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PubMed2006

Improvement effect on the depth-dose distribution by CSF drainage and air infusion of a tumour-removed cavity in boron neutron capture therapy for malignant brain tumours.

Boron neutron capture therapy (BNCT) without craniotomy for malignant brain tumours was started using an epi-thermal neutron beam at the Kyoto University Reactor in June 2002. We have tried some techniques to overcome the treatable-depth limit in BNCT. One of the effective techniques is void formation utilizing a tumour-removed cavity. The tumorous part is removed by craniotomy about 1 week before a BNCT treatment in our protocol. Just before the BNCT irradiation, the cerebro-spinal fluid (CSF) in the tumour-removed cavity is drained out, air is infused to the cavity and then the void is made. This void improves the neutron penetration, and the thermal neutron flux at depth increases. The phantom experiments and survey simulations modelling the CSF drainage and air infusion of the tumour-removed cavity were performed for the size and shape of the void. The advantage of the CSF drainage and air infusion is confirmed for the improvement in the depth-dose distribution. From the parametric surveys, it was confirmed that the cavity volume had good correlation with the improvement effect, and the larger effect was expected as the cavity volume was larger.

Air↗

PubMed1993

Maximum therapeutic depth in thermal neutron capture therapy.

The effective treatment depth in boron neutron capture therapy with thermal neutrons depends on the beam aperture, heavy water concentration, boron concentrations in the tumor, normal tissue and blood, tolerance dose to normal tissue and the capillary dose modification factor. In this study a 15 cm aperture is used and the tolerance dose to normal tissue is evaluated to be 15 Gy. Human pharmacokinetic data are evaluated for BSH and D, L-BPA, the two compounds currently used in thermal BNCT. Results show that the average measured tumor to blood boron ratios and standard deviations are 1.4 (0.4) for BSH and 4.3 (1.8) for subcutaneous melanoma. Experimental dose-depth phantom results for the Musashi Institute of Technology reactor are used with expected boron concentrations to calculate the maximum therapeutic depth in the brain for a thermal neutron beam. For BPA, the subcutaneous melanoma boron concentrations are assumed for intracranial metastases, and no allowance is made for possible enhanced uptake in the dopamine and noradrenaline tracts. Results for BSH are enhanced by inclusion of the capillary dose reduction factor. Calculations show that for expected boron tumor to blood ratios, the modified advantage depth is about 4 cm and the maximum therapeutic depth is about 1.5 cm for both BSH and BPA. Typical heavy water ratios of 15% increase the treatment depth by 0.5 cm, but this is offset by the use of smaller beam aperture in practice.

Boranes↗

PubMed2002

Treatment planning and dosimetry for the Harvard-MIT Phase I clinical trial of cranial neutron capture therapy.

PURPOSE: A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain. METHODS AND MATERIALS: Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons. The study began with a prescribed biologically weighted dose of 8.8 RBE (relative biologic effectiveness) Gy, escalated in compounding 10% increments, and ended at 14.2 RBE Gy. BPA-f was infused at a dose 250-350 mg/kg body weight. Treatments were planned using MacNCTPlan and MCNP 4B. Irradiations were delivered as one, two, or three fields in one or two fractions. RESULTS: Peak biologically weighted normal tissue dose ranged from 8.7 to 16.4 RBE Gy. The average dose to brain ranged from 2.7 to 7.4 RBE Gy. Average tumor dose was estimated to range from 14.5 to 43.9 RBE Gy, with a mean of 25.7 RBE Gy. CONCLUSIONS: We have demonstrated that BPA-f-mediated NCT can be precisely planned and delivered in a carefully controlled manner. Subsequent clinical trials of boron neutron capture therapy at Harvard and MIT will be initiated with a new high-intensity, high-quality epithermal neutron beam.

Adult↗

PubMed1995

Comparative assessment of single-dose and fractionated boron neutron capture therapy.

