Research of treatment planning technology combination with micro-dosimetry and macro-dosimetry for particle radiotherapy

科学研究費助成事業(学術研究助成基金助成金)研究成果報告書：挑戦的萌芽研究2011-2012課題番号：2365957

あらゆる放射線外部照射の治療計画が可能なオールモダリティ治療計画システムの開発

科学研究費助成事業 研究成果報告書：挑戦的萌芽研究2016-2017課題番号 : 16K1534

Microdosimetric Modeling of Biological Effectiveness for Boron Neutron Capture Therapy Considering Intra- and Intercellular Heterogeneity in 10B Distribution

We here propose a new model for estimating the biological effectiveness for boron neutron capture therapy (BNCT) considering intra- and intercellular heterogeneity in 10B distribution. The new model was developed from our previously established stochastic microdosimetric kinetic model that determines the surviving fraction of cells irradiated with any radiations. In the model, the probability density of the absorbed doses in microscopic scales is the fundamental physical index for characterizing the radiation fields. A new computational method was established to determine the probability density for application to BNCT using the Particle and Heavy Ion Transport code System PHITS. The parameters used in the model were determined from the measured surviving fraction of tumor cells administrated with two kinds of 10B compounds. The model quantitatively highlighted the indispensable need to consider the synergetic effect and the dose dependence of the biological effectiveness in the estimate of the therapeutic effect of BNCT. The model can predict the biological effectiveness of newly developed 10B compounds based on their intra- and intercellular distributions, and thus, it can play important roles not only in treatment planning but also in drug discovery research for future BNCT

Boron neutron capture therapy in the new age of accelerator-based neutron production and preliminary progress in Canada

Each year more than 3000 Canadians are diagnosed with brain cancers like glioblastoma multiforme or recurrent head and neck cancers, which are difficult to treat with conventional radiotherapy techniques. One of the most clinically promising treatments for these cancers is boron neutron capture therapy (BNCT). This procedure involves selectively introducing a boron delivery agent into tumor cells and irradiating them with a neutron beam, which kills the cancer cells due to the high-linear energy transfer radiation produced by the 10B(n,α)7Li capture reaction. The theory of BNCT has been around for a long time since 1936, but has historically been limited by poor boron delivery agents and non-optimal neutron source facilities. Although significant improvements have been made in both of these domains, it is mainly the advancements of accelerator-based neutron sources that have led to the expansion of over 20 new BNCT facilities worldwide in the past decade. Additionally in this work, particle and heavy ion transport code system simulations, in collaboration with the University of Tsukuba, were performed to examine the effectiveness of the Ibaraki BNCT beam shaping assembly to moderate a neutron beam suitable for BNCT at the proposed prototype Canadian compact accelerator-based neutron source (CANS) site, which uses a similar but slightly higher energy 10MeV proton accelerator with a 1mA average current. The advancements of CANSs in recent decades have enabled significant improvements in BNCT technologies, allowing it to become a more viable clinical treatment option

Boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma : Comparison of clinical results obtained with BNCT and conventional treatment

The purpose of this study was to evaluate the clinical outcome of boron neutron capture therapy (BNCT) and conventional treatment in patients with newly diagnosed glioblastoma. Since 1998 we treated 23 newly-diagosed GBM patients with BNCT without any additional chemotherapy. Their median survival time was 19.5 months ; the 2-, 3-, and 5-year survival rates were 31.8%, 22.7%, and 9.1%, respectively. The clinical results of BNCT in patients with GBM are similar to those of recent conventional treatments based on radiotherapy with concomitant and adjuvant temozolomide

Prediction of Boron Concentrations in Blood from Patients on Boron Neutron Capture Therapy

Background: In boron neutron capture therapy, blood boron concentration is the key factor to calculate radiation dose, however, blood sampling is difficult during neutron irradiation. Materials and Methods: The prediction of blood boron concentrations for BNCT treatment planning has been prospectively investigated using patient data obtained at first craniotomy after the infusion of a low dose of sodium undecahydroclosododecaborate. Results: The boron biodistribution data showed a biexponential pharmacokinetic profile. If the final boron concentration at 6 or 9 hours after the end of the infusion is within the 95% confidence interval of the prediction, direct prediction from biexponential fit will reduce the error of blood boron concentrations during irradiation to around 6%. Conclusion: Actual boron concentrations during BNCT were reasonably and accurately predictable from the test data

