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PubMedDate not supplied

Evaluation of an iron-filtered epithermal neutron beam for neutron-capture therapy.

An epithermal neutron filter using iron, aluminum, and sulfur was evaluated to determine if the therapeutic performance could be improved with respect to aluminum-sulfur-based filters. An empirically optimized filter was developed that delivered a 93% pure beam of 24-keV epithermal neutrons. It was expected that a thick filter using iron with a density thickness greater than 200 g/cm2 would eliminate the excess gamma contamination found in Al-S filters. This research showed that prompt gamma production from neutron interactions in iron was the dominant dose component. Dosimetric parameters of the beam were determined from the measurement of absorbed dose in air, thermal neutron flux in a head phantom, neutron and gamma spectroscopy, and microdosimetry.

Brain Neoplasms↗
PubMed2004

A parameter study to determine the optimal source neutron energy in boron neutron capture therapy of brain tumours.

The values of the parameters used in boron neutron capture therapy (BNCT) to calculate a given dose to human tissue vary with patients due to different physical, biological and/or medical circumstances. Parameters include the tissue dimensions, the 10B concentration and the relative biological effectiveness (RBE) factors for the different dose components associated with BNCT. Because there is still no worldwide agreement on RBE values, more often than not, average values for these parameters are used. It turns out that the RBE-problem can be circumvented by taking into account all imaginable parameter values. Approaching this quest from another angle: the outcome will also provide the parameters (and values) which influence the optimal source neutron energy. For brain tumours it turns out that the 10B concentration, the RBE factors for 10B as well as fast neutrons, together with the dose limit set for healthy tissue, affect the optimal BNCT source neutron energy. By using source neutrons of a few keV together with neutrons of a few eV, it ensures that, under all imaginable circumstances, a maximum of alpha (and lithium) particles can be delivered in the tumour.

Algorithms↗
PubMed1996

Synthesis and evaluation of a boronated nitroimidazole for boron neutron capture therapy.

We postulated that nitroimidazoles, previously used for radiosensitizing solid tumors, may be interesting templates as carriers of 10B for boron neutron capture therapy. To test this hypothesis, we synthesized a 10B-enriched nitroimidazole, 1-2[(undecahydro-closo-dodecaborato)thio]ethyl]-2- methyl-5-nitroimidazole (imidocaptate), by coupling the Cs salt of BSH (Cs2-10B12H11SH) with 1-(2-bromoethyl)-2-methyl-5-nitroimidazole followed by purification of the adduct. Imidocaptate was taken up by V-79 cells in culture and showed no inherent toxicity under euoxic conditions up to 1.05 mM (126 micrograms of 10B/mL of culture medium). Imidocaptate showed a dose-dependent decrease in D0 when the treated cells were irradiated with a thermal neutron beam. At the highest dose tested (126 micrograms of 10B/mL of culture medium), the ratio of control to sample D0 values was 2.6 for both linear quadratic and single-hit multitarget models. At 33 micrograms of 10B/mL, imidocaptate showed a control/treated D0 ration (1.5) equal to that observed with the disulfide form of BSH at 28 micrograms of 10B/mL. Compared to BSH and its disulfide, the reduced toxicity and equipotency of imidocaptate suggest that this agent may be useful for boron neutron capture therapy of cancer.

Animals↗
PubMed1994

Enhancement of fast neutron beams with boron neutron capture therapy. A mechanism for achieving a selective, concomitant tumor boost.

Both fast neutron radiotherapy and boron neutron capture therapy (BNCT) have been utilized to treat malignant disease. Herein we discuss the potential of combining these treatments to enhance the effectiveness of fast neutron therapy through a concomitant BNCT boost. Using a fast neutron beam generated from a 50 MeV proton on beryllium reaction, we have determined that 0.1% of the beam per microgram of boron-10 per gram of tissue (microgram/g) can be deposited via BNCT. Our mathematical modeling predicts that BNCT enhancement of our beam will lead to an additional 1-2 logs of tumor cell kill for boron-10 concentrations of 30-50 micrograms/g. We have validated this via V-79 cell line in vitro measurements. A Poisson model estimation of how this additional cell kill will influence local tumor control, predicts that BNCT enhancement of fast neutron radiation will lead to a clinically significant improvement in outcome.

