Experimental verification of improved depth-dose distribution using hyper-thermal neutron incidence in neutron capture therapy

We have proposed the utilization of 'hyper-thermal neutrons' for neutron capture therapy (NCT) from the viewpoint of the improvement in the dose distribution in a human body. In order to verify the improved depth-dose distribution due to hyper-thermal neutron incidence, two experiments were carried out using a test-type hyper-thermal neutron generator at a thermal neutron irradiation field in Kyoto University Reactor (KUR), which is actually utilized for NCT clinical irradiation. From the free-in-air experiment for the spectrum-shift characteristics, it was confirmed that the hyper-thermal neutrons of approximately 860 K at maximum could be obtained by the generator. From the phantom experiment, the improvement effect and the controllability for the depth-dose distribution were confirmed. For example, it was found that the relative neutron depth-dose distribution was about 1 cm improved with the 860 K hyper-thermal neutron incidence, compared to the normal thermal neutron incidence.     

Studies on depth-dose-distribution controls by deuteration and void formation in boron neutron capture therapy

Physical studies on (i) replacement of heavy water for body water (deuteration), and (ii) formation of a void in human body (void formation) were performed as control techniques for dose distribution in a human head under neutron capture therapy. Simulation calculations were performed for a human-head-size cylindrical phantom using a two-dimensional transport calculation code for mono-energetic incidences of higher-energy epi-thermal neutrons (1.2-10 keV), lower-energy epi-thermal neutrons (3.1-23 eV) and thermal neutrons (1 meV to 0.5 eV). The deuteration was confirmed to be effective both in thermal neutron incidence and in epi-thermal neutron incidence from the viewpoints of improvement of the thermal neutron flux distribution and elimination of the secondary gamma rays. For the void formation, a void was assumed to be 4 cm in diameter and 3 cm in depth at the surface part in this study. It was confirmed that the treatable depth was improved almost 2 cm for any incident neutron energy in the case of the 10 cm irradiation field diameter. It was made clear that the improvement effect was larger in isotropic incidence than in parallel incidence, in the case that an irradiation field size was delimited fitting into a void diameter.     

Improvement of dose distribution by central beam shielding in boron neutron capture therapy

Since boron neutron capture therapy (BNCT) with epithermal neutron beams started at the Kyoto University Reactor (KUR) in June 2002, nearly 200 BNCT treatments have been carried out. The epithermal neutron irradiation significantly improves the dose distribution, compared with the previous irradiation mainly using thermal neutrons. However, the treatable depth limit still remains. One effective technique to improve the limit is the central shield method. Simulations were performed for the incident neutron energies and the annular components of the neutron source. It was clear that thermal neutron flux distribution could be improved by decreasing the lower energy neutron component and the inner annular component of the incident beam. It was found that a central shield of 4-6 cm diameter and 10 mm thickness is effective for the 12 cm diameter irradiation field. In BNCT at KUR, the depth dose distribution can be much improved by the central shield method, resulting in a relative increase of the dose at 8 cm depth by about 30%. In addition to the depth dose distribution, the depth dose profile is also improved. As the dose rate in the central area is reduced by the additional shielding, the necessary irradiation time, however, increases by about 30% compared to normal treatment.     

A prototype epithermal neutron beam for boron neutron capture therapy

An epithermal neutron beam has been designed and tested at the Georgia Institute of Technology's 5-MW Research Reactor. The prototype facility consists of aluminum and sulfur disks in a tangential beam port for fast neutron filtration. A cadmium sheet at the port exit removes the thermal neutrons from the transmitted beam, leaving an intensely epithermal neutron beam spanning five energy decades, each contributing to the flux demanded by boron neutron capture therapy. The thermal neutron flux generated by the incident epithermal neutrons in a polyethylene head phantom peaks at a depth of 3 cm and remains above the incident thermal flux to a 7-cm depth. The beam thus provides the penetration required for treating deep-seated gliomas. Photon contamination in the prototype facility is high, and a number of basic modifications are proposed for reducing it to safer levels.     

