**1. Introduction**

324 Advances in the Biology, Imaging and Therapies for Glioblastoma

Whittle, I.R., Midgley, S., Georges, H., Pringle, A.M. & Taylor, R. (2005) Patient perceptions

Wiedemayer, H., Sandalcioglu, I.E., Armbruster, W., Regel, J., Schaefer, H. & Stolke, D.

Wu, J.S., Zhou, L.F., Tang, W.J., Mao, Y., Hu, J., Song, Y.Y. et al (2007) Clinical evaluation

Yaşargil, M.G. (1996) Neuropathology, In: *Microneurosurgery*, *Vol IVA*. Yaşargil MG (Ed), pp.

Yaşargil, M.G. (1996) Surgical approaches, In: *Microneurosurgery*, *Vol IVB*. Yaşargil MG (Ed),

Yaşargil, M.G. (1996) Strategies, tactics and Techniques, In: *Microneurosurgery*, *Vol IVB*.

Yaşargil, M.G., Kadri, P.A. & Yaşargil, D.C. (2004) Microsurgery for malignant gliomas.

Yoshii, Y., Tominaga, D., Sugimoto, K., Tsuchida, Y., Hyodo, A., Yonaha, H. & Kushi, S.

*Journal of Neuro-Oncology*, Vol.69, No.1, (August-Sptember 2004), pp. 67–81, ISSN

(2008) Cognitive function of patients with brain tumor in pre- and postoperative stage. *Surgical Neurology*, Vol.69, No.1, (January 2008) pp. 51-61, ISSN 0090-3019

(March 2005), pp. 275-277, ISSN 0001-6268

ISSN 0022-3050

0148-396X

0167-594X

115-188, Thieme, New York

pp. 29-68, Thieme, New York

Yaşargil MG (Ed), pp. 69-91, Thieme, New York

of ''awake'' brain tumour surgery. *Acta Neurochirurgica (Wien)*, Vol.147, No.3,

(2004) False negative findings in intraoperative SEP monitoring: analysis of 658 consecutive neurosurgical cases and review of published reports. *Journal of Neurology, Neurosurgery and Psychiatry*, Vol.75, No.2, (February 2004), pp. 280-286,

and follow-up outcome of diffusion tensor imaging-based functional neuronavigation: a prospective, controlled study in patients with gliomas involving pyramidal tracts. *Neurosurgery*, Vol.61, No.5, (November 2007), pp. 935–949, ISSN

> Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10 (10B) is irradiated with neutrons of the appropriate energy to yield high energy alpha particles (4He) and recoiling lithium-7 (7Li) nuclei. Since these particles have pathlengths of approximately one cell diameter, their lethality primarily is limited to boron containing cells. BNCT, therefore, can be regarded as both a biologically and a physically targeted type of radiation therapy (Fig. 1). Its success is dependent upon the selective delivery of sufficient amounts of 10B to cancer cells with only small amounts localized in the surrounding normal tissues. A wide variety of boron delivery agents have

Fig. 1. The principle of boron neutron capture therapy (BNCT).

Clinical Study on Modified Boron Neutron Capture Therapy for Newly Diagnosed Glioblastoma 327

accumulation prior to neutron irradiation (Imahori *et al.* 1998). Fifth, we filled the tumor removed cavity with air to obtain enough neutron flux, especially for the bottom of deepseated tumors (Sakurai *et al.* 2006). Sixth, we developed a central shielding method with a lithium plate at the center of the irradiation field to obtain uniform neutron distribution and increase the neutron flux relativey at the periphery in the radiation field (Ono 2006, Ono *et al.* 2000). With these modifications, even patients with deep-seated tumors can be treated by BNCT without craniotomy with a short hospital stay. In the present study, the revised

Fig. 2. 18F labeled BPA positron emmision tomography (18F - BPA PET) has been applied for the estimation of the boron compound accumulation prior to BNCT. The tracer is fluororide

accumulates well and distributes precisely in the tumor lesion and the infiltrating tumor

Twelve hours before the neutron irradiation, the patients were administered 100mg/kg of BSH intravenously for one hour. 700mg/kg of BPA was infused continuously to the patients for 6 hours before the irradiation, and they were positioned for neutron irradiation in the reactor (KURRI or JRR-4 (Japan Atomic Energy Agency Research Reactor 4)). Just after termination of continuous BPA infusion for 6hrs, neutrons were irradiated. We used the dose-planning workstation to calculate the radiation dose for tumors from the 18F-BPA-PET data and blood 10B concentrations obtained every 2 hours after BSH administration. We used an epithermal neutron beam. Following this, a 2 Gy daily fraction of XRT was applied, for a total of 20 to 30Gy. The total dose of XRT was decided based on the BNCT dose for the normal brain. In Protocol 1, we aimed to apply more than 30 gray-equivalent (Gy-Eq) for gross tumor volume (GTV) and less than 12 Gy-Eq for normal brain, as BNCT. In Protocol 2, we aimed to apply more than 40 Gy-Eq for GTV and less than 15 Gy-Eq for normal brain. No chemotherapy was applied for any of the patients until the tumor progression was

Survival time from histologically diagnosed as GB was compared with the survival time for the institutional historical controls who were treated by surgical removal followed by XRT and chemotherapy (mainly nitrosourea) from 1990 to 2006 in OMC. In this historical control

labelled boron compound. This PET ensures the effectiveness of BNCT. 18F-BPA

confirmed histologically or by 18F-BPA-PET (Miyashita *et al.* 2008).

protocol was used as a new protocol as follows.

zone.

been synthesized (Hiramatsu *et al.* 2011, Miyata *et al.* 2011, Wu *et al.* 2007, Yang *et al.* 2006), but only two of these currently are being used in clinically. The first, which has been used primarily in Japan, is sodium borocaptate or BSH, and the second is a dihydroxyboryl derivative of phenylalanine referred to as boronophenylalanine or BPA (Barth *et al.* 2005). The latter has been used in clinical trials in Japan, Europe and the United States, primarily for the treatment of high grade gliomas, and more recently for recurrent tumors of the head and neck region (Ariyoshi *et al.* 2007, Haginomori *et al.* 2009, Kimura *et al.* 2009). Following i.v. administration of either BPA or BSH by i.v. infusion, the tumor site is irradiated with neutrons, the source of which is a nuclear reactor.

Recently, BNCT studies carried out by us at Osaka Medical College (OMC) and Kyoto University Research Reactor Institute (KURRI), in which BPA and BSH were administered in combination (Kawabata *et al.* 2003, Miyatake *et al.* 2005, Miyatake *et al.* 2009) for the patients with recurrent tumor after irradiation, or BNCT followed by an X-ray boost showed favorable responses in patients with newly-diagnosed glioblastoma (GB) and especially those in high risk groups (Kawabata *et al.* 2009a).
