Boron Neutron Capture Therapy Dose Research Articles

A physically constrained Monte Carlo-Neural Network coupling algorithm for BNCT dose calculation.

In boron neutron capture therapy (BNCT)-a form of binary radiotherapy-the primary challenge in treatment planning systems for dose calculations arises from the time-consuming nature of the Monte Carlo (MC) method. Recent progress, including the use of neural networks (NN), has been made to accelerate BNCT dose calculations. However, this approach may result in significant dose errors in both the tumor and the skin, with the latter being a critical organ in BNCT. Furthermore, owing to the lack of physical processes in purely NN-based approaches, their reliability for clinical dose calculations in BNCT is questionable. In this study, a physically constrained MC-NN (PCMC-NN) coupling algorithm is proposed to achieve fast and accurate computation of the BNCT three-dimensional (3D) therapeutic dose distribution. This approach synergizes the high precision of the MC method with the speed of the NN and utilizes physical conservation laws to constrain the coupling process. It addresses the time-consuming issue of the traditional MC method while reducing dose errors. Clinical data were collected from 113 glioblastoma patients. For each patient, the 3D dose distributions for both the coarse and detailed dose grids were calculated using the MC code PHITS. Among these patients, the data from 14 patients were allocated to the test set, 9 to the validation set, and the remaining to the training set. A neural network, 3D-Unet, was built based on the coarse grid dose and patient CT information to enable fast and accurate computation of the 3D detailed grid dose distribution of BNCT. Statistical evaluations, including relative deviation, dose deviation, mean absolute error (MAE), and mean absolute percentage error (MAPE) were conducted. Our findings suggested that the PCMC-NN algorithm substantially outperformed the traditional NN and interpolation methods. Furthermore, the proposed algorithm significantly reduced errors, particularly in the skin and GTV, and improved computational accuracy (hereinafter referred to simply as 'accuracy') with a MAPE range of 1.6%-4.0% and a maximum MAE of 0.3Gy (IsoE) for different organs. The dose-volume histograms generated by the PCMC-NN aligned well with those obtained from the MC method, further validating its accuracy. The PCMC-NN algorithm enhanced the speed and accuracy of BNCT dose calculations by combining the MC method with the NN algorithm. This indicates the significant potential of the proposed algorithm for clinical applications in optimizing treatment planning.

Neutron flux evaluation algorithm with a combination of Monte Carlo and removal-diffusion calculation methods for boron neutron capture therapy.

In Japan, the clinical treatment of boron neutron capture therapy (BNCT) has been applied to unresectable, locally advanced, and recurrent head and neck carcinomas using an accelerator-based neutron source since June of 2020. Considering the increase in the number of patients receiving BNCT, efficiency of the treatment planning procedure is becoming increasingly important. Therefore, novel and rapid dose calculation algorithms must be developed. We developed a novel algorithm for calculating neutron flux, which comprises of a combination of a Monte Carlo (MC) method and a method based on the removal-diffusion (RD) theory (RD calculation method) for the purpose of dose calculation of BNCT. We present the details of our novel algorithm and the verification results of the calculation accuracy based on the MC calculation result. In this study, the "MC-RD" calculation method was developed, wherein the RD calculation method was used to calculate the thermalization process of neutrons and the MC method was used to calculate the moderation process. The RD parameters were determined by MC calculations in advance. The MC-RD calculation accuracy was verified by comparing the results of the MC-RD and MC calculations with respect to the neutron flux distributions in each of the cubic and head phantoms filled with water. Comparing the MC-RD calculation results with those of MC calculations, it was found that the MC-RD calculation accurately reproduced the thermal neutron flux distribution inside the phantom, with the exception of the region near the surface of the phantom. The MC-RD calculation method is useful for the evaluation of the neutron flux distribution for the purpose of BNCT dose calculation, except for the region near the surface.

Using the photon isoeffective dose formalism to compare and combine BNCT and CIRT in a head and neck tumour

Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours.

