Cancer Letters

Cancer Letters

Volume 262, Issue 2, 18 April 2008, Pages 143-152
Cancer Letters

Mini-review
Boron neutron capture therapy for glioblastoma

https://doi.org/10.1016/j.canlet.2008.01.021Get rights and content

Abstract

Boron neutron capture therapy (BNCT) theoretically allows the preferential destruction of tumor cells while sparing the normal tissue, even if the cells have microscopically spread to the surrounding normal brain. The tumor cell-selective irradiation used in this method is dependent on the nuclear reaction between the stable isotope of boron (10B) and thermal neutrons, which release α and 7Li particles within a limited path length (−9 μm) through the boron neutron capture reaction, 10B(n, α) 7Li. Recent clinical studies of BNCT have focused on high-grade glioma and cutaneous melanoma; however, cerebral metastasis of melanoma, anaplastic meningioma, head and neck tumor, and lung and liver metastasis have been investigated as potential candidates for BNCT. To date, more than 350 high-grade gliomas have been treated in BNCT facilities worldwide. Current clinical BNCT trials for glioblastoma (GBM) have used the epithermal beam at a medically optimized research reactor, and p-dihydroxyboryl-phenylalanine (BPA) and/or sulfhydryl borane Na2B12H11SH (BSH) as the boron delivery agent(s). The results from these rather small phase I/II trials for GBM appear to be encouraging, but prospective randomized clinical trials will be needed to confirm the efficacy of this theoretically promising modality. Improved tumor-targeting boron compounds and optimized administration methods, improved boron drug delivery systems, development of a hospital-based neutron source, and/or other combination modalities will enhance the therapeutic effectiveness of BNCT in the future.

Introduction

The glioblastoma (GBM), a common type of a radio- and chemo-resistant malignant brain tumor in adults, shows rapid tumor growth and wide microscopic invasion to the surrounding normal brain tissue. Despite the improvements in diagnostic modality and the use of intensive multimodal therapies that include surgery, radiotherapy and chemotherapy, there have been rather small survival benefits for patients with GBM, which continues to have a median survival time (MST) of less than one year, and even in emerging therapeutic modalities for selected patients, MST is generally less than 2 years. Investigations have revealed the presence of microscopic invading cells at distances of 2–3 cm or even further from the main tumor mass that can be clinically identified by contrast enhancement area on a magnetic resonance image (MRI), and that are found in the microsurgical field during surgical operation. Extensive surgical resection or high-dose radiation therapy sufficient to cover microscopic invasion into the healthy brain tissue inevitably leads to some degree of post-therapeutic neurological deterioration. Consequently, 80–90% of GBM recur locally, indicating the need for more intensive and tumor-selective therapy [1], [2], [3]. Recently, image-guided surgery utilizing fluorescence with 5-aminolevulinic acid, neuronavigation and intraoperative MRI has enabled more complete resections of contrast-enhancing tumor [4], [5]. Concomitant and adjuvant use of temozolomide with a standard photon radiotherapy has demonstrated a significant survival advantage compared to the radiotherapy alone with minimal additional toxicity: the MST was 14.6 months with temozolomide plus radiotherapy and 12.1 months with radiotherapy alone [6].

Several randomized trials have demonstrated a significant improvement of survival time by post-operative fractionated photon radiation at a total dose of 45–60 Gy [7], [8], [9], [10], [11], [12]. Among many dose-escalation studies, some small case series found favorable results, which involved dose-escalation mainly in a main tumor mass using an additional stereotactic radiosurgery or other conformal radiotherapy [13], [14], [15], [16], [17]. A dose of 90 Gy in accelerated fractionation with photon and proton irradiation almost completely prevented central recurrence, extending the MST of GBM patients treated by this modality to 20 months. However, recurrence occurred in areas immediately peripheral to the 90 Gy volume, mostly in the 70–80 Gy volume, and radiation necrosis also frequently occurred [13]. Therefore, there is urgent need of a method that can deliver high-dose radiotherapy to an extended target area encompassing the microscopic invasion while avoiding radiation necrosis.

Boron neutron capture therapy (BNCT) is the unique high-dose tumor-selective radiotherapy for cancer treatment. BNCT theoretically allows the preferential destruction of 10B-loaded tumor cells, while sparing the normal tissue without 10B, based on the a nuclear reaction between 10B and thermal neutrons, which release high linear energy transfer (LET) α and 7Li particles through the boron neutron capture reaction, 10B(n, α) 7Li (Fig. 1). The boron neutron capture reaction provide the tumor-selective dose (boron dose), and the other non-selective dose components consist of the proton recoils due to fast neutrons, 1H(n, n′)p, 0.54 MeV protons from the nitrogen capture reaction, 14N(n, p)14C, the γ ray arising from contamination in the primary beam, and 2.2 MeV, the prompt γ rays from the hydrogen capture. Recent clinical studies of BNCT have focused on high-grade glioma [18] and cutaneous melanoma [19], [20], malignant meningioma [21], [22], head and neck tumor [23], and lung and liver tumors [24], [25] as potential candidates for BNCT. Single session of BNCT seems to be more or at least equally effective as conventional fractionated photon radiation (e.g. 60 Gy by 30 fractions for GBM). However, the procedure is one of the most complex of all anti-tumor treatments and the effectiveness of this therapy is highly dependent on neutron and boron distributions. So far, only a simple-shaped, one direction neutron beam is available in exclusive research reactors. This article provides a review of the clinical trials for BNCT of GBM, and discusses future prospects for this treatment.

Section snippets

Thermal neutron beam era

The first theoretical account of the biological effects and therapeutic possibilities of BNCT was published by Locher [26]. Early clinical trials of BNCT for brain tumors were conducted by Farr et al. [27], [28] at the Brookhaven National Laboratory (BNL) and by Sweet et al. [29], [30] at the Massachusetts Institute of Technology (MIT) in the 1950s and 1960s. Thermal beams were combined with boron delivery agents, such as borax (Na2B4O71OH2O), p-carboxy-phenylboronic acid, and sodium

Conclusion

BNCT is an emerging therapeutic modality for cancers which can theoretically allow tumor-selective destruction while sparing normal tissue. The selectivity is highly dependent on the dose from the boron neutron capture reaction, 10B(n, α) 7Li, i.e., the accumulation of boron-10 in tumor cells. Recent clinical studies of BNCT have focused on the treatment of high-grade gliomas and cutaneous melanomas. More than 350 high-grade gliomas have been treated in BNCT facilities worldwide. Cerebral

Acknowledgments

This study was supported in part by the Fund-in Trust for Cancer Research from the Governor of Ibaraki Prefecture, a Grant-in-Aid from the University of Tsukuba Research Project, a Research Award from the YASUDA Medical Research Foundation, and a Grant-in-Aid for Society Collaboration from the Ministry of Education, Science and Culture, Japan (17390390).

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