The effects of fractionating boron neutron capture therapy (BNCT) were evaluated in the intracerebral rat 9L gliosarcoma and rat spinal cord models using the Brookhaven Medical Research Reactor (BMRR) thermal neutron beam. The amino acid analog p-boronophenylalanine (BPA) was administered prior to each exposure to the thermal neutron beam. The total physical absorbed dose to the tumor during BNCT using BPA was 91% high-linear energy transfer (LET) radiation. Two tumor doses of 5.1 Gy spaced 48 h apart (n = 14) or three tumor doses of 5.2 Gy, each separated by 48 h (n = 10), produced 43 and 70% long-term (> 1 year) survivors, respectively [corrected]. The outcome of neither the two nor the three fractions of radiation was statistically different from that of the corresponding single-fraction group. In the rat spinal cord, the ED50 for radiation myelopathy (as indicated by limb paralysis within 7 months) after exposure to the thermal beam alone was 13.6 +/- 0.4 Gy. Dividing the beam-only irradiation into two or four consecutive daily fractions increased the ED50 to 14.7 +/- 0.2 Gy and 15.5 +/- 0.4 Gy, respectively. Thermal neutron irradiation in the presence of BPA resulted in an ED50 for myelopathy of 13.8 +/- 0.6 Gy after a single fraction and 14.9 +/- 0.9 Gy after two fractions. An increase in the number of fractions to four resulted in an ED50 of 14.3 +/- 0.6 Gy. The total physical absorbed dose to the blood in the vasculature of the spinal cord during BNCT using BPA was 80% high-LET radiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Teatment planning figures of merit in thermal and epithermal boron neutron capture therapy of brain tumours.

The boron neutron capture therapy (BNCT) figures of merit of advantage depth, therapeutic depth, modified advantage depth and maximum therapeutic depth have been studied as functions of 10B tumour to blood ratios and absolute levels. These relationships were examined using the Monte Carlo neutron photon transport code, MCNP, with an ideal 18.4 cm diameter neutron beam incident laterally upon all ellipsoidal neutron photon brain-equivalent model. Mono-energetic beams of 0.025 eV (thermal) and 35 eV (epithermal) were simulated. Increasing the tumour to blood 10B ratio predictably increases all figures of merit. concentration was also shown to have a strong bearing on the figures of merit when low levels were present in the system. This is the result of a non-10B dependent background dose. At higher levels however, the concentration of 10B has a diminishing influence. For boron sulphydryl (BSH), little advantage is gained by extending the blood 10B level beyond 30 ppm, whilst for D,L,-p-boronophenylalanine (BPA) this limit is 10 ppm. To achieve a therapeutic depth of 6 cm (brain mid-line from brain surface) using the thermal beam, a tumour to blood ratio of 25 with 10 ppm 10B in the blood is required for BPA. Similarly, a tumour to blood ratio of 8.5 with 30 ppm blood 10B is required for the maximum therapeutic depth of BSH to reach the brain mid-line. These requirements are five times above current values for these compounds in humans. Applying the epithermal beam under identical conditions, the therapeutic depth reaches the brain mid-line with a tumour to blood 10B ratio of only 5.7 for BPA. For BSH, the maximum therapeutic depth reaches the brain mid-line with a tumour to blood ratio of only 1.9 with 30 ppm in the blood. Human data for these compounds are very close to these requirements.

Benchmarking↗

PubMed2005

Combination of boron and gadolinium compounds for neutron capture therapy. An in vitro study.

In neutron capture therapy, the therapeutic effect of the boron compound is based on alpha particles produced by the B(n, alpha) reaction while with the gadolinium compound the main radiation effect is from gamma rays derived from the Gd(n, gamma) reaction. The uptake and distribution within the tumor may be different among these compounds. Thus, the combination of the boron and gadolinium compounds may be beneficial for enhancing the radiation dose to the tumor. Chinese hamster fibroblast V79 cells were used. For the neutron targeting compounds, 10B (BSH) at 0, 5, 10, and 15 ppm, and 157Gd (Gd-BOPTA) at 0, 800, 1600, 2400, 3200, and 4800 ppm, were combined. The neutron irradiation was performed with thermal neutrons for 30 min. (neutron flux: 0.84 x 10(8) n/cm2/s in free air). The combination of the boron and gadolinium compounds showed an additive effect when the gadolinium concentration was lower than 1600 ppm. This additive effect decreased as a function of gadolinium concentration at 2400 ppm and resulted in no additive effect at more than 3200 ppm of gadolinium. In conclusion, the combination of the boron and gadolinium compounds can enhance the therapeutic effect with an optimum concentration ratio. When the gadolinium concentration is too high, it may weaken the boron neutron capture reaction due to the high cross-section of gadolinium compound against neutrons.

Animals↗

PubMed2002

Boron microquantification in oral muscosa and skin following administration of a neutron capture therapy agent.

