Histamine reduces boron neutron capture therapy-induced mucositis in an oral precancer model.

OBJECTIVES: Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and inhibit long-term tumor development from field-cancerized tissue in the hamster cheek pouch model. However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT-induced severe mucositis in field-cancerized tissue. MATERIALS AND METHODS: Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh : histamine 5 mg kg(-1) ; Hislow : histamine 1 mg kg(-1) ; and JNJ7777120: 10 mg kg(-1). RESULTS: Hislow reduced the incidence of severe mucositis in field-cancerized tissue to 17% vs CONTROL: 55%; Hishigh : 67%; JNJ7777120: 57%. Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration. CONCLUSION: Histamine reduces BNCT-induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT-induced radiotoxicity in patients with head and neck cancer.

Biodistribution of the boron carriers boronophenylalanine (BPA) and/or decahydrodecaborate (GB-10) for Boron Neutron Capture Therapy (BNCT) in an experimental model of lung metastases.

BNCT was proposed for the treatment of diffuse, non-resectable tumors in the lung. We performed boron biodistribution studies with 5 administration protocols employing the boron carriers BPA and/or GB-10 in an experimental model of disseminated lung metastases in rats. All 5 protocols were non-toxic and showed preferential tumor boron uptake versus lung. Absolute tumor boron concentration values were therapeutically useful (25-76ppm) for 3 protocols. Dosimetric calculations indicate that BNCT at RA-3 would be potentially therapeutic without exceeding radiotolerance in the lung.

Boron neutron capture therapy for oral precancer: proof of principle in an experimental animal model.

OBJECTIVES: Field-cancerized tissue can give rise to second primary tumours, causing therapeutic failure. Boron neutron capture therapy (BNCT) is based on biological targeting and would serve to treat undetectable foci of malignant transformation. The aim of this study was to optimize BNCT for the integral treatment for oral cancer, with particular emphasis on the inhibitory effect on tumour development originating in precancerous conditions, and radiotoxicity of different BNCT protocols in a hamster cheek pouch oral precancer model. MATERIALS AND METHODS: Groups of cancerized hamsters were locally exposed to single or double (2 or 4 weeks apart) applications of BNCT at different dose levels, mediated by the boron compounds boronophenylalanine (BPA) or BPA and decahydrodecaborate (GB-10) administered jointly. Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumour development from field-cancerized tissue and mucositis were followed for 8 months. RESULTS: A double application (4 weeks apart) of BNCT mediated by GB-10+ BPA at a total dose of 10 Gy in two 5-Gy doses rendered the best therapeutic advantage (63-100% inhibition of tumour development from field-cancerized tissue), minimizing dose-limiting mucositis. CONCLUSION: BNCT can be optimized for the integral treatment for head and neck cancer, considering the implications for field-cancerized tissue.

Spectral performance of a composite single-crystal filtered thermal neutron beam for BNCT research at the University of Missouri.

Parameter studies, design calculations and initial neutronic performance measurements have been completed for a new thermal neutron beamline to be used for neutron capture therapy cell and small-animal radiobiology studies at the University of Missouri Research Reactor. The beamline features the use of single-crystal silicon and bismuth sections for neutron filtering and for reduction of incident gamma radiation. The calculated and measured thermal neutron fluxes produced at the irradiation location are 9.6 x 10(8) and 8.8 x 10(8)neutrons/cm(2)s, respectively. Calculated and measured cadmium ratios (Au foils) are 217 and 132. These results indicate a well-thermalized neutron spectrum with sufficient thermal neutron flux for a variety of small animal BNCT studies.

Dosimetry and radiobiology at the new RA-3 reactor boron neutron capture therapy (BNCT) facility: application to the treatment of experimental oral cancer.

