In-phantom neutron dose measurement using Gafchromic film dosimeter for QA of BNCT beams.

In order to improve the quality assurance (QA) procedure for beams of boron neutron capture therapy (BNCT), this study introduced using the Gafchromic film dosimeter for neutron dose measurement of BNCT beams. The crucial part of this study was investigating an approach to employ the Gafchromic film dosimeter placed inside a PMMA phantom irradiated by a BNCT beam. The spatial distribution of neutron dose of the film was determined using measurements and Monte Carlo calculations. By employing the present approach, the two-dimensional distributions of the neutron dose component of the film at specific depths in the phantom were successfully obtained. The determined neutron dose profiles were in good agreement with the calculated ones. This study also confirmed the finding that the film dosimeter is sensitive to thermal neutrons by comparing the depth-capture-reaction-rate and depth-dose distributions. Results of this work not only proved the feasibility of using the proposed method for the QA measurement of beam delivery but also revealed the advantages of easy-handling and remarkable spatial resolution of the film dosimeter when applied to BNCT fields. The present work can help to verify the dose uniformity and output stability of BNCT beams prior to clinical irradiation.

Radiation safety analysis for the A-BNCT facility in Korea.

A Proton Accelerator based Boron Neutron Capture Therapy (A-BNCT) facility is under development in Korea. Neutron beams for treatment are produced from a beryllium (Be) target and an 8 mA, 10 MeV proton beam. The purpose of the research is a radiation shielding analysis and an activation analysis for the facility design satisfying the radiation safety requirements as well as obtaining an operating license for the radiation facility according to a domestic nuclear commissioning procedure. The radiation shielding analysis was performed using the MCNPX computational particle transport code. The radiation source terms in the facility were evaluated and utilized in the shielding calculations. The minimum concrete thickness satisfying the designated dose rate of 5 µSv/h for the worker's area and 0.25 µSv/h for the public area were estimated and applied to the design. For an assessment of the radiation safety inside the facility, the dose rates were evaluated at several positions, such as behind the shielding door, around the primary barriers near the radiation sources, and in the penetrations of the ducts. The dose rate distribution was mapped for verification of the radiation safety for the entire facility. An activation analysis was carried out for the concrete walls, air, target assembly, beryllium target, and cooling water using FISPACT-2010 code. Concentrations of the activation products and dose rate induced by the radionuclides after shutdown were evaluated for the purpose of safe operation of the facility. The results were reviewed with the radiation safety regulations in Korea. As a result, it was proved that the final facility design satisfies the safety requirements.

Boron Neutron Capture Therapy of Malignant Gliomas.

Boron neutron capture therapy (BNCT) is a promising modality for biochemically targeted, highly selective radiation treatment of various cancers, including malignant gliomas. Currently available results demonstrate the beneficial effect of such therapy on survival of patients with both recurrent and newly diagnosed glioblastomas. The main drawback of BNCT in cases of previously irradiated neoplasms is high rates of symptomatic pseudoprogression and radiation necrosis. For prevention of these complications, concurrent administration of bevacizumab may be helpful. Further studies are needed to establish the optimal therapeutic protocols and to define the exact role of this management option in multimodality treatment strategies. Recent technological developments of accelerator-based neutron sources may simplify placement of the device for BNCT within clinical facilities and lead to wider application of this technique in cases of various cancers.

QA measurement of gamma-ray dose and neutron activation using TLD-400 for BNCT beam.

TLD-400 (CaF2:Mn) chips were applied for the gamma-ray dose measurement in a PMMA phantom exposed to a BNCT beam because of their very low neutron sensitivity. Since TLD-400 chips possess an adequate amount of Mn activator they have been employed in this work simultaneously for neuron activation measurement. The self-irradiation TL signals owing to the decay of the neutron induced 56Mn activity have been applied for a calibration of the TLD-400 chip in situ, where the activities were measured by an HPGe detector system and the energy deposition per disintegration of 56Mn was calculated by applying a Monte Carlo code. It was accidentally found that the irradiated TLD-400 chips were capable of emitting prominent scintillation lights owing to the induced 56Mn activity, which can easily be recorded by the TLD reader without heating and after a calibration can be used to determine the 56Mn activity.

Demonstration of the importance of a dedicated neutron beam monitoring system for BNCT facility.