Introduction to the Monte Carlo dose engine COMPASS for BNCT.

The Monte Carlo method is the most commonly used dose calculation method in the field of boron neutron capture therapy (BNCT). General-purpose Monte Carlo (MC) code (e.g., MCNP) has been used in most treatment planning systems (TPS) to calculate dose distribution, which takes overmuch time in radiotherapy planning. Based on this, we developed COMPASS (COMpact PArticle Simulation System), an MC engine specifically for BNCT dose calculation. Several optimization algorithms are used in COMPASS to make it faster than general-purpose MC code. The parallel computation of COMPASS is performed by the message passing interface (MPI) library and OpenMP commands, which allows the user to increase computational speed by increasing the computer configurations. The physical dose of each voxel is calculated for developing a treatment plan. Comparison results show that the computed dose distribution of COMPASS is in good agreement with MCNP, and the computational efficiency is better than MCNP. These results validate that COMPASS has better performance than MCNP in BNCT dose calculation.

Estimating 10B and 14N doses using a pair of LiF-based TLD-600 and TLD-700 as an alternative to gold activation method

Purpose:A new method using TLD-600 and TLD-700 was proposed to measure a thermal neutron flux, which is used to evaluate 10B and 14N doses for boron neutron capture therapy (BNCT). Material and method:TLD-600 and TLD-700 were enriched by 6Li (95.6%) and 7Li (99.99%), respectively. The TLDs were calibrated using a 252Cf neutron source within a 30 cm-diameter D2O sphere to produce a thermal neutron flux calibration factor. The calibration factor was obtained by dividing the neutron-induced TLD readings by the delivered thermal neutron fluence. In addition, a neutron self-shielding correction was calculated to compensate for the perturbed neutron fluence between adjacent TLDs. To validate the procedure involved in this new method, TLDs were irradiated by thermal neutron fluxes from the research/educational reactor. The results were compared with the thermal neutron fluxes by the conventional gold activation method. Results and discussion:The calibration factor from TLDs irradiated by the thermal neutron flux from the 252Cf neutrons was determined 3.80 × 104 cm−2 nC−1. Using this factor, the thermal neuron flux at the reactor was measured 2.28 × 105 cm−2 W−1 s−1 by the TLD method. The one measured by the gold activation method was 2.17 × 105 cm−2 W−1 s−1 showing a difference of 5%. With the thermal neutron fluence measured by TLDs, a Li-6 dose of TLD-600 (Dn,αTLD) can be calculated. Then the two major components of BNCT dosimetry, a B-10 dose (D(n,α)B−10) and an N-14 dose (D(n,p)N−14) can be calculated by multiplying Dn,αTLD with constants due to a strong 1/v behavior of the three reactions. Conclusions:The TLD method developed in this study was successfully validated against an unknown mixed neutron/gamma field from the reactor, showing about 5% difference in measured thermal neutron fluences when compared to the conventional gold activation method. Therefore, we concluded that the two major dose components of BNCT, 10B and 14N doses can be accurately evaluated by the neutron-induced TLD dose.

Use of a neural network-based prediction method to calculate the therapeutic dose in boron neutron capture therapy of patients with glioblastoma.

