Jyrki Vähätalo

Boron neutron capture therapy of brain tumors: clinical trials at the Finnish facility using boronophenylalanine

SummaryTwo clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400 mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61 Gy (W), and the average normal brain dose from 3 to 6 Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50–60 Gy, were treated with BPA-based BNCT using the BPA dosage of 290 mg/kg. The average planning target dose in these patients was 25–29 Gy (W), and the average whole brain dose 2–3 Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photo radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.

Modelling of brain tissue substitutes for phantom materials in neutron capture therapy (NCT) dosimetry

The aim of this study was to define the most suitable brain tissue phantom material for neutron capture therapy (NCT). The calculated distributions of the thermal neutron fluence and the fast neutron and γ dose in normal brain tissue defined by ICRU were compared to those in four brain tissue substitutes: water, PMMA and two normal brain tissue substitute liquids, A and B, defined by us. Liquid B is an excellent material to simulate the neutron and γ interactions in normal brain tissue and it can be considered for use in situations for which higher accuracy is required, although it may not be suitable for routine use. Water is a suitable brain tissue substitute for periodic epithermal beam calibration, for routine quality control and for intercomparison of beams in NCT dosimetry.

Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway.

Boron neutron capture therapy (BNCT) is an experimental therapeutic modality combining a boron pharmaceutical with neutron irradiation. 4-Dihydroxyborylphenylalanine (L-BPA) synthesised via the asymmetric pathway by Malan and Morin [Synlett. 167-168 (1996)] was developed to be the boron containing pharmaceutical in the first series of Finnish BNCT clinical trials. The final product was >98.5% chemically pure L-BPA with L-phenylalanine and L-tyrosine as the residual impurities. The solubility of L-BPA was enhanced by complex formation with fructose (BPA-F). The pH and osmolarity of the BPA-F preparation is in the physiological range. Careful attention was given to the pharmaceutical quality of the BPA-F preparations. Prior to starting clinical trials the acute toxicity of L-BPA was studied in male albino Sprague-Dawley rats. In accordance with earlier studies no adverse effects were observed. After completion of the development work L-BPA solution was administered to brain tumour patients in conjunction with clinical studies for development and testing of BPA-based BNCT. No clinically significant adverse events attributable to the L-BPA i.v. infusions were observed. We conclude that our synthesis development, complementary preclinical and clinical observations justify the safe use of L-BPA up to clinical phase III studies with L-BPA produced by the asymmetric pathway, originally presented by Malan and Morin in 1996.

Trace impurities identified by high performance liquid chromatography/electrospray mass spectrometry in two different synthetic batches of 4‐boronophenylalanine

The chemical purity of two synthetic 4-boronophenylalanine (BPA, C9H12O4BN) batches produced by two different pathways were investigated by high performance liquid chromatography/electrospray mass spectrometry. Currently, BPA is one of the most important clinical boron carriers in boron neutron capture therapy (BNCT). Low energy tandem mass spectrometry was used to elucidate the structure of BPA and two minor signals eluting later than the major compound. In the mass spectrom a very intense singly charged [M+H]+ ion m/z 209 was observed. The ratio of 10B/11B was estimated also. The product-ion spectrum of BPA shows distinct losses of 18, 46 and 89 u. Based on the fragmentation of the major compound two impurities were characterized. In both cases an intense molecular ion, 244 u and 285 u was observed. Knowing the synthetic pathway and fragmentation of the major compound we suggest the following formulae for the impurities: C9H10O2BrN and C15H16O4BN. Further evidence to the first impurity is the detected isotope pattern, corresponding to bromine. The existence of the impurities can be explained and avoided by exploring the synthetic pathways used. High performance liquid chromatography/electrospray mass spectrometry was demonstrated to be an important novel analytical instrument to check the purity of BPA prior to clinical studies in BNCT.

Compartmental and Non-Compartmental Methods in Studying the Kinetics of Boron-10 after Boronophenylalanine Fructose Complex (BPA-F)-Infusion in Dogs

One of the essential requirements for optimising BNC-treatment is to know the boron-10 concentration in tissues under irradiation. A model which describes the kinetics of boron-10 in the patient would be valuable. The primary aim of the present study was to create a model for the pharmacokinetics of boron-10 in dogs after 4-dihydroxy-borylphenylalanine fructose complex (BPA-F) infusion so that we could predict the boron-10 concentration in blood during the irradiation.1 In addition we wanted to clarify if it is possible to design a simple compartmental model which could be used in defining the kinetic behaviour of boron-10 in the blood circulation.

At the Threshold of Clinical Trials

The aim of the Finnish BNCT-project is to start BNC-treatments of malignant brain tumors. The first clinical trial is planned to start in early 1999 at the treatment facility of the 250kW FiR 1 TRIGA research reactor. Excellent patient treatment facilities have been built at the reactor which is located only 5 km from the Helsinki University Central Hospital making the treatment facility very easy to reach.

On-Line Boron-10 Determination from Blood Samples by ICP-MS

Accurate and fast boron analysis is essential in BNC-treatment of glioma patients. Standard boron analytical assay from biological samples are direct current plasma atomic emission spectrometry,1 inductively coupled plasma-atomic emission spectrometry,2 inductively coupled plasma-mass spectrometry3 or prompt gamma-ray analysis.4 Various standard and alternative techniques for boron analysis have been tested by the Finnish BNCT research group.5

Radioiodination Techniques for Aromatic Amino Acids

Prevailing boron carriers for BNCT are disodium mercaptoundecahydro-closo-dodecaborate (borocaptate sodium, BSH) and 4-dihydroxyboryl phenylalanine (4-boronophenylalanine, BPA).1,2 For clinical patient studies BPA is administred as an anionic fructose complex (BPA-F) infusions. As an aromatic amino acid without the fructose moiety BPA is a structural analogue for natural aromatic amino acid tyrosine. In BPA the hydroxyl group of tyrosine is substituted by the dihydroxyboryl group (or borono group), —B(OH)2. The dihydroxyboryl group is known to be fragile in aromatic molecules and B(OH)2-group can be substituted by electrophiles.3,4 However, by direct electrophilic fluorination of BPA with [18F]AcOF or [18F]F2 followed by HPLC separation, 4-borono-2-[18F]fluorophenylalanine (18FBPA) was prepared with radiochemical yields of 25-35% and with a radiochemical purity of over 99%.5 Clinical patient studies have shown that positron emission tomography (PET) with fluorinated analogue of BPA is a valuable technique for prediction of the effectiveness of boron neutron capture therapy using BPA as a boron carrier.6,7