Calculation of dose components in head phantom for boron neutron capture therapy.

Application of neutrons to cancer treatment has been a subject of considerable clinical and research interest since the discovery of the neutron by Chadwick in 1932 (3). Boron neutron capture therapy (BNCT) is a technique of radiation oncology which is used in treating brain cancer (glioblastoma multiform) or melanoma and that consists of preferentially loading a compound containing 10B into the tumor location, followed by the irradiation of the patient with a beam of neutron. Dose distribution for BNCT is mainly based on Monte Carlo simulations. In this work, the absorbed dose spatial distribution resultant from an idealized neutron beam incident upon ahead phantom is investigated using the Monte Carlo N-particles code, MCNP 4B. The phantom model used is based on the geometry of a circular cylinder on which sits an elliptical cylinder capped by half an ellipsoid representing the neck and head, both filled with tissue-equivalent material. The neutron flux and the contribution of individual absorbed dose components, as a function of depths and of radial distance from the beam axis (dose profiles) in phantom model, is presented and discussed. For the studied beam the maximum thermal neutron flux is at a depth of 2 cm and the maximum gamma dose at a depth of 4 cm.     

Characterization of neutron beams for boron neutron capture therapy: in-air radiobiological dosimetry

The survival curves and the RBE for the dose components generated in boron neutron capture therapy (BNCT) were determined separately in neutron beams at Japan Research Reactor No. 4. The surviving fractions of V79 Chinese hamster cells with or without 10B were obtained using an epithermal neutron beam (ENB), a mixed thermal-epithermal neutron beam (TNB-1), and a thermal (TNB-2) neutron beam; these beams were used or are planned for use in BNCT clinical trials. The cell killing effect of the neutron beam in the presence or absence of 10B was highly dependent on the neutron beam used and depended on the epithermal and fast-neutron content of the beam. The RBEs of the boron capture reaction for ENB, TNB-1 and TNB-2 were 4.07 +/- 0.22, 2.98 +/- 0.16 and 1.42 +/- 0.07, respectively. The RBEs of the high-LET dose components based on the hydrogen recoils and the nitrogen capture reaction were 2.50 +/- 0.32, 2.34 +/- 0.30 and 2.17 +/- 0.28 for ENB, TNB-1 and TNB-2, respectively. The RBEs of the neutron and photon components were 1.22 +/- 0.16, 1.23 +/- 0.16, and 1.21 +/- 0.16 for ENB, TNB-1 and TNB-2, respectively. The approach to the experimental determination of RBEs outlined in this paper allows the RBE-weighted dose calculation for each dose component of the neutron beams and contributes to an accurate inter-beam comparison of the neutron beams at the different facilities employed in ongoing and planned BNCT clinical trials.     

Biological dosimetry for epithermal neutron beams

The radiobiological effectiveness of an epithermal neutron beam is described using cell survival as the end point. The M67 epithermal neutron beam at the Nuclear Reactor Laboratory, Massachusetts Institute of Technology, that was used for clinical trials of boron neutron capture therapy was used to irradiate Chinese hamster ovary cells at seven depths in a water-filled phantom that simulated healthy tissue. No boron was added to the samples. Therefore, this experiment evaluates the biological effectiveness of the neutron and photon components, which comprise 80-95% of the dose to healthy tissue. Cell survival was dependent upon the depth in the phantom, as a result of moderation and attenuation of the epithermal neutron beam components by the overlying water. The results were compared with 250 kVp X irradiations to determine relative biological effectiveness values. Cell survival as a function of the dose delivered was lowest at the most shallow depth of 0.5 cm, and increased at depths of 1.5, 3, 4, 5.6, 6.6 and 8.1 cm. The gradual increase in cell survival with increasing depth in the phantom is due to the exponential drop of the fast-neutron intensity of the beam. These results are applicable to clinical boron neutron capture therapy Phase I/II trials in which healthy tissue toxicity was an end point.     

