Boron Neutron Capture Therapy Treatment Research Articles

Optimization study for BNCT facility based on a DT neutron generator

Background : A Boron Neutron Capture Therapy (BNCT) facility, based on a DT neutron generator, with the final goal to find out a potenal, alternave, soluon to exisng BNCT treatment facilies which a re based on nuclear reactors is examined. Materials and Method s: With the aim of the MCNP4B Monte Carlo code different beam-shaping assembly (BSA) configuraons were considered. Lead was selected as reflector material while CF 2, D 2O, Fluental, PbF 4, PbF 2, BiF 3, BiF 5, MgF 2, Al 2O3, AlF 3, TiF 3, BeD 2, CaF 2 and 7 LiF were examined as spectrum shi3ers. In order to improve t he quality of the beam �tanium, nickel-60, iron andtanium alloy (Ti 6Al 14 V) were simulated as fast neutrons filters while lead and bismuth were considered as gamma filters. Results: An extensive set of calculaons performed with MCNP4B Monte Carlo code have shown that the combinaon of 7 LiF which accommodates a conic part made of D 2O, then followed by a TiF 3 layer is the opmum moderator design. The use of three different materials for further reducon of fast neutrons, thermal neutrons and gamma rays is necessary. 60

Histological and biochemical analysis of DNA damage after BNCT in rat model

To understand the mechanism of tumor cell death induced by boron neutron capture therapy (BNCT) and to optimize BNCT condition, we used rat tumor graft models and histological and biochemical analyses were carried out focusing on DNA damage response. Rat lymphosarcoma cells were grafted subcutaneously into male Wister rats. The rats with developed tumors were then treated with neutron beam irradiation 45min after injection of 330mg/kg bodyweight boronophenylalanine (10BPA) (+BPA) or saline control (–BPA). BNCT was carried out in the National Nuclear Center of the Republic of Kazakhstan (neutron flux: 1×109nvt/s, fluence: 6×1011nvt) with the presence of background γ-irradiation of 33Gy. 6 and 20h after BNCT treatment, tumors were resected, fixed and subjected to immunohistochemistry and biochemical analyses. Immunostaining of nuclei showed that double strand break (DSB) marker gamma H2AX staining was high in 20h/+BPA sample but not in 20h/–BPA samples. Poly(ADP-ribose), DSB and single strand break markers of DNA, also demonstrated this tendency. These two markers were observed at low levels in unirradiated tissues or 6h after BNCT either under −BPA and +BPA conditions. HMGB1 level increased in 6h/+BPA but not in 6h/−BPA or 20h/+BPA samples. The persistent staining of γH2AX and poly(ADP-ribose) in +BPA group suggests accumulated DSB damage after BNCT. The early HMGB1 upregulation and γH2AX and poly(ADP-ribose) observed later might be the markers for monitoring the DNA damage induced by BNCT.

The Pros and Cons of Preliminary R&D of Boron Neutron Capture Therapy Based on Compact Neutron Generators: A Plan of Collaboration

The characteristics of boron neutron capture therapy (BNCT) for cancer treatment demand, in addition to sufficient fluxes of epithermal neutrons, proper conditions of the neutron sources—compact layout, flexible operation, compatibility with hospital setting, etc. These requirements are best satisfied by compact accelerator-driven sources (CANS). We discuss the trade-offs among different CANS options and the needed R&D in order to advance BNCT to an acceptable level of practical prevalence and cancer treatment scope. We focus our attention on compact neutron generators (CNGs) which are the most compact and least expensive. We argue that the usefulness of D-D CNGs for preliminary studies, in spite of the substantial lower fluxes, can be augmented by high-performance beam-shaping assemblies and discoveries of superior 10B-containing cancer-cell seeking drugs. The plausibility of BNCT treatment of breast cancer using neutrons from a DD-109 CNG (Adelphi Technology, Inc.) is assessed by calculating the distribution of photon equivalent dose on a breast phantom using Monte-Carlo (MCNPX) simulations.

