Disposition and tissue distribution of boron after infusion of borocaptate sodium in patients with malignant brain tumors.

PURPOSE: In the frame of the Czech boron neutron capture therapy (BNCT) project, a clinical Phase I study of borocaptate sodium [Na2B12H11SH (BSH)] as the boron-10 delivery agent was performed to obtain data on disposition and tissue distribution of boron after an infusion of this compound, as well as to establish an optimal protocol for BNCT of malignant cerebral tumors. METHODS AND MATERIALS: The kinetics of boron disposition after an infusion of borocaptate sodium (25 mg/kg body wt over the period of 1 h) was studied in a group of 10 patients with astrocytoma or glioblastoma of cerebral hemispheres using a modification of the Soloway-Messer colorimetric method. The boron content of tissues (tumor, healthy brain, dura mater, muscle, skin, and cranial bone) removed during the operation performed with latencies varying between 3 and 18 h was investigated by atomic emission spectrometry. RESULTS: Compartmental analysis of boron blood concentrations has shown that in the majority of patients (four males and three females), the concentration decline can be adequately described by a two-compartment pharmacokinetic model (i.e., by a biexponential relationship). The calculated half-lives of the initial (fast) phase of the concentration decline varied between 0.85 and 3.65 h, whereas the half-life values for the terminal (slow) phase ranged between 22.2 and 111.8 h. However, in the remaining three patients (all females), the goodness of fit of the boron concentration data was significantly better when a pharmacokinetic model with three compartments was assumed. In these patients, therefore, an additional ultrafast phase with a half-life varying between 17 and 37 min was detected in the beginning of the boron blood concentration decline. On the other hand, in one of these patients, the half-life of the terminal phase was found to be 415 h (i.e., more than 17 days). Such a long persistence in the body is explained by the very high value of the total distribution volume, indicating extensive binding of BSH in peripheral tissues. Another reason may be enterohepatic recycling of BSH. CONCLUSION: Tumor-to-blood ratios higher than 1.5, which are necessary for an effective outcome of BNCT, can be obtained only if the time interval elapsing between the onset of surgery and termination of BSH infusion is at least 12 h.

The diuretic effect of borocaptate sodium in rats and in patients with brain tumors.

Kidney function changes after single-dose administration of borocaptate sodium were studied in rats and in patients with brain tumors. Changes of glomerular filtration rate (GFR) measured as 14C-inulin clearance and urine flow rate (UFR) after a slow intravenous injection of BSH (25 and 50 mg/kg b.w., respectively) were investigated in rats under pentobarbital anesthesia. The effect of BSH has been compared with that of its disulfide (BSSB) which is spontaneously generated by oxidation of BSH during storage. It was found that BSH decreases GFR in relation to dose and, in the same way, causes a temporary increase of UFR. On the other hand, BSSB (50 mg/kg) induced a large reversible decrease of GFR as well as a decrease of urine excretion. Measurements of GFR (inulin clearance), renal plasma flow (PAH clearance) and urine excretion were taken in a group of patients with brain tumors in which boron disposition after an infusion of BSH (25 mg/kg b.w. over 1 h) had been studied. An increase in urine production was the dominant effect (up to 200% of the initial value), with the alterations of GFR and RPF being of minor significance except in one patient with a GFR reduction up to almost 50% the original value. Kidney function changes after BSH or BSSB administration are supposedly related to the high retention of BSH in kidney.

[A case of arteriovenous malformation, grade IV, with two giant aneurysms in dominant side speech and motor-senosry area--evaluation of grades, operability with microsurgical technique and pre- and post-operative performance status in 37 cases of cerebral vascular malformation (author's transl)].

A case of grade IV arteriovenous malformation(AVM) with 2 giant aneurysms, deeply seated in the dominant hemisphere speech and motor-sensory area, improved remarkably by a total excision, after an incapacitating rebleeding which occurred 4 months after a subtotal excision of the AVM. The author has learned importance of audacity on the part of the neurosurgeon. Personal experience of 37 CVM's (including 30 AV angiomas, 4 cryptic AVM's, and 3 other types of CVM's was analyzed. Of 37, 34 were operated on. Three were considered inoperable and were treated with radiotherapy (including proton beam). Of the 34 operated (30 AVM), 31 (24 AVM) were totally removed. None of them died or exhibitied deterioration. Of the 3 partially operated cases, one improved, two remained unchanged, but one of the two died of rebleeding 3 months later. Two of the radiated cases were later severely incapacitated due to rebleeding. One that underwent proton therapy is still under observation without deterioration after 18 months.

[Neutron capture therapy in the treatment of glioblastoma multiforme. Initial experience in the Czech Republic]. / Neutronová záchytová terapie v lécbe glioblastoma multiforme. První zkusenosti v Ceské republice.

BACKGROUND: Glioblastoma multiforme is the most frequent primary brain tumor in adults. Despite advances in surgery, radiotherapy and chemotherapy, its treatment remains unsatisfactory with very limited overall survival. In the year 2001, in cooperation with Department of Neurosurgery, Nemocnice Na Homolce and Nuclear Research Institute in Rez, we have started to treat glioblastoma patients with boron neutron capture therapy (BNCT). METHODS AND RESULTS: Cells of malignant brain tumors, especially that of glioblastomas, are able to accumulate boron compounds. If BNCT should be successful, it is necessary to reach selective accumulation of sufficient amount of 10B in the tumor and low accumulation in the normal brain tissue. After BSH administration, radiation with low energy thermal neutrons is delivered. It results in nuclear capture and fission reactions with subsequent selective damage of tumor cells. At the time of analysis 9 patients have been enrolled. Therapy was completed in 5 patients. Treatment has been very well tolerated. We observed minimal acute toxicity associated with radiation and no laboratory abnormalities after administrations of BSH. Unfortunately treatment results were quite unsatisfactory. The median time to progression and overall survival were shorter then expected with conventional treatment. CONCLUSIONS: BNCT is very well tolerated with only a modest toxicity. In contrast to standard radiation, BNCT patients receive only one dose of radiation. Nevertheless, in this small pilot study first results were inferior when compared either to outcomes of conventional therapy or to results reported from other BNCT groups. It might be explained that lower dose of radiation had been used. Further study will show whether the higher dose radiation can improve treatment results.