Common challenges and problems in clinical trials of boron neutron capture therapy of brain tumors

Summary Clinical trials for binary therapies, like boron neutron capture therapy (BNCT), pose a number of unique problems and challenges in design, performance, and interpretation of results. In neutron beam development, different groups use different optimization parameters, resulting in beams being considerably different from each other. The design, development, testing, execution of patient pharmacokinetics and the evaluation of results from these studies differ widely. Finally, the clinical trials involving patient treatments vary in many aspects such as their dose escalation strategies, treatment planning methodologies, and the reporting of data. The implications of these differences in the data accrued from these trials are discussed. The BNCT community needs to standardize each aspect of the design, implementation, and reporting of clinical trials so that the data can be used meaningfully.     

Boron Neutron Capture Therapy of Brain Tumors: Clinical Trials at the Finnish Facility Using Boronophenylalanine

Two 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 400mg/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 61Gy (W), and the average normal brain dose from 3 to 6Gy (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 50–60Gy, were treated with BPA-based BNCT using the BPA dosage of 290mg/kg. The average planning target dose in these patients was 25–29Gy (W), and the average whole brain dose 2–3Gy (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 photon 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.     

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden

A boron neutron capture therapy (BNCT) facility has been constructed at Studsvik, Sweden. It includes two filter/moderator configurations. One of the resulting neutron beams has been optimized for clinical irradiations with a filter/moderator system that allows easy variation of the neutron spectrum from the thermal to the epithermal energy range. The other beam has been designed to produce a large uniform field of thermal neutrons for radiobiological research. Scientific operations of the Studsvik BNCT project are overseen by the Scientific Advisory Board comprised of representatives of major universities in Sweden. Furthermore, special task groups for clinical and preclinical studies have been formed to facilitate collaboration with academia. The clinical Phase II trials for glioblastoma are sponsored by the Swedish National Neuro-Oncology Group and, presently, involve a protocol for BNCT treatment of glioblastoma patients who have not received any therapy other than surgery. In this protocol, p-boronophenylalanine (BPA), administered as a 6-h intravenous infusion, is used as the boron delivery agent. As of January 2002, 17 patients were treated. The 6-h infusion of 900mg BPA/kg body weight was shown to be safe and resulted in the average blood–boron concentration of 24g/g (range: 15–32g/g) at the time of irradiation (approximately 2–3h post-infusion). Peak and average weighted radiation doses to the brain were in the ranges of 8.0–15.5Gy(W) and 3.3–6.1Gy(W), respectively. So far, no severe BNCT-related acute toxicities have been observed. Due to the short follow-up time, it is too early to evaluate the efficacy of these studies.     

Accelerator-based Epithermal Neutron Sources for Boron Neutron Capture Therapy of Brain Tumors

This paper reviews the development of low-energy light ion accelerator-based neutron sources (ABNSs) for the treatment of brain tumors through an intact scalp and skull using boron neutron capture therapy (BNCT). A major advantage of an ABNS for BNCT over reactor-based neutron sources is the potential for siting within a hospital. Consequently, light-ion accelerators that are injectors to larger machines in high-energy physics facilities are not considered. An ABNS for BNCT is composed of: (1) the accelerator hardware for producing a high current charged particle beam, (2) an appropriate neutron-producing target and target heat removal system (HRS), and (3) a moderator/reflector assembly to render the flux energy spectrum of neutrons produced in the target suitable for patient irradiation. As a consequence of the efforts of researchers throughout the world, progress has been made on the design, manufacture, and testing of these three major components. Although an ABNS facility has not yet been built that has optimally assembled these three components, the feasibility of clinically useful ABNSs has been clearly established. Both electrostatic and radio frequency linear accelerators of reasonable cost ($1.5M) appear to be capable of producing charged particle beams, with combinations of accelerated particle energy (a few MeV) and beam currents (10mA) that are suitable for a hospital-based ABNS for BNCT. The specific accelerator performance requirements depend upon the charged particle reaction by which neutrons are produced in the target and the clinical requirements for neutron field quality and intensity. The accelerator performance requirements are more demanding for beryllium than for lithium as a target. However, beryllium targets are more easily cooled. The accelerator performance requirements are also more demanding for greater neutron field quality and intensity. Target HRSs that are based on submerged-jet impingement and the use of microchannels have emerged as viable target cooling options. Neutron fields for reactor-based neutron sources provide an obvious basis of comparison for ABNS field quality. This paper compares Monte Carlo calculations of neutron field quality for an ABNS and an idealized standard reactor neutron field (ISRNF). The comparison shows that with lithium as a target, an ABNS can create a neutron field with a field quality that is significantly better (by a factor of 1.2, as judged by the relative biological effectiveness (RBE)-dose that can be delivered to a tumor at a depth of 6cm) than that for the ISRNF. Also, for a beam current of 10mA, the treatment time is calculated to be reasonable (30min) for the boron concentrations that have been assumed.     

