Microdosimetric study for interpretation of outcomes from boron neutron capture therapy clinical trials

Boron neutron capture therapy is a brachyradiotherapy utilizing the (10)B(n,alpha)(7)Li reaction that has been used to treat glioblastoma multiforme (GBM), melanoma and colon carcinoma liver metastases. GBM clinical trials resulted in modestly improved life expectancies compared with conventional therapies. Early results trials focused on malignant melanoma and colon carcinoma provide dramatically better results. Macrodosimetry cannot explain these apparent differences. The dichotomy can only be understood using microdosimetry techniques. A computer program has been created to provide an improved tissue model. This model permits the dose in each cell's cytoplasm, nucleus, and the interstitium to be calculated for ellipsoidal cells placed in either random or ordered locations. The nuclei can be centered or eccentric. The new model provides insight into the micro level for differences in the trials. The differences arise from the tissue's cellular geometry and the effects of neighboring cells. These results help to explain the observed clinical outcomes.     

Dose measuring system for boron neutron capture therapy

Dose measuring systems for boron neutron capture therapy (BNCT) of brain tumors are presented. The systems are a real-time monitoring system, an integral measuring system and a ¹⁰B concentration measuring system. The real-time monitoring with a small PN junction silicon detector made it possible to simultaneously measure the thermal neutron flux and the gamma dose rate in a patient during neutron therapy. Another monitoring of dose equivalents of thermal neutrons and gamma rays was performed with a BGO scintillation detector connected to an optical fiber. The accurate neutron fluence and gamma dose were determined with the integral measurements of the foil activation method and thermoluminescent dosimeters (TLDs) after irradiation. Kerma doses of thermal neutrons and gamma-rays were also measured with the TLD at the same time. Preliminary measurements of ¹⁰B concentration in tissue and blood of a patient were carried out by prompt gamma-ray spectroscopy.     

On the development of computational tools for the design of beam assemblies for boron neutron capture therapy

This article is the first in a series devoted to the development of efficient and accurate computational tools for the design of beam assemblies for boron neutron capture therapy within the framework of discrete ordinates spectral nodal methods of neutron transport theory. We begin our study with a multi-layer representation of an assembly, and we derive a discrete ordinates matrix operator that replaces without spatial truncation error the entire multi-layer domain in neutron transmission computations. With the matrix operator derived here, we compute without further ado the angular distribution of neutrons leaving the multi-layer assembly, avoiding thus the use of general-purpose discrete ordinates codes founded in the discretization and numerical solution of the neutron transport equation over a number of spatial cells and angular directions throughout the domain. We perform numerical experiments with a four-layer model assembly, and we conclude this article with a discussion and directions for further developments.     

Fricke gel dosimetry in boron neutron capture therapy

Gel dosimetry allows three-dimensional (3D) measurement of absorbed dose in tissue-equivalent dosemeter phantoms. Gel phantoms are imaged using optical techniques. In neutron capture therapy (NCT), properly designed gel dosemeters can give 3D dose distributions, due to the various components of the secondary radiation, in phantoms exposed in the thermal or epithermal column of a nuclear reactor. In addition to the therapeutic dose arising from the reaction 10B(n,alpha)7Li, the other dose components are also obtainable, i.e. the gamma dose (due to reactor background and to the reaction 1H(n,gamma)2H of thermal neutrons with hydrogen, the dose due to protons emitted in the reaction 14N(n,p)14C of thermal neutrons with nitrogen and the dose due to recoil protons resulting from elastic scattering of epithermal neutrons.     

Microdosimetry of neutron field for boron neutron capture therapy at Kyoto university reactor

Microdosimetric single event spectrum in a human body simulated by an acrylic phantom has been measured for the clinical BNCT field at the Kyoto University Reactor (KUR). The recoil particles resulting from the initial reaction and subsequent interactions, namely protons, electrons, alpha particles and carbon nuclei are identified in the microdosimetric spectrum. The relative contributions to the neutron dose from proton, alpha particles and carbon are estimated to be about 0.9, 0.07 and 0.3, respectively, four depths between 5 and 41 mm. We estimate that the dose averaged lineal energy, yD decreased with depth from 64 to 46 keV microm(-1). Relative biological effectiveness (RBE) of this neutron field using a response function for the microdosimetric spectrum was estimated to decrease from 3.6 to 2.9 with increasing depth.     