Validation of the physical and RBE-weighted dose estimator based on PHITS coupled with a microdosimetric kinetic model for proton therapy

The microdosimetric kinetic model (MKM) is widely used for estimating relative biological effectiveness (RBE)-weighted doses for various radiotherapies because it can determine the surviving fraction of irradiated cells based on only the lineal energy distribution, and it is independent of the radiation type and ion species. However, the applicability of the method to proton therapy has not yet been investigated thoroughly. In this study, we validated the RBE-weighted dose calculated by the MKM in tandem with the Monte Carlo code PHITS for proton therapy by considering the complete simulation geometry of the clinical proton beam line. The physical dose, lineal energy distribution, and RBE-weighted dose for a 155 MeV mono-energetic and spread-out Bragg peak (SOBP) beam of 60 mm width were evaluated. In estimating the physical dose, the calculated depth dose distribution by irradiating the mono-energetic beam using PHITS was consistent with the data measured by a diode detector. A maximum difference of 3.1% in the depth distribution was observed for the SOBP beam. In the RBE-weighted dose validation, the calculated lineal energy distributions generally agreed well with the published measurement data. The calculated and measured RBE-weighted doses were in excellent agreement, except at the Bragg peak region of the mono-energetic beam, where the calculation overestimated the measured data by ~15%. This research has provided a computational microdosimetric approach based on a combination of PHITS and MKM for typical clinical proton beams. The developed RBE-estimator function has potential application in the treatment planning system for various radiotherapies

Functionalized mesoporous silica nanoparticles for innovative boron-neutron capture therapy of resistant cancers

Treatment resistance, relapse and metastasis remain critical issues in some challenging cancers, such as chondrosarcomas. Boron-neutron capture therapy (BNCT) is a targeted radiation therapy modality that relies on the ability of boron atoms to capture low energy neutrons, yielding high linear energy transfer alpha particles. We have developed an innovative boron-delivery system for BNCT, composed of multifunctional fluorescent mesoporous silica nanoparticles (B-MSNs), grafted with an activatable cell penetrating peptide (ACPP) for improved penetration in tumors and with gadolinium for magnetic resonance imaging (MRI) in vivo. Chondrosarcoma cells were exposed in vitro to an epithermal neutron beam after B-MSNs administration. BNCT beam exposure successfully induced DNA damage and cell death, including in radio-resistant ALDH+ cancer stem cells (CSCs), suggesting that BNCT using this system might be a suitable treatment modality for chondrosarcoma or other hard-to-treat cancers

3D‐printable lung phantom for distal falloff verification of proton Bragg peak

In proton therapy, the Bragg peak of a proton beam reportedly deteriorates when passing though heterogeneous structures such as human lungs. Previous studies have used heterogeneous random voxel phantoms, in which soft tissues and air are randomly allotted to render the phantoms the same density as human lungs, for conducting Monte Carlo (MC) simulations. However, measurements of these phantoms are complicated owing to their difficult‐to‐manufacture shape. In the present study, we used Voronoi tessellation to design a phantom that can be manufactured, and prepared a Voronoi lung phantom for which both measurement and MC calculations are possible. Our aim was to evaluate the effectiveness of this phantom as a new lung phantom for investigating proton beam Bragg peak deterioration. For this purpose, we measured and calculated the percentage depth dose and the distal falloff widths (DFW) passing through the phantom. For the 155 MeV beam, the measured and calculated DFW values with the Voronoi lung phantom were 0.40 and 0.39 cm, respectively. For the 200 MeV beam, the measured and calculated DFW values with the Voronoi lung phantom were both 0.48 cm. Our results indicate that both the measurements and MC calculations exhibited high reproducibility with plastinated lung sample from human body in previous studies. We found that better results were obtained using the Voronoi lung phantom than using other previous phantoms. The designed phantom may contribute significantly to the improvement of measurement precision. This study suggests that the Voronoi lung phantom is useful for simulating the effects of the heterogeneous structure of lungs on proton beam deterioration