Computational dosimetry and treatment planning for Boron Neutron Capture Therapy

The technology for computational dosimetry and treatment planning for Boron Neutron Capture Therapy (BNCT) has advanced significantly over the past few years. Because of the more complex nature of the problem, the computational methods that work well for treatment planning in photon radiotherapy are not applicable to BNCT. The necessary methods have, however, been developed and have been successfully employed both for research applications as well as human trials, although further improvements in speed are needed for routine clinical applications. Computational geometry for BNCT applications can be constructed directly from tomographic medical imagery and computed radiation dose distributions can be readily displayed in formats that are familiar to the radiotherapy community.     

Boron Neutron Capture Therapy: Clinical Application and Research Progress

Boron neutron capture therapy (BNCT) is a binary modality that is used to treat a variety of malignancies, using neutrons to irradiate boron-10 (¹⁰B) nuclei that have entered tumor cells to produce highly linear energy transfer (LET) alpha particles and recoil ⁷Li nuclei (¹⁰B [n, α] ⁷Li). Therefore, the most important part in BNCT is to selectively deliver a large number of ¹⁰B to tumor cells and only a small amount to normal tissue. So far, BNCT has been used in more than 2000 cases worldwide, and the efficacy of BNCT in the treatment of head and neck cancer, malignant meningioma, melanoma and hepatocellular carcinoma has been confirmed. We collected and collated clinical studies of second-generation boron delivery agents. The combination of different drugs, the mode of administration, and the combination of multiple treatments have an important impact on patient survival. We summarized the critical issues that must be addressed, with the hope that the next generation of boron delivery agents will overcome these challenges.     

Ligand Liposomes and Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) has been used both experimentally and clinically for the treatment of gliomas and melanomas, with varying results. However, the therapeutic effects on micro-invasive tumor cells are not clear. The two drugs that have been used clinically, p-boronophenylalanine, (BPA), and the sulfhydryl borane, (BSH), seem to be taken up preferentially in solid tumor areas but it is uncertain whether enough boron is taken up by micro-invasive tumor cells. To increase the selective uptake of boron by such cells, would be to exploit tumor transformation related cellular changes such as over-expression of growth factor receptors. However, the number of receptors varies from small to large and the uptake of large amounts of boron for each receptor interaction is necessary in order to deliver sufficient amounts of boron. Therefore, each targeting moiety must deliver large number of boron atoms. One possible way to meet these requirements would be to use receptor-targeting ligand liposomes, containing large number of boron atoms. This will be the subject of this review and studies of boron containing liposomes, with or without ligand, will be discussed. Two recent examples from the literature are ligand liposomes targeting either folate or epidermal growth factor (EGF) receptors on tumor cells. Other potential receptors on gliomas include PDGFR and EGFRvIII. Besides the appropriate choice of target receptor, it is also important to consider delivery of the ligand liposomes, their pharmacodynamics and pharmacokinetics and cellular processing, subjects that also will be discussed in this review.     

The Effects of Boron Neutron Capture Therapy on Liver Tumors and Normal Hepatocytes in Mice

To explore the feasibility of employing boron neutron capture therapy (BNCT) to treat liver tumors, the effects of BNCT were investigated by using liver tumor models and normal hepatocytes in mice. Liver tumor models in C3H mice were developed by intrasplenic injection of SCCVII tumor cells. After borocaptate sodium (BSH) and boronophenylalanine (BPA) administration, ¹⁰B concentrations were measured in tumors and liver and the liver was irradiated with thermal neutrons. The effects of BNCT on the tumor and normal hepatocytes were studied by using colony formation assay and micronucleus assay, respectively. To compare the effects of BSH-BNCT and BPA-BNCT, the compound biological effectiveness (CBE) factor was determined. The CBE factors for BSH on the tumor were 4.22 and 2.29 using D ₁₀ and D ₀ as endpoints, respectively. Those for BPA were 9.94 and 5.64. In the case of hepatocytes, the CBE factors for BSH and BPA were 0.94 and 4.25, respectively. Tumor-to-liver ratios of boron concentration following BSH and BPA administration were 0.3 and 2.8, respectively. Considering the accumulation ratios of ¹⁰B, the therapeutic gain factors for BSH and BPA were 0.7-1.3 and 3.8-6.6, respectively. Therefore, it may be feasible to treat liver tumors with BPA-BNCT.     