First experiments on neutron detection on the accelerator-based source for boron neutron capture therapy

A pilot accelerator-based source of epithermal neutrons, which is intended for wide application in clinics for boron neutron capture therapy, has been constructed at the Budker Institute of Nuclear Physics (Novosibirsk). A stationary proton beam has been obtained and near-threshold neutron generation regime has been realized. Results of the first experiments on neutron generation using the proposed source are described.     

Application of TEPC microdosimetry to boron neutron capture therapy

Boron neutron capture therapy (BNCT) is a bimodal radiation therapy used primarily for highly malignant gliomas. Tissue-equivalent proportional counter (TEPC) microdosimetry has proven an ideal dosimetry technique for BNCT, facilitating accurate separation of the photon and neutron absorbed dose components, assessment of radiation quality and measurement of the BNC dose. A miniature dual-TEPC system has been constructed to facilitate microdosimetry measurements with excellent spatial resolution in high-flux clinical neutron capture therapy beams. A 10B-loaded TEPC allows direct measurement of the secondary charged particle spectrum resulting from the BNC reaction. A matching TEPC fabricated from brain-tissue-equivalent plastic allows evaluation of secondary charged particle spectra from photon and neutron interactions in normal brain tissue. Microdosimetric measurements performed in clinical BNCT beams using these novel miniature TEPCs are presented, and the advantages of this technique for such applications are discussed.     

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.     

Improved methods for the generation of 24.5 keV neutron beams with possible application to boron neutron capture therapy

The production of epithermal neutron beams, filtered to provide a spectrum in which a small energy range predominates, is of importance for radiobiological research and in the development and calibration of instruments for monitoring intermediate energy neutrons. The penetration characteristics of intermediate energy neutrons in tissue lead to the possibility of application in the field of neutron capture therapy if beams of sufficient intensity and adequate spectral properties can be generated. In this paper methods of utilising the 24.5 keV antiresonance in the iron neutron cross section are described, and the DENIS (depth enhanced neutron intense source) principle by which beam intensities may be optimised is explained. Calculations and experimental measurements in an in-core facility in the DIDO reactor at Harwell have indicated that a DENIS scatterer can achieve a 6-fold improvement in 24.5 keV beam intensity compared with a conventional titanium disc scatterer.     

Filter, collimator and moderating material to achieve boron neutron capture enhanced fast neutron therapy

The combination of fast neutron therapy and boron neutron capture therapy is currently being studied as a possible treatment for some radio-resistant brain tumours. In an attempt to design a boron-enhanced fast neutron therapy beam for the Fermilab Fast Neutron Therapy Facility, the use of moderating material surrounding the patient's head has been investigated. Graphite, polyethylene, water and heavy water were studied as moderating materials, using MCNP. The use of tungsten, iron, lead and bismuth as materials for a small filter and collimator near the patient's head was investigated. Calculations showed that a filter and collimator made of tungsten with a graphite moderator was capable of producing a dose enhancement of 17.3 +/- 0.6% for a 100 microg g(-1) loading of 10B for a 5.6 cm diameter beam while delivering 1.5 Gy in 7 min.     

The microdosimetry of boron neutron capture therapy in a randomised ellipsoidal cell geometry

Two reactions deliver the majority of local dose in boron neutron capture therapy. The ionised particles (protons, alpha particles and lithium nuclei) produced in the two reactions, 10B(n,alpha,gamma)7Li and 14N(n,p)14O, have short ranges that are less than -14 microm (which is on the order of the diameter of a typical human cell). The ionised particles are heavy and are in the 2+ charge state in the case of the boron reactions. These heavy 2+ ions will do significant damage to molecules near their tracks. Thus, the distribution of nitrogen and, in particular, of boron determines the spatial characteristics of the radiation field. Since the distribution of nitrogen is nearly homogeneous in the brain and is not easily altered for the purpose of radiotherapy, the spatial variation in the radiation dose is due mainly to the spatial distribution of boron. This implies that the spatial distribution of boron determines the microscopic energy deposition and therefore the spatial characteristics of the microscopic dose. The microscopic dose from the (n,alpha) and (n,p) reactions has been examined in detail and, as averred, the proton dose is relatively homogeneous except for statistical variability. The statistical variability in essence adds a false spatial variability that would not be seen if a large number of histories were performed. Since the majority of spatial variability occurs in the boron distribution, the (n,p) reaction can be suppressed to better understand the spatial distribution effects on the microscopic dose. Programs have been written in FORTRAN using Monte Carlo techniques to model ellipsoidal cells that are either randomly sized and located in the region of interest or are arranged in a face centred cubic array and are identical except for the location of the nuclei, which may be random. It is shown that closely packed prolate ellipsoidal cells with a large eccentricity in one dimension will receive a larger nuclear dose than cells that are more sparsely packed. This demonstrates that the boron content of a cell and its nucleus can have a significant impact upon the dose to neighbouring cells. The local boron distribution in a region of interest can be shown to affect the macrodosimetric dose, with possible implications for clinical outcomes.     