Clinical trials of boron neutron capture therapy (BNCT) for intracranial tumours using boronophenylalanine-fructose undertaken at Harvard-MIT and Brookhaven National Laboratory have observed acute normal tissue reactions in the skin and oral mucosa. Because the range of the 10B(n, alpha)7Li reaction products is very short, 10-14 microns combined, knowledge of the 10B microdistribution in tissue is critical for understanding the microdosimetry and radiobiology of BNCT. This paper reports measurements of the microdistribution of 10B in an animal model, rat skin and tongue, using high resolution quantitative autoradiography (HRQAR), a neutron-induced etched track autoradiographic technique. The steep spatial gradient and high absolute value relative to blood of the 10B concentration observed in some strata of the rat tongue epithelium and skin are important for properly evaluating the radiobiology and the biological effectiveness factors for normal tissue reactions such as oral mucositis, which are generally assessed using the blood boron concentration rather than the tissue boron concentration.

Animals↗

PubMedDate not supplied

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 10B(n, alpha)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 15 Gy or, alternatively, a minimum target volume dose of 18 Gy. The maximum vascular dose should not exceed 15 Gy (physical dose of boron n-alpha reaction) and the total amount of gamma rays should remain below 10 Gy, 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.

Adolescent↗

PubMed1994

Thick beryllium target as an epithermal neutron source for neutron capture therapy.

Accelerator-based intense epithermal neutron sources for Neutron Capture Therapy (NCT) have been considered as an alternative to nuclear reactors. Lithium (Li) has generally received the widest attention for this application, since the threshold energy is low and neutron yield is high. Because of the poor thermal and chemical properties of Li and the need for heat removal in the target, the design of Li targets has been quite difficult. Beryllium (Be) has been thought of as an alternative target because of its good thermal and chemical properties and reasonable neutron yield. However, in order to have a neutron yield comparable to that of a thick Li target bombarded with 2.5 MeV protons, the proton energy required for a thick Be target must be approaching 4 MeV. Consequently, the neutrons emitted are more energetic. In addition, a significant amount of high-energy gamma rays, which is undesirable, will occur when Be is bombarded with low-energy protons. Regardless of the more energetic neutrons and additional gamma rays, in this paper it is shown that it is possible to develop a high-quality and high-intensity epithermal neutron beam based on a thick Be target for NCT treatment. For a fixed proton current, the optimal Be-target-based beam (with 4-MeV protons) can produce a neutron beam, with both quality and intensity slightly better than those produced by the optimal Li-target-based beam (with 2.5-MeV protons). The single-session NCT treatment time for the optimal Be-target-based beam is estimated to be 88 min for a proton current of 50 mA.(ABSTRACT TRUNCATED AT 250 WORDS)

Beryllium↗

PubMed1996

Progress in the field of compounds for boron neutron capture therapy.

For successful application of boron neutron capture therapy to the treatment of cancer, selective accumulation of boron is required. This can be achieved by the preparation of suitable substances, which must contain boron and at the same time accumulate or be retained in tumor tissue. The radiobiological rationale for selection of suitable compounds is discussed. Examples of useful new compounds are given for which boronated analogues exist.

Boron Compounds↗

PubMed1995

A stochastic model for subcellular dosimetry in boron neutron capture therapy.

The therapeutic effectiveness of boron neutron capture therapy is highly dependent on the microscopic distribution of the administered boron compound. Two boron compounds with different uptake mechanisms in the tumour cells may thus cause effects of different degrees even if the macroscopic boron concentrations in the tumour tissue are the same. This difference is normally expressed quantitatively by the so-called relative local efficiency (RLE). In this work, a stochastic model for the subcellular dosimetry has been developed. This model can be used to calculate the probability for an energy deposition above a certain threshold level in the cell nucleus due to a single neutron capture reaction. If a threshold cell-kill function is assumed, and if the dose is low enough that multiple energy depositions are rare, the model can also be applied to calculations of the survival probability for a cell population. Subcellular boron distributions in rats carrying RG 2 rat gliomas were measured by subcellular fractionation after administration of two different boron compounds: a sulphydryl boron hydride (BSH) and a boronated porphyrin (BOPP). Based on these data, the RLE factors were then calculated for these compounds using the stochastic model.

Animals↗

PubMed2002

Molecular targeting of the epidermal growth factor receptor for neutron capture therapy of gliomas.