Boron neutron capture therapy (BNCT) is a binary radiotherapy based on the 10 B(n, α)7 Li capture reaction. Nonradioactive isotope 10 B atoms which selectively concentrated in tumor cells will react with low energy neutrons (mainly thermal neutrons) to produce secondary particles with high linear energy transfer, thus depositing dose in tumor cells. In clinical practice, an appropriate treatment plan needs to be set on the basis of the treatment planning system (TPS). Existing BNCT TPSs usually use the Monte Carlo method to determine the three-dimensional (3D) therapeutic dose distribution, which often requires a lot of calculation time due to the complexity of simulating neutron transportation. A neural network-based BNCT dose prediction method is proposed to achieve the rapid and accurate acquisition of BNCT 3D therapeutic dose distribution for patients with glioblastoma to solve the time-consuming problem of BNCT dose calculation in clinic. The clinical data of 122 patients with glioblastoma are collected. Eighteen patients are used as a test set, and the rest are used as a training set. The 3D-UNET is constructed through the design optimization of input and output data sets based on radiation field information and patient CT information to enable the prediction of 3D dose distribution of BNCT. The average mean absolute error of the predicted and simulated equivalent doses of each organ are all less than 1Gy. For the dose to 95% of the GTV volume (D95 ), the relative deviation between predicted and simulated results are all less than 2%. The average 2mm/2% gamma index is 89.67%, and the average 3mm/3% gamma index is 96.78%. The calculation takes about 6h to simulate the 3D therapeutic dose distribution of a patient with glioblastoma by Monte Carlo method using Intel Xeon E5-2699 v4, whereas the time required by the method proposed in this study is almost less than 1 s using a Titan-V graphics card. This study proposes a 3D dose prediction method based on 3D-UNET architecture in BNCT, and the feasibility of this method is demonstrated. Results indicate that the method can remarkably reduce the time required for calculation and ensure the accuracy of the predicted 3D therapeutic dose-effect. This work is expected to promote the clinical development of BNCT in the future.

Comprehensive evaluation of dosimetric impact against position errors in accelerator-based BNCT under different treatment parameter settings.

BackgroundPatients who undergo accelerator‐based (AB) boron neutron capture therapy (BNCT) for head and neck cancer in the sitting position are generally uncomfortably immobilized, and patient motion during this treatment may be greater than that in other radiotherapy techniques. Furthermore, the treatment time of BNCT is relatively long (up to approximately 1 h), which increases the possibility of patient movement during treatment. As most BNCT irradiations are performed in a single fraction, the dosimetric error due to patient motion is of greater consequence and needs to be evaluated and accounted for. Several treatment parameters are required for BNCT dose calculation.PurposeTo investigate the dosimetric impacts (DIs) against position errors using a simple cylindrical phantom for an AB‐BNCT system under different treatment parameter settings.MethodsThe treatment plans were created in RayStation and the dose calculation was performed using the NeuCure® dose engine. A cylindrical phantom (16 cm diameter × 20 cm height) made of soft tissue was modeled. Dummy tumors in the form of a 3‐cm‐diameter sphere were arranged at depths of 2.5 and 6.5 cm (denoted by T 2.5 and T 6.5, respectively). Reference plans were created by setting the following parameters: collimator size = 10, 12, or 15 cm in diameter, collimator‐to‐surface distance (CSD) = 4.0 or 8.0 cm, tumor‐to‐blood ratio (T/B ratio) using 18F‐fluoro‐borono‐phenylalanine = 2.5 or 5.0, and 10B concentration in blood = 20, 25, or 30 ppm. The prescribed dose was D 95% ≥ 20 Gy‐eq for both T 2.5 and T 6.5. Based on the reference plans, phantom‐shifted plans were created in 26 directions [all combinations of left–right (LR), anterior–posterior (AP), and superior–inferior (SI) directions) and three distances (1.0, 2.0, and 3.0 cm). The DIs were evaluated at D 80% of the tumors. The shift direction dependency of the DI in the LR, AP, and SI directions was evaluated by conducting a multiple regression analysis (MRA) and other analyses where required.ResultsThe coefficients of the MRA of the DIs for LR, AP, and SI shifts were −0.08, 2.16, and −0.04 (p‐values = 0.084, <0.01, and 0.334) for T 2.5 and −0.05, 2.08, and 0.15 (p‐values = 0.526, <0.01, and 0.065) for T 6.5, respectively. The analysis of variance showed that DIs due to the AP shift were significantly greater for smaller collimator sizes on T 2.5 and smaller CSD on T 6.5. Dose reduction due to SI or LR (lateral) shifts was significantly greater for smaller collimator sizes on both T 2.5 and T 6.5 and smaller CSD on T2.5, according to the Student's t‐test. There were no significant differences in the DIs against both the AP shift and the lateral shift between the different T/B ratios and 10B concentrations.ConclusionThe DIs were largely affected by the shift in the AP direction and were influenced by the different treatment parameters.