The Early Successful Treatment of Glioblastoma Patients with Modified boron Neutron Capture Therapy

We very effectively treated two patients with recurrent glioblastoma with modified boron neutron capture therapy (BNCT). In this paper, we describe the effectiveness of this treatment, and discuss the ways in which we modified the treatment. A 61-year-old man had a first operation for a right temporal glioblastoma, followed by full-dose chemo-radiotherapy. One year after the operation a partial removal was performed for the recurrent tumor at the same site. Fifty days after the second surgery, the patient received BNCT. We used an epithermal neutron beam as the neutron source, and used both sodium borocapate and boronophenylalanine as boron compounds with the craniotomy. Forty-eight hours after the BNCT, the follow-up MRI was applied to estimate the early effect of this treatment, which showed a 70% reduction in the contrast enhanced lesion, compared with the pretreatment MRI. In addition, the lesion/normal brain ratio of thallium-SPECT had improved markedly. No serial sequelae appeared after this treatment, and the patient remains healthy 6 months after the treatment. A 29-year-old young lady had a right temporal brain tumor, which was partially resected and followed by stereotactic radiosurgery for the residual mass. Seven months after the radiosurgery, a second operation was performed, which revealed the glioblastoma as diagnosis. We applied BNCT uneventfully for this patient with epithermal beam and two kinds of boron compounds as described above. For the treatment of the patient irradiation was applied without craniotomy with marked reduction of tumor volume immediately after the treatment.     

A Critical Assessment of Boron Target Compounds for Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) has undergone dramatic developments since its inception by Locher in 1936 and the development of nuclear energy during World War II. The ensuing Cold War spawned the entirely new field of polyhedral borane chemistry, rapid advances in nuclear reactor technology and a corresponding increase in the number to reactors potentially available for BNCT. This effort has been largely oriented toward the eradication of glioblastoma multiforme (GBM) and melanoma with reduced interest in other types of malignancies. The design and synthesis of boron-10 target compounds needed for BNCT was not channeled to those types of compounds specifically required for GBM or melanoma. Consequently, a number of potentially useful boron agents are known which have not been biologically evaluated beyond a cursory examination and only three boron-10 enriched target species are approved for human use following their Investigational New Drug classification by the US Food and Drug Administration; BSH, BPA and GB-10. All ongoing clinical trials with GBM and melanoma are necessarily conducted with one of these three species and most often with BPA. The further development of BNCT is presently stalled by the absence of strong support for advanced compound evaluation and compound discovery driven by recent advances in biology and chemistry. A rigorous demonstration of BNCT efficacy surpassing that of currently available protocols has yet to be achieved. This article discusses the past history of compound development, contemporary problems such as compound classification and those problems which impede future advances. The latter include means for biological evaluation of new (and existing) boron target candidates at all stages of their development and the large-scale synthesis of boron target species for clinical trials and beyond. The future of BNCT is bright if latitude is given to the choice of clinical disease to be treated and if a recognized study demonstrating improved efficacy is completed. Eventually, BNCT in some form will be commercialized.     

Pharmacokinetics of Sodium Borocaptate: A Critical Assessment of Dosing Paradigms for Boron Neutron Capture Therapy