Success of boron neutron capture therapy (BNCT) is dependent on cellular and molecular targeting of sufficient amounts of boron-10 to sustain a lethal (10)B (n, alpha) (7)Li capture reaction. The purpose of the present study was to determine the efficacy of boronated epidermal growth factor (EGF) either alone or in combination with boronophenylalanine (BPA) as delivery agents for an epidermal growth factor receptor (EGFR) -positive glioma, designated F98(EGFR). A heavily boronated precision macromolecule [boronated starburst dendrimer (BSD)] was chemically linked to EGF by heterobifunctional reagents. Either F98 wild-type (F98(WT)) receptor (-) or EGFR gene-transfected F98(EGFR) cells, which expressed 5 x 10(5) receptor sites/cell, were stereotactically implanted into the brains of Fischer rats, and 2 weeks later biodistribution studies were initiated. For biodistribution studies rats received an intratumoral (i.t.) injection of (125)I-labeled BSD-EGF and were euthanized either 6 or 24 h later. At 6 h, equivalent amounts of BSD-EGF were detected in F98(EGFR) and F98(WT) tumors. Persistence of the bioconjugate in F98(EGFR) tumors was specifically determined by EGFR expression. By 24 h 33.2% of injected dose/g of EGF-BSD was retained by F98(EGFR) gliomas compared with 9.4% % of injected dose/g in F98(WT) gliomas, and the corresponding boron concentrations were 21.1 microg/g and 9.2 microg/g, respectively. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (<0.5 microg/g). On the basis of these results, BNCT was initiated at the Brookhaven National Laboratory Medical Research Reactor. Two weeks after implantation of 10(3) F98(EGFR) or F98(WT) tumor cells, rats received an i.t. injection of BSD-EGF (approximately 60 microg (10)B/approximately 15 microg EGF) either alone or in combination with i.v. BPA (500 mg/kg). Rats were irradiated at the Brookhaven Medical Research Reactor 24 h after i.t. injection, which was timed to coincide with 2.5 h after i.v. injection of BPA for those animals that received both capture agents. Untreated control rats had a mean survival time (MST) +/- SE of 27 +/- 1 day, and irradiated controls had a MST of 31 +/- 1 day. Animals bearing F98(EGFR) gliomas, which had received i.t. BSD-EGF and BNCT, had a MST of 45 +/- 5 days compared with 33 +/- 2 days for animals bearing F98(WT) tumors (P = 0.0032), and rats that received i.t. BSD-EGF in combination with i.v. BPA had a MST of 57 +/- 8 days compared with 39 +/- 2 days for i.v. BPA alone (P = 0.016). Our data are the first to show in vivo efficacy of BNCT using a high molecular weight boronated bioconjugate to target amplified EGFR expressed on gliomas, and they provide a platform for the future development of combinations of high and low molecular weight agents for BNCT.

Animals↗

PubMed2000

Changed delivery of boron to tumours using electroporation for boron neutron capture therapy with BSH.

For effective boron neutron capture therapy (BNCT) it is important that a sufficient concentration of boron (10B) is present in the tumour during irradiation. This requirement represents a specific problem. The aim of this study was to test whether electroporation can be used as a non-specific drug delivery system to increase the delivery of sodium borocaptate-10B (BSH) into MCF7 (breast carcinoma) and B16F1 (melanoma) tumour cells in vitro and in B16F1 tumours in vivo. For the in vitro determination of 10B uptake, the cells were incubated in medium containing BSH and exposed to electric pulses. Boron levels were determined by inductively coupled plasma atomic emission spectrometry. In vivo, tumours were exposed to electric pulses 3 min after intravenous BSH injection. At different times after exposure the 10B concentration was determined in tumours and in blood. A difference in the 10B accumulation in the two cell lines was observed after continuous incubation of cells with BSH. No accumulation of 10B was observed in MCF7 cells, whereas in B16F1 cells, 10B accumulated well and reached a plateau within 30 min. Electroporation of these cells resulted in an accumulation of 10B into MCF7 cells up to the level of 10B in B16F1 cells. In vivo, the application of electric pulses increased and prolonged the entrapment of 10B (BSH) in the B16F1 melanoma tumours. A sufficient concentration of 10B was present in the tumour exposed to electric pulses for up to 24 h. Boron was quickly washed out from the blood and the level was below the concentrations in the tumours exposed to electric pulses at 2 h. The results of this study show that electroporation may provide a tool to increase boron concentration in the cells that have impaired transport of BSH through the plasma membrane. Furthermore, prolonged entrapment of BSH in tumours in vivo may, in addition to electroporation, be caused by the modifying effect of electric pulses on blood flow.