A Monte Carlo investigation of the dosimetric properties of monoenergetic neutron beams for neutron capture therapy

A Monte Carlo simulation study has been carried out to investigate the suitability of neutron beams of various energies for therapeutic efficacy in boron neutron capture therapy. The dosimetric properties of unidirectional, monoenergetic neutron beams of varying diameters in two different phantoms (a right-circular cylinder and an ellipsoid) made of brain-equivalent material were examined. The source diameter was varied from 0.0 to 20.0 cm; neutron energies ranged from 0.025 eV up to 800 keV, the maximum neutron energy generated by a tandem cascade accelerator using 2.5-MeV protons in a 7Li(p,n)7Be reaction. Such a device is currently under investigation for use as a neutron source for boron neutron capture therapy. The simulation studies indicate that the maximum effective treatment depth (advantage depth) in the brain is 10.0 cm and is obtainable with a 10-keV neutron beam. A useful range of energies, defined as those neutron energies capable of effectively treating to a depth of 7 cm in brain tissue, is found to be 4.0 eV to 40.0 keV. Beam size is shown not to affect advantage depth as long as the entire phantom volume is used in determining this depth. Dose distribution in directions parallel to and perpendicular to the beam direction are shown to illustrate this phenomenon graphically as well as to illustrate the differences in advantage depth and advantage ratio and the contribution of individual dose components to tumor dose caused by the geometric differences in phantom shape.     

Configuration and validation of an analytical model predicting secondary neutron radiation in proton therapy using Monte Carlo simulations and experimental measurements

PurposeThis study focuses on the configuration and validation of an analytical model predicting leakage neutron doses in proton therapy.MethodsUsing Monte Carlo (MC) calculations, a facility-specific analytical model was built to reproduce out-of-field neutron doses while separately accounting for the contribution of intra-nuclear cascade, evaporation, epithermal and thermal neutrons. This model was first trained to reproduce in-water neutron absorbed doses and in-air neutron ambient dose equivalents, H*(10), calculated using MCNPX. Its capacity in predicting out-of-field doses at any position not involved in the training phase was also checked. The model was next expanded to enable a full 3D mapping of H*(10) inside the treatment room, tested in a clinically relevant configuration and finally consolidated with experimental measurements.ResultsFollowing the literature approach, the work first proved that it is possible to build a facility-specific analytical model that efficiently reproduces in-water neutron doses and in-air H*(10) values with a maximum difference less than 25%. In addition, the analytical model succeeded in predicting out-of-field neutron doses in the lateral and vertical direction. Testing the analytical model in clinical configurations proved the need to separate the contribution of internal and external neutrons. The impact of modulation width on stray neutrons was found to be easily adjustable while beam collimation remains a challenging issue. Finally, the model performance agreed with experimental measurements with satisfactory results considering measurement and simulation uncertainties.ConclusionAnalytical models represent a promising solution that substitutes for time-consuming MC calculations when assessing doses to healthy organs.     

Production of the PET isotope 11C in hadron therapy via neutron knockout

PurposePositron emitting isotopes such as ¹¹C and ¹⁰C can be used for vital dose verification in hadron therapy. These isotopes are produced when the high energy ¹²C primary beam particles undergo nuclear reactions within the patient.MethodsWe discuss a model for calculating cross sections for the production ¹¹C in ¹²C + ¹²C collisions, applicable at hadron therapy energies.ResultsGood agreement with the available cross section measurements is found for ¹²C(−1n), though more detailed, systematic measurements would be very valuable.ConclusionsNuclear structure plays a crucial role in the reactions of light nuclei, particularly when those reactions are peripheral and involve only a few nucleons. For such reactions, nuclear structure has a strong influence on the energy and angular distribution of the cross section, and is an important consideration for reliable dose verification using ¹¹C in hadron therapy.     

Calculation of boron neutron capture cell inactivation in vitro based on particle track structure and x-ray sensitivity

The Monte-Carlo technique was used to perform quantitative microdosimetric model calculations of cell survival after boron neutron capture irradiations in vitro. The high energy ⁷Li and alpha-particles resulting from the neutron capture reaction ¹⁰B (n,α)⁷Li are of short range and are highly damaging to cells. The biophysical model of the Monte-Carlo calculations is based on the track structure of these α-particles and ⁷Li-ions and the x-ray sensitivity of the irradiated cells. The biological effect of these particles can be determined if the lethal effect of local doses deposited in very small fractional volumes of the cell nucleus is known. This lethal effect can be deduced from experimental data of cell survival after x-ray irradiation assuming a Poisson distribution for lethal events. The input data used in a PC-based computer program are the radial dose distribution inside the track of the released particles, cell survival after x-ray irradiation, geometry of the tumor cells, subcellular ¹⁰B concentration, and thermal neutron fluence. The basic concept of this Monte-Carlo computer model is demonstrated. Validations of computer calculations are presented by comparing them with experimental data on cell survival.     

