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PubMed2004

The design, construction and performance of a variable collimator for epithermal neutron capture therapy beams.

A patient collimator for the fission converter based epithermal neutron beam (FCB) at the Massachusetts Institute of Technology Research Reactor (MITR-II) was built for clinical trials of boron neutron capture therapy (BNCT). A design was optimized by Monte Carlo simulations of the entire beam line and incorporates a modular construction for easy modifications in the future. The device was formed in-house by casting a mixture of lead spheres (7.6 mm diameter) in epoxy resin loaded with either 140 mg cm(-3) of boron carbide or 210 mg cm(-3) of lithium fluoride (95% enriched in 6Li). The cone shaped collimator allows easy field placement anywhere on the patient and is equipped with a laser indicator of central axis, beam's eye view optics and circular apertures of 80, 100, 120 and 160 mm diameter. Beam profiles and the collateral dose in a half-body phantom were measured for the 160 mm field using fission counters, activation foils as well as tissue equivalent (A-150) and graphite walled ionization chambers. Leakage radiation through the collimator contributes less than 10% to the total collateral dose up to 0.15 m beyond the edge of the aperture and becomes relatively more prominent with lateral displacement. The measured whole body dose equivalent of 24 +/- 2 mSv per Gy of therapeutic dose is comparable to doses received during conventional therapy and is due principally (60-80%) to thermal neutron capture reactions with boron. These findings, together with the dose distributions for the primary beam, demonstrate the suitability of this patient collimator for BNCT.

Boron Neutron Capture Therapy↗
PubMed1988

A review of boron neutron capture therapy (BNCT) and the design and dosimetry of a high-intensity, 24 keV, neutron beam for BNCT research.

This paper reviews the development of boron neutron capture therapy (BNCT) and describes the design and dosimetry of an intermediate energy neutron beam, developed at the Harwell Laboratory, principally for BNCT research. Boron neutron capture therapy is a technique for the treatment of gliomas (a fatal form of brain tumour). The technique involves preferentially attaching 10B atoms to tumour cells and irradiating them with thermal neutrons. The thermal neutron capture products of 10B are short range and highly damaging, so they kill the tumour cells, but healthy tissue is relatively undamaged. Early trials required extensive neurosurgery to exposure the tumour to the thermal neutrons used and were unsuccessful. It is thought that intermediate-energy neutrons will overcome many of the problems encountered in the early trials, because they have greater penetration prior to thermalization, so that surgery will not be required. An intermediate-energy neutron beam has been developed at the Harwell Laboratory for research into BNCT. Neutrons from the core of a high-flux nuclear reactor are filtered with a combination of iron, aluminium and sulphur. Dosimetry measurements have been made to determine the neutron and gamma-ray characteristics of this beam, and to monitor them throughout the four cycles used for BNCT research. The beam is of high intensity (approximately 2 x 10(7) neutrons cm-2 s-1, equivalent to a neutron kerma rate in water of 205 mGy h-1) and nearly monoenergetic (93% of the neutrons have energies approximately 24 keV, corresponding to 79% of the neutron kerma rate).

Boron↗
PubMed1994

Enhanced boron uptake in RG 2 rat gliomas by electropermeabilization in vivo--a new possibility in boron neutron capture therapy.

Accumulation of boron in tumor tissue is an indispensable requirement for boron neutron capture therapy and it is important that the uptake is as high as possible. In this work we have studied the influence of electropermeabilization in vivo on the uptake of boron in normal and RG 2 glioma bearing Fischer 344 rats. Two different boron compounds, a sulfhydryl boron hydride (BSH) and a boronated porphyrin (BOPP), have been investigated. The rats were infused intravenously during 5 min with 175 micrograms BSH/g body weight or 12 micrograms BOPP/g body weight. Two electrodes were placed 5 mm apart in the brain and electropermeabilization was performed with eight square 400 V pulses at 4 and 7 min after the end of the infusion. After 6 h the animals were killed, and the boron content in the tumors and the surrounding brain was measured with neutron-activated autoradiography. In electropermeabilized healthy animals the BOPP uptake was low and limited to the electrode lesions, whereas BSH was spread extensively throughout the hemisphere. Rats with gliomas showed doubled (BOPP) to 10-fold (BSH) uptake of boron in the tumor when electropermeabilization was performed as compared with untreated animals. We conclude that electropermeabilization in the future may provide an interesting possibility to increase the uptake of certain boron compounds before neutron capture therapy.

Animals↗
PubMed1994

Clinical phase-I study of Na2B12H11SH (BSH) in patients with malignant glioma as precondition for boron neutron capture therapy (BNCT).

