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Background: Osteosarcoma (OS) is the most common primary malignancy of the bone and is notoriously resistant to radiation therapy. High-dose cytotoxic chemotherapy and surgical resection have improved the survival rate and prognosis of patients with OS. Nonetheless, treatment challenges remain when the tumor cannot be removed by surgery. Boron neutron capture therapy (BNCT) provides high linear energy transfer (LET) radiation, and its internal targeted characteristics make BNCT a novel therapy for removing OS and reducing radiation damage to adjacent healthy tissues. Methods: In this study, a UMR-106-grafted OS rat model was developed, and boric acid (BA) was used as the boron drug for BNCT. The pharmacokinetics of BA, following intravenous injection, were evaluated to determine the optimal time window for neutron irradiation. OS-bearing rats were irradiated by an epithermal neutron beam at Tsing Hua Open-Pool Reactor (THOR). The therapeutic efficacy of and tissue response after BNCT were evaluated by radiographic and histopathological observations. Results: OS-bearing rats were irradiated by neutrons in the first hour following the intravenous injection of BA. The prescription-absorbed doses in the tumor regions were 5.8 and 11.0 Gy. BNCT reduced the body weight of the tumor-bearing rats, but they recovered after a few days. The BA-mediated BNCT effectively controlled the orthotopic OS tumor, reduced osteolysis, and induced bone healing. Autoradiography and histological analysis confirmed that the BA retention region is consistent with the calcification region in OS tissue. Conclusion: BA is specifically retained in OS, and the BA-mediated BNCT can significantly reduce the tumor burden and osteolysis in OS-bearing rats. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a particle therapy that involves the use of boron-containing drugs and neutron irradiation for the treatment of tumors, such as head and neck cancer. Boron atoms accumulated in a tumor capture neutrons through the nuclear reaction, then generating charged particles responsible for the therapeutic action. However, other elements in the patient's tissues or metal implants are activated during the treatment. Therefore, patients emit radiation after receiving BNCT. In this study, to develop release criteria for patients who have received BNCT, patients underwent spectroscopy using calibrated high-purity germanium to identify which elements were activated during the procedure. The ambient dose equivalent rate, H ˙ ∗ (10), was measured at the surface of a patient's treatment site and 1 m away from the patient using a plastic dosimeter. This cohort study included 84 patients and was conducted from March 2017 to February 2020. The predominant radionuclides activated during the procedures were 49Ca, 38Cl, and 24Na. According to the International Commission on Radiological Protection Publication 103, the European Commission Radiation Protection No. 194 report, and the United States Nuclear Regulatory Commission Regulatory Guide 8.39, the main criterion for the release of patients following BNCT comprises an ambient dose equivalent rate lower than 10 μSv/h at a distance of 1 m from the patient. All of the patients in this study exhibited a rate lower than this limit. The average ambient dose equivalent rate measured at the surfaces of the patients' treatment sites was approximately 30–50 μSv/h. The maximum occupational exposure of the BNCT staff from patient-emitted radiation was approximately 20 μSv per 20-min treatment course. • Predominant activated radionuclides of 50 BNCT patients were 49Ca, 38Cl, and 24Na. • Release criteria of BNCT patients is the ambient dose equivalent rate of 10 μSv/h at 1 m. • Occupational exposure from patient to BNCT staff in 20 min was about 20 μSv. [ABSTRACT FROM AUTHOR]

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 B 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 B 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 W B dosimeter for BNCT. [ABSTRACT FROM AUTHOR]

Meningiomas are the most frequently diagnosed primary intracranial tumors in adults. Surgical resection is preferred if the meningioma is accessible; for those that are not suitable for surgical resection, radiotherapy should be considered to improve local tumor control. However, recurrent meningiomas are challenging to treat, as the recurrent tumor might be located in the previously irradiated area. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy modality in which the cytotoxic effect focuses mainly on cells with increased uptake of boron-containing drugs. In this article, we describe four patients with recurrent meningiomas treated with BNCT in Taiwan. The mean boron-containing drug tumor-to-normal tissue uptake ratio was 4.125, and the tumor mean dose was 29.414 GyE, received via BNCT. The treatment response showed two stable diseases, one partial response, and one complete response. We also introduce and support the effectiveness and safety of BNCT as an alternative salvage treatment for recurrent meningiomas. [ABSTRACT FROM AUTHOR]