The National Atomic Energy Commission of Argentina (CNEA) constructed a novel thermal neutron source for use in boron neutron capture therapy (BNCT) applications at the RA-3 research reactor facility located in Buenos Aires. The aim of the present study was to perform a dosimetric characterization of the facility and undertake radiobiological studies of BNCT in an experimental model of oral cancer in the hamster cheek pouch. The free-field thermal flux was 7.1 x 10(9) n cm(-2)s(-1) and the fast neutron flux was 2.5 x 10(6) n cm(-2)s(-1), indicating a very well-thermalized neutron field with negligible fast neutron dose. For radiobiological studies it was necessary to shield the body of the hamster from the neutron flux while exposing the everted cheek pouch bearing the tumors. To that end we developed a lithium (enriched to 95% in (6)Li) carbonate enclosure. Groups of tumor-bearing hamsters were submitted to BPA-BNCT, GB-10-BNCT, (GB-10+BPA)-BNCT or beam only treatments. Normal (non-cancerized) hamsters were treated similarly to evaluate normal tissue radiotoxicity. The total physical dose delivered to tumor with the BNCT treatments ranged from 6 to 8.5 Gy. Tumor control at 30 days ranged from 73% to 85%, with no normal tissue radiotoxicity. Significant but reversible mucositis in precancerous tissue surrounding tumors was associated to BPA-BNCT. The therapeutic success of different BNCT protocols in treating experimental oral cancer at this novel facility was unequivocally demonstrated.

Boron neutron capture therapy (BNCT) inhibits tumor development from precancerous tissue: an experimental study that supports a potential new application of BNCT.

We previously demonstrated the efficacy of boron neutron capture therapy (BNCT) mediated by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and (GB-10+BPA) to control tumors, with no normal tissue radiotoxicity, in the hamster cheek pouch oral cancer model. Herein we developed a novel experimental model of field-cancerization and precancerous lesions (globally termed herein precancerous tissue) in the hamster cheek pouch to explore the long-term potential inhibitory effect of the same BNCT protocols on the development of second primary tumors from precancerous tissue. Clinically, second primary tumor recurrences occur in field-cancerized tissue, causing therapeutic failure. We performed boron biodistribution studies followed by in vivo BNCT studies, with 8 months follow-up. All 3 BNCT protocols induced a statistically significant reduction in tumor development from precancerous tissue, reaching a maximum inhibition of 77-100%. The inhibitory effect of BPA-BNCT and (GB-10+BPA)-BNCT persisted at 51% at the end of follow-up (8 months), whereas for GB-10-BNCT it faded after 2 months. Likewise, beam-only elicited a significant but transient reduction in tumor development. No normal tissue radiotoxicity was observed. At 8 months post-treatment with BPA-BNCT or (GB-10+BPA)-BNCT, the precancerous pouches that did not develop tumors had regained the macroscopic and histological appearance of normal (non-cancerized) pouches. A potential new clinical application of BNCT would lie in its capacity to inhibit local regional recurrences.

MINERVA: a multi-modality plugin-based radiation therapy treatment planning system.

Researchers at the INEEL, MSU, LLNL and UCD have undertaken development of MINERVA, a patient-centric, multi-modal, radiation treatment planning system, which can be used for planning and analysing several radiotherapy modalities, either singly or combined, using common treatment planning tools. It employs an integrated, lightweight plugin architecture to accommodate multi-modal treatment planning using standard interface components. The design also facilitates the future integration of improved planning technologies. The code is being developed with the Java programming language for interoperability. The MINERVA design includes the image processing, model definition and data analysis modules with a central module to coordinate communication and data transfer. Dose calculation is performed by source and transport plugin modules, which communicate either directly through the database or through MINERVA's openly published, extensible markup language (XML)-based application programmer's interface (API). All internal data are managed by a database management system and can be exported to other applications or new installations through the API data formats. A full computation path has been established for molecular-targeted radiotherapy treatment planning, with additional treatment modalities presently under development.

MINERVA-a multi-modal radiation treatment planning system.

