Boron Neutron Capture Therapy of Brain Tumors

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when non-radioactive boron-10 is irradiated with low-energy thermal neutrons to yield high-linear energy transfer α particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas (HGG), and either cutaneous primaries or cerebral metastases of melanoma. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, and several European countries. Accelerators also can be used to produce epithermal neutrons and these are being developed in a number of countries, but at this time none are being used for BNCT. Two boron drugs have been used clinically, sodium borocaptate (BSH) (Na2B12H11SH), and a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine (BPA). The major challenge in the development of boron delivery agents has been the requirement for selective tumor-targeting in order to achieve boron concentrations sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 yr, a wide variety of boron-containing compounds have been designed and synthesized. These include boron containing amino acids, biochemical precursors of nucleic acids, DNA binding molecules, and porphyrin derivatives. In addition, high-molecular-weight delivery agents have been developed, including liposomes and monoclonal antibodies (MAbs) and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor. However, it is unlikely that any single agent will target all or even most of cells of brain tumors, and that combinations of agents will be required and their dosage and delivery will have to be optimized. Current or recently completed clinical trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had HGG. Treatment has consisted, first, of “debulking” surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. BSH and BPA have been used as the boron delivery agents, administered either intravenously or intra-arterially as was the case in the early studies with BSH. The best survival data from these studies are at least comparable to those obtained with surgery and external beam photon irradiation, and the safety of the procedure has been established. Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content prior to treatment, improvements in clinical implementation of BNCT, and finally, a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.