The neutron beam monitoring system is indispensable to BNCT facility in order to achieve an accurate patient dose delivery. The neutron beam monitoring of a reactor-based BNCT (RB-BNCT) facility can be implemented through the instrumentation and control system of a reactor provided that the reactor power level remains constant during reactor operation. However, since the neutron flux in reactor core is highly correlative to complicated reactor kinetics resulting from such as fuel depletion, poison production, and control blade movement, some extent of variation may occur in the spatial distribution of neutron flux in reactor core. Therefore, a dedicated neutron beam monitoring system is needed to be installed in the vicinity of the beam path close to the beam exit of the RB-BNCT facility, where it can measure the BNCT beam intensity as closely as possible and be free from the influence of the objects present around the beam exit. In this study, in order to demonstrate the importance of a dedicated BNCT neutron beam monitoring system, the signals originating from the two in-core neutron detectors installed at THOR were extracted and compared with the three dedicated neutron beam monitors of the THOR BNCT facility. The correlation of the readings between the in-core neutron detectors and the BNCT neutron beam monitors was established to evaluate the improvable quality of the beam intensity measurement inferred by the in-core neutron detectors. In 29 sampled intervals within 16 days of measurement, the fluctuations in the mean value of the normalized ratios between readings of the three BNCT neutron beam monitors lay within 0.2%. However, the normalized ratios of readings of the two in-core neutron detectors to one of the BNCT neutron beam monitors show great fluctuations of 5.9% and 17.5%, respectively.

Inter-comparison of boron concentration measurements at INFN-University of Pavia (Italy) and CNEA (Argentina).

An inter-comparison of three boron determination techniques was carried out between laboratories from INFN-University of Pavia (Italy) and CNEA (Argentina): alpha spectrometry (alpha-spect), neutron capture radiography (NCR) and quantitative autoradiography (QTA). Samples of different nature were analysed: liquid standards, liver homogenates and tissue samples from different treatment protocols. The techniques showed a good agreement in a concentration range of interest in BNCT (1-100ppm), thus demonstrating their applicability as precise methods to quantify boron and determine its distribution in tissues.

A prospective study to assess the performance of the improved Boron Neutron Capture Therapy Facility in Argentina.

From 2008 to 2011, several planned modifications were implemented at the RA-6 reactor in Argentina, leading to significant benefits for future BNCT treatments. New capabilities have been implemented in NCTPlan treatment planning system. To assess the performance of the new BNCT facility, a dosimetric reevaluation of previous clinical cases was performed, taking into account the modifications carried out in the new facility and compared the results of the original treatment plans with optimized plans that are considered as feasible patient setups.

A new approach to dose estimation and in-phantom figure of merit measurement in BNCT by using artificial neural networks.

In-phantom figures of merit of the radiobiological dose distribution are the main criteria for evaluation of the boron neutron capture therapy (BNCT) plan and neutron beam evaluation. Since in BNCT there are several reactions, which contribute to the total dose of the tissue, the calculation of the dose distribution is complicated and requires lengthy and time-consuming simulations. Any changes in the beam shaping assembly (BSA) design would lead to the change of the neutron/gamma spectrum at exit of therapeutic window. As a result of any changes in the beam spectrum, the dose distribution in the tissue will be altered; therefore, another set of lengthy and time-consuming simulations to recalculate the dose distribution would have to be performed. This study proposes a method that applies artificial neural network (ANN) for quick dose prediction in order to avoid lengthy calculations. This method allows us to estimate the depth-dose distribution and in-phantom figures of merit for any energy spectrum without performing a complete Monte Carlo code (MCNP) simulation. To train the ANNs for modeling the depth-dose distribution, this study used a database containing 500 simulations of the neutron depth-dose distribution and 280 simulations of the gamma depth-dose distribution. The calculations were carried out by the MCNP for various mono-energetic neutrons, ranging from thermal up to 10 MeV energy and 280 gamma energy group, ranging from 0.01 MeV up to 20 MeV, through the SNYDER head phantom which is located at the exit of the BSA. The trained ANN was capable of establishing a map between the neutron/gamma beam energy and the dose distribution in the phantom as an input and a response, respectively. The current method is founded upon the observation that the dose which is released by the beam of composite energy spectrum can be decomposing into the various energy components which make the neutron/gamma spectrum. Therefore, in this procedure the neutron/gamma energy spectrum was converted into several energy groups and dose response of each group was predicted by the trained ANN. Total dose distribution of the entire spectrum is equal to summation of dose response of each group. If the neutron/gamma spectrum as an input changes, the dose response of that as an output can be predicted by the trained ANN in no time rather than hours or days by MCNP simulations. To check the validity of this method, this study compared full calculation of the depth-dose distribution with prediction of ANN for that. The result of this comparison shows that artificial neural networks model the dose distribution in phantom successfully and result in a great accurate prediction.

Extension of the calibration curve for the PGRA facility in Petten.

