Boron neutron capture therapy (BNCT): Clinical optimization of uptake parameters of Boronophenylalanine (BPA)

INTRODUCTION: MGMT studies have demonstrated that a limited number of patients with glioblastoma benefit from Temozolamide. The remainder of the patients depend on radiotherapy at a maximum radiation dosage of 60 Gy, with no safe means of dose escalation. Boron neutron capture therapy (BNCT) is a binary treatment modality which represents a biologically targeted means of radiation dose escalation targeting both cyclical and noncyclical glioma cells1 without precluding other therapies. METHODS: We report on a Cancer Research UK clinical pharmacokinetic study of Boronophenylalanine (BPA) in patients with high-grade glioma to optimize uptake parameters for clinical trials of BNCT. The goals of the study were: • to investigate the pharmacokinetic profile of BPA in the new mannitolbased formulation; • to evaluate the toxicity profile of BPA-mannitol; and • to optimize the dose and uptake parameters for BPA-mannitol for use in future clinical trials of BNCT by integrating the tumor-handling data based on LAT-1 distribution and activity into the final pharmokinetic model for clinical studies. The study investigates the route of infusion and, in each case, will assess the effect of administration of mannitol as a blood-brain barrier disrupter. Measurements were made by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) of 10B concentration in blood, urine, extra-cellular fluid (via brain microdialysis), brain tissue around tumor and tumor tissue. Additional analysis was performed using Secondary Ion Mass Spectrometry (SIMS). RESULTS: Peak Boron (10B) levels in blood were in keeping with previously published data but were significantly enhanced by the addition of mannitol. Tumor concentrations were variable, reflecting the heterogeneity of glioblastoma. Peak concentrations were not achieved in some patients until as late 6 hours after infusion, later than previously shown. This peak concentration correlated with concentrations in extracellular fluid. Administration via the intra-arterial route enhanced the tumor concentration, peaking 2 hours after blood BPA levels. CONCLUSIONS: Previous clinical studies into BNCT for glioblastoma have instituted early irradiation at 1hr after the end of BPA infusion.2 Our study shows delayed peak boron levels in brain and ECF suggesting that the optimal window for delivery of the radiation dose may be approximately 4 hours after infusion. Escalation of tumor boron dose without additional dose to normal brain is possible and likely to further facilitate therapeutic response.