Cell cycle arrest, extracellular matrix changes and intrinsic apoptosis in human melanoma cells are induced by Boron Neutron Capture Therapy

Boron Neutron Capture Therapy (BNCT) involves the selective accumulation of boron carriers in tumor tissue followed by irradiation with a thermal or epithermal neutron beam. This therapy is therefore a cellular irradiation suited to treat tumors that have infiltrated into healthy tissues. BNCT has been used clinically to treat patients with cutaneous melanomas which have a high mortality. Human normal melanocytes and melanoma cells were treated with BNCT at different boronophenylalanine concentrations for signaling pathways analysis. BNCT induced few morphological alterations in normal melanocytes, with a negligible increase in free radical production. Melanoma cells treated with BNCT showed significant extracellular matrix (ECM) changes and a significant cyclin D1 decrease, suggesting cell death by necrosis and apoptosis and cell cycle arrest, respectively. BNCT also induced a significant increase in cleaved caspase-3 and a decrease in the mitochondrial electrical potential with selectivity for melanoma cells. Normal melanocytes had no significant differences due to BNCT treatment, confirming the data from the literature regarding the selectivity of BNCT. The results from this study suggest that some signaling pathways are involved in human melanoma treatment by BNCT, such as cell cycle arrest, ECM changes and intrinsic apoptosis.

Rhodium self‐powered neutron detector as a suitable on‐line thermal neutron flux monitor in BNCT treatments

A rhodium self-powered neutron detector (Rh SPND) has been specifically developed by the Comisión Nacional de Energía Atómica (CNEA) of Argentina to measure locally and in real time thermal neutron fluxes in patients treated with boron neutron capture therapy (BNCT). In this work, the thermal and epithermal neutron response of the Rh SPND was evaluated by studying the detector response to two different reactor spectra. In addition, during clinical trials of the BNCT Project of the CNEA, on-line neutron flux measurements using the specially designed detector were assessed. The first calibration of the detector was done with the well-thermalized neutron spectrum of the CNEA RA-3 reactor thermal column. For this purpose, the reactor spectrum was approximated by a Maxwell-Boltzmann distribution in the thermal energy range. The second calibration was done at different positions along the central axis of a water-filled cylindrical phantom, placed in the mixed thermal-epithermal neutron beam of CNEA RA-6 reactor. In this latter case, the RA-6 neutron spectrum had been well characterized by both calculation and measurement, and it presented some marked differences with the ideal spectrum considered for SPND calibrations at RA-3. In addition, the RA-6 neutron spectrum varied with depth in the water phantom and thus the percentage of the epithermal contribution to the total neutron flux changed at each measurement location. Local (one point-position) and global (several points-positions) and thermal and mixed-field thermal neutron sensitivities were determined from these measurements. Thermal neutron flux was also measured during BNCT clinical trials within the irradiation fields incident on the patients. In order to achieve this, the detector was placed on patient's skin at dosimetric reference points for each one of the fields. System stability was adequate for this kind of measurement. Local mixed-field thermal neutron sensitivities and global thermal and mixed-field thermal neutron sensitivities derived from measurements performed at the RA-6 were compared and no significant differences were found. Global RA-6-based thermal neutron sensitivity showed agreement with pure thermal neutron sensitivity measurements performed in the RA-3 spectrum. Additionally, the detector response proved nearly unchanged by differences in neutron spectra from real (RA-6 BNCT beam) and ideal (considered for calibration calculations at RA-3) neutron source descriptions. The results confirm that the special design of the Rh SPND can be considered as having a pure thermal response for neutron spectra with epithermal-to-thermal flux ratios up to 12%. In addition, the linear response of the detector to thermal flux allows the use of a mixed-field thermal neutron sensitivity of 1.95 ± 0.05 × 10(-21) A n(-1)[middle dot]cm² [middle dot]s. This sensitivity can be used in spectra with up to 21% epithermal-to-thermal flux ratio without significant error due to epithermal neutron and gamma induced effects. The values of the measured fluxes in clinical applications had discrepancies with calculated results that were in the range of -25% to +30%, which shows the importance of a local on-line independent measurement as part of a treatment planning quality control system. The usefulness of the CNEA Rh SPND for the on-line local measurement of thermal neutron flux on BNCT patients has been demonstrated based on an appropriate neutron spectra calibration and clinical applications.

Dosimetric feasibility study for an extracorporeal BNCT application on liver metastases at the TRIGA Mainz

This study investigates the dosimetric feasibility of Boron Neutron Capture Therapy (BNCT) of explanted livers in the thermal column of the research reactor in Mainz. The Monte Carlo code MCNP5 is used to calculate the biologically weighted dose for different ratios of the (10)B-concentration in tumour to normal liver tissue. The simulation results show that dosimetric goals are only partially met. To guarantee effective BNCT treatment the organ has to be better shielded from all gamma radiation.