Animals↗
PubMed2000

Treatment of isografted 9L rat brain tumors with beta-5-o-carboranyl-2'-deoxyuridine neutron capture therapy.

beta-5-o-Carboranyl-2'-deoxyuridine (D-CDU) is a nontoxic pyrimidine nucleoside analogue designed for boron neutron capture therapy of brain tumors. In vitro studies indicated that D-CDU accumulates to levels 92- and 117-fold higher than the extracellular concentration in rat 9L and human U-251 glioma cells, respectively, and persists for several hours at levels 5-fold higher than the extracellular concentration. Furthermore, D-CDU was not toxic to rats injected i.p. with up to 150 mg/kg. On the basis of these studies, D-CDU was evaluated as a neutron capture therapy agent using rats bearing stereotactically implanted intracranial 9L tumors at single i.p. doses of 30 mg/kg and 150 mg/kg of D-CDU (20% 10B enriched), given 2 h before irradiation with thermal neutrons. Boron concentrations in tumors 2 h after dosing were 2.3 +/- 1.6 and 7.4 +/- 1.3 micrograms boron/g tissue (mean +/- SD), corresponding to tumor/brain ratios of 11.5 +/- 3.6 and 6.8 +/- 2.0 micrograms boron/g tissue for the low and high doses, respectively. All untreated animals died within 28 days, whereas half survived at days 32, 55, and 38 for groups receiving neutrons only, 30 mg/kg D-CDU, and 150 mg/kg D-CDU, respectively. Odds ratios of all treatment groups differed significantly from the untreated group (P < 0.002; logrank test). The median survival time for the 30 mg/kg-treated group but not for the 150 mg/kg-treated group was significantly longer than for rats treated with neutrons only (P = 0.036), which may correlate with the decreased tumor selectivity for D-CDU observed at the higher dose. Additional pharmacodynamic studies are warranted to determine optimal dosing strategies for D-CDU.

Animals↗
PubMedDate not supplied

Estimation of absorbed dose in the covering skin of human melanoma treated by neutron capture therapy.

A patient with malignant melanoma was treated by thermal neutron capture therapy using 10B-paraboronophenylalanine. The compound was injected subcutaneously into ten locations in the tumor-surrounding skin, and the patient was then irradiated with thermal neutrons from the Musashi Reactor at reactor power of 100 KW and neutron flux of 1.2 X 10(9) n/cm2/s. Total absorbed dose to the skin was 11.7-12.5 Gy in the radiation field. The dose equivalents of these doses were estimated as 21.5 and 24.4 Sv, respectively. Early skin reaction after irradiation was checked from day 1 to day 60. The maximum and mean skin scores were 2.0 and 1.5, respectively, and the therapy was safely completed as far as skin reaction was concerned. Some factors influencing the absorbed dose and dose equivalent to the skin are discussed.

Aged↗
PubMed2006

Improvement of the tumor-suppressive effect of boron neutron capture therapy for amelanotic melanoma by intratumoral injection of the tyrosinase gene.