Development and characteristics of the HANARO neutron irradiation facility for applications in the boron neutron capture therapy field

The HANARO neutron irradiation facility for various applications in the boron neutron capture therapy (BNCT) field was developed, and its characteristics were investigated. In order to obtain the sufficient thermal neutron flux with a low level of contamination by fast neutrons and gamma rays, a radiation filtering method was adopted. The radiation filter was designed by using a silicon single crystal, cooled by liquid nitrogen, and a bismuth crystal. The installation of the main components of the irradiation facility and the irradiation room was finished. Neutron beam characteristics were measured by using bare and cadmium-covered gold foils and wires. The in-phantom neutron flux distribution was measured for flux mapping inside the phantom. The gamma-ray dose was determined by using TLD-700 thermoluminescence dosimeters. The thermal and fast neutron fluxes and the gamma-ray dose were calculated by using the MCNP code, and they were compared with experimental data. The thermal neutron flux and Cd ratio available at this facility were confirmed to be 1.49 x 10(9) n cm(-2) s(-1) and 152, respectively. The maximum neutron flux inside the phantom was measured to be 2.79 x 10(9) n cm(-2) s(-1) at a depth of 3 mm in the phantom. The two-dimensional in-phantom neutron flux distribution was determined, and significant neutron irradiation was observed within 20 mm from the phantom surface. The gamma-ray dose rate for the free beam condition was expected to be about 80 cGy h(-1). These experimental results were reasonably well supported by calculation using the facility design code. This HANARO thermal neutron facility can be used not only for clinical trials, but also for various pre-clinical studies in the BNCT field.     

Controllability of depth dose distribution for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor

The updating construction of the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor has been performed from November 1995 to March 1996 mainly for the improvement in neutron capture therapy. On the performance, the neutron irradiation modes with the variable energy spectra from almost pure thermal to epi-thermal neutrons became available by the control of the heavy-water thickness in the spectrum shifter and by the open-and-close of the cadmium and boral thermal neutron filters. The depth distributions of thermal, epi-thermal and fast neutron fluxes were measured by activation method using gold and indium, and the depth distributions of gamma-ray absorbed dose rate were measured using thermo-luminescent dosimeter of beryllium oxide for the several irradiation modes. From these measured data, the controllability of the depth dose distribution using the spectrum shifter and the thermal neutron filters was confirmed.     

Increased neutron penetration in partially deuterated water: application to neutron capture therapy

Theoretically, partial deuteration of body water should allow significantly increased neutron penetration in tissue. To evaluate the possible usefulness of partially deuterated water in neutron capture therapy (NCT), neutron flux density distributions were measured in a 23 x 16.5 cm (length x diameter) cylinder for incident thermal and epithermal neutron beams, at 20 and 40 at. % deuteration of water. Relative to neutron flux densities in nondeuterated water, flux densities increased significantly with increasing depth and increasing levels of deuteration. For example, at a depth of 6 cm, flux density was increased approximately 20% to 50% for 20 to 40 at. % deuteration. In a clinical situation, this would increase tumor dose by approximately 30%. Further benefits include the reduced hydrogen neutron capture and the chemical radioprotective effects of partial deuteration for photon radiation.     

Accelerator-based epithermal neutron beam design for neutron capture therapy.

Recent interest in the production of epithermal neutrons for use in boron neutron capture therapy (BNCT) has promoted an investigation into the feasibility of generating such neutrons with a high current proton accelerator. Energetic protons (2.5 MeV) on a 7Li target produce a spectrum of neutrons with maximum energy of roughly 800 keV. A number of combinations of D2O moderator, lead reflector, 6Li thermal neutron filtration, and D2O/6Li shielding will result in a useful epithermal flux of 1.6 x 10(8) n/s at the patient position. The neutron beam is capable of delivering 3000 RBE-cGy to a tumor at a depth of 7.5 cm in a total treatment time of 60-93 min (depending on RBE values used and based on a 24-cm diameter x 19-cm length D2O moderator). Treatment of deeper tumors with therapeutic advantage would also be possible. Maximum advantage depths (RBE weighted) of 8.2-9.2 (again depending on RBE values and precise moderator configuration) are obtained in a right-circular cylindrical phantom composed of brain-equivalent material with an advantage ratio of 4.7-6.3. A tandem cascade accelerator (TCA), designed and constructed at Science Research Laboratory (SRL) in Somerville MA, can provide the required proton beam parameters for BNCT of deep-seated tumors. An optimized configuration of materials required to shift the accelerator neutron spectrum down to therapeutically useful energies has been designed using Monte Carlo simulation in the Whitaker College Biomedical Imaging and Computation Laboratory at MIT. Actual construction of the moderator/reflector assembly is currently underway.     