Boron Determination in Liver Tissue by Combining Quantitative Neutron Capture Radiography (QNCR) and Histological Analysis for BNCT Treatment Planning at the TRIGA Mainz

The typical primary malignancies of the liver are hepatocellular carcinoma and cholangiocarcinoma, whereas colorectal liver metastases are the most frequently occurring secondary tumors. In many cases, only palliative treatment is possible. Boron neutron capture therapy (BNCT) represents a technique that potentially destroys tumor tissue selectively by use of externally induced, locally confined secondary particle irradiation. In 2001 and 2003, BNCT was applied to two patients with colorectal liver metastases in Pavia, Italy. To scrutinize the rationale of BNCT, a clinical pilot study on patients with colorectal liver metastases was carried out at the University of Mainz. The distribution of the (10)B carrier (p-borono-phenylalanine) in the liver and its uptake in cancerous and tumor-free tissue were determined, focusing on a potential correlation between the uptake of p-borono-phenylalanine and the biological characteristics of cancerous tissue. Samples were analyzed using quantitative neutron capture radiography of cryosections combined with histological analysis. Methodological aspects of the combination of these techniques and results from four patients enrolled in the study are presented that indicate that the uptake of p-borono-phenylalanine strongly depends on the metabolic activity of cells.

Kohonen classification applying ‘missing variables’ criterion to evaluate the p‐boronophenylalanine human‐body‐concentration decreasing profile of boron neutron capture therapy patients

AbstractThe irradiation dose in tumor and healthy tissue of a boron neutron capture therapy (BNCT) patient depends on the boron concentration in blood. In most treatments, this concentration is experimentally determined before and after irradiation but not while irradiation is being carried out because it is troublesome to take the blood samples when the patient remains isolated in the irradiation room. A few models are used to predict the boron profile during that period, which until now involves a biexponential decay. For the prediction of decay concentration profiles of the p‐boronophenylalanine (BPA) in the human body during BNCT treatment, a Kohonen‐based neural network method is suggested. The results of various (20 × 20 × 40 Kohonen network) models based on different trainings on the data set of 67 concentration sets (profiles) are described and discussed. The prediction ability and robustness of the modeling method were tested by the leave‐one‐out procedure. The results show that the method is very robust and mostly independent of small variations. It can yield predictions, root mean squared prediction error (RMSPE), with a maximum of 3.30 µg g−1 for the present cases. In order to show the abilities and limitations of the method, the best and the few worst results are discussed in detail. It should be emphasized that one of the main advantages of this method is the automatic improvement in the prediction ability and robustness of the model by feeding it with an increasing number of data. Copyright © 2011 John Wiley & Sons, Ltd.

BNCT treatment planning of recurrent head-and-neck cancer using THORplan

A cooperation program on Boron Neutron Capture Therapy (BNCT) between National Tsing Hua University (NTHU) and Taipei Veterans General Hospital (TPEVGH) was established in 2008. Clinical trial of recurrent head-and-neck cancer is the goal of the program. In this study, treatment plannings of two head-and-neck cancer cases are performed using treatment planning system THORplan developed at NTHU of Taiwan. The patients are assumed to be irradiated under current THOR epithermal neutron beam. The prescription dose is 20 Gy-Eq for at least 80% of tumor volume. The irradiation time to reach the target tumor dose can be kept within 1h. The skin dose is within the limiting dose of 11 Gy-Eq. The spinal cord dose is well within the limiting dose of 10 Gy-Eq. The use of an extension collimator for easier patient positioning is helpful in reducing the dose of eye lens to within the dose limit of 5 Gy-Eq. The irradiation time, however, will increase slightly due to the increase of source-to-tumor distance. The CPU time for treatment planning calculation is ~10 h. With the use of user friendly treatment planning system THORplan, dose planning for BNCT at THOR can be easily performed.

Computational dosimetry of a simulated combined standard X-Rays and BNCT treatment

There has been increasing interest in combining Boron Neutron Capture Therapy (BNCT) with standard radiotherapy, either concomitantly or as a BNCT treatment of a recurrent tumor that was previously irradiated with a medical electron linear accelerator (LINAC). In this work we report the simulated dosimetry of treatments combining X-rays and BNCT.

“Sequential” Boron Neutron Capture Therapy (BNCT): A Novel Approach to BNCT for the Treatment of Oral Cancer in the Hamster Cheek Pouch Model

In the present study the therapeutic effect and potential toxicity of the novel "Sequential" boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential" BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential" BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 ± 12% and 60 ± 22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential" BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue.