Boron neutron capture therapy (BNCT) is successful when there is a sufficient (10)B concentration in tumor cells. In melanoma, (10)B-para-boronophenylalanine (BPA) accumulation is proportional to melanin-producing activity. This study was done to confirm enhancement of the tumor-suppressive effect of BNCT on amelanotic melanoma by intratumoral injection of the tyrosinase gene. D178 or FF amelanotic melanomas were implanted s.c. in Syrian hamsters. One group of D178- or FF-bearing hamsters (TD178 or TFF group) received intratumoral injections of pcDNA-Tyrs constructed as a tyrosinase expression plasmid. The other hamsters (pD178 and pFF groups) were injected with pUC119, and control hamsters (D178 and FF groups) only with transfection reagents. All the groups underwent immunofluorescence analysis of tyrosinase expression and BPA biodistribution studies. BNCT experiments were done at the Kyoto University Research Reactor. Tyrosinase expression increased in the tumors of the TD178 and TFF groups but remained the same in the pD178 and pFF groups. Tumor boron concentrations in the TD178 and TFF groups increased significantly (TD178: 49.7 +/- 12.6 versus D178: 27.2 +/- 4.9 microg/g, P < 0.0001; TFF: 30.7 +/- 6.6 versus FF: 13.0 +/- 4.7 microg/g, P < 0.0001). The BNCT tumor-suppressive effect was marked in the TD178 and TFF groups. In vivo transfection with the tyrosinase gene increased BPA accumulation in the tumors, the BNCT tumor-suppressive effect on amelanotic melanoma being significantly enhanced. These findings suggest a potential new clinical strategy for the treatment of amelanotic melanoma with BNCT.

Animals↗
PubMed2004

A state-of-the-art epithermal neutron irradiation facility for neutron capture therapy.

At the Massachusetts Institute of Technology (MIT) the first fission converter-based epithermal neutron beam (FCB) has proven suitable for use in clinical trials of boron neutron capture therapy (BNCT). The modern facility provides a high intensity beam together with low levels of contamination that is ideally suited for use with future, more selective boron delivery agents. Prescriptions for normal tissue tolerance doses consist of 2 or 3 fields lasting less than 10 min each with the currently available beam intensity, that are administered with an automated beam monitoring and control system to help ensure safety of the patient and staff alike. A quality assurance program ensures proper functioning of all instrumentation and safety interlocks as well as constancy of beam output relative to routine calibrations. Beam line shutters and the medical room walls provide sufficient shielding to enable access and use of the facility without affecting other experiments or normal operation of the multipurpose research reactor at MIT. Medical expertise and a large population in the greater Boston area are situated conveniently close to the university, which operates the research reactor 24 h a day for approximately 300 days per year. The operational characteristics of the facility closely match those established for conventional radiotherapy, which together with a near optimum beam performance ensure that the FCB is capable of determining whether the radiobiological promise of NCT can be realized in routine practice.

Academic Medical Centers↗
PubMed2002

Improved treatment planning for boron neutron capture therapy for glioblastoma multiforme using fluorine-18 labeled boronophenylalanine and positron emission tomography.

Boron neutron capture therapy (BNCT) is a cancer brachytherapy based upon the thermal neutron reaction: 10B(n,alpha)7Li. The efficacy of the treatment depends primarily upon two conditions being met: (a) the preferential concentration of a boronated compound in the neoplasm and (b) an adequate fluence of thermal neutrons delivered to the neoplasm. The boronated amino acid, para-boronophenylalanine (BPA), is the agent widely used in clinical trials to deliver 10B to the malignancy. Positron emission tomography (PET) can be used to generate in vivo boron distribution maps by labeling BPA with the positron emitting nuclide fluorine-18. The incorporation of the PET-derived boron distribution maps into current treatment planning protocols is shown to provide improved treatment plans. Using previously established protocols, six patients with glioblastoma had 18BPA PET scans. The PET distribution maps obtained were used in the conventional BNCT treatment codes. The isodose curves derived from the PET data are shown to differ both qualitatively and quantitatively from the conventional isodose curves that were derived from calculations based upon the assumption of uniform uptake of the pharmaceutical in tumor and normal brain regions. The clinical course of each of the patients who eventually received BNCT (five of the six patients) was compared using both sets of isodose calculations. The isodose contours based upon PET derived distribution data appear to be more consistent with the patients' clinical course.

Boron Compounds↗
PubMed1994

Mixed field dosimetry of epithermal neutron beams for boron neutron capture therapy at the MITR-II research reactor.

