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Development of real-time thermal neutron monitor using boron-loaded plastic scintillator with optical fiber for boron neutron capture therapy.

A new thermal neutron monitor for boron neutron capture therapy was developed in this study. We called this monitor equipped boron-loaded plastic scintillator that uses optical fiber for signal transmission as an [scintillator with optical fiber] SOF detector. A water phantom experiment was performed to verify how the SOF detector compared with conventional method of measuring thermal neutron fluence. Measurements with a single SOF detector yielded indistinguishable signals for thermal neutrons and gamma rays. To account for the gamma ray contribution in the signal recorded by the SOF detector, a paired SOF detector system was employed. This was composed of an SOF detector with boron-loaded scintillator and an SOF detector with a boron-free scintillator. The difference between the recorded counts of these paired SOF detectors was used as the measure of the gamma ray contribution in the measured neutron fluence. The paired SOF detectors were ascertained to be effective in measuring thermal neutron flux in the range above 10(6)(n/cm(2)/s). Clinical trials using paired SOF to measure thermal neutron flux during therapy confirmed that paired SOF detectors were effective as a real-time thermal neutron flux monitor.

Boron Neutron Capture Therapy↗

Subcellular distribution of various boron compounds and implications for their efficacy in boron neutron capture therapy by Monte Carlo simulations.

Neutron capture therapy has a promising role in cancer treatment since it can achieve selectivity at the cellular level. The effect of this therapy depends on the subcellular localization of boron atoms in the target cell. Five boron compounds were investigated in this study: the monomeric and dimeric sulfhydryl boranes (BSH and BSSB), a boronated phenylalanine (BPA), and two porphyrin complexes (BOPP and VCDP). The study shows that when exponentially growing rat 9L gliosarcoma cells are exposed to an isoeffective concentration of each of the five compounds for 1 h, BOPP produces a much higher intracellular level of boron than the other four compounds; BSSB produces the second highest level, while exposure to BSH, VCDP, and BPA resulted in lower intracellular boron levels. Subcellular fractionation studies showed that most of the boron localized in the cytoplasm of the cells with all five compounds. A significantly higher boron concentration was found in the lysosomes of the cells, but the nuclei contained only minimal concentrations of boron. Computer simulations of neutron capture reactions with boron using a Monte Carlo simulation code indicated that BOPP would yield the highest potential effectiveness, followed by BSSB, BSH, VCDP, and BPA, in that order.

Animals↗

The medical-irradiation characteristics for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

At the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor, the mix irradiation of thermal and epi-thermal neutrons, and the solo irradiation of epi-thermal neutrons are available additionally to the thermal neutron irradiation, and then the neutron capture therapy (NCT) at this facility became more flexible, after the update in 1996. The estimation of the depth dose distributions in NCT clinical irradiation, were performed for the standard irradiation modes of thermal, mixed and epi-thermal neutrons, from the both sides of experiment and calculation. On the assumption that the 10B concentration in tumor part was 40 ppm and the ratio of tumor to normal tissue was 3.5, the advantage depth were estimated to 5.4, 6.0, and 8.0, for the respective standard irradiation modes. It was confirmed that the various irradiation conditions can be selected according to the target-volume conditions, such as size, depth, etc. Besides, in the viewpoint of the radiation shielding for patient, it was confirmed that the whole-body exposure is effectively reduced by the new clinical collimators, compared with the old one.

Antineoplastic Agents↗

Verification of the computational dosimetry system in JAERI (JCDS) for boron neutron capture therapy.