Gamma ray energy emission from thick target Be(p,n) reaction

In this work the angular gamma ray spectra emitted from the thick target Be(p,n) reaction with 4 and 5 MeV proton beam were measured with a calibrated high purity germanium detector. The Be(p,n) reaction will be used for neutron production in the BNCT (Boron Neutron Capture Therapy) treatment of the skin melanoma and the explanted liver. A facility for this type of tumor treatment is in progress at the INFN-LNL in the framework of the SPES-BNCT project. The gamma rays determine an additional dose to the patient during the BNCT treatment and the knowledge of their spectrum and yield is absolutely necessary for a correct design of the BNCT facility.

Validation of dose planning calculations for boron neutron capture therapy using cylindrical and anthropomorphic phantoms

In this paper, the accuracy of dose planning calculations for boron neutron capture therapy (BNCT) of brain and head and neck cancer was studied at the FiR 1 epithermal neutron beam. A cylindrical water phantom and an anthropomorphic head phantom were applied with two beam aperture-to-surface distances (ASD). The calculations using the simulation environment for radiation application (SERA) treatment planning system were compared to neutron activation measurements with Au and Mn foils, photon dose measurements with an ionization chamber and the reference simulations with the MCNP5 code. Photon dose calculations using SERA differ from the ionization chamber measurements by 2–13% (disagreement increased along the depth in the phantom), but are in agreement with the MCNP5 calculations within 2%. The 55Mn(n,γ) and 197Au(n,γ) reaction rates calculated using SERA agree within 10% and 8%, respectively, with the measurements and within 5% with the MCNP5 calculations at depths >0.5 cm from the phantom surface. The 55Mn(n,γ) reaction rate represents the nitrogen and boron depth dose within 1%. Discrepancy in the SERA fast neutron dose calculation (of up to 37%) is corrected if the biased fast neutron dose calculation option is not applied. Reduced voxel cell size (⩽0.5 cm) improves the SERA calculation accuracy on the phantom surface. Despite the slight overestimation of the epithermal neutrons and underestimation of the thermal neutrons in the beam model, neutron calculation accuracy with the SERA system is sufficient for reliable BNCT treatment planning with the two studied treatment distances. The discrepancy between measured and calculated photon dose remains unsatisfactorily high for depths >6 cm from the phantom surface. Increasing discrepancy along the phantom depth is expected to be caused by the inaccurately determined effective point of the ionization chamber.

EORTC trial 11001: distribution of two 10B‐compounds in patients with squamous cell carcinoma of head and neck, a translational research/phase 1 trial

Boron neutron capture therapy (BNCT) provides highly targeted delivery of radiation through the limited spatial distribution of its effects. This translational research/phase I clinical trial investigates whether BNCT might be developed as a treatment option for squamous cell carcinoma of head and neck (SCCHN) relying upon preferential uptake of the two compounds, sodium mercaptoundecahydro-closo-dodecaborate (BSH) or L-para-boronophenylalanine (BPA) in the tumour. Before planned tumour resection, three patients received BSH and three patients received BPA. The (10)B-concentration in tissues and blood was measured with prompt gamma ray spectroscopy. Adverse effects from compounds did not occur. After BPA infusion the (10)B-concentration ratio of tumour/blood was 4.0 +/- 1.7. (10)B-concentration ratios of tumour/normal tissue were 1.3 +/- 0.5 for skin, 2.1 +/- 1.2 for muscle and 1.4 +/- 0.01 for mucosa. After BSH infusion the (10)B-concentration ratio of tumour/blood was 1.2 +/- 0.4. (10)B-concentration ratios of tumour/normal tissue were 3.6 +/- 0.6 for muscle, 2.5 +/- 1.0 for lymph nodes, 1.4 +/- 0.5 for skin and 1.0 +/- 0.3 for mucosa. BPA and BSH deliver (10)B to SCCHN to an extent that might allow effective BNCT treatment. Mucosa and skin are the most relevant organs at risk.

Improvement of dose distribution in phantom by using epithermal neutron source based on the Be(p,n) reaction using a 30 MeV proton cyclotron accelerator

In order to generate epithermal neutrons for boron neutron capture therapy (BNCT), we proposed the method of filtering and moderating fast neutrons, which are emitted from the reaction between a beryllium target and 30 MeV protons accelerated by a cyclotron, using an optimum moderator system composed of iron, lead, aluminum, calcium fluoride, and enriched 6LiF ceramic filter. At present, the epithermal-neutron source is under construction since June 2008 at Kyoto University Research Reactor Institute. This system consists of a cyclotron to supply a proton beam of about 1 mA at 30 MeV, a beam transport system, a beam scanner system for heat reduction on the beryllium target, a target cooling system, a beam shaping assembly, and an irradiation bed for patients. In this article, an overview of the cyclotron-based neutron source (CBNS) and the properties of the treatment neutron beam optimized by using the MCNPX Monte Carlo code are presented. The distribution of the RBE (relative biological effectiveness) dose in a phantom shows that, assuming a 10B concentration of 13 ppm for normal tissue, this beam could be employed to treat a patient with an irradiation time less than 30 min and a dose less than 12.5 Gy-eq to normal tissue. The CBNS might be an alternative to the reactor-based neutron sources for BNCT treatments.