PURPOSE: Within the European collaboration on boron neutron capture therapy (BNCT), a clinical Phase I study is being carried out to establish BNCT as an alternative treatment modality for malignant glioma (WHO III/IV). Data about the pharmacokinetics, biodistribution and toxicity of the boron compound Na2B12H11SH (BSH) are of great importance to avoid radiation damage of healthy tissue and to deliver a sufficient radiation dose. METHODS AND MATERIALS: Twenty four patients suffering from a glioblastoma multiforme entered the study to date, infused with a maximum concentration of up to 50 mg BSH/kg. Boron concentration measurements in tissues, urine, and blood were carried out, using inductively coupled plasma-atomic spectroscopy (ICP-AES) and quantitative neutron capture radiography (QNCR). A cross-calibration of these boron determination techniques was carried out. RESULTS: In tumor tissue, confirmed by histopathology of small biopsies, we found a consistently high but heterogeneous boron uptake. Necrotic parts contain much lower amounts of boron; normal brain tissue has shown no significant uptake. In skin, bone, muscle, and dura mater only small amounts of boron were found. In blood samples, we found biphasic kinetics, but with variations of the half-lives from patient to patient. The compound is mainly excreted through the urine, but an additional entero-hepatic pathway can be demonstrated. Systematic investigations revealed no toxic side effect of the intravenously administered BSH. Comparable data were obtained by using ICP-AES and QNCR for boron concentration measurements. CONCLUSION: Taking into account the radiobiological considerations of the neutron beam source, we found promising facts that BNCT could be a useful irradiation method for highly malignant brain tumors. Favorable amounts of the boron compound BSH were found in tumor tissue, whereas healthy brain tissue has shown no significant uptake.

Aged↗
PubMed1996

The neutron sensitivity of dosimeters applied to boron neutron capture therapy.

To obtain a high accuracy in the dosimetry of an epithermal neutron beam used for boron neutron capture therapy (BNCT), the neutron sensitivity of dosimeters applied to determine the various dose components in-phantom has been investigated. The thermal neutron sensitivity of Mg(Ar) ionization chambers, TE(TE) ionization chambers, and thermoluminescent dosimeters (TLD) has been experimentally determined in a "pure" thermal neutron beam. Values much higher than theoretically expected were obtained and a variation up to a factor of 2.5 was found between values for the thermal neutron sensitivity of different Mg(Ar) ionization chambers of the same type. The sensitivity of the TE(TE) ionization chamber to intermediate and fast neutrons (kt) has been calculated for the neutron energy spectrum in a phantom irradiated by a clinical epithermal BNCT beam, obtained using Monte Carlo simulations. The kt value for muscle tissue ranged from 0.87 at small depths to 0.93 at larger depths in the phantom. The application of the thermal neutron sensitivities to measurements in a phantom irradiated by the epithermal BNCT beam yielded up to 17% higher gamma-ray dose rate values compared with measurements using 6Li containing caps to shield the detectors from thermal neutrons, due to a substantial perturbation of the in-phantom radiation field by the 6Li cap. The application of the new kt values resulted in a dose from intermediate and fast neutrons about 10% higher than the dose based on currently applied relative neutron sensitivities of TE(TE) chambers in BNCT beams. The resulting improvement in the accuracy of the determination of the dose from gamma rays and intermediate and fast neutrons is important in view of the required accuracy for dosimetry in radiotherapy.

Biophysical Phenomena↗
PubMed1998

Development of a high-power water cooled beryllium target for use in accelerator-based boron neutron capture therapy.

In order for ABNCT (accelerator-based boron neutron capture therapy) to be successful, 10-16 kW or more must be dissipated from a target. Beryllium is well suited as a high-power target material. Beryllium has a thermal conductivity of 200 W/mK at 300 K which is comparable to aluminum, and it has one of the highest strength to weight ratios of any metal even at high temperatures (100 MPa at 600 degrees C). Submerged jet impingement cooling has been investigated as an effective means to remove averaged power densities on the order of 2 x 10(7) W/m2 with local power densities as high as 6 x 10(7) W/m2. Water velocities required to remove these power levels are in excess of 24 m/s with volumetric flow rates of nearly 100 GPM. Tests on a prototype target revealed that the heat transfer coefficient scaled as Re0.6. With jet-Reynolds numbers as high as 5.5 x 10(5) heat transfer coefficients of 2.6 x 10(5) W/m2K were achieved. With this type of cooling configuration 30 kW of power could be effectively removed from a beryllium target placed on the end of an accelerator. A beryllium target utilizing a proton beam of 3.7 MeV and cooled by submerged jet impingement could be used to deliver a dose of 13 RBE cGy/min mA to a tumor at a depth of 4 cm. With a beam power of 30 kW, 1500 cGy could be delivered in 14.2 min.

