T. Kuroiwa1, H. Tanaka2, Y. Sakurai2, S-I. Masunaga2, M. Suzuki2, K. Ono2   1Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka, Japan 2 Department of Radiation Life Science and Radiation Medical Science, Kyoto University Research Reactor Institute, Kumatori, Osaka, Japan email: neu046@poh.osaka-med.ac.jp