At the boron neutron capture therapy (BNCT) facility in Petten, the Netherlands, (10)B concentrations in biological materials are measured with the prompt gamma ray analyses facility that is calibrated using certified (10)B solutions ranging from 0 to 210 ppm. For this study, newly certified (10)B solutions ranging up to 1972 ppm are added. MCNP simulations of the setup range to 5000 ppm. A second order polynomial (as already used) will fit (10)B-concentrations less than 300 ppm. Above 300 ppm a fitted third order polynomial is needed to describe the calibration curve accurately.

Unifying dose specification between clinical BNCT centers in the Americas.

A dosimetry intercomparison between the boron neutron capture therapy groups of the Massachusetts Institute of Technology (MIT) and the Comisión Nacional de Energía Atómica (CNEA), Argentina was performed to enable combined analyses of NCT patient data between the different centers. In-air and dose versus depth measurements in a rectangular water phantom were performed at the hyperthermal neutron beam facility of the RA-6 reactor, Bariloche. Calculated dose profiles from the CNEA treatment planning system NCTPlan that were calibrated against in-house measurements required normalizations of 1.0 (thermal neutrons), 1.13 (photons), and 0.74 (fast neutrons) to match the dosimetry of MIT.

An international dosimetry exchange for BNCT part II: computational dosimetry normalizations.

The meaningful sharing and combining of clinical results from different centers in the world performing boron neutron capture therapy (BNCT) requires improved precision in dose specification between programs. To this end absorbed dose normalizations were performed for the European clinical centers at the Joint Research Centre of the European Commission, Petten (The Netherlands), Nuclear Research Institute, Rez (Czech Republic), VTT, Espoo (Finland), and Studsvik, Nyköping (Sweden). Each European group prepared a treatment plan calculation that was bench-marked against Massachusetts Institute of Technology (MIT) dosimetry performed in a large, water-filled phantom to uniformly evaluate dose specifications with an estimated precision of +/-2%-3%. These normalizations were compared with those derived from an earlier exchange between Brookhaven National Laboratory (BNL) and MIT in the USA. Neglecting the uncertainties related to biological weighting factors, large variations between calculated and measured dose are apparent that depend upon the 10B uptake in tissue. Assuming a boron concentration of 15 microg g(-1) in normal tissue, differences in the evaluated maximum dose to brain for the same nominal specification of 10 Gy(w) at the different facilities range between 7.6 and 13.2 Gy(w) in the trials using boronophenylalanine (BPA) as the boron delivery compound and between 8.9 and 11.1 Gy(w) in the two boron sulfhydryl (BSH) studies. Most notably, the value for the same specified dose of 10 Gy(w) determined at the different participating centers using BPA is significantly higher than at BNL by 32% (MIT), 43% (VTT), 49% (JRC), and 74% (Studsvik). Conversion of dose specification is now possible between all active participants and should be incorporated into future multi-center patient analyses.

Normalisation of prescribed dose in BNCT.

Normalisation of prescribed dose in boron neutron capture therapy (BNCT) is needed to facilitate combining clinical data from different centres in the world to help expedite development of the modality. The approach being pursued within the BNCT community is based upon improving precision in the measurement and specification of absorbed dose. Beam characterisations using a common method are complete as are comparative dosimetry measurements between clinical centres in Europe and the USA. Results from treatment planning systems at these centres have been compared with measurements performed by MIT, and the scale factors determined are being confirmed with independent tests using measurements in an ellipsoidal water phantom. Dose normalisations have successfully been completed and applied to retrospectively analyse treatment plans from Brookhaven National Laboratory (1994-99) so that reported doses are consistently expressed with the trials performed during 1994-2003 at Harvard-MIT. Dose response relationships for adverse events and other endpoints can now be more accurately established.

Calibration of the borated ion chamber at NIST reactor thermal column.