The pharmacokinetics of sodium borocaptate (BSH), a drug that has been used clinically for boron neutron capture therapy (BNCT) of malignant brain tumors, have been characterized by measuring boron concentrations by direct current plasma-atomic emission spectroscopy (DCP-AES) in a group of 23 patients with high-grade gliomas. The disposition of BSH following intravenous (i.v.) infusion, which was determined by measuring plasma boron concentrations by DCP-AES, was consistent with a three-compartment open model with zero-order input and first-order elimination from the central compartment. Boron disposition was linear over the dose range of 26.5–88.2mg BSH/kg body weight (b.w.), corresponding to 15–50mg boron/kg b.w. Mean total body boron plasma clearance was 14.4±3.5ml/min and the harmonic mean half-lives (range) were 0.6 (0.3–3.7), 6.5 (4.8–10.1) and 77.8 (49.6–172.0)h for the ,, and disposition phases, respectively. Using an empirically determined plasma:blood boron concentration ratio of 1.3±0.2, the calculated total body boron blood clearance was 18.5±4.5ml/min. In order to develop a model for selecting the optimum dosing paradigm, a pharmacokinetic correlation was established between the boron content of normal brain, solid tumor, and infiltrating tumor to the shallow tissue pharmacokinetic compartment (C₂). Based on our model, it was concluded that although multiple i.v. infusions of BSH might increase absolute tumor boron concentrations, they will not improve the tumor:plasma boron concentration ratios over those attainable by a single i.v. infusion. The results from our study are confirmatory of those previously reported by others when blood sampling has been carried out for a sufficient period of time to adequately characterize the pharmacokinetics.     

Computational Dosimetry and Treatment Planning Considerations for Neutron Capture Therapy

Specialized treatment planning software systems are generally required for neutron capture therapy (NCT) research and clinical applications. The standard simplifying approximations that work well for treatment planning computations in the case of many other modalities are usually not appropriate for application to neutron transport. One generally must obtain an explicit three-dimensional numerical solution of the governing transport equation, with energy-dependent neutron scattering completely taken into account. Treatment planning systems that have been successfully introduced for NCT applications over the past 15 years rely on the Monte Carlo stochastic simulation method for the necessary computations, primarily because of the geometric complexity of human anatomy. However, historically, there has also been interest in the application of deterministic methods, and there have been some practical developments in this area. Most recently, interest has turned toward the creation of treatment planning software that is not limited to any specific therapy modality, with NCT as only one of several applications. A key issue with NCT treatment planning has to do with boron quantification, and whether improved information concerning the spatial biodistribution of boron can be effectively used to improve the treatment planning process. Validation and benchmarking of computations for NCT are also of current developmental interest. Various institutions have their own procedures, but standard validation models are not yet in wide use.     

Chemistry and biology of some low molecular weight boron compounds for Boron Neutron Capture Therapy

Boronated DNA targeting agents are especially attractive candidatesfor BNCT because they may deliver boron-10 tothe nuclei of tumor cells. Numerous boron-containing analogshave been synthesized and some have shown promisingresults in initial biological tests. One of themost challenging tasks in this special field ofresearch remains the finding of suitable targeting strategiesfor the selective delivery of boron rich DNA-intercalator/alkylatorto tumor cells. Synthetic and biological studies ofboron compounds suitable for DNA-binding are reviewed.The amino acid p-boronophenylalanine (BPA) is presently ofconsiderable clinical interest. Other boronated amino acids mightalso be candidates for BNCT either per se,as part of part of tumor-seeking peptides orconjugated to targeting macromolecules. A large number ofboronated L- and D-amino acids with varying liphophicilityand sterical requirements are now available for evaluation.Recent synthetic and biological studies of aromatic boronoaminoacids, carboranylamino acids and carboranyl amines are alsoreviewed.     