Boron neutron capture therapy for the treatment of cerebral gliomas. I. Theoretical evaluation of the efficacy of various neutron beams.

The technique of boron neutron capture therapy in the treatment of cerebral gliomas depends upon the selective loading of the tumor with a 10B-enriched compound and subsequent irradiation of the brain with low-energy neutrons. The charged particles produced in the 10B (n,alpha) 7Li reaction have ranges in tissue of less than 10 mum so that the dose distribution closely follows the 10B distribution even to the cellular level. The effectiveness of this therapy procedure is dependent not only on the 10B compound but on the spectral characteristics of the neutron source as well. Hence, an optimization of these characteristics will increase the chances of therapeutic success. Transport calculations using a neutral particle transport code have been made to determine the dose-depth distributions within a simple head phantom for five different incident neutron beams. Comparison of these beams to determine their relative therapeutic efficacy was made by the use of a maximum useable depth criterion. In particular, with presently available compounds, the MIT reactor (MITR) therapy beam (a) is not inferior to a pure thermal neutron beam, (b) would be marginally improved if its gamma-ray contamination were eliminated, (c) is superior to a partially 10B-filtered MITR beam, and (d) produces a maximum useable depth which is strongly dependent upon the tumor-to-blood ratio of 10B concentrations and weakly dependent upon the absolute 10B concentration in tumor. A pure epithermal neutron beam with a mean energy of 37 eV is shown to have close to the optimal characteristics for boron neutron capture therapy. Futhermore, these optimal characteristics can be approximated by a judiciously D2O moderated and 10B-filtered 252Cf neutron source. This tailored 252Cf source would have at least a 1.5 cm greater maximum useable depth than the MITR therapy beam for realistic 10B concentrations. However, at least one gram of 252Cf would be needed to make this a practical therapy source. If the moderated 252Cf source is not 10B filtered, the resultant neutron beam has characteristics similar to those of the MITR beam with no gamma-ray contamination. For usch a beam, 100 mg of 252Cf would produce a flux of 2.4 X 10(8) neutrons/(cm2 sec), which is an intensity suitable for therapy applications.     

Design studies related to an in vivo neutron activation analysis facility for measuring total body nitrogen.

Design studies relating to an in vivo prompt capture neutron activation analysis facility measuring total body nitrogen are presented. The basis of the design is a beryllium-graphite neutron collimator and reflector configuration for (alpha, n) type radionuclide neutron sources (238PuBe or 241AmBe), so as to reflect leaking, or out-scattered, neutrons towards the subject. This improves the ratio of thermal neutron flux to dose and the spatial distribution of thermal flux achieved with these sources, whilst retaining their advantage of long half-lives as compared to 252Cf based systems. The common problem of high count-rate at the detector, and therefore high nitrogen region of interest background due to pile-up, is decreased by using a set of smaller (5.1 cm diameter x 10.2 cm long) NaI(Tl) detectors instead of large ones. The facility described presents a relative error of nitrogen measurement of 3.6% and a nitrogen to background ratio of 2.3 for 0.45 mSv skin dose (assuming ten 5.1 cm x 10.2 cm NaI(Tl) detectors).     

In-phantom dosimetry for the 13C(d,n)14N reaction as a source for accelerator-based BNCT

The use of the 13C(d,n) 14N reaction at Ed=1.5 MeV for accelerator-based boron neutron capture therapy (AB-BNCT) is investigated. Among the deuteron-induced reactions at low incident energy, the 3C(d,n)14N reaction turns out to be one of the best for AB-BNCT because of beneficial materials properties inherent to carbon and its relatively large neutron production cross section. The deuteron beam was produced by a tandem accelerator at MIT's Laboratory for Accelerator Beam Applications (LABA) and the neutron beam shaping assembly included a heavy water moderator and a lead reflector. The resulting neutron spectrum was dosimetrically evaluated at different depths inside a water-filled brain phantom using the dual ionization chamber technique for fast neutrons and photons and bare and cadmium-covered gold foils for the thermal neutron flux. The RBE doses in tumor and healthy tissue were calculated from experimental data assuming a tumor 10B concentration of 40 ppm and a healthy tissue 10B concentration of 11.4 ppm (corresponding to a reported ratio of 3.5:1). All results were simulated using the code MCNP, a general Monte Carlo radiation transport code capable of simulating electron, photon, and neutron transport. Experimental and simulated results are presented at 1, 2, 3, 4, 6, 8, and 10 cm depths along the brain phantom centerline. An advantage depth of 5.6 cm was obtained for a treatment time of 56 min assuming a 4 mA deuteron current and a maximum healthy tissue dose of 12.5 RBE Gy.     