Beryllium↗
PubMed2004

Self-shielding effects in neutron spectra measurements for neutron capture therapy by means of activation foils.

The design and optimisation of a neutron beam for neutron capture therapy (NCT) is accompanied by the neutron spectra measurements at the target position. The method of activation detectors was applied for the neutron spectra measurements. Epithermal neutron energy region imposes the resonance structure of activation cross sections resulting in strong self-shielding effects. The neutron self-shielding correction factor was calculated using a simple analytical model of a single absorption event. Such a procedure has been applied to individual cross sections from pointwise ENDF/B-VI library and new corrected activation cross sections were introduced to a spectra unfolding algorithm. The method has been verified experimentally both for isotropic and for parallel neutron beams. Two sets of diluted and non-diluted activation foils covered with cadmium were irradiated in the neutron field. The comparison of activation rates of diluted and non-diluted foils has demonstrated the correctness of the applied self-shielding model.

Absorption↗
PubMed2003

Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with (10)B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT. Much of the complexity has been unravelled through a combination of preclinical experimentation and clinical dose escalation experience. Over 350 patients have been treated in a number of different facilities worldwide. The accumulated clinical experience has demonstrated that BNCT can be delivered safely but is still defining the limits of normal brain tolerance. Several independent BNCT clinical protocols have demonstrated that BNCT can produce median survivals in patients with glioblastoma that appear to be equivalent to conventional photon therapy. This review describes the individual components and methodologies required for effect BNCT: the boron delivery agents; the analytical techniques; the neutron beams; the dosimetry and radiation biology measurements; and how these components have been integrated into a series of clinical studies. The single greatest weakness of BNCT at the present time is non-uniform delivery of boron into all tumor cells. Future improvements in BNCT effectiveness will come from improved boron delivery agents, improved boron administration protocols, or through combination of BNCT with other modalities.

Animals↗
PubMedDate not supplied

Boron neutron capture therapy for the treatment of cerebral gliomas. I. Theoretical evaluation of the efficacy of various neutron beams.

The technique of boron neutron capture therapy in the treatment of cerebral gliomas depends upon the selective loading of the tumor with a 10B-enriched compound and subsequent irradiation of the brain with low-energy neutrons. The charged particles produced in the 10B (n,alpha) 7Li reaction have ranges in tissue of less than 10 mum so that the dose distribution closely follows the 10B distribution even to the cellular level. The effectiveness of this therapy procedure is dependent not only on the 10B compound but on the spectral characteristics of the neutron source as well. Hence, an optimization of these characteristics will increase the chances of therapeutic success. Transport calculations using a neutral particle transport code have been made to determine the dose-depth distributions within a simple head phantom for five different incident neutron beams. Comparison of these beams to determine their relative therapeutic efficacy was made by the use of a maximum useable depth criterion. In particular, with presently available compounds, the MIT reactor (MITR) therapy beam (a) is not inferior to a pure thermal neutron beam, (b) would be marginally improved if its gamma-ray contamination were eliminated, (c) is superior to a partially 10B-filtered MITR beam, and (d) produces a maximum useable depth which is strongly dependent upon the tumor-to-blood ratio of 10B concentrations and weakly dependent upon the absolute 10B concentration in tumor. A pure epithermal neutron beam with a mean energy of 37 eV is shown to have close to the optimal characteristics for boron neutron capture therapy. Futhermore, these optimal characteristics can be approximated by a judiciously D2O moderated and 10B-filtered 252Cf neutron source. This tailored 252Cf source would have at least a 1.5 cm greater maximum useable depth than the MITR therapy beam for realistic 10B concentrations. However, at least one gram of 252Cf would be needed to make this a practical therapy source. If the moderated 252Cf source is not 10B filtered, the resultant neutron beam has characteristics similar to those of the MITR beam with no gamma-ray contamination. For usch a beam, 100 mg of 252Cf would produce a flux of 2.4 X 10(8) neutrons/(cm2 sec), which is an intensity suitable for therapy applications.

Boron↗
PubMed1993

Physical and tumor biological aspects and calculation model of dosage in boron neutron capture therapy (BNCT).

