**2.3.1 Back ground of our recently up-dated protocol using BNCT**

Prior to design of new version of the protocol for multi-centric study, we analyzed our previous clinical results of all the patients with malignant glioma treated by BNCT. Main part of the retrospective analysis was as follows. 1. Efficacy of additional fractionated X-ray irradiation, 2. Administration of the boron compouns, 3. Toxicity of our previous study. The median ST of the patients treated with BNCT followed by XRT boost was 23.5 months (95% CI: 10. 2 – undetermined, HR (*vs* control) = 0.32) after diagnosis (n = 11), and that of the patients treated with BNCT only (n = 10) was 14.1 months (95% CI: 9.9–18.5), although the difference was not statistically significant among these two groups.

In our previous study for all of the patients with malignant brain tumor included several doses of boron compounds especially for BPA, 250, 500, 700mg/kg body weight. Blood boron concentration was increased by escalation of the BPA dose. The continuous infusion with reduced BPA dose during irradiation (400mg/kg for 2h + 100mg/kg for 1h, previously used for head and neck cancer in KURRI) was also used and this was useful for dose estimation of BNCT because the blood boron concentration similar as 700mg BPA/kg was kept during irradiation whereas a decline of the blood level was remarkable when we terminated BPA just before neutron irradiation. Adverse events were assessed by common terminology criteria for adverse events (CTCAE) v3.0. Grade 3/4 blood/bone marrow toxicity (hemoglobin, leukocytes, neutrophils, and platelets) were 11% in 250mg/kg, 17% in 500mg/kg, and 28% in 700mg/kg. Other Grade 3/4 adverse events (seizure, AST, ALT, amylase, creatinine) were 64% in 250mg/kg, 25% in 500mg/kg, and 73% in 700mg/kg. All of these adverse events were reversible and transient. Radiation induced edema and/or necrosis occurred mainly in the area that was available for high-dose irradiation by BNCT nearly the surface of the brain of the patients treated with BNCT+XRT. Based on this retrospective analysis, the Multi-centric Phase II clinical study was planned and now ongoing.

#### **2.3.2 On-going protocol using BNCT for the newly diagnosed glioblastoma**

Based on our former BNCT clinical experience, we included the following points in a new protocol using the two boron compounds, BSH and BPA, in combination (Ono et al. 1999, Yokoyama et al. 2006). The schedule of the administration of boron compounds is settled as follows; 13 hours before the neutron irradiation, 100 mg/kg of BSH will be intravenously infused for one hour, and 500 mg/kg of BPA will be infused continuously 200 mg/kg/h for 2 hours before the irradiation and reduced for 100 mg/kg/h during irradiation to the patients. During continuous BPA infusion of reduced dose as 100 mg/kg, neutrons irradiation is performed. Protocol treatments consist of BNCT, additional 24Gy XRT and

Results of our clinical study showed the efficacy of combination therapy with external beam XRT and BNCT. For our future study, we planned the Multi-centric Phase II clinical study named "*Boron Neutron Capture Therapy, Radiation Therapy, and Temozolomide in Treating Patients with Newly Diagnosed Glioblastoma Multiforme*" in Japan (OSAKA-TRIBRAIN0902, NCT00974987). The major differences of our protocol from the other past BNCT studies

Prior to design of new version of the protocol for multi-centric study, we analyzed our previous clinical results of all the patients with malignant glioma treated by BNCT. Main part of the retrospective analysis was as follows. 1. Efficacy of additional fractionated X-ray irradiation, 2. Administration of the boron compouns, 3. Toxicity of our previous study. The median ST of the patients treated with BNCT followed by XRT boost was 23.5 months (95% CI: 10. 2 – undetermined, HR (*vs* control) = 0.32) after diagnosis (n = 11), and that of the patients treated with BNCT only (n = 10) was 14.1 months (95% CI: 9.9–18.5), although the

In our previous study for all of the patients with malignant brain tumor included several doses of boron compounds especially for BPA, 250, 500, 700mg/kg body weight. Blood boron concentration was increased by escalation of the BPA dose. The continuous infusion with reduced BPA dose during irradiation (400mg/kg for 2h + 100mg/kg for 1h, previously used for head and neck cancer in KURRI) was also used and this was useful for dose estimation of BNCT because the blood boron concentration similar as 700mg BPA/kg was kept during irradiation whereas a decline of the blood level was remarkable when we terminated BPA just before neutron irradiation. Adverse events were assessed by common terminology criteria for adverse events (CTCAE) v3.0. Grade 3/4 blood/bone marrow toxicity (hemoglobin, leukocytes, neutrophils, and platelets) were 11% in 250mg/kg, 17% in 500mg/kg, and 28% in 700mg/kg. Other Grade 3/4 adverse events (seizure, AST, ALT, amylase, creatinine) were 64% in 250mg/kg, 25% in 500mg/kg, and 73% in 700mg/kg. All of these adverse events were reversible and transient. Radiation induced edema and/or necrosis occurred mainly in the area that was available for high-dose irradiation by BNCT nearly the surface of the brain of the patients treated with BNCT+XRT. Based on this retrospective analysis, the Multi-centric Phase II clinical study was planned and now on-

**2.3.2 On-going protocol using BNCT for the newly diagnosed glioblastoma** 

Based on our former BNCT clinical experience, we included the following points in a new protocol using the two boron compounds, BSH and BPA, in combination (Ono et al. 1999, Yokoyama et al. 2006). The schedule of the administration of boron compounds is settled as follows; 13 hours before the neutron irradiation, 100 mg/kg of BSH will be intravenously infused for one hour, and 500 mg/kg of BPA will be infused continuously 200 mg/kg/h for 2 hours before the irradiation and reduced for 100 mg/kg/h during irradiation to the patients. During continuous BPA infusion of reduced dose as 100 mg/kg, neutrons irradiation is performed. Protocol treatments consist of BNCT, additional 24Gy XRT and

**2.3 Phase II clinical study of boron neutron capture therapy combined with X-ray radiotherapy / Temozolomide in patients with newly diagnosed glioblastoma** 

were simultaneous use of both BSH and BPA, and combination with XRT.

