**2. Background BNCT for brain tumors**

In the 1950s, the first clinical trial was initiated at Brookhaven National Laboratory (BNL) in New York, and several low-molecular-weight boron compounds were tested as boron delivery agents [4]. Thereafter, it was progressed on to a full-scale clinical application using the Massachusetts Institute of Technology Nuclear Reactor (MITR), but the results of this study were unanticipated and clinical trials in the United States halted. In 1967, Hatanaka et al., who were deeply involved in research in the United States, launched a clinical trial using thermal neutrons and the boron drug sodium borocaptate (BSH) in Japan, with more than 200 cases treated. Although various tumor tissue types and patient backgrounds were mixed, leading to inconclusive conclusions about the effectiveness of the therapeutic effect on specific diseases and conditions, the results of the standard treatment of refractory malignant glioma at that time were as long as those of the standard treatment and have shown expectations for cure [5].

In the United States, BNCT of patients with brain tumors was resumed in the mid-1990s. Boronophenylalanine (BPA), a novel boron drug, was used in clinical trials for the first time, and BNCT in non-craniotomy was achieved using epithermal neutrons with excellent tissue depth. BPA has been developed to target malignant melanoma with the essential amino acid phenylalanine in the skeleton, but it is a boron drug that exploits the amino acid requirements that are elevated in cancer cells and has been shown to be applicable to various cancer types. Clinical trials were conducted at Harvard University in collaboration with MITR to first treat patients with malignant melanoma of the skin, from which indications were expanded to patients with brain tumors (especially glioblastoma and metastatic melanoma). Twenty-two patients have been treated using BPA, five cutaneous malignant melanomas followed by brain tumor patients. Treatment was well tolerated, but did not outperform the results of conventional X-ray fractionated external beam radiation. A detailed review has conducted of BNCT using the nuclear reactor that has been implemented in Japan and overseas in the past [2].

Recent treatment outcomes of BNCT using the nuclear reactor for glioblastoma (World Health Organization (WHO) Grade 4) have been reported by BNCT research groups in Japan, Sweden, and Finland. However, the background of the targeted cases according to patient selection criteria varied, making it difficult to make a simple comparison with other standard treatment groups. Therefore, there is a limitation of the interpretation of the analysis divided into historical control and recursive partitioning analysis (RPA) subgroup. In our report, we performed a clinical trial using the Kyoto University Nuclear Reactor with a protocol combining BPA (500 mg/kg) and BSH (sodium borocaptate) (100 mg/kg) as "multi-targeted type BNCT," which uses multiple types of target boron drugs at once and irradiates a single neutron, with a median survival time (MST) of 15.6 months (n = 10) with BNCT alone and experiencing long-term survivors (>5 years) [6]. BSH can introduce a large amount of boron atoms, including 12 10B atoms, but its cell selectivity is low. However, in brain tumors, it remains tissue-selective by exploiting the breakdown of the blood-brain

*Boron Compounds for Neutron Capture Therapy in the Treatment of Brain Tumors DOI: http://dx.doi.org/10.5772/intechopen.106202*

barrier. The MST of BNCT combined with X-ray fractionated external irradiation (20–30Gy) was 23.5 months. No significant toxicity other than hair loss was observed in this protocol, indicating that BNCT with cell selectivity remains highly tolerated in combination with existing radiotherapy (**Figure 3**).

The University of Tsukuba also reported that the median survival time was 27.1 months, the 1-year and 2-year survival rates after BNCT were 87.5% and 62.5%, respectively [7]. In Sweden, the dosage of BPA was increased to 900 mg, and the clinical trial was carried out [8]. BPA was administered over a duration of 6 h, and neutron irradiation was performed from two directions. The mean total brain dose was 3.2–6.1 Gy (X-ray equivalent), and the minimum dose to the tumor ranged from 15.4 to 54.3 Gy (X-ray equivalent). Progression-free survival and median overall survival were reported as 5.8 and 14.2 months, respectively. Adverse events associated with this protocol were only 14%, which was lower than the standard treatment with X-ray fractionated external beam radiation alone or with temozolomide. Our findings also suggested that the combination of BNCT with X-ray fractionated external beam radiation or temozolomide was tolerable and prolonged survival in primary gliomas [9].

Next, the treatment outcome of recurrent malignant glioma (of which the attention is especially high in BNCT of the brain tumor region) was introduced. The prognosis of recurrent malignant glioma is very poor, and especially in the case of radiotherapy, the treatment is difficult. Though surgery followed with radiotherapy has also been carried out, the survival time is approximately 6 months. A prospective trial of BNCT for recurrent malignant glioma has reported 22 treated cases from our institution and 19 cases of Phase I with increased dosage of BPA at the University of Helsinki. The median survival was 10.8 months and 7 months, respectively. Outcomes limited to recurrent glioblastoma included with survival of 9.6 months (n = 19) and 8.7 months (n = 12) after BNCT [10, 11]. To further improve the outcomes of these BNCT-alone treatments, we performed improved efficacy and safety validation when the angiogenesis inhibitor bevacizumab was also used after treatment and has performed very well at the pilot study stage [12].

Clinical trials for brain tumors using the accelerator as a neutron source have been performed for recurrent malignant gliomas, especially for refractory recurrent glioblastoma [13], and are ready for approval in the brain tumor area in addition to the preceding head and neck cancer.

#### **Figure 3.**

*A case of reactor-based BNCT for malignant glioma with significant response. In this case, favorable boron drug distribution was observed on the pretreatment PET images. (left: FBPA-PET fusion, middle: Before treatment, right: After BNCT of contrast-enhanced MRI T1WI).*