Clinical trials for boron neutron capture therapy (BNCT) by using the medical irradiation facility installed in Japan Research Reactor No. 4 (JRR-4) at Japan Atomic Energy Research Institute (JAERI) have been performed since 1999. To carry out the BNCT procedure based on proper treatment planning and its precise implementation, the JAERI computational dosimetry system (JCDS) which is applicable to dose planning has been developed in JAERI. The aim of this study was to verify the performance of JCDS. The experimental data with a cylindrical water phantom were compared with the calculation results using JCDS. Data of measurements obtained from IOBNCT cases at JRR-4 were also compared with retrospective evaluation data with JCDS. In comparison with phantom experiments, the calculations and the measurements for thermal neutron flux and gamma-ray dose were in a good agreement, except at the surface of the phantom. Against the measurements of clinical cases, the discrepancy of JCDS's calculations was approximately 10%. These basic and clinical verifications demonstrated that JCDS has enough performance for the BNCT dosimetry. Further investigations are recommended for precise dose distribution and faster calculation environment.

Algorithms↗

Selective boron accumulation in human ocular melanoma vs surrounding eye components after 10B1-p-boronophenylalanine administration. Prerequisite for clinical trial of neutron-capture therapy.

We have developed neutron-capture therapy (NCT) for cutaneous malignant melanoma using a melanoma-seeking 10B-dopa, analogue, 10B1-para-boronophenylalanine (10B1-BPA). In order to explore the feasibility of applying NCT further to ocular melanoma, we investigated the boron concentrations in ocular melanomas and normal ocular tissues by 10B1-BPA administration to three patients, because success of NCT depends mainly upon selective boron accumulation in melanoma. In the first and second ocular melanoma patients, to whom 10B1-BPA fructose complex (total dose of 10B1-BPA: 170 mg/kg body weight) was administered orally in two divided doses, the boron concentrations in blood, vitreous body, sclera and retina choroidea were lower than that in melanoma examined. In the third conjunctival melanoma patient, to whom 10B1-BPA fructose complex (dose of 10B1-BPA: 85 mg/kg body weight) was administered by intravenous drip infusion, the average boron concentration in four melanoma samples was 17.7 ppm, which was estimated to be within the range necessary for melanoma eradication by thermal neutron irradiation. Boron uptake by lens, vitreous body, retina choroidea and sclera was much lower than that by melanoma. It was suggested that such a superficial ocular melanoma as iris melanoma can be destroyed by NCT, although vision may be affected--mainly due to cataract formation.

Boron↗

3-Carboranyl thymidine analogues (3CTAs) and other boronated nucleosides for boron neutron capture therapy.

One category of boron neutron capture therapy (BNCT) agents that has received extensive attention during recent years is 3-carboranyl thymidine analogues (3CTAs). These molecules are phosphorylated to the corresponding 5'-monophosphates by human thymidine kinase 1 (TK1), an enzyme that is up-regulated in dividing malignant cells. Thus, these phosphorylated molecules are selectively entrapped in tumor cells due to the acquired negative charge. This review will analyze design strategies applied for the synthesis of boron-containing nucleosides in general and in particular reference to 3CTAs. Results of biological studies with these molecules will be discussed.

Animals↗

Effect of dose and infusion time on the delivery of p-boronophenylalanine for neutron capture therapy.

Clinical trials of boron neutron capture therapy (BNCT) for glioblastoma multiforme are currently in progress using p-boronophenylalanine (BPA) as the 10B delivery agent. Enhancement of tumor boron uptake and/or the tumor-to-blood (T:B) boron concentration ratio would have the potential of significantly improving the therapeutic gain of BNCT. The effects of total dose, infusion time, and route of administration of BPA on tumor and blood boron concentrations were studied in rats bearing the 9L gliosarcoma. Increasing the total dose of BPA from 250 to 1000 mg/kg, administered intravenously over a 2-h infusion period, resulted in an increase in tumor boron concentration from approximately 30 to approximately 70 microg 10B/g, with a constant T:B boron concentration ratio of about 3.7:1. Similarly, extension of the infusion time from 2 to 6 h, at a constant dose-rate of 125 mg BPA/kg/h, resulted in an increase in tumor boron concentration from approximately 30 to approximately 80 microg 10B/g, while, again, maintaining a constant T:B ratio of about 3.7:1. In contrast, intracarotid infusion of BPA for 1 h at a dose rate of 125 mg BPA/kg resulted in an increase in the tumor boron concentration from approximately 26 to approximately 38 microg 10B/g with a corresponding increase in the T:B ratio from 3.5:1 to 5.0:1. The effects of these results on the therapeutic gain potentially achievable with BNCT are discussed.