Researchers at the Idaho National Engineering and Environmental Laboratory and Montana State University have undertaken development of MINERVA, a patient-centric, multi-modal, radiation treatment planning system. This system can be used for planning and analyzing several radiotherapy modalities, either singly or combined, using common modality independent image and geometry construction and dose reporting and guiding. It employs an integrated, lightweight plugin architecture to accommodate multi-modal treatment planning using standard interface components. The MINERVA design also facilitates the future integration of improved planning technologies. The code is being developed with the Java Virtual Machine for interoperability. A full computation path has been established for molecular targeted radiotherapy treatment planning, with the associated transport plugin developed by researchers at the Lawrence Livermore National Laboratory. Development of the neutron transport plugin module is proceeding rapidly, with completion expected later this year. Future development efforts will include development of deformable registration methods, improved segmentation methods for patient model definition, and three-dimensional visualization of the patient images, geometry, and dose data. Transport and source plugins will be created for additional treatment modalities, including brachytherapy, external beam proton radiotherapy, and the EGSnrc/BEAMnrc codes for external beam photon and electron radiotherapy.

Flux and instrumentation upgrade for the epithermal neutron beam facility at Washington State University.

An epithermal neutron beam facility for preclinical neutron capture therapy research has been constructed at the Washington State University TRIGA research reactor installation. Subsequent to a recent upgrade, this new facility offers a high-purity epithermal beam with intensity on the order of 1.2x10(9)n/cm(2)s. Key features include a fluoride-based design for the neutron filtering and moderating components as well as a novel collimator design that allows ease of assembly and disassembly of the beamline components.

Optimization of an accelerator-based epithermal neutron source for neutron capture therapy.

A modeling investigation was performed to choose moderator material and size for creating optimal epithermal neutron beams for BNCT based on a proton accelerator and the (7)Li(p,n)(7)Be reaction as a neutrons source. An optimal configuration is suggested for the beam shaping assembly made from polytetrafluoroethylene and magnesium fluorine to be placed on high current IPPE proton accelerator KG-2.5. Results of calculation were experimentally tested and are in good agreement with measurements.

Modification of the University of Washington Neutron Radiotherapy Facility for optimization of neutron capture enhanced fast-neutron therapy.

A modified neutron production target assembly has been developed to provide improved performance of the proton-cyclotron-based neutron radiotherapy facility at the University of Washington for applications involving neutron capture enhanced fast-neutron therapy. The new target produces a neutron beam that yields essentially the same fast-neutron physical depth-dose distribution as is produced by the current UW clinical system, but that also has an increased fraction of BNCT enhancement relative to the total therapeutic dose. The modified target is composed of a 5-millimeter layer of beryllium, followed by a 2.5-millimeter layer of tungsten, with a water-cooled copper backing. Measurements of the free-field neutron spectrum of the beam produced by the new target were performed using activation foils with a direct spectral unfolding technique. Water phantom measurements were performed using a tissue-equivalent ion chamber to characterize the fast-neutron depth-dose curve and sodium activation in soda-lime glass beads to characterize the thermal-neutron flux (and thus the expected neutron capture dose enhancement) as a function of depth. The results of the various measurements were quite consistent with expectations based on the design calculations for the modified target. The spectrum of the neutron beam produced by the new target features an enhanced low-energy flux component relative to the spectrum of the beam produced by the standard UW target. However, it has essentially the same high-energy neutron flux, with a reduced flux component in the mid-range of the energy spectrum. As a result, the measured physical depth-dose curve in a large water phantom has the same shape compared to the case of the standard UW clinical beam, but approximately twice the level of BNCT enhancement per unit background neutron dose at depths of clinical interest. In-vivo clinical testing of BNCT-enhanced fast-neutron therapy for canine lung tumors using the new beam was recently initiated.

Boron neutron capture therapy (BNCT): implications of neutron beam and boron compound characteristics.