Boron Neutron Capture Therapy: Effects of Split Dose and Overall Treatment Time

New clinical protocols are being developed that will entail the administration of considerably higher doses of the boron delivery agent boronophenylalanine (BPA) than those in current clinical use. Fractionation (2 or 4 fractions) of BPA mediated boron neutron capture therapy (BNCT) is also under consideration at some clinical centres. Given the considerably higher infusion volumes that will be entailed in the delivery of BPA in the new high dosage protocols, there will be a requirement to extend the gap between fractions to 2 or more days. In order to assess the effects of a 2 fraction protocol on the therapeutic efficacy of BPA mediated BNCT, a series of split dose irradiations (two equal fractions) were undertaken using the rat intracranially implanted 9L gliosarcoma model. A single dose exposure to BPA mediated BNCT of 3.0Gy resulted in long term survival levels of 50%. Survival levels increased to 71% and 77% with a 3 and 5 day gap between dose fractions (two equal fractions), respectively, using the same total dose. A further increase in the time interval between dose fractions to 7 days resulted in a reduction in survival to 36%. However, there was no significant difference between the single dose and the 3, 5 and 7 day survival data (P > 0.1) The difference between the 5 and 7 day split dose survival data was of border-line significance (P = 0.05). It is anticipated that mucositis, could become a potential problem in future BNCT clinical protocols involving higher doses, larger field sizes or multiple fields. The potential sparing of the oral mucosa, due to repopulation during the interval between the two fractions, was investigated using a series of split dose BPA mediated BNC irradiations. The ventral surface of the rat tongue was utilised as a model for oral mucosa. The ED₅₀ (50% incidence) values for the ulceration end point were 3.0±0.1,3.2±0.1,3.0±0.1 and 3.6±0.1Gy, for 3, 5, 7 and 9 day splits between doses, respectively. It is evident from this data that there were no significant changes in the ED₅₀ (p < 0.001) until the 9 day dose split, when the ED₅₀ value was 20% higher than the ED₅₀ value after a 7 day split. It was concluded that the two fraction BNCT protocol, with dose splits of up to 5 days, did not diminish the therapeutic response of the rat 9L gliosarcoma, when compared with a single dose BNCT protocol. Tolerance of the oral mucosa to BNC irradiation was not increased until there was a 9 day gap between fractions. However, the beneficial effects of dose sparing at this time interval between doses, would probably be counteracted by a reduction in the therapeutic effectiveness of the BNCT modality, due to repopulation of tumour clonogens between doses.     

Clinical Review of the Japanese Experience with Boron Neutron Capture Therapy and A Proposed Strategy Using Epithermal Neutron Beams

Our concept of boron neutron capture therapy (BNCT) is selective destruction of tumor cells using the heavy-charged particles yielded through ¹⁰ B(n, )⁷ Li reactions. To design a new protocol that employs epithermal neutron beams in the treatment of glioma patients, we examined the relationship between the radiation dose, histological tumor grade, and clinical outcome. Since 1968, 183 patients with different kinds of brain tumors were treated by BNCT; for this retrospective study, we selected 105 patients with glial tumors who were treated in Japan between 1978 and 1997. In the analysis of side effects due to radiation, we included all the 159 patients treated between 1977 and 2001.With respect to the radiation dose (i.e. physical dose of boron n-alpha reaction), the new protocol prescribes a minimum tumor volume dose of 15Gy or, alternatively, a minimum target volume dose of 18Gy. The maximum vascular dose should not exceed 15Gy (physical dose of boron n-alpha reaction) and the total amount of gamma rays should remain below 10Gy, including core gamma rays from the reactor and capture gamma in brain tissue.The outcomes for 10 patients who were treated by the new protocol using a new mode composed of thermal and epithermal neutrons are reported.     

Effects of Boron Neutron Capture Therapy Using Borocaptate Sodium in Combination with a Tumor-selective Vasoactive Agent in Mice

Boron neutron capture therapy (BNCT) destroys tumor cells by means of α particles and recoil protons emitted by ¹⁰B(n,α)⁷Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of ¹⁰B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of ¹⁰B-enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of ¹⁰B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The ¹⁰B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor ¹⁰B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7- to 2.7-fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, ¹⁰B concentrations 2.1- to 6.9-fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor ¹⁰B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on ¹⁰B levels at the time of irradiation. Because ¹⁰B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15–180 min after FAA+BSH, or in those in skin irradiated at 120 and 180 min.     

Pharamacokinetic Modeling for Boronophenylalanine-fructose Mediated Neutron Capture Therapy: 10B Concentration Predictions and Dosimetric Consequences

A two-compartment open model has been developed for predicting ¹⁰B concentrations in blood following intravenous infusion of the L-p-boronophenylalanine-fructose complex in humans and derived from pharmacokinetic studies of 24 patients in Phase I clinical trials of boron neutron capture therapy. The ¹⁰B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of 32g/g (for infusion of 350mg/kg over 90min) followed by a biexponential disposition profile with harmonic mean half-lives of 0.32±0.08 and 8.2±2.7h, most likely due to redistribution and primarily renal elimination, respectively. The mean model rate constants k ₁₂, k ₂₁, and k ₁₀ are (mean ± SD) 0.0227±0.0064min^–1, 0.0099±0.0027min^–1, 0.0052±0.0016min^–1, respectively, and the central compartment volume of distribution V ₁ is 0.235±0.042L/kg. In anticipation of the initiation of clinical trials using an intense neutron beam with concomitantly short irradiations, the ability of this model to predict, in advance, the average blood ¹⁰B concentration during brief irradiations was simulated in a retrospective analysis of the pharmacokinetic data from these patients. The prediction error for blood boron concentration and its effect on simulated dose delivered for each irradiation field are reported for three different prediction strategies. In this simulation, error in delivered dose (or, equivalently, neutron fluence) for a given single irradiation field resulting from error in predicted blood ¹⁰B concentration was limited to less than 10%. In practice, lower dose errors can be achieved by delivering each field in two fractions (on two separate days) and by adjusting the second fraction's dose to offset error in the first.     

