Boron neutron capture therapy of brain tumors: Biodistribution, pharmacokinetics, and radiation dosimetry of sodium borocaptate in patients with gliomas

OBJECTIVE: The purpose of this study was to obtain tumor and normal brain t issue biodistribution data and pharmacokinetic profiles for sodium borocapt ate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was per formed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were cand idates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and the y constituted the study population. METHODS: BSH (non-B-10-enriched) was infused intravenously, in a 1-hour per iod, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 2 6.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tis sue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic stud ies were obtained at times up to 120 hours after termination of the infusio n. Sixteen of the patients underwent surgery at the Beijing Neurosurgical I nstitute and three at The Ohio State University, where all tissue samples w ere subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTS: Blood boron values peaked at the end of the infusion and then decr eased triexponentially during the 120-hour sampling period. At 6 hours afte r termination of the infusion, these values had decreased to 20.8, 29.1, an d 62.6 mu g/ml for boron doses of 15, 25, and 50 mg/kg body weight, respect ively. For a boron dose of 50 mg/kg body weight, the maximum (mean +/- stan dard deviation) solid tumor boron values at 3 to 7 hours after infusion wer e 17.1 +/- 5.8 and 17.3 +/- 10.1 mu g/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 mu g/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged ac ross all samples, were 4.6 +/- 5.1 and 5.5 +/- 3.9 mu g/g and the tumor/nor mal brain tissue ratios were 3.8 and 3.2 for patients with GBMs and AAs, re spectively. The large standard deviations indicated significant heterogenei ty in uptake in both tumor and normal brain tissue. Regions histopathologic ally classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron con centrations in blood decreased from 104 mu g/ml at 2 hours to 63 mu g/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 mu g/g, r espectively, during the 3- to 7-hour sampling period. CONCLUSION: When tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of th e infusion. Although blood boron levels were high, normal brain tissue boro n levels were almost always lower than tumor levels. However, tumor boron c oncentrations were less than those necessary for boron neutron capture ther apy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose deliv ered to the tumor very difficult. It is unlikely that intravenous administr ation of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compo und that has been used clinically, and optimizing their delivery could incr ease tumor boron uptake and potentially improve the efficacy of boron neutr on capture therapy.