Objective: Glioblastoma (WHO classification Grade IV) is a highly malignant brain tumor with a high propensity for recurrence even after standard treatments. Patient death is inevitable, as the available methods are largely ineffective for remediation and treatment once recurrence has occurred. This review presents recent advancements in boron neutron capture therapy (BNCT) that have allowed for its clinical use in treating glioblastoma. Data Sources: We retrospectively reviewed the results of clinical trials and articles published in the past 30 years worldwide. Study Selection: All included studies addressed the use of BNCT to treat high-grade gliomas, including glioblastoma. Results: The development of boron-containing agents exhibiting specificity and improvements in technologies that generate neutron sources have led to the clinical use of BNCT for treating tumors. BNCT involves the delivery of a boron-10-containing drug specifically to tumor cells, followed by irradiation with low-energy thermal neutrons to generate two biologically active particles (helium [α particle] and lithium nuclei). Although these particles are highly effective at destroying cells, their field of destruction is limited to the tumor cells. Therefore, BNCT serves as an excellent mode of targeted particle therapy for tumors, particularly those that are infiltrative. The published articles reviewed here demonstrate the gradual refinement of the BNCT technique and prolonged survival for glioma patients compared to conventional treatments. Conclusion: With continued improvements, BNCT may become the first-choice treatment for malignant infiltrative glioblastoma in the near future. [ABSTRACT FROM AUTHOR]

Brainstem tumors are heterogenous and cancerous glioma tumors arising from the midbrain, pons, and the medulla that are relatively common in children, accounting for 10% to 20% of all pediatric brain tumors. However, the prognosis of aggressive brainstem gliomas remains extremely poor despite aggressive treatment with chemotherapy and radiotherapy. That means there are many life-threatening patients who have exhausted all available treatment options and are beginning to face end-of-life stage. Therefore, the unique properties of highly selective heavy particle irradiation with boron neutron capture therapy (BNCT) may be well suited to prolong the lives of patients with end-stage brainstem gliomas. Herein, we report a case series of life-threatening patients with end-stage brainstem glioma who eligible for Emergency and Compassionate Use, in whom we performed a scheduled two fractions of salvage BNCT strategy with low treatment dosage each time. No patients experienced acute or late adverse events related to BNCT. There were 3 patients who relapsed after two fractionated BNCT treatment, characterized by younger age, lower T/N ratio, and receiving lower treatment dose. Therefore, two fractionated low-dose BNCT may be a promising treatment for end-stage brainstem tumors. For younger patients with low T/N ratios, more fractionated low-dose BNCT should be considered. [ABSTRACT FROM AUTHOR]

Abstract: This paper presents a way to determine the angular and spatial distributions of the thermal neutron source strength of a boron neutron capture therapy (BNCT) beam. The experiments applied 1) the indirect neutron radiography, 2) the cadmium difference method, and 3) the instrumental neutron activation analysis. The measured data were processed by the spectrum deconvolution technique to resolve into a proper set of angular and spatial distributions. This paper took the epithermal neutron beam of the BNCT facility at the Tsing Hua Open-pool Reactor as an example. [ABSTRACT FROM AUTHOR]

Abstract: This study aims to measure the neutronic characteristics of the 14-cm diameter boron neutron capture therapy beam at the Tsing Hua Open-pool Reactor and to provide essential information for the neutron source adjustment and validation. The measurements were performed both in air and inside a cubic PMMA phantom at the beam, with and without an 18-cm long extended PE collimator. The neutron intensity was determined by neutron activation analysis; the indirect neutron radiography and the cadmium difference method were coupled to provide the two-dimensional neutron flux distributions. According to the measurements, the angular distribution is highly forward for epithermal neutrons but much more divergent for thermal ones. A PE extended collimator will modify the beam characteristics and could benefit the treatment for head and neck tumors, which often needs higher therapeutical boron dose at the shallow region. [ABSTRACT FROM AUTHOR]

Abstract: Activation foils, stacked in a package, together with a spectrum adjustment code are generally the means to characterize the neutron spectrum of a BNCT epithermal neutron beam. When using foil stacks, the phenomenon of neutron scattering is appreciably enhanced, especially in an epithermal neutron beam, as compared to a thermal neutron field. Contrary to the conventional idea of the self-shielding effect, self-shielding correction factors in most of the foils in the stack are larger than one. This paper demonstrates a way to correct the complex self-shielding effect using groupwise cross-sections modified for self-shielding, as calculated by the Monte Carlo neutron transport code, MCNP. This methodology can solve the perturbation problems caused by the foil stack applied in an epithermal neutron beam. In this study, the adjusted spectrum of the HB11 epithermal neutron beam, dedicated for BNCT research in Petten, The Netherlands, is utilized and two adjusted spectra are presented with and without the self-shielding correction. The difference between the spectra is highly significant and demonstrates that the self-shielding correction cannot be ignored. [Copyright &y& Elsevier]

Purpose: To investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy.Methods and Materials: In this prospective phase 1/2 trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA-positron emission tomography was conducted to determine the tumor/normal tissue ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively.Results: Seventeen patients with a previous cumulative radiation dose of 63-165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median tumor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants exhibited a complete response and 6 exhibited a partial response. Regarding acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40 Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locoregional control was 28%.Conclusions: Our results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H&N cancer. Modifications to our protocol may yield more satisfactory results in the future. [ABSTRACT FROM AUTHOR]

