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Purpose: A cooperative study in Europe and Japan was conducted to determine the pharmacokinetics and boron uptake of sodium borocaptate (BSH: Na(2)B(12)H(11)SH), which has been introduced clinically as a boron carrier for boron neutron capture therapy in patients with glioblastoma., Methods and Materials: Data from 56 patients with glioblastoma who received BSH intravenous infusion were retrospectively reviewed. The pharmacokinetics were evaluated in 50 patients, and boron uptake was investigated in 47 patients. Patients received BSH doses between 12 and 100 mg/kg of body weight. For the evaluation, the infused boron dose was scaled linearly to 100 mg/kg BSH., Results: In BSH pharmacokinetics, the average value for total body clearance, distribution volume of steady state, and mean residence time was 3.6 +/- 1.5 L/h, 223.3 +/- 160.7 L, and 68.0 +/- 52.5 h, respectively. The average values of the boron concentration in tumor adjusted to 100 mg/kg BSH, the boron concentration in blood adjusted to 100 mg/kg BSH, and the tumor/blood boron concentration ratio were 37.1 +/- 35.8 ppm, 35.2 +/- 41.8 ppm, and 1.53 +/- 1.43, respectively. A good correlation was found between the logarithmic value of T(adj) and the interval from BSH infusion to tumor tissue sampling. About 12-19 h after infusion, the actual values for T(adj) and tumor/blood boron concentration ratio were 46.2 +/- 36.0 ppm and 1.70 +/- 1.06, respectively. The dose ratio between tumor and healthy tissue peaked in the same interval., Conclusion: For boron neutron capture therapy using BSH administered by intravenous infusion, this work confirms that neutron irradiation is optimal around 12-19 h after the infusion is started.

To determine binding and distribution of Na2B12H11SH (BSH) in glioma tissue in case of boron neutron capture therapy, an antibody to this compound was produced and used in immunohistochemical investigations. It is possible to trace BSH in immunohistochemistry, because BSH is firmly bound to the glioma tissue. The antibody against BSH is specific for that antigen, as tumor tissue from patients without BSH administration did not stain. In areas of healthy brain from BSH infused patients, no staining of tissue was detectable. In tumor tissues, BSH is presenting as a strong staining in cytoplasm and nucleus areas.

The disposition of Na2B12H11SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.

The aim of the present study was to monitor the blood-10B concentration of laboratory dogs receiving boron neutron capture therapy, in order to obtain optimal agreement between prescribed and actual dose. A prompt gamma-ray analysis system was developed for this purpose at the High Flux Reactor in Petten. The technique was compared with inductively coupled plasma-atomic emission spectrometry and showed good agreement. A substantial variation in 10B clearance pattern after administration of borocaptate sodium was found between the different dogs. Consequently, the irradiation commencement was adjusted to the individually determined boron elimination curve. Mean blood-10B concentrations during irradiation of 25.8 +/- 2.2 micrograms/g (1 SD, n = 18) and 49.3 +/- 5.3 micrograms/g (1 SD, n = 17) were obtained for intended concentrations of 25 micrograms/g and 50 micrograms/g, respectively. These variations are a factor of two smaller than irradiations performed at a uniform post-infusion irradiation starting time. Such a careful blood-10B monitoring procedure is a prerequisite for accurately obtaining such steep dose-response curves as observed during the dog study.

Purpose: Within the European collaboration on boron neutron capture therapy (BNCT), a clinical Phase I study is being carried out to establish BNCT as an alternative treatment modality for malignant glioma (WHO III/IV). Data about the pharmacokinetics, biodistribution and toxicity of the boron compound Na2B12H11SH (BSH) are of great importance to avoid radiation damage of healthy tissue and to deliver a sufficient radiation dose., Methods and Materials: Twenty four patients suffering from a glioblastoma multiforme entered the study to date, infused with a maximum concentration of up to 50 mg BSH/kg. Boron concentration measurements in tissues, urine, and blood were carried out, using inductively coupled plasma-atomic spectroscopy (ICP-AES) and quantitative neutron capture radiography (QNCR). A cross-calibration of these boron determination techniques was carried out., Results: In tumor tissue, confirmed by histopathology of small biopsies, we found a consistently high but heterogeneous boron uptake. Necrotic parts contain much lower amounts of boron; normal brain tissue has shown no significant uptake. In skin, bone, muscle, and dura mater only small amounts of boron were found. In blood samples, we found biphasic kinetics, but with variations of the half-lives from patient to patient. The compound is mainly excreted through the urine, but an additional entero-hepatic pathway can be demonstrated. Systematic investigations revealed no toxic side effect of the intravenously administered BSH. Comparable data were obtained by using ICP-AES and QNCR for boron concentration measurements., Conclusion: Taking into account the radiobiological considerations of the neutron beam source, we found promising facts that BNCT could be a useful irradiation method for highly malignant brain tumors. Favorable amounts of the boron compound BSH were found in tumor tissue, whereas healthy brain tissue has shown no significant uptake.