In boron neutron capture therapy and boron neutron capture enhanced fast neutron therapy, the absorbed dose of tissue due to the boron neutron capture reaction is difficult to measure directly. This dose can be computed from the measured thermal neutron fluence rate and the (10)B concentration at the site of interest. A borated tissue-equivalent (TE) ion chamber can be used to directly measure the boron dose in a phantom under irradiation by a neutron beam. Fermilab has two Exradin 0.5 cm(3) Spokas thimble TE ion chambers, one loaded with boron, available for such measurements. At the Fermilab Neutron Therapy Facility, these ion chambers are generally used with air as the filling gas. Since alpha particles and lithium ions from the (10)B(n,alpha)(7)Li reactions have very short ranges in air, the Bragg-Gray principle may not be satisfied for the borated TE ion chamber. A calibration method is described in this paper for the determination of boron capture dose using paired ion chambers. The two TE ion chambers were calibrated in the thermal column of the National Institute of Standards and Technology (NIST) research reactor. The borated TE ion chamber is loaded with 1,000 ppm of natural boron (184 ppm of (10)B). The NIST thermal column has a cadmium ratio of greater than 400 as determined by gold activation. The thermal neutron fluence rate during the calibration was determined using a NIST fission chamber to an accuracy of 5.1%. The chambers were calibrated at two different thermal neutron fluence rates: 5.11 x 10(6) and 4.46 x 10(7)n cm(-2) s(-1). The non-borated ion chamber reading was used to subtract collected charge not due to boron neutron capture reactions. An optically thick lithium slab was used to attenuate the thermal neutrons from the neutron beam port so the responses of the chambers could be corrected for fast neutrons and gamma rays in the beam. The calibration factor of the borated ion chamber was determined to be 1.83 x 10(9) +/- 5.5% (+/- 1sigma) n cm(-2) per nC at standard temperature and pressure condition.

An international dosimetry exchange for boron neutron capture therapy. Part I: Absorbed dose measurements.

An international collaboration was organized to undertake a dosimetry exchange to enable the future combination of clinical data from different centers conducting neutron capture therapy trials. As a first step (Part I) the dosimetry group from the Americas, represented by MIT, visited the clinical centers at Studsvik (Sweden), VTT Espoo (Finland), and the Nuclear Research Institute (NRI) at Rez (Czech Republic). A combined VTT/NRI group reciprocated with a visit to MIT. Each participant performed a series of dosimetry measurements under equivalent irradiation conditions using methods appropriate to their clinical protocols. This entailed in-air measurements and dose versus depth measurements in a large water phantom. Thermal neutron flux as well as fast neutron and photon absorbed dose rates were measured. Satisfactory agreement in determining absorbed dose within the experimental uncertainties was obtained between the different groups although the measurement uncertainties are large, ranging between 3% and 30% depending upon the dose component and the depth of measurement. To improve the precision in the specification of absorbed dose amongst the participants, the individually measured dose components were normalized to the results from a single method. Assuming a boron concentration of 15 microg g(-1) that is typical of concentrations realized clinically with the boron delivery compound boronophenylalanine-fructose, systematic discrepancies in the specification of the total biologically weighted dose of up to 10% were apparent between the different groups. The results from these measurements will be used in future to normalize treatment plan calculations between the different clinical dosimetry protocols as Part II of this study.

Quality assurance procedures for the neutron beam monitors at the FiR 1 BNCT facility.

In order to assure the stability of the beam, the reliability of the beam monitoring system and the quality of the patient dose delivered, several procedures are followed at the FiR 1 epithermal beam in Finland. Routine procedures include in-phantom activation measurements before each patient treatment and a long-term follow-up of the results. The sensitivity of the beam monitors to external objects in the beam and to variations in the control rod positions in the reactor has been checked and found insignificant. The linearity of the beam monitor channels has been checked with activation measurements. It was found that due to saturation effects a correction of 11% has to be applied when extrapolating results from experiments at low power to full power using the reference monitor channel. The correction is even larger for other channels with higher count rates.

Advantage and limitations of weighting factors and weighted dose quantities and their units in boron neutron capture therapy.

Defining the parameters influencing the biological reaction due to absorbed dose is a continuous topic of research. The main goal of radiobiological research is to translate the measurable dose of ionizing radiation to a quantitative expression of biological effect. Mathematical models based on different biological approaches (e.g., skin reaction, cell culture) provide some estimations that are often misleading and, to some extent, dangerous. Conventional radiotherapy is the simplest case because the primary radiation and secondary radiation are both low linear energy transfer (LET) radiation and have about the same relative biological effectiveness (RBE). Nevertheless, for this one-dose-component case, the dose-effect curves are not linear. In fact, the total absorbed dose and the absorbed dose per fraction as well as the time schedule of the fractionation scheme influence the biological effects. Mathematical models such as the linear-quadratic model can only approximate biological effects. With regard to biological effects, fast neutron therapy is more complex than conventional radiotherapy. Fast neutron beams are always contaminated by gamma rays. As a consequence, biological effects are due to two components, a high-LET component (neutrons) and a low-LET component (photons). A straight transfer of knowledge from conventional radiotherapy to fast neutron therapy is, therefore, not possible: RBE depends on the delivered dose and several other parameters. For dose reporting, the European protocol for fast neutron dosimetry recommends that the total absorbed dose with gamma-ray absorbed dose in brackets is stated. However, boron neutron capture therapy (BNCT) is an even more complex case, because the total absorbed dose is due to four dose components with different LET and RBE. In addition, the terminology and units used by the different BNCT groups is confusing: absorbed dose and weighted dose are both to be stated in grays and are never "photon equivalent." The ICRU/IAEA made proposals, which should be followed by all BNCT groups, to report always the four absorbed dose components, boron dose DB, proton dose Dp, gamma-ray dose Dgamma, and neutron dose Dn, as well as the sum DT of all components, as total absorbed dose, together with the total weighted dose Dw (to be used only for internal purposes, indicating the used weighting factors) at all points of interest and the treatment conditions.