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

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

Induction of DNA double-strand breaks by 157Gd neutron capture

The rationale of boron (10B) neutron capture therapy (BNCT) is based on the high thermal neutron capture cross section of 10B and the limited maximum range (about one cell diameter) of the high LET fission products of the boron neutron capture (NC) reaction. The resulting radiochemical damage is confined to the cell containing the BNC reaction. Although other nuclides have higher thermal neutron capture cross sections than 10B, NC by such nuclides results in the emission of highly penetrating gamma rays. However, gadolinium-157 (157Gd) n-gamma reaction is also accompanied by some internal conversion and, by implication, Auger electron emission. Irradiation of Gd3+-DNA complexes with thermal neutrons results in the induction of DNA double-strand (ds) breaks, but the effect is largely abrogated in the presence of EDTA. Thus, by analogy with the effects of decay of Auger electron-emitting isotopes such as 125I, the Gd NC event must take place in the close proximity of DNA in order to induce a DNA ds break. It is proposed that 157Gd-DNA ligands therefore have potential in NCT. The thermal neutron capture cross section of 157Gd, a nonradioactive isotope, is more than 50 times that of 10B.     

An MCNP-based model for the evaluation of the photoneutron dose in high energy medical electron accelerators

The development of a computational model for the treatment head of a medical electron accelerator (Elekta/Philips SL-18) by the Monte Carlo code mcnp-4C2 is discussed. The model includes the major components of the accelerator head and a pmma phantom representing the patient body. Calculations were performed for a 14 MeV electron beam impinging on the accelerator target and a 10 cm×10 cm beam area at the isocentre. The model was used in order to predict the neutron ambient dose equivalent at the isocentre level and moreover the neutron absorbed dose distribution within the phantom. Calculations were validated against experimental measurements performed by gold foil activation detectors. The results of this study indicated that the equivalent dose at tissues or organs adjacent to the treatment field due to photoneutrons could be up to 10% of the total peripheral dose, for the specific accelerator characteristics examined. Therefore, photoneutrons should be taken into account when accurate dose calculations are required to sensitive tissues that are adjacent to the therapeutic X-ray beam. The method described can be extended to other accelerators and collimation configurations as well, upon specification of treatment head component dimensions, composition and nominal accelerating potential.     

Vibrational neutron spectroscopy of collagen and model polypeptides.

A pulsed source neutron spectrometer has been used to measure vibrational spectra (20-4000 cm-1) of dry and hydrated type I collagen fibers, and of two model polypeptides, polyproline II and (prolyl-prolyl-glycine)10, at temperatures of 30 and 120 K. the collagen spectra provide the first high resolution neutron views of the proton-dominated modes of a protein over a wide energy range from the low frequency phonon region to the rich spectrum of localized high frequency modes. Several bands show a level of fine structure approaching that of optical data. The principal features of the spectra are assigned. A difference spectrum is obtained for protein associated water, which displays an acoustic peak similar to pure ice and a librational band shifted to lower frequency by the influence of the protein. Hydrogen-weighted densities of states are extracted for collagen and the model polypeptides, and compared with published calculations. Proton mean-square displacements are calculated from Debye-Waller factors measured in parallel quasi-elastic neutron-scattering experiments. Combined with the collagen density of states function, these yield an effective mass of 14.5 a.m.u. for the low frequency harmonic oscillators, indicating that the extended atom approximation, which simplifies analyses of low frequency protein dynamics, is appropriate.     