Fundamentally different aspects apply to dosage in boron neutron capture therapy (BNCT) compared to that in the case of normal radiotherapy with photons, electrons or heavy particles such as neutrons. The reason is that the latter only requires a knowledge of the stochastic distribution of the absorbed dose within cells, radiation quality and atomic composition of tissue in the regions of interest, whereas for the former the absolute concentration and microscopic distribution of 10B atoms in inter- and intracellular spaces of tumor and healthy cells is additionally of equal importance. The effects of radiation without 10B must always be superimposed on those of heavy particles resulting from neutron capture reactions on 10B atoms. Complex geometrical calculations are necessary with respect to ranges of the heavy particles smaller than a cell diameter. Apart from the direct effects of radiation without 10B, the dosage therefore depends on thermal neutron fluence, 10B concentration, its extreme inhomogeneous macroscopic distribution in the tumor tissue, the cellular localization of the 10B atoms in the large intercellular space, the cell membrane, within cytoplasm or the cell nucleus, the geometrical probability of hitting the cell nucleus, and that such a hit finally results in a cell killing, and a Poisson statistical enhancement factor, which describes the dose-effect relation for cell survival. The calculations necessary are demonstrated in the case of a normal and a tumor cell type, each with representative cell diameter and nucleus size. It is evident that the microscopic distribution of 10B atoms is one of the most critical parameters which is still insufficiently known.

Boron Neutron Capture Therapy↗
PubMed2003

Biodistribution of a carborane-containing porphyrin as a targeting agent for Boron Neutron Capture Therapy of oral cancer in the hamster cheek pouch.

Boron Neutron Capture Therapy (BNCT) is a bimodal cancer treatment based on the selective accumulation of 10B in tumors and concurrent irradiation with thermalized neutrons. The short-range, high-LET radiation produced by the capture of neutrons by 10B could potentially control tumor while sparing normal tissue if the boron compound targets tumor selectively within the treatment volume. In previous studies, we proposed and validated the hamster cheek pouch model of oral cancer for BNCT studies, proved that absolute and relative uptake of the clinically employed boron compound boronophenylalanine (BPA) would be potentially therapeutic in this model and provided evidence of the efficacy of in vivo BPA-mediated BNCT to control hamster oral mucosa tumors with virtually no damage to normal tissue. We herein present the biodistribution and pharmacokinetics of a lipophilic, carborane-containing tetraphenylporphyrin (CuTCPH) in the hamster oral cancer model. CuTCPH is a novel, non-toxic compound that may be advantageous in terms of selective and absolute delivery of boron to tumor tissues. For potentially effective BNCT, tumor boron concentrations from a new agent should be greater than 30 ppm and tumor/blood and tumor/normal tissue boron concentration ratios should be greater than 5/1 without causing significant toxicity. We administered CuTCPH intraperitoneally (i.p.) as a single dose of 32 microg/g body weight (b.w.) (10 microg B/g b.w.) or as four doses of 32 microg/g b.w. over 2 days. Blood (Bl) and tissues were sampled at 3, 6, 12, 24, 48, and 72 h in the single-dose protocol and at 1-4 days after the last injection in the multidose protocol. The tissues sampled were tumor (T), precancerous tissue surrounding tumor, normal pouch (N), skin, tongue, cheek and palate mucosa, liver, spleen, parotid gland and brain. The maximum mean B ratios for the single-dose protocol were T/N: 9.2/1 (12h) and T/Bl: 18.1/1 (72 h). The B value peaked to 20.7+/-18.5 ppm in tumor at 24h. The multidose protocol maximum mean ratios were T/N: 11.9/1 (3 days) and T/Bl: 235/1 (4 days). Absolute boron concentration in tumor reached a maximum value of 116 ppm and a mean value of 71.5+/-48.3 ppm at 3 days. The fact that absolute and relative B values markedly exceeded the BNCT therapeutic threshold with no apparent toxicity may confer on this compound a therapeutic advantage. CuTCPH-mediated BNCT would be potentially useful for the treatment of oral cancer in an experimental model.

Animals↗
PubMed1998

Neutron capture therapy with a new boron-porphyrin compound in the rat 9L glioma model.

Neutron capture therapy with a new boron-porphyrin compound was tested in a rat brain tumor model. Although the concentration of boron in the tumor was too low to elicit a therapeutic effect, prominent histopathologic changes, such as necrosis, congestion and bleeding were observed in the tumors of the rats which were administered the boron neutron capture therapy.

Animals↗
PubMed2004

Intra-arterial administration of sodium borocaptate (BSH)/lipiodol emulsion delivers B-10 to liver tumors highly selectively for boron neutron capture therapy: experimental studies in the rat liver model.