Similar T/N ratio between 18F-FBPA diagnostic and BPA therapeutic dosages for boron neutron capture therapy in orthotropic tongue cancer model.

The tumor-to-normal tissue (T/N) boron ratio is determined in a patient prior to boron neutron capture therapy (BNCT) using 4-borono-2-18F-fluoro-L-phenylalanine (18F-FBPA) positron emission tomography (PET). The T/N ratio is used as a reference parameter to calculate BNCT dose and to evaluate treatment effects. The boronophenylalanine (BPA) dosage for BNCT treatment is higher than the 18F-FBPA dosage for PET diagnosis. Therefore, we aimed to determine whether the T/N ratios between diagnosis and treatment were correlated. In this study, SAS tongue cancer cells were used to develop an orthotopic nude mouse model. Micro-PET was performed after the mice were injected a dose of 3.7 ± 0.74MBq of 18F-FBPA via the tail vein. The 18F radioactivity in the tumor, muscle, and heart blood pool was calculated using AMIND software. Organs and blood were collected for boron concentration analysis using inductively coupled plasma-atomic emission spectroscopy after the mice were injected with 400mg/kg BPA at 15, 30, 45, and 60min. Pharmacokinetics of the tumor and muscle from 45 to 60min after 18F-FBPA and BPA injections were slightly increased, whereas that of blood was slightly decreased. Median T/N ratios at 60min after 18F-FBPA and BPA injections were 3.5 and 3.43, respectively. Median value of the T/N ratio between them was 3.49 at 60min. The T/N ratio at 60min after 18F-FBPA injection was similar to that after BPA injection. However, median tumor-to-blood (T/B) boron ratios of 18F-FBPA and BPA at 60min were 1.63 and 3.35, respectively. Median value between them was 1.83 at 60min. In this study, the T/B ratios demonstrate the spread of a distribution between 18F-FBPA and BPA injections. At 60min, the T/N ratio of the 18F-FBPA injection was similar to that of the BPA injection. Boron concentration in normal tissue was almost equal to that in blood. Therefore, the representative T/N ratio could be obtained at 60min after 18F-FBPA injection, and it was used as a reference parameter for calculating accurate radiation dose.

A Retrospective Study of Predictors for Radiation Induced Severe Oral Mucositis in BPA-Mediated BNCT of Head and Neck Cancer Patients

