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, the 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.

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24-78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The 10B carrier, L-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg(-1) over 1 h (10 subjects), 300 mg kg(-1) over 1.5 h (two subjects), or 350 mg kg(-1) over 1.5-2 h (10 subjects). The pharmacokinetic profile of 10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

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 IntroductionIn all conventional radiation therapy modalities, the sensitivity of the normal tissues is the limiting factor that determines the dose that can be delivered to tumor. A particular problem facing the radiation oncologist is the treatment of micrometastatic disease: tumor sites too small to be detected by current imaging or nuclear medicine techniques, or disease too widespread and diffuse to be treated without unacceptable damage to normal tissues. Boron neutron capture therapy (BNCT) is a binary therapy that has the potential to address these issues: selective targeting of high linear energy transfer (LET) radiation to tumor with sparing of the normal tissue; and the potential to deliver high-LET radiation to individual cells or micrometastatic sites. BNCT requires the selective delivery of a boron-labeled compound to tumor. The tumor region, invariably including some of the surrounding normal tissues, is then irradiated with low-energy neutrons. The nucleus of the minor stable isotope of boron, 10 B, absorbs (captures) a low energy (thermal) neutron, and immediately undergoes a fission reaction The short combined track lengths of the alpha (9 µm) and lithium (5 µm) particles produced by the boron neutron capture reaction essentially limits the radiation damage to cells containing 10 B. In practice, there is also a non-specific background dose to both tumor and the normal tissues from the neutron beam, and with currently available boron compounds there is a low level of boron in the normal tissues. However, the therapeutic ratio in BNCT is primarily governed by the tumor-targeting capacity of the boron delivery agent. A number of Phase I and Phase I/II safety and dose escalation BNCT clinical studies have been carried on patients with glioblastoma or melanoma. Historically, glioblastoma has been the target for BNCT clinical applications, due in large part to the poor prognosis for these patients with the best conventional treatments. This situation is as true today as it was at the time of the first clinical trial of BNCT in 1951. This article will review: i) BNCT dosimetry; ii) boron delivery agents; iii) macroscopic and microscopic boron detection methods; iv) neutron beams; v) the radiobiology of BNCT; vi) current BNCT clinical studies; and vii) future developments. Boron Delivery AgentsA boron compound with a high degree of tumor specificity, long retention in the tumor, and complete clearance from blood and normal tissues would be optimal for BNCT, producing very substantial therapeutic ratios. The short-range of the alpha particles and lithium ions released from the boron neutron capture reaction make BNCT critically dependent on the boron delivery agent in two ways: i) there is a minimum requirement for accumulation...