Feasibility of assessing the carcinogenicity of neutrons among neutron therapy patients

Nuclear workers, oil well loggers, astronauts, air flight crews, and frequent fliers can be exposed to low doses of neutrons, but the long-term human health consequences of neutron exposure are unknown. While few of these exposed populations are suitable for studying the effects of neutron exposure, patients treated with neutron-beam therapy might be a source of information. To assess the feasibility of conducting a multi-center international study of the late effects of neutron therapy, we surveyed 23 cancer centers that had used neutron beam therapy. For the 17 responding institutions, only 25% of the patients treated with neutrons (2,855 of 11,191) were alive more than 2 years after treatment. In a two-center U.S. pilot study of 484 neutron-treated cancer patients, we assessed the feasibility of obtaining radiotherapy records, cancer incidence and other follow-up data, and of estimating patient organ doses. Patients were treated with 42 MeV neutrons between 1972 and 1989. Applying a clinical equivalence factor of 3.2 for neutrons, total average organ doses outside the treatment beam ranged from 0.14 to 0.29 Gy for thyroid, 0.40 to 2.50 Gy for breast, 0.63 to 2.35 Gy for kidney, and 1.12 to 1.76 Gy for active bone marrow depending upon the primary cancer treatment site. We successfully traced 97% of the patients, but we found that patient survival was poor and that chemotherapy was not confirmable in a quarter of the patients. Based on our findings from the international survey and the feasibility study, we conclude that a large investigation could detect a fivefold or higher leukemia risk, but would be inadequate to evaluate the risk of solid cancers with long latent periods and therefore would likely not be informative with respect to neutron-related cancer risk in humans.     

Vibrational mode analysis of guanine by neutron inelastic scattering

The low-temperature neutron inelastic spectrum of guanine has been measured. In order to assign the intense peaks observed in this spectrum, a normal mode analysis has been performed, using the Wilson GF-method. The theoretical treatment is based on a non-redundant set of internal coordinates, and a simplified valence force-field approximation. Only the fundamentals have been considered for simulating the internal vibrational mode spectrum. The calculations account for the spectral shape as well as the main observed peaks. Offprint requests to: M. Ghomi     

Neutron, proton, and photonuclear cross-sections for radiation therapy and radiation protection

I review recent work at Los Alamos undertaken to evaluate neutron, proton, and photonuclear cross-sections up to 150 MeV (to 250 MeV for protons), based on experimental data and nuclear model calculations. These data are represented in the ENDF format and can be used in computer codes to simulate radiation transport. They permit calculations of absorbed dose in the body from therapy beams, and through use of kerma coefficients allow absorbed dose to be estimated for a given neutron energy distribution. In radiation protection, these data can be used to determine shielding requirements in accelerator environments and to calculate neutron, proton, gamma-ray, and radionuclide production. Illustrative comparisons of the evaluated cross-section and kerma coefficient data with measurements are given.     

Microdosimetry model for boron neutron capture therapy: II. Theoretical estimation of the effectiveness function and surviving fractions

A model has been developed to obtain a better understanding of the effects of boron neutron capture therapy (BNCT) on a cellular scale. This model, the microdosimetry model MICOR, has been developed to include all reactions important for BNCT. To make the model more powerful in the translation from energy deposition to biological effect, it has been designed to be capable of calculating the effectiveness function. Based on this function, the model can calculate surviving fractions, RBE values and boron concentration distributions. MICOR has been used to analyze an extensive set of biological experiments performed at the HB11 beam in Petten. For V79 Chinese hamster cells, the effectiveness function is determined and used to generate surviving fractions. These fractions are compared with measured surviving fractions, which results in a good agreement between the measured and calculated surviving fractions (within the uncertainties of the measurements).     

Mechanism of force generation studied by neutron scattering

Neutron scattering has been used to compare the structure of myosin S1 that is free in solution to that when it is bound to F-actin. To achieve this, deuterated actin was obtained from D. discoideum that had been fed deuterated E. coli. This deuterated actin was rendered “invisible” to neutrons when dissolved in 94% D₂O. The neutron scattering patterns obtained from S1 bound to deuterated actin were identical to those of free S1 except for oscillations due to S1's bound to the same actin filament. At low S1 to actin stoichiometrics, these oscillations diminish and the patterns become indistinguishable. The apparent radius of gyration of S1 bound to actin is identical to that of free S1 when the stoichiometry is low. Thus, no changes in the structure of S1 were observed to a resolution of 2.5 nm. Computer modelling studies were used to evaluate the compatibility of models for the mechanism of force generation with the neutron data. These studies show that for powerstrokes greater than 5.0 nm, the data are consistent with more than 80% of the crossbridge maintaining a rigid conformation during force generation.     