In-phantom spectra and dose distributions from a high-energy neutron therapy beam

In radiotherapy with external beams, healthy tissues surrounding the target volumes are inevitably irradiated. In the case of neutron therapy, the estimation of dose to the organs surrounding the target volume is particularly challenging, because of the varying contributions from primary and secondary neutrons and photons of different energies. The neutron doses to tissues surrounding the target volume at the Louvain-la-Neuve (LLN) facility were investigated in this work. At LLN, primary neutrons have a broad spectrum with a mean energy of about 30 MeV. The transport of a 10×10 cm² beam through a water phantom was simulated by means of the Monte Carlo code MCNPX. Distributions of energy-differential values of neutron fluence, kerma and kerma equivalent were estimated at different locations in a water phantom. The evolution of neutron dose and dose equivalent inside the phantom was deduced. Measurements of absorbed dose and of dose equivalent were then carried out in a water phantom using an ionization chamber and superheated drop detectors (SDDs). On the beam axis, the calculations agreed well with the ionization chamber data, but disagreed significantly from the SDD data due to the detector's under-response to neutrons above 20 MeV. Off the beam axis, the calculated absorbed doses were significantly lower than the ionization chamber readings, since gamma fields were not accounted for. The calculated data are doses from neutron-induced charge particles, and these agreed with the values measured by the photon-insensitive SDDs. When exposed to the degraded spectra off the beam axis, the SDD offered reliable estimates of the neutron dose equivalent.     

Brain tumour and infiltrations dosimetry of boron neutron capture therapy combined with 252Cf brachytherapy

This article presents a dosimetric investigation of boron neutron capture therapy (BNCT) combined with (252)Cf brachytherapy for brain tumour control. The study was conducted through computational simulation in MCNP5 code, using a precise and discrete voxel model of a human head, in which a hypothetical brain tumour was incorporated. A boron concentration ratio of 1:5 for healthy-tissue: tumour was considered. Absorbed and biologically weighted dose rates and neutron fluency in the voxel model were evaluated. The absorbed dose rate results were exported to SISCODES software, which generates the isodose surfaces on the brain. Analyses were performed to clarify the relevance of boron concentrations in occult infiltrations far from the target tumour, with boron concentration ratios of 1:1 up to 1:50 for healthy-tissue:infiltrations and healthy-tissue:tumour. The average biologically weighted dose rates at tumour area exceed up to 40 times the surrounding healthy tissue dose rates. In addition, the biologically weighted dose rates from boron have the main contribution at the infiltrations, especially far from primary tumour. In conclusion, BNCT combined with (252)Cf brachytherapy is an alternative technique for brain tumour treatment because it intensifies dose deposition at the tumour and at infiltrations, sparing healthy brain tissue.     

硼中子俘获治疗人脑胶质母细胞瘤的前景和困惑

硼中子俘获疗法是一种可以选择性杀伤肿瘤细胞的放射疗法,其产生的α粒子对临床治疗新诊断和复发的脑胶质母细胞瘤有较好的疗效.发达国家20世纪五六十年代就已进入临床试验,但一直受到硼携带载体和中子源发展的限制.现就其治疗脑胶质母细胞瘤的前景做一综述.     

Determination of the neutron fluence spectra in the neutron therapy room of KIRAMS

High energy proton induced neutron fluence spectra were determined at the Korea Institute of Radiological and Medical Sciences (KIRAMS) using an extended Bonner Sphere (BS) set from the Korea Atomic Energy Research Institute (KAERI) in a series of measurements to quantify the neutron field. At the facility of the MC50 cyclotron of KIRAMS, two Be targets of different thicknesses, 1.0 and 10.5 mm, were bombarded by 35 and 45-MeV protons to produce six kinds of neutron fields, which were classified according to the measurement position and the use or no use of a beam collimator such as the gantry of the neutron therapy unit. In order to obtain a priori information to unfold the measured BS data the MCNPX code was used to calculate the neutron spectrum, and the influence of the surrounding materials for cooling the target assembly were also reviewed through this calculation. Some dosimetric quantities were determined by using the spectra determined in this measurement. Dose equivalent rates of these neutron fields ranged from 0.21 to 5.66 mSv h(-1)nA(-1) and the neutron yields for a thick Be target were 3.05 and 4.77% in the case of using a 35 and a 45-MeV proton, respectively.     