The potential efficacy of boron neutron capture therapy (BNCT) for malignant glioma is a significant function of epithermal-neutron beam biophysical characteristics as well as boron compound biodistribution characteristics. Monte Carlo analyses were performed to evaluate the relative significance of these factors on theoretical tumor control using a standard model. The existing, well-characterized epithermal-neutron sources at the Brookhaven Medical Research Reactor (BMRR), the Petten High Flux Reactor (HFR), and the Finnish Research Reactor (FiR-1) were compared. Results for a realistic accelerator design by the E. O. Lawrence Berkeley National Laboratory (LBL) are also compared. Also the characteristics of the compound p-Boronophenylaline Fructose (BPA-F) and a hypothetical next-generation compound were used in a comparison of the BMRR and a hypothetical improved reactor. All components of dose induced by an external epithermal-neutron beam fall off quite rapidly with depth in tissue. Delivery of dose to greater depths is limited by the healthy-tissue tolerance and a reduction in the hydrogen-recoil and incident gamma dose allow for longer irradiation and greater dose at a depth. Dose at depth can also be increased with a beam that has higher neutron energy (without too high a recoil dose) and a more forward peaked angular distribution. Of the existing facilities, the FiR-1 beam has the better quality (lower hydrogen-recoil and incident gamma dose) and a penetrating neutron spectrum and was found to deliver a higher value of Tumor Control Probability (TCP) than other existing beams at shallow depth. The greater forwardness and penetration of the HFR the FiR-1 at greater depths. The hypothetical reactor and accelerator beams outperform at both shallow and greater depths. In all cases, the hypothetical compound provides a significant improvement in efficacy but it is shown that the full benefit of improved compound is not realized until the neutron beam is fully optimized.

Computational dosimetry and treatment planning for boron neutron capture therapy.

The technology for computational dosimetry and treatment planning for Boron Neutron Capture Therapy (BNCT) has advanced significantly over the past few years. Because of the more complex nature of the problem, the computational methods that work well for treatment planning in photon radiotherapy are not applicable to BNCT. The necessary methods have, however, been developed and have been successfully employed both for research applications as well as human trials, although further improvements in speed are needed for routine clinical applications. Computational geometry for BNCT applications can be constructed directly from tomographic medical imagery and computed radiation dose distributions can be readily displayed in formats that are familiar to the radiotherapy community.

Methods for radiation dose distribution analysis and treatment planning in boron neutron capture therapy.

This article presents a survey of recent progress in the development and application of analytical methods for calculating macroscopic and microscopic radiation dose distributions for Boron Neutron Capture Therapy (BNCT). Such calculations are an essential component of in vivo BNCT research and will ultimately also be required for human BNCT treatment planning. Calculations of macroscopic absorbed dose distributions for BNCT are more complex than for photon therapy. There are several different dose components, each of which has its own characteristic spatial distribution, linear energy transfer, and relative biological effectiveness (RBE). Three-dimensional (3-D) energy-dependent radiation transport models with a detailed treatment of particle scattering are required. Geometric descriptions for such models are typically constructed directly from medical image data and both the Monte Carlo stochastic simulation method and the discrete-ordinates deterministic approach have been successfully used to perform the necessary radiation transport calculations. Microdosimetric effects can profoundly influence the therapeutic benefit that may be attainable in BNCT. These effects must be carefully taken into account in the interpretation of experimental data, especially when correlating observed in vivo radiobiological response with absorbed radiation dose. Calculations of microdosimetric parameters for BNCT are typically performed using the Monte Carlo method to generate single-event energy deposition frequency distributions for critical targets in various cell types of interest. This information is useful in the development of apparent RBE factors, or "compound factors" for the various dose components in BNCT.

Macroscopic geometric heterogeneity effects in radiation dose distribution analysis for boron neutron capture therapy.