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 7.1×10 9 n cm −2 s −1 and the fast neutron flux was 2.5×10 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 6Li) 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.

Development of a new multi-modal Monte-Carlo radiotherapy planning system

A new multi-modal Monte-Carlo radiotherapy planning system (developing code: JCDS-FX) is under development at Japan Atomic Energy Agency. This system builds on fundamental technologies of JCDS applied to actual boron neutron capture therapy (BNCT) trials in JRR-4. One of features of the JCDS-FX is that PHITS has been applied to particle transport calculation. PHITS is a multi-purpose particle Monte-Carlo transport code. Hence application of PHITS enables to evaluate total doses given to a patient by a combined modality therapy. Moreover, JCDS-FX with PHITS can be used for the study of accelerator based BNCT. To verify calculation accuracy of the JCDS-FX, dose evaluations for neutron irradiation of a cylindrical water phantom and for an actual clinical trial were performed, then the results were compared with calculations by JCDS with MCNP. The verification results demonstrated that JCDS-FX is applicable to BNCT treatment planning in practical use.

Verification of the accuracy of BNCT treatment planning system THORplan

THORplan is a treatment planning system developed at Tsing Hua University, Taiwan, for boron neutron capture therapy (BNCT) purpose. It is recently developed with user-friendly interface using Interactive Data Language. In this article the accuracy of THORplan is verified by comparing results of Snyder phantom calculation with the analytical model results of MCNP. Neutron source from THOR epithermal neutron beam is used as the source for the calculation. The thermal neutron flux calculated by THORplan is very close to the reference results. SERA overestimates thermal neutron flux by 2–5%. NCTPlan underestimates thermal neutron flux by 4–9% in most locations. The total weighted dose calculated by THORplan is accurate to within 3% except at the tissue interface. SERA overestimates the total weighted dose at depth > 1.5 cm by 2–5%. NCTPlan underestimates the total weighted dose by ∼10% at depth > 1 cm .

Not boring at all

The element boron is not renowned among biologists, short of a few specialists who know that it is an essential nutrient for plants and an element in boromycin—an antibiotic compound produced by Streptomyces . Yet, on the whole, molecular biologists and, in particular, those in drug development seem to have little use for carbon's left‐hand neighbour in the periodic table. This is about to change. Currently, boron is largely produced in Turkey and the USA, and is used in a wide range of products, including glass, detergents, fire retardants, fibres to reinforce plane fuselages and body armour, and in superhard materials. Now, both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design. > …both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design A series of recent scientific and commercial developments indicate that boron‐based compounds are interesting drug candidates against all disease categories and might even speed up drug development. Pharmaceutical companies have already increased their boron research, particularly GlaxoSmithKline (GSK; Brentford, UK), which announced a US$2.5 billion investment in the US company Anacor (Palo Alto, CA, USA) in November 2008. Anacor was founded in 2002 to develop boron‐based antibacterial drugs, but has since expanded into antivirals and other targets with its boron‐based platform. Co‐founders Lucy Shapiro and Stephen Benkovic began collaborating in 2001 to look for novel inhibitors of several newly identified bacterial target sites that, they thought, could lead to more effective antibiotics. “They randomly inserted boron and got good activity,” said David Perry, CEO of Anacor. This serendipitous discovery led to the formation of Anacor a year later. “We were lucky,” Perry conceded. “At that stage we had no idea what the broader potential of boron …

Spatial and spectral characteristics of a compact system neutron beam designed for BNCT facility

The development of suitable neutron sources and neutron beam is critical to the success of Boron Neutron Capture Therapy (BNCT). In this work a compact system designed for BNCT is presented. The system consists of 252Cf fission neutron source and a moderator/reflector/filter/shield assembly. The moderator/reflector/filter arrangement has been optimized to maximize the epithermal neutron component which is useful for BNCT treatment of deep seated tumors with the suitably low level of beam contamination. The MCMP5 code has been used to calculate the different components of neutrons, secondary gamma rays originating from 252Cf source and the primary gamma rays emitted directly by this source at the exit face of the compact system. The fluence rate distributions of such particles were also computed along the central axis of a human head phantom.