**2.3.1 Back ground of our recently up-dated protocol using BNCT** 

difference was not statistically significant among these two groups.

**multiforme** 

going.

chemotherapy with TMZ. Prescription dose by BNCT is regulated as not to be more than 13Gy-Eq for normal brain. Additional XRT is given with 3 gradient such as 8, 16, 24Gy from the surface of scalp to the bottom of tumor infiltrated zone (Fig. 7). Chemotherapy with TMZ is applied concomitantly during XRT treatments and adjuvant chemotherapy with the same agent is repeated in outpatient clinic (Fig. 8) (Stupp *et al.* 2005).

Fig. 7. Illustrated image of the protocol combined with boron neutron capture therapy (BNCT) and 3 gradient fractionated X-ray irradiation (XRT). Gy: gray, fr: fraction.

Based on our previous clinical study, the Hazard ratio of BNCT vs. XRT was simulated as 0.4, so the total estimated number of the patients who should be included in our new study become 45 totally. Primary end point is overall survival and these patients will be followed up for 2 years after the last patient treatment. The most important point in our protocol is diagnosis and treatment of radiation effects such as swelling, radiation induced edema, transient expansion of the tumor, pseudo- progression / response, and radiation necrosis. 18F-BPA-PET study is included for the diagnosis of these pathologies.

Clinical Study on Modified Boron Neutron Capture Therapy for Newly Diagnosed Glioblastoma 335

15.6 months without TMZ. Moreover additional 20 to 30Gy XRT prolonged the MST up to 23.5 months in 11 cases without TMZ (Kawabata *et al.* 2009b). These strategies were also confirmed by pre-clinical bench works (Barth *et al.* 2004). These are the background of our on-going clinical trial. Thereafter in this trial, the protocol is composed of BNCT, followed by 24Gy XRT with concomitant and adjuvant chemotherapy with TMZ for newly diagnosed

This project was supported by the grant-in-aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan to S-I. Miyatake. This work was also supported in part by the Takeda Science Foundation for S. Kawabata (PI; H. Matsui, Okayama University). This work was also partly supported by Scientific Research from the Japanese Ministry of Education, Science, and Culture to S. Kawabata, M. Furuse (Scientific Research C), and Y.

This project was approved by the Ethical Committee of Osaka Medical College and by the BNCT Committee of Kyoto University Research Reactor Institute or Japan Atomic Energy Agency. Individual cases were discussed and selected by the latter committee and the

Ariyoshi, Y., Miyatake, S., Kimura, Y., Shimahara, T., Kawabata, S., Nagata, K., Suzuki, M.,

Barth, R. F., Grecula, J. C., Yang, W., Rotaru, J. H., Nawrocky, M., Gupta, N., Albertson, B. J.,

Curran, W. J., Jr., Scott, C. B., Horton, J., Nelson, J. S., Weinstein, A. S., Fischbach, A. J.,

Haginomori, S., Miyatake, S., Inui, T., Araki, M., Kawabata, S., Takamaki, A., Lee, K.,

Hiramatsu, R., Kawabata, S., Miyatake, S., Kuroiwa, T., Easson, M. W. & Vicente, M. G.

Maruhashi, A., Ono, K. & Shimahara, M. (2007). Boron neuron capture therapy using epithermal neutrons for recurrent cancer in the oral cavity and cervical lymph node metastasis. *Oncol Rep,* Vol. 18, No. 4 pp. (861-866), ISSN. 1021-335X Barth, R. F., Coderre, J. A., Vicente, M. G. & Blue, T. E. (2005). Boron neutron capture

therapy of cancer: current status and future prospects. *Clin Cancer Res,* Vol. 11, No.

Ferketich, A. K., Moeschberger, M. L., Coderre, J. A. & Rofstad, E. K. (2004). Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors. *Int J Radiat Oncol Biol Phys,* Vol. 58, No. 1 pp. (267-277), ISSN. 0360-

Chang, C. H., Rotman, M., Asbell, S. O., Krisch, R. E. & et al. (1993). Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. *J Natl Cancer Inst,* Vol. 85, No. 9 pp. (704-710), ISSN.

Takenaka, H., Kuroiwa, T., Uesugi, Y., Kumada, H. & Ono, K. (2009). Planned fractionated boron neutron capture therapy using epithermal neutrons for a patient with recurrent squamous cell carcinoma in the temporal bone: a case report. *Head Neck,* Vol. 31, No. 3 pp. (412-418), ISSN. 1097-0347 (Electronic), 1043-3074 (Linking)

(2011). Application of a novel boronated porphyrin (HOCP) as a dual sensitizer for

GB patients.

**5. References** 

3016

0027-8874

**4. Acknowledgment** 

Matsushita (Grant-in-Aid for Young Scientist B).

signing of the informed consent by each patient.

11 pp. (3987-4002), ISSN. 1078-0432

Fig. 8. Treatment protocol of BNCT combination with EBRT/TMZ for Newly diagnosed Malignant Glioma