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

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

Fission converter and metal-oxide-semiconductor field effect transistor study of thermal neutron flux distribution in an epithermal neutron therapy beam.

The depth distribution of the thermal neutron flux is a major factor in boron neutron capture therapy (BNCT) in determining the efficiency of cell sterilization. In this paper the fission detector method is developed and applied to measure the in-phantom thermal neutron flux depth distribution. Advantages of the fission detector include small size, direct measurement of thermal neutron flux in a mixed radiation field of BNCT beam, self-calibration, and the possibility of on-line measurement. The measurements were performed at epithermal a BNCT facility. The experimental results were compared with the thermal neutron flux calculated by the Monte Carlo method and found to be in good agreement.     

Measurement of total body nitrogen and oxygen by irradiation with cyclotron neutrons and 'delayed' gamma ray counting

Measurement of total body nitrogen is assuming increasing importance in the nutritional evaluation of seriously ill patients. Nitrogen has been previously measured either by counting (i) the annihilation radiation from 13N immediately after neutron irradiation with 14 MeV neutrons or (ii) the 'prompt' gamma rays from thermal neutron capture by 14N during irradiation with 14 MeV neutrons or with those produced by isotopic sources or a cyclotron. The present work describes studies into the feasibility of measuring 13N produced by irradiation with a neutron beam from the MRC Cyclotron. A complication of this method is that 13N is also produced in a reaction with 16O. Direct measurement of oxygen by use of the reactions 16O(n, p)16N or 16O(n, 2n)15O enables this interference to be estimated. The former reaction is possible with both 14 meV and cyclotron-produced neutrons but the 7.1 s half-life of 16N requires detectors to be placed in or very close to the irradiation site. In our particular circumstances this is not possible but the more energetic cyclotron neutron spectrum allows the production of 15O which has a half-life of 2.05 min and can be measured in a remote whole-body counter. A disadvantage with the cyclotron beam, in comparison with 14 MeV neutrons, is that a higher dose is required for similar accuracy. A reproducibility of about 4% is obtained with a dose equivalent of 0.01 Sv.     

Boron self-shielding effects on dose delivery of neutron capture therapy using epithermal beam and boronophenylalanine

Previous dosimetry studies for boron neutron capture therapy have often neglected the thermal neutron self-shielding effects caused by the 10B accumulation in the brain and the tumor. The neglect of thermal neutron flux depression, therefore, results in an overestimation of the actual dose delivery. The relevant errors are expected to be more pronounced when boronophenylalanine is used in conjunction with an epithermal neutron beam. In this paper, the boron self-shielding effects are calculated in terms of the thermal neutron flux depression across the brain and the dose delivered to the tumors. The degree of boron self-shielding is indicated by the difference between the thermal neutron fluxes calculated with and without considering a 10B concentration as part of the head phantom composition. The boron self-shielding effect is found to increase with increasing 10B concentrations and penetration depths from the skin. The calculated differences for 10B concentrations of 7.5-30 ppm are 2.3%-8.3% at 2.3 cm depth (depth of the maximum brain dose) and 4.6%-17% at 7.3 cm depth (the center of the brain). The additional self-shielding effects by the 10B concentration in a bulky tumor are investigated for a 3-cm-diam spherical tumor located either near the surface (3.3 cm depth) or at the center of the brain (7.3 cm depth) along the beam centerline. For 45 ppm of 10B in the tumor and 15 ppm of 10B in the brain, the dose delivered to the tumors is approximately 10% lower at 3.3 cm depth and 20% lower at the center of the brain, compared to the dose neglecting the boron self-shielding in transport calculations.     

Neutron uniformity studies related to clinical total body in vivo neutron activation analysis.

Methods of assessing the uniformity of thermal and fast neutron fluence in relation to total body in vivo neutron activation analysis are described. Results are presented for 14 MeV neutrons emitted by sealed tube generators housed in a massive concrete shield, representing a substantial source of neutrons degraded in energy. Optimisation of conditions for patient irradiations is discussed and it is shown that acceptable uniformity of fluence can be achieved with little or no premoderation of the incident neutrons.     