PURPOSE: Boron neutron capture therapy (BNCT) is particle radiotherapy with alpha ((4)He) particle and recoiled lithium nucleus ((7)Li) derived from a reaction of boron ((10)B) and thermal neutron. We investigated applying BNCT to malignant liver tumors. The purpose of the present study was to reveal the efficacy for administration of emulsion of a boron compound (sodium borocaptate; BSH) and lipiodol via a hepatic artery using a rat liver tumor model. METHODS AND MATERIALS: Rat liver tumors were developed by direct injection of Walker 256 cells into the liver parenchyma. BSH (75 mg/kg)/lipiodol (0.3 mL/kg) emulsion was administered via the hepatic artery. Boron concentrations in the tumors, liver, and blood were measured at 1, 6, and 12 h after administration. Neutron capture radiography (NCR) was taken to confirm the selective accumulation of (10)B in the liver tumors. RESULTS: Boron concentrations in the liver tumors and the tumor/liver (T/L) boron concentration ratio at 1, 6, and 12 h after administration of BSH/lipiodol emulsion (concentration: T/L ratio) were 479.2 ppm: 4.0, 197.3 ppm: 14.9, and 96.5 ppm: 6.6, respectively. Highly selective irradiation was clearly demonstrated by the NCR images. CONCLUSIONS: Intra-arterial administration of BSH/lipiodol emulsion is effective method for delivering high concentration of (10)B selectively to the liver tumors.

Animals↗
PubMed1999

Boron self-shielding effects on dose delivery of neutron capture therapy using epithermal beam and boronophenylalanine.

Previous dosimetry studies for boron neutron capture therapy have often neglected the thermal neutron self-shielding effects caused by the 10B accumulation in the brain and the tumor. The neglect of thermal neutron flux depression, therefore, results in an overestimation of the actual dose delivery. The relevant errors are expected to be more pronounced when boronophenylalanine is used in conjunction with an epithermal neutron beam. In this paper, the boron self-shielding effects are calculated in terms of the thermal neutron flux depression across the brain and the dose delivered to the tumors. The degree of boron self-shielding is indicated by the difference between the thermal neutron fluxes calculated with and without considering a 10B concentration as part of the head phantom composition. The boron self-shielding effect is found to increase with increasing 10B concentrations and penetration depths from the skin. The calculated differences for 10B concentrations of 7.5-30 ppm are 2.3%-8.3% at 2.3 cm depth (depth of the maximum brain dose) and 4.6%-17% at 7.3 cm depth (the center of the brain). The additional self-shielding effects by the 10B concentration in a bulky tumor are investigated for a 3-cm-diam spherical tumor located either near the surface (3.3 cm depth) or at the center of the brain (7.3 cm depth) along the beam centerline. For 45 ppm of 10B in the tumor and 15 ppm of 10B in the brain, the dose delivered to the tumors is approximately 10% lower at 3.3 cm depth and 20% lower at the center of the brain, compared to the dose neglecting the boron self-shielding in transport calculations.

Boron Compounds↗
PubMed1992

Borocaptate sodium: a potential boron delivery compound for boron neutron capture therapy evaluated in dogs with spontaneous intracranial tumors.

Borocaptate sodium (Na2B12H11SH) is a boron-carrying compound under consideration for use in boron neutron capture therapy. The biodistribution of boron from borocaptate sodium administration will partly determine boron neutron capture therapy efficacy and normal tissue radiation tolerance. The biodistribution of boron was determined in 30 dogs with spontaneous intracranial tumors at 2, 6, or 12 hr after intravenous borocaptate sodium infusion. Blood and tissue boron concentrations were measured using inductively coupled plasma atomic emission spectroscopy. Mean tumor boron concentration (mean +/- standard error) was 35.9 +/- 4.6 (n = 15), 22.5 +/- 6.0 (n = 9), and 7.0 +/- 1.1 micrograms of boron per g (n = 6) at 2, 6, and 12 hr, respectively, after borocaptate sodium infusion. Peritumor boron concentrations were elevated above that of normal brain in half of the dogs. Normal brain boron concentration (mean +/- standard error) was 4.0 +/- 0.5, 2.0 +/- 0.4, and 2.0 +/- 0.3 micrograms of boron per g at 2, 6, and 12 hr after infusion, respectively. Some cranial and systemic tissues, and blood, had high boron concentration relative to tumor tissue. Geometric dose sparing should partly offset these relatively high normal tissue and blood concentrations. Borocaptate sodium biodistribution is favorable because tumor boron concentrations of recommended magnitude for boron neutron capture therapy were obtained and there was a high tumor-to-normal brain boron concentration ratio.

Animals↗