Radiation dose in boron neutron capture therapy (BNCT) consists of high-LET dose from 10B(n,a)7Li reaction, nitrogen capture dose, recoil proton dose and photon dose. Traditionally, the biological radiation dose in BNCT is obtained as a sum of the dose components after multiplying each with a constant relative biological effectiveness (RBE) factor. An alternative biological dose calculation method, the photon iso-effective dose formalism, considers also the dose rate, cumulative dose per fraction and synergistic interactions. Results of our previous study suggested that the photon iso-effective dose model predicts mucosal membrane toxicity after BNCT more reliably than the traditional RBE model or the physical absorbed doses. We aim here to verify this finding in a larger patient series. In addition, we study the relation of chemotherapy, tumor location, tumor histology, patient age, and gender to the perceived mucosal toxicity. Data of 93 patients with recurrent inoperable HN carcinoma, who were treated with BNCT in Finland from 2003 to 2011, was analyzed. Photon iso-effective dose formalism and traditional RBE factors were applied to calculate the biological dose delivered to mucosal membrane. Since exact nitrogen concentration of mucosal membrane is unknown, the dose was calculated using three different tissue concentrations (muscle 3.4 %, skin 4.2%, and melanoma 6.8%). The maximum mucosal membrane doses were compared with the clinically observed mucositis at 2 to 4 weeks after the 1st BNCT. Severe mucositis (CTCAE 4.0 grade 3) of oral mucositis was observed in 40 (43%) out of the 93 patients. The maximum RBE doses were 16-43% lower than the photon iso-effective doses (table 1), being below the reported tolerance dose limit of 15 Gy for a single radiotherapy fraction. All median photon iso-effective doses were higher than the tolerance dose. The other examined clinical factors did not predict the perceived mucositis in binary logistic regression analysis (p>0.05). The preliminary results confirm that the photon iso-effective dose model predicts mucosal membrane dose after BNCT more reliably than the traditional RBE model. However, maximum dose, tumor location, previously given chemotherapy, patient age and gender, and tumor histology do not seem to correlate with the mucosal toxicity. Dose volume distribution in the oral cavity, blood boron concentration, and irradiation time may be needed to predict the mucosal toxicity better.Abstract 2934; Table 1Maximum biological RBE and photon iso-effective dose to mucosal membrane from single BNCT calculated using nitrogen concentration of muscle, skin, and melanoma.Muscle Median (min, max)Skin Median (min, max)Melanoma Median (min, max)Gy-RBEGy-IsoEGy-RBEGy-IsoEGy-RBEGy-IsoE12.1 (5.6, 15.2)16.2 (9.8, 18.9)12.4 (5.8, 15.6)16.3 (10.1, 19.0)13.3 (6.1, 16.7)17.0 (10.3, 19.9) Open table in a new tab

Dependence of neutrons generated by 7Li(p,n) reaction on Li thickness under free-air condition in accelerator-based boron neutron capture therapy system employing solid-state Li target

PurposeAn accelerator-based boron neutron capture therapy (BNCT) system with a solid-state Li target is reported to have degradation of the Li target. The degradation reduces the Li thickness, which may change spectra of the generated neutrons corresponding to the Li thickness. This study aims to examine the relationship between the Li thickness and the generated neutrons and to investigate the effects of the Li thickness on the absorbed dose in BNCT. MethodThe neutron energy spectra were calculated via Monte Carlo simulation for Li thicknesses ranging from 20 to 150 μm. Using the system, the saturated radioactivity of gold induced by reactions between 197Au and the generated neutrons was evaluated with the simulation and the measurement, and those were compared. Additionally, for each Li thickness, the saturated radioactivity was compared with the number of generated neutrons. The absorbed doses delivered by 10B(n,α)7Li, 14N(n,p)14C, 1H(n, g)2H, and (n,n′) reactions in water were also calculated for each Li thickness. ResultsThe measurement and simulation indicated a reduction in the number of neutrons due to the degradation of the Li target. However, the absorbed doses were comparable for each Li thickness when the requisite number of neutrons for BNCT was delivered. Additionally, the saturated radioactivity of 198Au could be a surrogate for the number of neutrons even if the Li thickness was varied. ConclusionsNo notable effect to the absorbed dose was observed when required neutron fluence was delivered in the BNCT even if the degradation of the Li was observed.

Comparison of the pharmacokinetics between L-BPA and L-FBPA using the same administration dose and protocol: a validation study for the theranostic approach using [18F]-L-FBPA positron emission tomography in boron neutron capture therapy.