Animals↗

Preliminary treatment planning and dosimetry for a clinical trial of neutron capture therapy using a fission converter epithermal neutron beam.

A Phase I/II clinical trial of neutron capture therapy (NCT) was conducted at Harvard-MIT using a fission converter epithermal neutron beam. This epithermal neutron beam has nearly ideal performance characteristics (high intensity and purity) and is well-suited for clinical use. Six glioblastoma multiforme (GBM) patients were treated with NCT by infusion of the tumor-selective amino acid boronophenylalanine-fructose (BPA-F) at a dose of 14.0 g/m(2) body surface area over 90 min followed by irradiation with epithermal neutrons. Treatments were planned using NCTPlan and an accelerated version of the Monte Carlo radiation transport code MCNP 4B. Treatments were delivered in two fractions with two or three fields. Field order was reversed between fractions to equalize the average blood boron concentration between fields. The initial dose in the dose escalation study was 7.0 RBEGy, prescribed as the mean dose to the whole brain volume. This prescription dose was increased by 10% to 7.7 RBEGy in the second cohort of patients. A pharmacokinetic model was used to predict the blood boron concentration for determination of the required beam monitor units with good accuracy; differences between prescribed and delivered doses were 1.5% or less. Estimates of average tumor doses ranged from 33.7 to 83.4 RBEGy (median 57.8 RBEGy), a substantial improvement over our previous trial where the median value of the average tumor dose was 25.8 RBEGy.

Aged↗

Depth-dose evaluation and optimisation of the irradiation facility for boron neutron capture therapy of brain tumours.

Boron neutron capture therapy (BNCT) of brain tumours was investigated using thermal neutrons generated by a middle-power research reactor such as the TRIGA-II. The spatial distributions of neutrons and gamma rays were measured using a head phantom at different collimator apertures. Total depth-dose distributions were deduced from these results and were evaluated. We also obtained an optimum condition in terms of the collimator aperture, the 10B concentration in the tumour and the ratio of 10B concentration in the tumour to that in normal tissue. We found that, under this condition, BNCT using thermal neutrons from the TRIGA-II could be successfully used to treat a deep tumour.

Boron↗

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

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 Compounds↗

Head phantom experiment and calculation for boron neutron capture therapy.

Head phantom experiments with various neutron beams and calculations were carried out in order to provide useful information for boron neutron capture therapy (BNCT). Thermal neutron beams for thermal neutron capture therapy were used for phantom experiments with various neutron collimator aperture sizes. The filtered beam neutrons of 24 and 144 keV generated with iron and silicon filters were also used to investigate the possible application of BNCT in the treatment of deep-seated cancers. Thermal neutron fluence and induced capture gamma dose distributions within the phantom were calculated with a transport code DOT 3.5 and compared with the experimental results. The results showed that the calculation used was consistent with the experimental results and provided useful information on BNCT. The filtered beam neutron may be very useful for the treatment of deep or widespread cancer, if there were a high power research reactor constructed for this purpose.

Brain Neoplasms↗

Boron neutron capture therapy using mixed epithermal and thermal neutron beams in patients with malignant glioma-correlation between radiation dose and radiation injury and clinical outcome.