Animals↗

PubMed1992

Boron neutron capture therapy for murine malignant gliomas.

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.

Animals↗

PubMed2000

Study of moderator thickness for an accelerator-based neutron irradiation facility for boron neutron capture therapy using the 7Li(p,n) reaction near threshold.

Accelerator neutron sources for epithermal neutron capture therapy utilizing the 7Li(p,n) nuclear reaction will require a moderator even in the threshold range of 1.89 to 1.95 MeV. The corresponding neutron energies allow for a thinner reflector and moderator, with less reduction of the epithermal flux. To estimate the useful neutron flux within the epithermal range (4 eV-40 keV), the optimal thickness of a heavy water moderator was determined using the two-dimensional neutron transport S(N) code DORT. Optimized results are compared with the epithermal fluxes reported for the higher proton energy range, and are found to be inferior. Thus, this study supports the 2.5-3.0 MeV proton energy range for accelerator boron neutron capture therapy.

Boron Neutron Capture Therapy↗

PubMed1995

Dose homogeneity in boron neutron capture therapy using an epithermal neutron beam.

Simulation models based on the neutron and photon Monte Carlo code MCNP were used to study the therapeutic possibilities of the HB11 epithermal neutron beam at the High Flux Reactor in Petten. Irradiations were simulated in two types of phantoms filled with water or tissue-equivalent material for benchmark treatment planning calculations. In a cuboid phantom the influence of different field sizes on the thermal-neutron-induced dose distribution was investigated. Various shapes of collimators were studied to test their efficacy in optimizing the thermal-neutron distribution over a planning target volume and healthy tissues. Using circular collimators of 8, 12 and 15 cm diameter it was shown that with the 15-cm field a relatively larger volume within 85% of the maximum neutron-induced dose was obtained than with the 8- or 12-cm-diameter field. However, even for this large field the maximum diameter of this volume was 7.5 cm. In an ellipsoid head phantom the neutron-induced dose was calculated assuming the skull to contain 10 ppm 10B, the brain 5 ppm 10B and the tumor 30 ppm 10B. It was found that with a single 15-cm-diameter circular beam a very inhomogenous dose distribution in a typical target volume was obtained. Applying two equally weighted opposing 15-cm-diameter fields, however, a dose homogeneity within +/- 10% in this planning target volume was obtained. The dose in the surrounding healthy brain tissue is 30% at maximum of the dose in the center of the target volume. Contrary to the situation for the 8-cm field, combining four fields of 15 cm diameter gave no large improvement of the dose homogeneity over the target volume or a lower maximum dose in the healthy brain. Dose-volume histograms were evaluated for the planning target volume as well as for the healthy brain to compare different irradiation techniques, yielding a graphical confirmation of the above conclusions. Therapy with BNCT on brain tumors must be performed either with an 8-cm four-field irradiation or with two opposing 15- or 12-cm fields to obtain an optimal dose distribution.

Boron Neutron Capture Therapy↗

PubMed1992

Transport calculations of depth-dose distributions for gadolinium neutron capture therapy.

Depth-dose distributions were calculated for thermal and epithermal neutron fluence and capture gamma ray dose rates using a two-dimensional neutron-coupled gamma-ray transport code (DOT 3.5) for gadolinium neutron capture therapy. The results show that (i) a capture gamma-ray dose rate of 10 Gy h-1 was obtained with a thermal neutron fluence rate of 1.5 x 10(9) cm-2 s-1 in a simulated tumour containing 5000 PPM gadolinium placed near the surface of a water phantom, (ii) deep-seated tumours may be treated with epithermal neutrons, and (iii) gadolinium neutron capture therapy appears to achieve comparable dose distributions to those of boron neutron capture therapy.

Gadolinium↗

PubMed1994

Boron neutron capture therapy (BNCT): a radiation oncology perspective.

Boron neutron capture therapy (BNCT) offers considerable promise in the search for the ideal cancer therapy, a therapy which selectively and maximally damages malignant cells while sparing normal tissue. This bimodal treatment modality selectively concentrates a boron compound in malignant cells, and then "activates" this compound with slow neutrons resulting in a highly lethal event within the cancer cell. This article will review this treatment modality from a radiation oncology, biology, and physics perspective. The remainder of the articles in this special issue of the Journal will provide a survey of the current "state-of-the-art" in this rapidly expanding field, including information with regard to boron compounds and their localization.

Boron Neutron Capture Therapy↗