BackgroundBoron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. L-p-Boronophenylalanine (L-BPA) is a boron compound now widely used in clinical situations. Determination of the boron distribution is required for successful BNCT prior to neutron irradiation. Thus, positron emission tomography with [18F]-L-FBPA, an 18F-labelled radiopharmaceutical analogue of L-BPA, was developed. However, several differences between L-BPA and [18F]-L-FBPA have been highlighted, including the different injection doses and administration protocols. The purpose of this study was to clarify the equivalence between L-BPA and [19F]-L-FBPA as alternatives to [18F]-L-FBPA.MethodsSCC-VII was subcutaneously inoculated into the legs of C3H/He mice. The same dose of L-BPA or [19F]-L-FBPA was subcutaneously injected. The time courses of the boron concentrations in blood, tumour tissue, and normal tissue were compared between the groups. Next, we administered the therapeutic dose of L-BPA or the same dose of [19F]-L-FBPA by continuous infusion and compared the effects of the administration protocol on boron accumulation in tissues.ResultsThere were no differences between L-BPA and [19F]-L-FBPA in the transition of boron concentrations in blood, tumour tissue, and normal tissue using the same administration protocol. However, the normal tissue to blood ratio of the boron concentrations in the continuous-infusion group was lower than that in the subcutaneous injection group.ConclusionsNo difference was noted in the time course of the boron concentrations in tumour tissue and normal tissues between L-BPA and [19F]-L-FBPA. However, the administration protocol had effects on the normal tissue to blood ratio of the boron concentration. In estimating the BNCT dose in normal tissue by positron emission tomography (PET), we should consider the possible overestimation of the normal tissue to blood ratio of the boron concentrations derived from the values measured by PET on dose calculation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2913-x) contains supplementary material, which is available to authorized users.

Verification of nuclear data for the Tsukuba plan, a newly developed treatment planning system for boron neutron capture therapy

Various verifications were performed to apply JENDL-4.0 as nuclear data for a newly developed treatment planning system with a homogeneous or precise human-like phantom. The nitrogen dose calculated by JENDL-4.0 differed slightly from that calculated by ENDF/B-VII.0. However, the total weighted dose-based dose volume histogram in the boron neutron capture therapy (BNCT) treatment for brain tumors calculated by JENDL-4.0 was in good agreement with the results of the ENDF/B-VII.0 calculation. Therefore, calculation with JENDL-4.0 can be applied to the BNCT dose calculation.

Estimation of relative biological effectiveness for boron neutron capture therapy using the PHITS code coupled with a microdosimetric kinetic model.

The absorbed doses deposited by boron neutron capture therapy (BNCT) can be categorized into four components: α and 7Li particles from the 10B(n, α)7Li reaction, 0.54-MeV protons from the 14N(n, p)14C reaction, the recoiled protons from the 1H(n, n) 1H reaction, and photons from the neutron beam and 1H(n, γ)2H reaction. For evaluating the irradiation effect in tumors and the surrounding normal tissues in BNCT, it is of great importance to estimate the relative biological effectiveness (RBE) for each dose component in the same framework. We have, therefore, established a new method for estimating the RBE of all BNCT dose components on the basis of the microdosimetric kinetic model. This method employs the probability density of lineal energy, y, in a subcellular structure as the index for expressing RBE, which can be calculated using the microdosimetric function implemented in the particle transport simulation code (PHITS). The accuracy of this method was tested by comparing the calculated RBE values with corresponding measured data in a water phantom irradiated with an epithermal neutron beam. The calculation technique developed in this study will be useful for biological dose estimation in treatment planning for BNCT.

Boron delivery with liposomes for boron neutron capture therapy (BNCT): biodistribution studies in an experimental model of oral cancer demonstrating therapeutic potential

Boron neutron capture therapy (BNCT) combines selective accumulation of (10)B carriers in tumor tissue with subsequent neutron irradiation. We previously demonstrated the therapeutic efficacy of BNCT in the hamster cheek pouch oral cancer model. Optimization of BNCT depends largely on improving boron targeting to tumor cells. Seeking to maximize the potential of BNCT for the treatment for head and neck cancer, the aim of the present study was to perform boron biodistribution studies in the oral cancer model employing two different liposome formulations that were previously tested for a different pathology, i.e., in experimental mammary carcinoma in BALB/c mice: (1) MAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a hypertonic buffer, administered intravenously at 6 mg B per kg body weight, and (2) MAC-TAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a concentrated aqueous solution of the hydrophilic species Na(3) [ae-B(20)H(17)NH(3)], administered intravenously at 18 mg B per kg body weight. Samples of tumor, precancerous and normal pouch tissue, spleen, liver, kidney, and blood were taken at different times post-administration and processed to measure boron content by inductively coupled plasma mass spectrometry. No ostensible clinical toxic effects were observed with the selected formulations. Both MAC and MAC-TAC delivered boron selectively to tumor tissue. Absolute tumor values for MAC-TAC peaked to 66.6 ± 16.1 ppm at 48 h and to 43.9 ± 17.6 ppm at 54 h with very favorable ratios of tumor boron relative to precancerous and normal tissue, making these protocols particularly worthy of radiobiological assessment. Boron concentration values obtained would result in therapeutic BNCT doses in tumor without exceeding radiotolerance in precancerous/normal tissue at the thermal neutron facility at RA-3.