Calculations of radiation flux and dose distributions for boron neutron capture therapy (BNCT) of brain tumors are typically performed using sophisticated three-dimensional analytical models based on either a homogeneous approximation or a simplified few-region approximation to the actual highly heterogeneous geometry of the irradiation volume. Such models should be validated by comparison with calculations using detailed models in which all significant macroscopic tissue heterogeneities and geometric structures are explicitly represented as faithfully as possible. This paper describes such a validation exercise for BNCT of canine brain tumors. Geometric measurements of the canine anatomical structures of interest for this work were performed by dissecting and examining two essentially identical Labrador retriever heads. Chemical analyses of various tissue samples taken during the dissections were conducted to obtain measurements of elemental compositions for the tissues of interest. The resulting geometry and tissue composition data were then used to construct a detailed heterogeneous calculational model of the Labrador head. Calculations of three-dimensional radiation flux distributions pertinent to BNCT were performed for this model using the TORT discrete-ordinates radiation transport code. The calculations were repeated for a corresponding volume-weighted homogeneous-tissue model. Comparison of the results showed that peak neutron and photon flux magnitudes were quite similar for the two models (within 5%), but that the spatial flux profiles were shifted in the heterogeneous model such that the fluxes in some locations away from the peak differed from the corresponding fluxes in the homogeneous model by as much as 10%-20%. Differences of this magnitude can be therapeutically significant, emphasizing the need for proper validation of simplified treatment planning models.

Demonstration of three-dimensional deterministic radiation transport theory dose distribution analysis for boron neutron capture therapy.

The Monte Carlo stochastic simulation technique has traditionally been the only well-recognized method for computing three-dimensional radiation dose distributions in connection with boron neutron capture therapy (BNCT) research. A deterministic approach to this problem would offer some advantages over the Monte Carlo method. This paper describes an application of a deterministic method to analytically simulate BNCT treatment of a canine head phantom using the epithermal neutron beam at the Brookhaven medical research reactor (BMRR). Calculations were performed with the TORT code from Oak Ridge National Laboratory (ORNL), an implementation of the discrete ordinates, or Sn method. Calculations were from first principles and used no empirical correction factors. The phantom surface was modeled by flat facets of approximately 1 cm2. The phantom interior was homogeneous. Energy-dependent neutron and photon scalar fluxes were calculated on a 32 x 16 x 22 mesh structure with 96 discrete directions in angular phase space. The calculation took 670 min on an Apollo DN10000 workstation. The results were subsequently integrated over energy to obtain full three-dimensional dose distributions. Isodose contours and depth-dose curves were plotted for several separate dose components of interest. Phantom measurements were made by measuring neutron activation (and therefore neutron flux) as a function of depth in copper-gold alloy wires that were inserted through catheters placed in holes drilled in the phantom. Measurements agreed with calculations to within about 15%. The calculations took about an order of magnitude longer than comparable Monte Carlo calculations but provided various conveniences, as well as a useful check.

Physics design for the Brookhaven Medical Research Reactor epithermal neutron source.

A collaborative effort by researchers at the Idaho National Engineering Laboratory and the Brookhaven National Laboratory has resulted in the design and implementation of an epithermal-neutron source at the Brookhaven Medical Research Reactor (BMRR). Large aluminum containers, filled with aluminum oxide tiles and aluminum spacers, were tailored to pre-existing compartments on the animal side of the reactor facility. A layer of cadmium was used to minimize the thermal-neutron component. Additional bismuth was added to the pre-existing bismuth shield to minimize the gamma component of the beam. Lead was also added to reduce gamma streaming around the bismuth. The physics design methods are outlined in this paper. Information available to date shows close agreement between calculated and measured beam parameters. The neutron spectrum is predominantly in the intermediate energy range (0.5 eV - 10 keV). The peak flux intensity is 6.4E + 12 n/(m2.s.MW) at the center of the beam on the outer surface of the final gamma shield. The corresponding neutron current is 3.8E + 12 n/(m2.s.MW). Presently, the core operates at a maximum of 3 MW. The fast-neutron KERMA is 3.6E-15 cGy/(n/m2) and the gamma KERMA is 5.0E-16 cGY/(n/m2) for the unperturbed beam. The neutron intensity falls off rapidly with distance from the outer shield and the thermal flux realized in phantom or tissue is strongly dependent on the beam-delimiter and target geometry.