Robust and optimal dose distribution for brain metastases with robotic radiosurgery system: recipe for an inflection point.

Purpose.This study aims to establish a robust dose prescription methodology in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) for brain metastases, considering geometrical uncertainty and minimising dose exposure to the surrounding normal brain tissue.Methods and Materials.Treatment plans employing 40%-90% isodose lines (IDL) at 10% IDL intervals were created for variously sized brain metastases. The plans were constructed to deliver 21 Gy in SRS. Robustness of each plan was analysed using parameters such as the near minimum dose to the tumour, the near maximum dose to the normal brain, and the volume of normal brain irradiated above 14 Gy.Results.Plans prescribed at 60% IDL demonstrated the least variation in the near minimum dose to the tumour and the near maximum dose to the normal brain under conditions of minimal geometrical uncertainty relative to tumour radius. When the IDL-percentage prescription was below 60%, geometrical uncertainties led to increases in these doses. Conversely, they decreased with IDL-percentage prescriptions above 60%. The volume of normal brain irradiated above 14 Gy was lowest at 60% IDL, regardless of geometrical uncertainty.Conclusions.To enhance robustness against geometrical uncertainty and to better spare healthy brain tissue, a 60% IDL prescription is recommended in SRS and SRT for brain metastases using a robotic radiosurgery system.

Boron Neutron Capture Therapy for Recurrent Glioblastoma Multiforme: Imaging Evaluation of a Case With Long-Term Local Control and Survival.

Glioblastoma (GBM) is difficult to cure with conventional multimodal treatment and has an extremely poor prognosis. Boron neutron capture therapy (BNCT) is a new particle therapy for malignant tumors in the brain and head and neck region. This radiotherapy utilizes a nuclear reaction between neutrons and a nonradioactive isotope, boron-10. In this method, a boron compound is administered transvenously into the body. The boron compound has the property of being selectively taken up only by the cells of malignant tumors, and the subsequent irradiation with neutrons can destroy malignant tumor cells without damaging normal cells. Since the irradiation dose to normal tissues is reduced in BNCT, it may be possible to re-irradiate malignant tumors that recur after radiotherapy. Clinical trials have reported prolonged survival and safety of BNCT in a small number of patients with refractory malignancies, including GBM, but these reports do not address quality of life or activities of daily living (ADL) after treatment, and there is no information on the assessment of local control by imaging. Here, we report a case of GBM that recurred after surgery, 60 Gy of conventional radiotherapy and standard treatment with temozolomide. The patient achieved long-term local control and survival over five years after BNCT and was able to maintain ADL at home without any specialist care. We describe the case with evaluation using longitudinal magnetic resonance imaging (MRI).

Initiatives Toward Clinical Boron Neutron Capture Therapy in Japan.

Boron neutron capture therapy (BNCT) has been performed at nuclear research reactors for many years. The development of accelerators for BNCT resulted in a paradigm shift from research to real clinical applications. In Japan, BNCT was approved as a clinical therapy covered by the National Health Insurance in 2020. In this article, the status of BNCT in Japan is briefly introduced.

Implementation of simplified stochastic microdosimetric kinetic models into PHITS for application to radiation treatment planning.

PURPOSE: The stochastic microdosimetric kinetic (SMK) model is one of the most sophisticated and precise models used in the estimation of the relative biological effectiveness of carbon-ion radiotherapy (CRT) and boron neutron capture therapy (BNCT). However, because of its complicated and time-consuming calculation procedures, it is nearly impractical to directly incorporate this model into a radiation treatment-planning system. MATERIALS AND METHODS: Through the introduction of Taylor expansion (TE) or fast Fourier transform (FFT), we developed two simplified SMK models and implemented them into the Particle and Heavy Ion Transport code System (PHITS). To verify the implementation, we calculated the photon isoeffective doses in a cylindrical phantom placed in the radiation fields of passive CRT and accelerator-based BNCT. RESULTS AND DISCUSSION: Our calculation suggested that both TE-based and FFT-based SMK models can reproduce the data obtained from the original SMK model very well for absorbed doses approximately below 5 Gy, whereas the TE-based SMK model overestimates the original data at higher doses. In terms of computational efficiency, the TE-based SMK model is much faster than the FFT-based SMK model. CONCLUSION: This study enables the instantaneous calculation of the photo isoeffective dose for CRT and BNCT, considering their cellular-scale dose heterogeneities. Treatment-planning systems that use the improved PHITS as a dose-calculation engine are under development.

Computational evaluation of dose distribution for BNCT treatment combined with X-ray therapy or proton beam therapy.

In this study, we performed Monte Carlo simulations to accurately reflect the beam delivery systems including patient-specific irradiation devices of X-ray and proton beam therapies. The dose distributions obtained from the simulations for X-rays or proton beams were successfully combined to the dose distribution of boron neutron capture therapy (BNCT), which was calculated by a treatment planning system called Tsukuba Plan. The results demonstrate the feasibility of dose evaluation for BNCT combined with other radiotherapy modalities using the Tsukuba Plan.