Boron neutron capture therapy (BNCT) for the treatment of liver metastases: biodistribution studies of boron compounds in an experimental model

We previously demonstrated the therapeutic efficacy of different boron neutron capture therapy (BNCT) protocols in an experimental model of oral cancer. BNCT is based on the selective accumulation of (10)B carriers in a tumor followed by neutron irradiation. Within the context of exploring the potential therapeutic efficacy of BNCT for the treatment of liver metastases, the aim of the present study was to perform boron biodistribution studies in an experimental model of liver metastases in rats. Different boron compounds and administration conditions were assayed to determine which administration protocols would potentially be therapeutically useful in in vivo BNCT studies at the RA-3 nuclear reactor. A total of 70 BDIX rats were inoculated in the liver with syngeneic colon cancer cells DHD/K12/TRb to induce the development of subcapsular tumor nodules. Fourteen days post-inoculation, the animals were used for biodistribution studies. We evaluated a total of 11 administration protocols for the boron compounds boronophenylalanine (BPA) and GB-10 (Na(2)(10)B(10)H(10)), alone or combined at different dose levels and employing different administration routes. Tumor, normal tissue, and blood samples were processed for boron measurement by atomic emission spectroscopy. Six protocols proved potentially useful for BNCT studies in terms of absolute boron concentration in tumor and preferential uptake of boron by tumor tissue. Boron concentration values in tumor and normal tissues in the liver metastases model show it would be feasible to reach therapeutic BNCT doses in tumor without exceeding radiotolerance in normal tissue at the thermal neutron facility at RA-3.

Determination of the 10B Dose in BNCT Using LiF-TLD

The 10B dose in boron neutron capture therapy (BNCT) was usually determined by multiplying the thermal neutron flux by the 10B concentration and the dose conversion factor. In this kind of application, the thermal neutron flux was commonly measured using gold foil activation techniques with and without the cadmium cover, assuming that the neutron spectrum has a Maxwellian distribution in the thermal range. This always generated uncertainties because the thermal neutron energy spectrum has no Maxwellian distribution in the body. The potential to determine the 10B dose by using a single LiF thermoluminescent dosimeter (TLD) is studied.The 10B dose in BNCT derives from the reaction of the thermal neutron with the 10B element. It always dominates the irradiation dose if the 10B concentration is higher than 20 ppm. Since the trends of the 10B absorption cross sections are similar to 6Li in the thermal neutron range, the LiF-TLD can be used for 10B dose determination in BNCT if the reaction of the thermal neutron with 6Li dominates the TLD response. The MCNP code is used to simulate the energy deposition in various LiF-TLDs and to show the suitability of LiF-TLD used for 10B dose determination in BNCT.The preliminary MCNP simulation shows that the TLD response strongly depends on the 6LiF content in the TLD. Comparing the TLD response, the 10B reaction, and the thermal neutron flux, they show the same distribution as a function of depth in a phantom irradiated with the BNCT neutron. On the other hand, not only is there a thermal neutron flux depression due to self-shielding within the TLD chip, but also there is significant perturbation around the TLD if the 6LiF content in the TLD is high enough. To balance these two factors, TLD-100 was recommended as a 10B dosimeter for BNCT.