Validation of a pencil beam model-based treatment planning system for fast neutron therapy

Treatment planning systems (TPSs) are used to compute dose delivered to the patient. In the case of fast neutron therapy, TPSs are mostly not of general purpose but are dedicated to one facility. This is due to the few fast neutron facilities worldwide and due to the high variation in the neutron energy distributions. Efforts have been undertaken to develop a new TPS that could be applied to all the existing fast neutron facilities. The University Hospital of Essen operates a d (14 MeV) + Be fast neutron beam and the TPS used is based on an empirical model. In a previous study, the empirical model has been evolved to a pencil beam model of 35 monoenergetic neutron beams. Monte Carlo techniques have been utilized to compute distributions of the energy deposition due to primary and scattered neutrons in a simple geometry water phantom. The experimental validation of the method is now presented. Depth dose curves in water of monoenergetic neutrons have been derived from the distributions of energy deposition. The resultant depth dose curves have been utilized in order to determine the depth dose curves of the fast neutron beam of the Essen facility for the 14 radiation field sizes available in this facility. This determination requires the initial neutron spectrum. As this spectrum could not be measured at the Essen facility, the initial neutron spectrum of the Physikalisch Technische Bundesanstalt, Braunschweig, Germany, which operates the same cyclotron, was used. The calculated depth dose curves were compared to experimental depth dose curves that have been obtained in water at the University Hospital of Essen. The comparison between calculated and experimental depth dose curves showed significant deviations in the case of large radiation fields and of depth less than 5 cm. In the case of radiation field areas less than 150 cm2 and depth more than 5 cm (usual clinical situation), the measured and calculated values are in a good agreement. In the case of clinical situation, the dependence on the radiation field size is relatively well taken into account by the model presented here.     

Gadolinium neutron capture therapy for brain tumors: a computer study.

A Monte Carlo computer study of the total dose distribution from neutrons and prompt gamma emissions (but excluding the contribution from conversion and Auger electrons) for gadolinium neutron capture therapy of brain tumors has been carried out in order to test the theoretic feasibility of this modality using commercially available magnetic resonance contrast media. The three-dimensional dose distribution calculations were performed in a spherical head phantom with a spherical tumor at the center. Potentially achievable gadolinium concentrations of 150 micrograms/g of tissue in tumor and 3 micrograms/g in normal tissue were assumed with enrichment to 79.9% gadolinium-157, as supplied by Oak Ridge National Laboratory. Irradiation was assumed to be with a 2-keV monoenergetic cylindrical epithermal neutron beam having a radius of 4 cm. The three-dimensional thermal neutron fluence resulting from the 2-keV beam propagation through the tissue was modeled. For a single neutron beam, the maximum dose is delivered within the tumor but the dose is very inhomogeneous across the tumor volume due to rapid decrease of thermal neutron fluence with depth. Two parallel opposed neutron beams deliver to the interface of normal and malignant tissue 70%-80% of the maximum dose received at the center of the tumor. To deliver an average tumor dose of 500 cGy in 10 min would require a 2-keV source neutrons number of 8.0 x 10(11) per s within the geometry of the beam.     

Gadolinium as a neutron capture therapy agent.

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

Towards in vivo monitoring of neutron distributions for quality control of BNCT

Dose delivery in boron neutron capture therapy (BNCT) is complex because several components contribute to the dose absorbed in tissue. This dose is largely determined by local boron concentration, thermal neutron distribution and patient positioning. In vivo measurements of these factors would considerably improve quality control and safety. During therapy, a y-ray telescope measures the y-rays emitted following neutron capture by hydrogen and boron in a small volume of the head of a patient. Scans of hydrogen y-ray emissions could be used to verify the actual distribution of thermal neutrons during neutron irradiation. The method was first tested on different phantoms. These measurements showed good agreement with calculations based on thermal neutron distributions derived from a treatment planning program and from Monte Carlo N-particle (MCNP) simulations. Next, the feasibility of telescope scans during patient irradiation therapy was demonstrated. Measurements were reproducible between irradiation fractions. In theory, this method can be used to verify the positioning of the patient in vivo and the delivery of thermal neutrons in tissue. However, differences between measurements and calculations based on a routine treatment planning program were observed. These differences could be used to refine the treatment planning. Further developments will be necessary for this method to become a standard quality control system.