Computational study of the required dimensions for standard sized phantoms in boron neutron capture therapy dosimetry.

The minimum size of a water phantom used for calibration of an epithermal neutron beam of the boron neutron capture therapy (BNCT) facility at the VTT FiR 1 research reactor is studied by Monte Carlo simulations. The criteria for the size of the phantom were established relative to the neutron and photon radiation fields present at the thermal neutron fluence maximum in the central beam axis (considered as the reference point). At the reference point, for the most commonly used beam aperture size at FiR 1 (14 cm diameter), less than 1% disturbance of the neutron and gamma radiation fields in a phantom were achieved with a minimum a 30 cm x 30 cm cross section of the phantom. For the largest 20 cm diameter beam aperture size, a minimum 40 cm x 40 cm cross-section of the phantom and depth of 20 cm was required to achieve undisturbed radiation field. This size can be considered as the minimum requirement for a reference phantom for dosimetry at FiR 1. The secondary objective was to determine the phantom dimensions for full characterization of the FiR 1 beam in a rectangular water phantom. In the water scanning phantom, isodoses down to the 5% level are measured for the verifications of the beam model in the dosimetric and treatment planning calculations. The dose distribution results without effects caused by the limited phantom size were achieved for the maximum aperture diameter (20 cm) with a 56 cm x 56 cm x 28 cm rectangular phantom. A similar approach to study the required minimum dimensions of the reference and water scanning phantoms can be used for epithermal neutron beams at the other BNCT facilities.

Monte Carlo model of the Studsvik BNCT clinical beam: description and validation.

The neutron beam at the Studsvik facility for boron neutron capture therapy (BNCT) and the validation of the related computational model developed for the MCNP-4B Monte Carlo code are presented. Several measurements performed at the epithermal neutron port used for clinical trials have been made in order to validate the Monte Carlo computational model. The good general agreement between the MCNP calculations and the experimental results has provided an adequate check of the calculation procedure. In particular, at the nominal reactor power of 1 MW, the calculated in-air epithermal neutron flux in the energy interval between 0.4 eV-10 keV is 3.24 x 10(9) n cm(-2) s(-1) (+/- 1.2% 1 std. dev.) while the measured value is 3.30 x 10(9) n cm(-20 s(-1) (+/- 5.0% 1 std. dev.). Furthermore, the calculated in-phantom thermal neutron flux, equal to 6.43 x 10(9) n cm(-2) s(-1) (+/- 1.0% 1 std. dev.), and the corresponding measured value of 6.33 X 10(9) n cm(-2) s(-1) (+/- 5.3% 1 std. dev.) agree within their respective uncertainties. The only statistically significant disagreement is a discrepancy of 39% between the MCNP calculations of the in-air photon kerma and the corresponding experimental value. Despite this, a quite acceptable overall in-phantom beam performance was obtained, with a maximum value of the therapeutic ratio (the ratio between the local tumor dose and the maximum healthy tissue dose) equal to 6.7. The described MCNP model of the Studsvik facility has been deemed adequate to evaluate further improvements in the beam design as well as to plan experimental work.

The EORTC Boron Neutron Capture Therapy (BNCT) Group: achievements and future projects.

Boron Neutron Capture Therapy (BNCT) is an experimental treatment modality that takes place in a nuclear research reactor. To progress from preclinical studies to patient treatment is a challenge requiring strict quality management and special solutions to licensing, liability, insurance, responsibility and logistics. The European Organisation for the Research and Treatment of Cancer (EORTC) BNCT group has started the first European clinical trial of BNCT for glioblastoma patients at the European High Flux Reactor (HFR) in Petten, The Netherlands, conducted by the Department of Radiotherapy of the University of Essen, Germany. A very strict quality management had to be installed following the European rules on safety and quality assurance for nuclear research reactors, for radioprotection, for radiotherapy and for clinical trials. The EORTC BNCT Group has created a virtual European-wide hospital to handle the complex management of patients treated with BNCT. New clinical trials are currently under development.