During the past several years, there has been growing interest in Boron Neutron Capture Therapy (BNCT) using epithermal neutron beams. The dosimetry of these beams is challenging. The incident beam is comprised mostly of epithermal neutrons, but there is some contamination from photons and fast neutrons. Within the patient, the neutron spectrum changes rapidly as the incident epithermal neutrons scatter and thermalize, and a photon field is generated from neutron capture in hydrogen. In this paper, a method to determine the doses from thermal and fast neutrons, photons, and the B-10(n, alpha)Li-7 reaction is presented. The photon and fast neutron doses are measured with ionization chambers, in realistic phantoms, using the dual chamber technique. The thermal neutron flux is measured with gold foils using the cadmium difference technique, the thermal neutron and B-10 doses are determined by the kerma factor method. Representative results are presented for a unilateral irradiation of the head. Sources of error in the method as applied to BNCT dosimetry, and the uncertainties in the calculated doses are discussed.

Boron Neutron Capture Therapy↗
PubMedDate not supplied

Macroscopic geometric heterogeneity effects in radiation dose distribution analysis for boron neutron capture therapy.

Calculations of radiation flux and dose distributions for boron neutron capture therapy (BNCT) of brain tumors are typically performed using sophisticated three-dimensional analytical models based on either a homogeneous approximation or a simplified few-region approximation to the actual highly heterogeneous geometry of the irradiation volume. Such models should be validated by comparison with calculations using detailed models in which all significant macroscopic tissue heterogeneities and geometric structures are explicitly represented as faithfully as possible. This paper describes such a validation exercise for BNCT of canine brain tumors. Geometric measurements of the canine anatomical structures of interest for this work were performed by dissecting and examining two essentially identical Labrador retriever heads. Chemical analyses of various tissue samples taken during the dissections were conducted to obtain measurements of elemental compositions for the tissues of interest. The resulting geometry and tissue composition data were then used to construct a detailed heterogeneous calculational model of the Labrador head. Calculations of three-dimensional radiation flux distributions pertinent to BNCT were performed for this model using the TORT discrete-ordinates radiation transport code. The calculations were repeated for a corresponding volume-weighted homogeneous-tissue model. Comparison of the results showed that peak neutron and photon flux magnitudes were quite similar for the two models (within 5%), but that the spatial flux profiles were shifted in the heterogeneous model such that the fluxes in some locations away from the peak differed from the corresponding fluxes in the homogeneous model by as much as 10%-20%. Differences of this magnitude can be therapeutically significant, emphasizing the need for proper validation of simplified treatment planning models.

Animals↗
PubMed2005

Epithermal neutron beams for clinical studies of boron neutron capture therapy: a dosimetric comparison of seven beams.

A comparison of seven epithermal neutron beams used in clinical studies of boron neutron capture therapy (BNCT) in Sweden (Studsvik), Finland (Espoo), Czech Republic (ReZ), The Netherlands (Petten) and the U.S. (Brookhaven and Cambridge) was performed to facilitate sharing of preclinical and clinical results. The physical performance of each beam was measured using a common dosimetry method under conditions pertinent to brain irradiations. Neutron fluence and absorbed dose measurements were performed with activation foils and paired ionization chambers on the central axis both in air and in an ellipsoidal water phantom. The overall quality of each beam was assessed by figures of merit determined from the total weighted dose profiles that assumed the presence of boron in tissue. The in-air specific beam contamination from both fast neutrons and gamma rays ranged between 8 and 65 x 10(-11) cGy(w) cm2 for the different beams and the epithermal neutron flux intensities available at the patient position differed by more than a factor of 20 from 0.2-4.3 x 10(9) n cm(-2) s(-1). Percentage depth dose profiles measured in-phantom for the individual photon, thermal and fast-neutron dose components differed only subtly in shape between facilities. Assuming uptake characteristics consistent with the currently used boronated phenylalanine, all the epithermal beams exhibit a useful penetration of 8 cm or greater that is sufficient to irradiate a lesion seated at the brain midline. The performance of the existing facilities will benefit from the introduction of advanced compounds through improved beam penetrability. This could increase by as much as 2 cm for the purest of beams, although the beam intensities generally need to be increased to between 2-5 x 10(9) n cm(-2) s(-1) to maintain manageable irradiation times. These data provide the first consistent measurement of beam performance at the different centers and will enable a preliminary normalization of the calculated patient dosimetry.