From radiation-induced chromosome damage to cell death: modelling basic mechanisms and applications to boron neutron capture therapy

Cell death is a crucial endpoint in radiation-induced biological damage: on one side, cell death is a reference endpoint to characterise the action of radiation in biological targets; on the other side, any cancer therapy aims to kill tumour cells. Starting from Lea's target theory, many models have been proposed to interpret radiation-induced cell killing; after briefly discussing some of these models, in this paper, a mechanistic approach based on an experimentally observed link between chromosome aberrations and cell death was presented. More specifically, a model and a Monte Carlo code originally developed for chromosome aberrations were extended to simulate radiation-induced cell death applying an experimentally observed one-to-one relationship between the average number of 'lethal aberrations' (dicentrics, rings and deletions) per cell and -ln S, S being the fraction of surviving cells. Although such observation was related to X rays, in the present work, the approach was also applied to protons and alpha particles. A good agreement between simulation outcomes and literature data provided a model validation for different radiation types. The same approach was then successfully applied to simulate the survival of cells enriched with boron and irradiated with thermal neutrons at the Triga Mark II reactor in Pavia, to mimic a typical treatment for boron neutron capture therapy.     

叶酸靶向含硼脂质体的制备及其包封率的测定

制备具有良好靶向性及包封率高的硼脂质体,为硼中子俘获治疗方法的研究与应用建立了一个有效的靶向给药途径.采用复乳法及薄膜—超声分散法制备叶酸靶向硼脂质体,利用高效液相色谱法检测4—羟基苯硼酸4—Hydroxyphenylboronicacid (HBA)脂质体、2—噻吩硼酸2—thiophenylboric acid(TBA)脂质体、4—叔丁基苯硼酸4—tert-Butylphenylboronic Acid(BBA)脂质体的含量及包封率,以包封率为评价指标,采用单因素法优化脂质体的制备处方和工艺条件.筛选出HBA、TBA、BBA最优的色谱条件,分别绘制出标准曲线,结果表明在1 ～ 100 μg/mL范围内线性关系良好.HBA、TBA、BBA脂质体在最优制备处方和工艺条件下包封率分别为25.7％、38.9％、94.8％.BBA脂质体优化后的制备处方和工艺条件如下:胆固醇与磷脂质量比为1∶1,药脂比为1∶50,pH值为7.4,按该处方工艺制备的BBA脂质体包封率在94.8％.制备叶酸靶向脂质体的优选处方和制备工艺稳定可行,质量控制方法简单、准确,包封率高.     

Microdosimetric investigation at the therapeutic proton beam facility of CATANA

Proton beams (62 Mev) are used by the Laboratori Nazionali del Sud of the Italian Institute of Nuclear Physics to treat eye melanoma tumours at the therapeutic facility called CATANA. A cylindrical slim tissue-equivalent proportional counter (TEPC) of 2.7 mm external diameter has been used to compare the radiation quality of two spread-out Bragg peaks (SOBP) at the CATANA proton beam.     

Alanine and TLD coupled detectors for fast neutron dose measurements in neutron capture therapy (NCT)

A method was investigated to measure gamma and fast neutron doses in phantoms exposed to an epithermal neutron beam designed for neutron capture therapy (NCT). The gamma dose component was measured by TLD-300 [CaF2:Tm] and the fast neutron dose, mainly due to elastic scattering with hydrogen nuclei, was measured by alanine dosemeters [CH3CH(NH2)COOH]. The gamma and fast neutron doses deposited in alanine dosemeters are very near to those released in tissue, because of the alanine tissue equivalence. Couples of TLD-300 and alanine dosemeters were irradiated in phantoms positioned in the epithermal column of the Tapiro reactor (ENEA-Casaccia RC). The dosemeter response depends on the linear energy transfer (LET) of radiation, hence the precision and reliability of the fast neutron dose values obtained with the proposed method have been investigated. Results showed that the combination of alanine and TLD detectors is a promising method to separate gamma dose and fast neutron dose in NCT.