Neutron-induced gamma dose from a reactor beam filter for boron neutron capture therapy

For the boron neutron capture therapy (NCT) of deep-seated metastatic melanoma, an epithermal (up to a few keV energy) neutron beam from a reactor horizontal facility could be useful if the inherent contamination from fast neutrons and gamma rays could be minimised. Calculations for ANSTO's 10 MW research reactor HIFAR have shown that, even though a filter material such as AlF3 attenuates the fast neutron dose, the beam quality improvement is counteracted by a relative increase in the gamma dose because of the gammas arising from neutron captures in the filter material, particularly the aluminium. The aluminium gammas, most of which arise from thermal neutron capture, are hard and cannot be attenuated by lead or bismuth without comparable attenuation of the epithermal neutron flux. Addition of an absorber such as 6Li to the AlF3 filter was investigated as a means of reducing the hard gamma dose, but the improvement in beam quality was small and at considerable cost to dose intensity. Dose characteristics calculations confirmed the superiority of a tangential beam over a radial beam with better results from an unfiltered tangential beam than from an AlF3 filter in a radial beam. This study showed conclusively that assessments of filter assemblies based on the effect of individual components on either the neutron or gamma dose in isolation are inadequate. In assessing any epithermal neutron filter, thermal neutron shield, and gamma shield combination, the total effect of each on the neutron, gamma, and boron-10 dose must be considered.     

Quantitative autoradiography in boron neutron capture therapy considering the particle ranges in the samples

PurposeBoron neutron capture therapy is a cellular-scale particle therapy exploiting boron neutron capture reactions in boron compounds distributed in tumour cells. Its therapeutic effect depends on both the accumulation of boron in tumour cells and the neutron fluence. Autoradiography is used to visualise the micro-distribution of boron compounds.MethodsHere, we present an equation for the relationship between boron concentration and pit density on the solid-state nuclear track detector, taking into consideration the particle ranges in the samples. This equation is validated using liver-tissue sections and boron standard solutions. Moreover, we present a simple co-localisation system for pit and tissue-section images that requires no special equipment.ResultsThe equation reproduces the experimentally observed trends between boron concentration and pit density. This equation provides a theoretical explanation for the widely used calibration curve between pit density and boron concentration; it also provides a method to correct for differences of tissue-section thickness in quantitative autoradiography.ConclusionsUsing the equation together with this co-localisation system could improve micro-scale quantitative estimation in tissue sections.     

Tissue composition effect on dose distribution in neutron brachytherapy/neutron capture therapy

Aim

The aim of this study is to assess the effect of the compositions of various soft tissues and tissue-equivalent materials on dose distribution in neutron brachytherapy/neutron capture therapy.

Background

Neutron brachytherapy and neutron capture therapy are two common radiotherapy modalities.

Materials and methods

Dose distributions were calculated around a low dose rate ²⁵²Cf source located in a spherical phantom with radius of 20.0 cm using the MCNPX code for seven soft tissues and three tissue-equivalent materials. Relative total dose rate, relative neutron dose rate, total dose rate, and neutron dose rate were calculated for each material. These values were determined at various radial distances ranging from 0.3 to 15.0 cm from the source.

Results

Among the soft tissues and tissue-equivalent materials studied, adipose tissue and plexiglass demonstrated the greatest differences for total dose rate compared to 9-component soft tissue. The difference in dose rate with respect to 9-component soft tissue varied with compositions of the materials and the radial distance from the source. Furthermore, the total dose rate in water was different from that in 9-component soft tissue.

Conclusion

Taking the same composition for various soft tissues and tissue-equivalent media can lead to error in treatment planning in neutron brachytherapy/neutron capture therapy. Since the International Commission on Radiation Units and Measurements (ICRU) recommends that the total dosimetric uncertainty in dose delivery in radiotherapy should be within ±5%, the compositions of various soft tissues and tissue-equivalent materials should be considered in dose calculation and treatment planning in neutron brachytherapy/neutron capture therapy.     

Saturation of the neutron yield from megajoule plasma focus facilities

A relation is investigated between the saturation of the neutron yield from megajoule plasma focus facilities and that of the total discharge current. An analytic formula for the neutron yield as a function of the facility energy is derived by simple calculations of the discharge circuit and is verified by computer simulations of the dynamics of the current sheath. The dependence obtained differs from the generally accepted one but agrees well with experimental data.