PURPOSE: To clarify the correlation between the radiation dose and clinical outcome of sodium borocaptate-based intraoperative boron neutron capture therapy in patients with malignant glioma. METHODS AND MATERIALS: The first protocol (P1998, n = 8) prescribed a maximal gross tumor volume (GTV) dose of 15 Gy. In 2001, a dose-escalated protocol was introduced (P2001, n = 11), which prescribed a maximal vascular volume dose of 15 Gy or, alternatively, a clinical target volume (CTV) dose of 18 Gy. RESULTS: The GTV and CTV doses in P2001 were 1.1-1.3 times greater than those in P1998. The maximal vascular volume dose of those with acute radiation injury was 15.8 Gy. The mean GTV and CTV dose in long-term survivors with glioblastoma was 26.4 and 16.5 Gy, respectively. A statistically significant correlation between the GTV dose and median survival time was found. In the 11 glioblastoma patients in P2001, the median survival time was 19.5 months and 1- and 2-year survival rate was 60.6% and 37.9%, respectively. CONCLUSION: Dose escalation contributed to the improvement in clinical outcome. To avoid radiation injury, the maximal vascular volume dose should be <12 Gy. For long-term survival in patients with glioblastoma after boron neutron capture therapy, the optimal mean dose of the GTV and CTV was 26 and 16 Gy, respectively.

Adolescent↗

Sensitivity studies of beam directionality, beam size, and neutron spectrum for a fission converter-based epithermal neutron beam for boron neutron capture therapy.

Sensitivity studies of epithermal neutron beam performance in boron neutron capture therapy are presented for realistic neutron beams with varying filter/moderator and collimator/delimiter designs to examine the relative importance of neutron beam spectrum, directionality, and size. Figures of merit for in-air and in-phantom beam performance are calculated via the Monte Carlo technique for different well-optimized designs of a fission converter-based epithermal neutron beam with head phantoms as the irradiation target. It is shown that increasing J/phi, a measure of beam directionality, does not always lead to corresponding monotonic improvements in beam performance. Due to the relatively low significance, for most configurations, of its effect on in-phantom performance and the large intensity losses required to produce beams with very high J/phi, beam directionality should not be considered an important figure of merit in epithermal neutron beam design except in terms of its consequences on patient positioning and collateral dose. Hardening the epithermal beam spectrum, while maintaining the specific fast neutron dose well below the inherent hydrogen capture dose, improves beam penetration and advantage depth and, as a desirable by-product, significantly increases beam intensity. Beam figures of merit are shown to be strongly dependent on beam size relative to target size. Beam designs with J/phi approximately 0.65-0.7, specific fast neutron doses of 2-2.6x10(-13) Gy cm2/n and beam sizes equal to or larger than the size of the head target produced the deepest useful penetration, highest therapeutic ratios, and highest intensities.

Biophysical Phenomena↗

[Development of the method of magnetic neutron capture therapy of cancer].

The method of magnetic neutron capture therapy (MNTC) of cancer can be described as a combination of two methods: the targeted delivery of drugs using magnetic carriers and the proper neutron capture therapy which consists in tumor irradiation with thermal neutrons following the delivery of 10B compounds to the tumor site. Two-component ultradispersed particles containing Fe and C were tested as magnetic adsorbents of boron phenylalanine and borax. The quantities of absorbed borax proved sufficient for high concentration of boron atoms at the tumor site. The kinetics of boron release to saline substantiates the application of Fe-B (10%) ultradispersed particles for efficient MNTC. Both particle types have high magnetization and magnetic homogeneity, can form stable magnetic suspensions, and have low toxicity.

Animals↗

A conceptual design of a beam-shaping assembly for boron neutron capture therapy based on deuterium-tritium neutron generators.

A conceptual design of a beam-shaping assembly for boron neutron capture therapy using deuterium-tritium accelerator based neutrons source is developed. Calculations based on a simple geometry model for the radiation transport are initially performed to estimate the assembly materials and their linear dimensions. Afterward, the assembly geometry is produced, optimized and verified. In order to perform these calculations the general-purpose MCNP code is used. Irradiation time and therapeutic gain are utilized as beam assessment parameters. Metallic uranium and manganese are successfully tested for fast-to-epithermal neutron moderation. In the present beam-shaping assembly proposal, the therapeutic gain is improved by 23% and the accelerator current required for a fixed irradiation period is reduced by six times compared to previous proposals based on the same D-T reaction.

Boron Neutron Capture Therapy↗

The possible use of a spallation neutron source for neutron capture therapy with epithermal neutrons.