Evaluation of the characteristics of the neutron beam of a linac-based neutron source for boron neutron capture therapy.

The linac-base neutron source "iBNCT" developed by the Tsukuba team has begun to generate a large intensity of neutrons. To confirm the applicability of the device to BNCT, several characteristic measurements have been implemented. In a water phantom experiment, when the accelerator was operated with an average current of 1.4 mA, the maximum thermal neutron flux was approximately 7.8 × 108 (n/cm2/s). Results demonstrate the stability of the linac over time, showing its promising potential for future patient treatment.

Folate-appended cyclodextrin improves the intratumoral accumulation of existing boron compounds.

In this study, the tumor accumulation and antitumor effect of folate-modified cyclodextrin (ND201) purified with folate receptor (FR) connotated with BSH were examined. ND201 and BSH were stably bound in blood, and the mixing ratio 1:1 was most efficient. ND-BSH showed higher boron concentration (38.5 ppm) than BSH alone (11.25 ppm). The maximum ND-BSH tumor/blood ratio was also markedly higher (6.58) than that of BSH alone (1.04). ND-BSH showed a significant antitumor effect compared with BSH after neutron irradiation.

Monitoring patient movement with boron neutron capture therapy and motion capture technology.

In boron neutron capture therapy (BNCT), a patient must remain in a fixed position during the irradiation process. In this study, a system was devised that can guide a patient to the correct position and the patient can be monitored during the irradiation process. This is achieved by using motion capture technology that consists of many cameras. The discrepancy of the measured coordinates for each marker on a phantom by the system was less than 5 mm. For practical applications, further research and verification are required.

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.

Establishment of a New Three-Dimensional Dose Evaluation Method Considering Variable Relative Biological Effectiveness and Dose Fractionation in Proton Therapy Combined with High-Dose-Rate Brachytherapy.

PURPOSE: The purpose of this study is to evaluate the influence of variable relative biological effectiveness (RBE) of proton beam and dose fractionation has on dose distribution and to establish a new three-dimensional dose evaluation method for proton therapy combined with high-dose-rate (HDR) brachytherapy. MATERIALS AND METHODS: To evaluate the influence of variable RBE and dose fractionation on dose distribution in proton beam therapy, the depth-dose distribution of proton therapy was compared with clinical dose, RBE-weighted dose, and equivalent dose in 2 Gy fractions using a linear-quadratic-linear model (EQD2LQL). The clinical dose was calculated by multiplying the physical dose by RBE of 1.1. The RBE-weighted dose is a biological dose that takes into account RBE variation calculated by microdosimetric kinetic model implemented in Monte Carlo code. The EQD2LQL is a biological dose that makes the RBE-weighted dose equivalent to 2 Gy using a linear-quadratic-linear (LQL) model. Finally, we evaluated the three-dimensional dose by taking into account RBE variation and LQL model for proton therapy combined with HDR brachytherapy. RESULTS: The RBE-weighted dose increased at the distal of the spread-out Bragg peak (SOBP). With the difference in the dose fractionation taken into account, the EQD2LQL at the distal of the SOBP increased more than the RBE-weighted dose. In proton therapy combined with HDR brachytherapy, a divergence of 103% or more was observed between the conventional dose estimation method and the dose estimation method we propose. CONCLUSIONS: Our dose evaluation method can evaluate the EQD2LQL considering RBE changes in the dose distribution.

DEPTH DISTRIBUTIONS OF RBE-WEIGHTED DOSE and PHOTON-ISOEFFECTIVE DOSE FOR BORON NEUTRON CAPTURE THERAPY.

Two types of dose were proposed for use in the treatment planning of boron neutron capture therapy (BNCT) for expressing its high relative biological effectiveness (RBE). On one hand, the RBE-weighted dose is the sum of the absorbed doses weighted by fixed RBE for each dose component of BNCT. On the other hand, photon-isoeffective dose is the photon dose to give the same biological effect calculated considering the dose dependence of RBE and the synergetic effect between different types of radiation. In this study, the depth distributions of the two types of dose in a phantom placed at an accelerator-based BNCT field were calculated using Particle and Heavy Ion Transport code System, PHITS, coupled with an extended stochastic microdosimetric kinetic model. Compared with the corresponding RBE-weighted dose, the calculated photon-isoeffective dose was larger at lower absorbed dose and was smaller at higher absorbed dose, primarily due to the consideration of the dose dependence of RBE. In addition, our calculation revealed that the large variance of the intercellular 10B concentration greatly reduces the photon-isoeffective doses. These results suggest that the considerations of the dose dependence of RBE as well as the intercellular heterogeneity in 10B distribution are indispensable for the precise estimate of the biological effect of BNCT.

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.

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.

DEVELOPMENT OF A MULTIMODAL MONTE CARLO BASED TREATMENT PLANNING SYSTEM.

