Mini-reviewBoron neutron capture therapy for glioblastoma
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).
References (77)
- et al.
Malkin MG: patterns of failure following treatment for glioblastoma multiform and anaplastic astrocytoma
J. Radiat. Oncol. Biol. Phys.
(1989) - et al.
Flentje M: 3D-recurrence-patterns of glioblastomas after CT-planned postoperative irradiation
Radiother. Oncol.
(1999) - et al.
Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomized controlled multicentre phase III trial
Lancet Oncol.
(2006) - et al.
High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison
Lancet Oncol.
(2005) - et al.
Fractionated stereotactic radiotherapy boost after post-operative radiotherapy in patients with high-grade gliomas
Radiother. Oncol.
(2003) - et al.
Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of RadiationTherapy Oncology Group 93-05 protocol
Int. J. Radiat. Oncol. Biol. Phys.
(2004) - et al.
Boron neutron capture therapy in the treatment of locally recurred head and neck cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2007) - et al.
Boron neutron capture therapy (BNCT) for high grade gliomas of the brain: A cautionary note
Int. J. Radiat. Oncol. Biol. Phys.
(1996) - et al.
Current clinical results of the Tsukuba BNCT trial
Appl. Radiat. Isot.
(2004) - et al.
Tolerance of normal human brain to boron neutron capture therapy
Appl. Radiat. Isot.
(2004)
Boron neutron capture therapy using mixed epithermal and thermal neutron beams in patients with malignant glioma-correlation between radiation dose and radiation injury and clinical outcome
Int. J. Radiat. Oncol. Biol. Phys.
Cell cycle dependence of boron uptake from two boron compounds used for clinical neutron capture therapy
Cancer Lett.
Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors
Int. J. Radiat. Oncol. Biol. Phys
Radiobiological evidence suggesting heterogeneous microdistribution of boron compounds in tumors: its relation to quiescent cell population and tumor cure in neutron capture therapy
Int. J. Radiat. Oncol. Biol. Phys.
Synthesis of ether- and carbonlinked polycarboranyl porphyrin dimers for cancer therapies
J. Organomet. Chem.
In-phantom characterization studies at the Birmingham Accelerator-Generated epIthermal Neutron Source (BAGINS) BNCT facility
Appl. Radiat. Isot.
Supratentorial malignant glioma: patterns of recurrence and implications for external beam local treatment
Int. J. Radiat. Oncol. Biol. Phys.
Intraoperative visualization for resection of gliomas: the role of functional neuronavigation and intraoperative 1.5 T MRI
Neurol. Res.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
N. Engl. J. Med.
Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: cooperative clinical trial
J. Neurosurg.
Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery
N. Engl. J. Med.
Combined modality therapy of operated astrocytomas grade III and IV: confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group
Cancer
A randomized study of chemotherapy with procarbazine, vincristine, and the lomustine with and without radiation therapy for astrocytoma grade 3 and/or 4
Cancer
Postoperative irradiation of glioblastomas. Results in a randomized series
Acta Radio Oncol. Radiat. Phys. Biol.
A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma
Br. J. Cancer
Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial
J. Neurosurg.
Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme
Neurosurgery
Boron neutron capture therapy for glioblastoma multiforme: interim results from the Phase I/II dose-escalation studies
Neurosurgery
Melanoma and non-melanoma neutron capture therapy using gene therapy: overview
Dual control of melanogenesis and melanoma growth: overview molecular to clinical level and the reverse
Pigm. Cell Res.
Boron neutron capture therapy for recurrent malignant meningioma. Case report
J. Neurosurg.
BNCT for recurrent intracranial meningeal tumours – case reports
Acta Neurol. Scand.
Uptake of two 10B-compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001)
Int. J. Cancer
First attempt of boron neutron capture therapy (BNCT) for hepatocellular carcinoma
Jpn. J. Clin. Oncol.
Biological effects and therapeutic possibilities of neutrons
Am. J. Roentgenol
Neutron capture therapy with boron in the treatment of glioblastoma multiforme
Am. J. Roentgenol.
Effects of alpha particles randomly induced in the brain in the neutron-capture treatment of intracranial neoplasm
Int. J. Neurol.
Boron-slow neutron capture therapy of gliomas
Acta Radiol.
Cited by (128)
Boron neutron capture therapy anti-tumor effect of nanostructured boron carbon nitride: A new potential candidate
2023, Inorganic Chemistry CommunicationsCarborane bearing pullulan nanogel-boron oxide nanoparticle hybrid for boron neutron capture therapy
2023, Nanomedicine: Nanotechnology, Biology, and MedicineBoron neutron capture therapy: Dosimetric evaluation of a brain tumor and surrounding healthy tissues using Monte Carlo Simulation
2022, Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated EquipmentIodophenyl-conjugated closo-dodecaborate as a promising small boron molecule that binds to serum albumin and accumulates in tumor
2022, Bioorganic and Medicinal Chemistry LettersIntroduction: basic concept of boron and its physical and chemical properties
2022, Fundamentals and Applications of Boron ChemistryBoron analysis and imaging of cells with 2-hr BPA exposure by using micro-proton particle-induced gamma-ray emission (PIGE)
2020, Applied Radiation and Isotopes