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.     

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.     

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.     

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.     

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.     

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.     

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.     

Determination of boron-containing compounds in urine and blood plasma from boron neutron capture therapy patients. The importance of using coupled techniques

The necessity of using coupled techniques to analyze samples from boron neutron capture therapy (BNCT) patients prior to element-specific detection has been demonstrated. BNCT patients were infused with p-boronophenylalanine (BPA)-fructose complex before the therapy started. Urine and blood plasma samples were collected at different times after the start of the BPA administration and were run on a porous graphitic carbon column coupled on-line to an inductively coupled plasma-atomic emission spectrometer (ICP-AES) and an ICP time-of-flight mass spectrometer (TOF-MS). In addition to BPA, a possible metabolite to BPA and some minor boron-containing compounds, eluting close to the front, were also found in the urine and plasma samples. Because only the total concentration of boron has been measured so far in earlier studies, the suspected metabolite could not be detected, and this is the first report indicating its presence in urine and plasma of BNCT patients. The abundance of 10B in urine was about the same for BPA and its possible metabolite (98-99%). The ratio between the possible metabolite and BPA was found to differ in the urine from different patients. Most of the patients had a metabolite concentration of approximately 10 mol % of the BPA content in their urine 5-11 h after the start of the BPA administration. This ratio increased to between 30 and 80% when 24 h had passed. The ratio of metabolite to BPA was found to be lower in the plasma than in the urine samples at comparable time after the start of BPA infusion. Preliminary results from micro-LC-electrospray ionization (ESI)-MS/MS measurements on four urine samples indicate that the metabolite has a higher mass than BPA.     

Microdosimetric measurements for neutron-absorbed dose determination during proton therapy

This work presents microdosimetric measurements performed at the Midwest Proton Radiotherapy Institute in Bloomington, Indiana, USA. The measurements were done simulating clinical setups with a water phantom and for a variety of stopping targets. The water phantom was irradiated by a proton spread out Bragg peak (SOBP) and by a proton pencil beam. Stopping target measurements were performed only for the pencil beam. The targets used were made of polyethylene, brass and lead. The objective of this work was to determine the neutron-absorbed dose for a passive and active proton therapy delivery, and for the interactions of the proton beam with materials typically in the beam line of a proton therapy treatment nozzle. Neutron doses were found to be higher at 45° and 90° from the beam direction for the SOBP configuration by a factor of 1.1 and 1.3, respectively, compared with the pencil beam. Meanwhile, the pencil beam configuration produced neutron-absorbed doses 2.2 times higher at 0° than the SOBP. For stopping targets, lead was found to dominate the neutron-absorbed dose for most angles due to a large production of low-energy neutrons emitted isotropically.     

Nanodosimetric measurements and calculations in a neutron therapy beam

A comparison of calculated and measured values of the dose mean lineal energy (y(D)) for the former neutron therapy beam at Louvain-la-Neuve is reported. The measurements were made with wall-less tissue-equivalent proportional counters using the variance-covariance method and simulating spheres with diameters between 10 nm and 15 microm. The calculated y(D)-values were obtained from simulated energy distributions of neutrons and charged particles inside an A-150 phantom and from published y(D)-values for mono-energetic ions. The energy distributions of charged particles up to oxygen were determined with the SHIELD-HIT code using an MCNPX simulated neutron spectrum as an input. The mono-energetic ion y(D)-values in the range 3-100 nm were taken from track-structure simulations in water vapour done with PITS/KURBUC. The large influence on the dose mean lineal energy from the light ion (A > 4) absorbed dose fraction, may explain an observed difference between experiment and calculation. The latter being larger than earlier reported result. Below 50 nm, the experimental values increase while the calculated decrease.     

Dynamic secondary ion mass spectrometry analysis of boron from boron neutron capture therapy drugs in co-cultures: single-cell imaging of two different cell types within the same ion microscopy field of imaging

A co-culture, cryogenic SIMS methodology is presented for the quantitative analysis of cell type-dependent accumulation of boron delivered by BPA-F and BSH, two clinically approved drugs used in boron neutron capture therapy of cancer. T98G human glioblastoma cells were co-cultured with morphologically different normal LLC-PK1 epithelial cells or GM3348 human skin fibroblasts. Our freeze-fracture method of cryogenic sample preparation successfully fractured the different cell types grown together in co-cultures. Quantitative observations revealed an active uptake of boron from BPA-F in both T98G and LLC-PK1 cells but did not show cell type-dependent differences. Accumulation of BSH in all three cell types examined also did not reveal any cell type-dependent differences in co-cultures. As this method relies on the analysis, within the same field of SIMS imaging, of two different cell types that have been maintained under identical conditions of growth, drug exposure, sample preparation, and instrumental analysis, it provides the most effective approach for comparing cell type-specific differences in boron concentrations. The most effective applications of this method will be realized in testing the selectivity of experimental boronated compounds designed to specifically target tumor cells.     

Microdosimetric evaluation of the neutron field for BNCT at Kyoto University reactor by using the PHITS code

In this study, microdosimetric energy distributions of secondary charged particles from the (10)B(n,α)(7)Li reaction in boron-neutron capture therapy (BNCT) field were calculated using the Particle and Heavy Ion Transport code System (PHITS). The PHITS simulation was performed to reproduce the geometrical set-up of an experiment that measured the microdosimetric energy distributions at the Kyoto University Reactor where two types of tissue-equivalent proportional counters were used, one with A-150 wall alone and another with a 50-ppm-boron-loaded A-150 wall. It was found that the PHITS code is a useful tool for the simulation of the energy deposited in tissue in BNCT based on the comparisons with experimental results.