To establish boron neutron capture therapy (BNCT), the University of Tsukuba is developing a treatment device and peripheral devices required in BNCT, such as a treatment planning system. We are developing a new multimodal Monte Carlo based treatment planning system (developing code: Tsukuba Plan). Tsukuba Plan allows for dose estimation in proton therapy, X-ray therapy and heavy ion therapy in addition to BNCT because the system employs PHITS as the Monte Carlo dose calculation engine. Regarding BNCT, several verifications of the system are being carried out for its practical usage. The verification results demonstrate that Tsukuba Plan allows for accurate estimation of thermal neutron flux and gamma-ray dose as fundamental radiations of dosimetry in BNCT. In addition to the practical use of Tsukuba Plan in BNCT, we are investigating its application to other radiation therapies.

Neutron spectral fluence measurements using a Bonner sphere spectrometer in the development of the iBNCT accelerator-based neutron source.

The neutron spectral fluence of an accelerator-based neutron source facility for boron neutron capture therapy (BNCT) based on a proton linac and a beryllium target was evaluated by the unfolding method using a Bonner sphere spectrometer (BSS). A 3He-proportional-counter-based BSS was used with weak beam during the development of the facility. The measured epithermal neutron spectra were consistent with calculations. The epithermal neutron intensity at the beam port was estimated and the results gave a numerical target for the enhancement of the proton beam intensity and will be used as reference data for measurements performed after the completion of the facility.

Development of Monte Carlo based real-time treatment planning system with fast calculation algorithm for boron neutron capture therapy.

PURPOSE: We simulated the effect of patient displacement on organ doses in boron neutron capture therapy (BNCT). In addition, we developed a faster calculation algorithm (NCT high-speed) to simulate irradiation more efficiently. METHODS: We simulated dose evaluation for the standard irradiation position (reference position) using a head phantom. Cases were assumed where the patient body is shifted in lateral directions compared to the reference position, as well as in the direction away from the irradiation aperture. For three groups of neutron (thermal, epithermal, and fast), flux distribution using NCT high-speed with a voxelized homogeneous phantom was calculated. The three groups of neutron fluxes were calculated for the same conditions with Monte Carlo code. These calculated results were compared. RESULTS: In the evaluations of body movements, there were no significant differences even with shifting up to 9mm in the lateral directions. However, the dose decreased by about 10% with shifts of 9mm in a direction away from the irradiation aperture. When comparing both calculations in the phantom surface up to 3cm, the maximum differences between the fluxes calculated by NCT high-speed with those calculated by Monte Carlo code for thermal neutrons and epithermal neutrons were 10% and 18%, respectively. The time required for NCT high-speed code was about 1/10th compared to Monte Carlo calculation. CONCLUSIONS: In the evaluation, the longitudinal displacement has a considerable effect on the organ doses. We also achieved faster calculation of depth distribution of thermal neutron flux using NCT high-speed calculation code.

Early clinical experience utilizing scintillator with optical fiber (SOF) detector in clinical boron neutron capture therapy: its issues and solutions.

BACKGROUND: Real-time measurement of thermal neutrons in the tumor region is essential for proper evaluation of the absorbed dose in boron neutron capture therapy (BNCT) treatment. The gold wire activation method has been routinely used to measure the neutron flux distribution in BNCT irradiation, but a real-time measurement using gold wire is not possible. To overcome this issue, the scintillator with optical fiber (SOF) detector has been developed. The purpose of this study is to demonstrate the feasibility of the SOF detector as a real-time thermal neutron monitor in clinical BNCT treatment and also to report issues in the use of SOF detectors in clinical practice and their solutions. MATERIAL AND METHODS: Clinical measurements using the SOF detector were carried out in 16 BNCT clinical trial patients from December 2002 until end of 2006 at the Japanese Atomic Energy Agency (JAEA) and Kyoto University Research Reactor Institute (KURRI). RESULTS: The SOF detector worked effectively as a real-time thermal neutron monitor. The neutron fluence obtained by the gold wire activation method was found to differ from that obtained by the SOF detector. The neutron fluence obtained by the SOF detector was in better agreement with the expected fluence than with gold wire activation. The estimation error for the SOF detector was small in comparison to the gold wire measurement. In addition, real-time monitoring suggested that the neutron flux distribution and intensity at the region of interest (ROI) may vary due to the reactor condition, patient motion and dislocation of the SOF detector. CONCLUSION: Clinical measurements using the SOF detector to measure thermal neutron flux during BNCT confirmed that SOF detectors are effective as a real-time thermal neutron monitor. To minimize the estimation error due to the displacement of the SOF probe during treatment, a loop-type SOF probe was developed.

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.

Development of beryllium-based neutron target system with three-layer structure for accelerator-based neutron source for boron neutron capture therapy.

The iBNCT project team with University of Tsukuba is developing an accelerator-based neutron source. Regarding neutron target material, our project has applied beryllium. To deal with large heat load and blistering of the target system, we developed a three-layer structure for the target system that includes a blistering mitigation material between the beryllium used as the neutron generator and the copper heat sink. The three materials were bonded through diffusion bonding using a hot isostatic pressing method. Based on several verifications, our project chose palladium as the intermediate layer. A prototype of the neutron target system was produced. We will verify that sufficient neutrons for BNCT treatment are generated by the device in the near future.