Spallation is induced in a heavy material by 72-MeV protons. The resulting neutrons can be characterized by an evaporation spectrum with a peak energy of less than 2 MeV. The neutrons are moderated in two steps: first in iron and then in carbon. Results from neutron fluence measurements in a perspex phantom placed close to the moderator are presented. Monte Carlo calculations of neutron fluence in a water phantom are also presented under some chosen configurations of spallation source and moderator. The calculations and measurements are in good agreement and show that, for proton currents of less than 0.5 mA, useful thermal-neutron fluences are attainable in the depth of the brain. However, the dose contribution from the unavoidable gamma background component has not been included in the present investigation.

Boron↗

Gadolinium as a neutron capture therapy agent.

The clinical results of treating brain tumors with boron neutron capture therapy are very encouraging. Researchers around the world are once again making efforts to develop this therapeutic modality. Gadolinium-157 is one of the nuclides that holds interesting properties of being a neutron capture therapy agent. It is estimated that tumor concentrations of up to 300 micrograms 157 Gd/g tumor can be achieved in brain tumors with some MRI contrast agents such as Gd-DTPA and Gd-DOTA, and up to 800 micrograms 157 Gd/g tumor can be established in bone tumors with Gd-EDTMP. Monte Carlo calculations indicate that with 250 ppm of 157Gd in tumor, neutron capture therapy can deliver 2000 cGy to a tumor of 2-cm diameter or larger with 5 x 10(12) n/cm2 of thermal neutron fluence at the tumor. Dose measurements with films and TLDs in phantoms verified these calculations. More extended Monte Carlo calculations demonstrate that neutron capture therapy with Gd possesses comparable dose distribution to B neutron capture therapy. With 5 x 10(12) n/cm2 thermal neutrons at the tumor, Auger electrons from the Gd produced an optical density enhancement on films that is similar to the effect caused by about 300 cGy of Gd prompt gamma dose and may further enhance the therapeutic effects.

Animals↗

Radiation injury of boron neutron capture therapy using mixed epithermal- and thermal neutron beams in patients with malignant glioma.

The purpose of this study was to clarify the radiation injury in acute or delayed stage after boron neutron capture therapy (BNCT) using mixed epithermal- and thermal neutron beams in patients with malignant glioma. Eighteen patients with malignant glioma underwent mixed epithermal- and thermal neutron beam and sodium borocaptate between 1998 and 2004. The radiation dose (i.e. physical dose of boron n-alpha reaction) in the protocol used between 1998 and 2000 (Protocol A, n = 8) prescribed a maximum tumor volume dose of 15 Gy. In 2001, a new dose-escalated protocol was introduced (Protocol B, n = 4); it prescribes a minimum tumor volume dose of 18 Gy or, alternatively, a minimum target volume dose of 15 Gy. Since 2002, the radiation dose was reduced to 80-90% dose of Protocol B because of acute radiation injury. A new Protocol was applied to 6 glioblastoma patients (Protocol C, n = 6). The average values of the maximum vascular dose of brain surface in Protocol A, B and C were 11.4+/-4.2 Gy, 15.7+/-1.2 and 13.9+/-3.6 Gy, respectively. Acute radiation injury such as a generalized convulsion within 1 week after BNCT was recognized in three patients of Protocol B. Delayed radiation injury such as a neurological deterioration appeared 3-6 months after BNCT, and it was recognized in 1 patient in Protocol A, 5 patients in Protocol B. According to acute radiation injury, the maximum vascular dose was 15.8+/-1.3 Gy in positive and was 12.6+/-4.3 Gy in negative. There was no significant difference between them. According to the delayed radiation injury, the maximum vascular dose was 13.8+/-3.8 Gy in positive and was 13.6+/-4.9 Gy in negative. There was no significant difference between them. The dose escalation is limited because most patients in Protocol B suffered from acute radiation injury. We conclude that the maximum vascular dose does not exceed over 12 Gy to avoid the delayed radiation injury, especially, it should be limited under 10 Gy in the case that tumor exists in speech center.

Adult↗