Subcellular Biodistribution of Sodium Borocaptate (BSH: Na2B12H11SH) in a Rat Glioma Model in Boron Neutron Capture Therapy

Mercaptoundecahydrododecaborate (Na₂B₁₂H₁₁SH, sodium borocaptate or BSH) has been used clinically as a boron compound for boron neutron capture therapy (BNCT) in patients with malignant glioma in Japan and Europe. Boron-10 is known to accumulate selectively only in brain tumor cells. This work was aimed to clarify the subcellular biodistribution of BSH in a rat glioma model using immunohistochemical approach.Wistar rats were used for this experiment. An intracerebral injection of 5.0 × 10⁶ C6 glioma cells was introduced into the region of cerebral hemisphere. Fifty milligrams of ¹⁰B/kg BSH was infused intravenously two weeks after implantation. Host rats were divided into six groups according to the sampling time: 1, 4, 8, 16, 24 and 48 h after the start of BSH infusion. Immunohistochemical study was carried out using anti-BSH antibody.Boron was already found in a whole cell 1 h after BSH infusion, and then seemed to collect in a cell nuclei around 8–16 h after infusion. It was still recognized in tumor cell 48 h after infusion.This study supports the following hypothesis on selective boron uptake in a tumor. BSH can pass through the disrupted blood–brain barrier (BBB) easily and can come in contact with tumor cells; there, BSH can bind on the extracellular surface of plasma membrane to choline residues. After binding to the plasma membrane, boron with choline residues may be internalized into the cell by endocytic pathways and eventually travel to cell nuclei, and then stay there for a long time.     

Preferential Recurrence of a Sarcomatous Component of a Gliosarcoma after Boron Neutron Capture Therapy: Case Report

Summary Gliosarcoma, a rare pathological entity composed of 2–8% malignant gliomas, is characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Here we report the preferential recurrence of a sarcomatous component in gliosarcoma after boron neutron capture therapy (BNCT), while a gliomatous component disappeared as a result of the treatment. A 56-year-old woman with a left frontal tumor was introduced to our clinic. After stereotactic biopsy, craniotomy was applied and 90% of the mass was resected. The histological diagnosis was glioblastoma with small amounts of sarcomatous component, that is, gliosarcoma. BNCT was applied 30 days after craniotomy. Two weeks after BNCT, almost all of the contrast-enhanced mass had disappeared on magnetic resonance images; however, a half year later, the mass recurred just below the original site and extended posteriorly. Irrespective of repetitive salvage surgeries, the patient died of the recurrent tumor. At autopsy, tumor cells of the frontal lobe were absent. A well-circumscribed mass of the parietal and occipital lobes was composed of sarcomatous material, with very little glial fibrillary acid protein-positive glial material. We found in this patient the preferential recurrence of the sarcomatous component of a gliosarcoma after potent radiotherapeutics in the form of BNCT.     

Tolerance of the Normal Canine Brain to Epithermal Neutron Irradiation in the Presence of p-boronophenylalanine

Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950mg of ¹⁰B-enriched BPA/kg as its fructose complex. The 5 × 10cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose–volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1cm³ of brain at the depth of maximum thermal neutron flux) ranged from 7.6Gy (photon-equivalent dose: 11.8Gy-Eq) to 11.6Gy (17.5Gy-Eq). The average dose to the brain ranged from 3.0Gy (4.5Gy-Eq) to 8.1Gy (11.9Gy-Eq) and to the left hemisphere, 6.6Gy (10.1Gy-Eq) to 10.0Gy (15.0Gy-Eq). Maximum tolerated threshold doses were 6.7Gy (9.8Gy-Eq) to the whole brain and 8.2Gy (12.3Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5Gy (14.3Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.