Comparison of different MC techniques to evaluate BNCT dose profiles in phantom exposed tovarious neutron fields

The absorbed dose in BNCT (boron neutron capture therapy) consists of several radiation components with different physical properties and biological effectiveness. In order to assess the clinical efficacy of the beams, determining the dose profiles in tissues, Monte Carlo (MC) simulations are used. This paper presents a comparison between dose profiles calculated in different phantoms using two techniques: MC radiation transport code, MCNP-4C2 and BNCT MC treatment planning program, SERA (simulation environment for radiotherapy application). In this study MCNP is used as a reference tool. A preliminary test of SERA is performed using six monodirectional and monoenergetic beams directed onto a simple water phantom. In order to deeply investigate the effect of the different cross-section libraries and of the dose calculation methodology, monoenergetic and monodirectional beams directed toward a standard Snyder phantom are simulated. Neutron attenuation curves and dose profiles are calculated with both codes and the results are compared.

A treatment planning study on glioblastoma with different techniques using boron neutron capture therapy, 3-dimensional conformal radiotherapy, and intensity modulated radiotherapy

To propose adequate indices predicting efficacy of boron neutron capture therapy (BNCT) for glioblastoma, a comparative treatment planning study between BNCT, 3-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT) was performed, and dose–volume histograms (DVHs) on planning target volume (PTV) and normal brain were calculated. Therapeutic benefit of BNCT was quantitatively evaluated using conformity indices, which have been previously suggested by radiation therapy oncology group (RTOG) and Saint-Anne, Lariboisière, Tenon (SALT). Although dose homogeneities from the BNCT plans were poor than the other modalities due to simple irradiation fields, lesion coverage factor, CVF, from the BNCT plans were comparable to those from the 3D-CRT and IMRT plans (median values, 0.991, 0.989, and 0.961, respectively). The geometrical factors, g, from the BNCT plans, which describes target volumes receiving doses under the prescribed doses and normal brain volume covered by the prescribed doses, were lowest compared to those for the other modalities (median values, 0.009, 0.115, and 0.043). For the BNCT plans, maximum dose escalation up to 2.080 times the prescribed dose was possible without exceeding normal brain tolerance dose. As the indices can evaluate the quantitative benefit of BNCT and maximum dose escalation for the individual patient, it is expected that the indices can effectively evaluate the treatment plan of BNCT.

Boron neutron capture therapy (BNCT) for the treatment of spontaneous nasal planum squamous cell carcinoma in felines

Recently, Boron neutron capture therapy (BNCT) was successfully applied to treat experimental squamous cell carcinomas (SCC) of the hamster cheek pouch mucosa, with no damage to normal tissue. It was also shown that treating spontaneous nasal planum SCC in terminal feline patients with low dose BNCT is safe and feasible. In an extension of this work, the present study aimed at evaluation of the response of tumor and dose-limiting normal tissues to potentially therapeutic BNCT doses. Biodistribution studies with (10)B-boronophenylalanine (BPA enriched in (10)B) as a (10)B carrier were performed on three felines that showed advanced nasal planum SCC without any standard therapeutic option. Following the biodistribution studies, BNCT mediated by (10)BPA was done using the thermalized epithermal neutron beam at the RA-6 Nuclear Reactor. Follow-up included clinical evaluation, assessment of macroscopic tumor and normal tissue response and biopsies for histopathological analysis. The treated animals did not show any apparent radiation-induced toxicity. All three animals exhibited partial tumor control and an improvement in clinical condition. Enhanced therapeutic efficacy was associated with a high (10)B content of the tumor and a small tumor size. BNCT is therefore believed to be potentially effective in the treatment of spontaneous SCC. However, improvement in targeting (10)B into all tumor cells and delivering a sufficient dose at a greater depth are still required for the treatment of deep-seated, large tumors. Future studies are needed to evaluate the potential efficacy of the dual mode cellular (e.g. BPA-BNCT) and vascular (e.g. GB-10-BNCT) targeting protocol in a preclinical scenario, employing combinations of (10)B compounds with different properties and complementary uptake mechanisms.

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.