O. K. Harling

Abstract Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or “BPA”, and sodium borocaptate or “BSH” (Na₂B₁₂H₁₁SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with (10)B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT. Much of the complexity has been unravelled through a combination of preclinical experimentation and clinical dose escalation experience. Over 350 patients have been treated in a number of different facilities worldwide. The accumulated clinical experience has demonstrated that BNCT can be delivered safely but is still defining the limits of normal brain tolerance. Several independent BNCT clinical protocols have demonstrated that BNCT can produce median survivals in patients with glioblastoma that appear to be equivalent to conventional photon therapy. This review describes the individual components and methodologies required for effect BNCT: the boron delivery agents; the analytical techniques; the neutron beams; the dosimetry and radiation biology measurements; and how these components have been integrated into a series of clinical studies. The single greatest weakness of BNCT at the present time is non-uniform delivery of boron into all tumor cells. Future improvements in BNCT effectiveness will come from improved boron delivery agents, improved boron administration protocols, or through combination of BNCT with other modalities.

During the past several years, there has been growing interest in Boron Neutron Capture Therapy (BNCT) using epithermal neutron beams. The dosimetry of these beams is challenging. The incident beam is comprised mostly of epithermal neutrons, but there is some contamination from photons and fast neutrons. Within the patient, the neutron spectrum changes rapidly as the incident epithermal neutrons scatter and thermalize, and a photon field is generated from neutron capture in hydrogen. In this paper, a method to determine the doses from thermal and fast neutrons, photons, and the B-10(n, alpha)Li-7 reaction is presented. The photon and fast neutron doses are measured with ionization chambers, in realistic phantoms, using the dual chamber technique. The thermal neutron flux is measured with gold foils using the cadmium difference technique, the thermal neutron and B-10 doses are determined by the kerma factor method. Representative results are presented for a unilateral irradiation of the head. Sources of error in the method as applied to BNCT dosimetry, and the uncertainties in the calculated doses are discussed.