Boron Neutron Capture Therapy↗
PubMed1998

Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas: part I.

Determination of tumor boron-10 (10B) levels is required for accurate neutron dosimetry during boron neutron capture therapy. We assessed a new method for quantitative measurement of boronated drug uptake in high-grade gliomas. This method uses positron emission tomography (PET) with fluorine-18-labeled L-fluoroborono-phenylalanine (L-18F-10B-FBPA), which was synthesized as an analogue of L-boronophenylalanine. We studied the accumulation of L-18F-10B-FBPA by PET in patients with high-grade gliomas. Dynamic PET studies of brain tumors revealed that L-18F-10B-FBPA accumulated gradually after bolus injection, and the value of PET activity divided by the integrated plasma activity reached a constant level 42 min after injection, which was defined as the incorporation constant (Ic*). This constant reflected the appropriate L-18F-10B-FBPA accumulation in tumor tissue. Based on the Ic* constant, the methods for estimating tumor 10B concentration were devised. With this method, the estimated values of 10B concentration in gliomas were very close to the 10B levels in surgical specimens. This method was based solely on PET and can potentially provide data that would assist in the selection of patients for future treatment with boron neutron capture therapy after surgical resection of their brain tumors.

Boron↗
PubMed1999

Gadolinium neutron capture therapy (GdNCT) of melanoma cells and solid tumors with the magnetic resonance imaging contrast agent Gadobutrol.

RATIONALE AND OBJECTIVES: The therapeutic gain of neutron capture therapy with a neutral macrocyclic gadolinium (Gd) complex (Gadobutrol) was evaluated through in vitro and in vivo studies in a beam of low-energy neutrons. METHODS: Neutron irradiation for both the in vitro and in vivo studies was performed in a beam of low-energy neutrons produced by the research reactor of the Hahn-Meitner-Institut, Berlin. Malignant melanoma cells of human origin were irradiated in the presence or absence of Gadobutrol. In vivo irradiation was performed on tumor-bearing nude mice. The tumor site was irradiated subsequent to intratumoral injection of Gadobutrol and compared with irradiation in the absence of the Gd complex. RESULTS: In vitro studies showed a Gd-dependent delay of cell proliferation as a consequence of neutron irradiation. In animals, intratumoral administration of the Gd complex at a dose of 1.2 mmol Gd/kg before neutron irradiation results in a significant delay in tumor growth with respect to the control groups. CONCLUSIONS: In vitro and in vivo studies showed a therapeutic benefit with the neutral Gd complex and suggest Gd-containing magnetic resonance contrast media are potential candidates for neutron capture therapy. The Gd dose used in the irradiation experiments was four times the presently accepted high dose in clinical magnetic resonance imaging.

Animals↗
PubMed1994

Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy.

PURPOSE: The present report is a review of long-term survivors in the patients with malignant brain tumors treated by boron neutron capture therapy. METHODS AND MATERIAL: One-hundred twenty patients with 119 intracranial tumors and one extracranial nerve-related tumor were treated by the current standard technique of boron-neutron capture therapy (BNCT) as of December 1992, using 10B-sodium-mercaptoundecahydrododecaborate. RESULTS: Out of 87 patients operated on before May 1987, 18 lived or have lived longer than 5 years. Nine of these 18 lived or have lived longer than 10 years out of 53 patients operated on before May 1982. Among more-than-10-year survivors, only two died at 17 and 12 years. All of the other are still alive. The two died of delayed radiation damage because BNCT was applied to glioblastomas which recurred after their conventional radiotherapy. They lacked evidence of tumors when they died. Out of these nine more-than-10-year survivors, three had been previously treated by conventional external radiotherapy and they developed radiation damage which brought all patients ultimately to an incapacitated condition. Two of the three died. All the other 6 who were free from previous radiation history are active in their jobs and have no evidence of tumors. CONCLUSION: It can be suggested that BNCT is a radiotherapy that can produce "cure" of both malignant and benign brain tumors while preserving a good quality of life if conducted without conventional radiotherapy.

Adult↗