Abstract: To introduce our experience of treating locally and regionally recurrent head and neck cancer patients with BNCT at Tsing Hua Open-Pool Reactor in Taiwan, 12 patients (M/F=10/2, median age 55.5 Y/O) were enrolled and 11 received two fractions of treatment. Fractionated BNCT at 30-day interval with adaptive planning according to changed T/N ratios was feasible, effective and safe for selected recurrent head and neck cancer in this trial. [Copyright &y& Elsevier]

Abstract: Various quality control (QC) and quality assurance (QA) procedures of the boron neutron capture therapy (BNCT) beam at the Tsing Hua Open-pool Reactor (THOR) are established to ensure beam availability and quality. The QC/QA methods mainly employ foil activation and paired ionization chambers, respectively, for beam intensity check and dose assessment. Beam intensity is monitored on-line by using three dead-time corrected fission chambers. In addition to the periodic QC/QA activities regarding beam quality and the monitoring system, the quick QC/QA performed in an all-in-one phantom will be executed less than 70min before the clinical treatment to guarantee beam quality. The QC/QA procedures have been gradually established and the actual performance satisfied the preset criteria defined for the BNCT facility at THOR. [Copyright &y& Elsevier]

Abstract: This paper aims to evaluate the performance of the source description of the THOR BNCT beam via different measurement techniques in different phantoms. The measurement included (1) the absolute reaction rate measurement of a set of triple activation foils, (2) the neutron and gamma-ray dose rates measured using the paired ionization chamber method, and (3) the relative reaction rate distributions obtained using the indirect neutron radiography. Three source descriptions, THOR-Y09, surface source file RSSA, and THOR-50C, were tested. The comparison results concluded that THOR-Y09 is a well-tested source description not only for neutron components, but also for gamma-ray component. [Copyright &y& Elsevier]

Abstract: A refined dose assessment method has been used now in the THOR BNCT facility, which takes into account more delicate corrections, carefully handled calibration factors, and the spectrum- and kerma-weighted kt value. The refined method solved the previous problem of negative derived neutron dose in phantom at deeper positions. With the improved dose assessment, the calculated and measured gamma-ray dose rates match perfectly in a 15×15×15cm3 PMMA phantom. [Copyright &y& Elsevier]

Abstract: The knowledge of gamma-ray spectrum highly affects the accuracy of the correspondingly derived gamma-ray dose and the correctness of calculated neutron dose in the neutron/gamma-ray mixed field dosimetry when using the paired ionization chambers technique. It is of our interest to develop a method to determine the gamma-ray spectrum in a strong neutron/gamma-ray mixed field. The current type detector, Mg(Ar) ionization chamber with 6 different thick caps incorporated with the unfolding technique, was used to determine the gamma-ray spectrum in the THOR epithermal neutron beam, which contains intense neutrons and gamma rays. The applied caps had nominal thicknesses from 1 to 6mm. Detector response functions of the applied Mg(Ar) chamber with different caps were calculated using MCNP5 with a validated chamber model. The spectrum unfolding process was performed using the well-known SAND-II algorithm. The unfolded result was found much softer than the originally calculated spectrum at the design stage. A large portion of low energy continuum was shown in the adjusted spectrum. This work gave us a much deeper insight into the THOR epithermal neutron beam and also showed a way to determine the gamma-ray spectrum. [Copyright &y& Elsevier]

Abstract: This study is a part of the beam comparison campaign, inter-center dose comparison, between boron neutron capture therapy facilities at the Tsing Hua Open-pool Reactor and the High Flux Reactor. The clinical information exchange can improve the dosimetry uncertainty for medical physics in a mixed field. The method of paired Mg(Ar) and TE(TE) ionization chambers was used to determine the gamma-ray and neutron dose rates. Furthermore, activation foils, including gold, copper, and manganese, were employed to estimate the thermal and epithermal neutron fluxes. Measurements were performed free in air and also in a PMMA phantom. All the chambers were calibrated using a 60Co primary standard source at the Institute of Nuclear Energy Research, Taiwan. Spectrum dependent neutron sensitivity of TE(TE) chamber is one of the important parameters to evaluate dose components. The requested neutron spectra were calculated by the Monte Carlo code MCNP. The measured thermal neutron fluxes, gamma-ray and neutron dose rates of the THOR beam in the phantom were 2.6, 2.2, and 2.1 times of the HFR beam at 2.5-cm depth, respectively. The higher thermal neutron flux and neutron and gamma-ray dose rates are due to the higher epithermal neutron beam intensity of the THOR. [ABSTRACT FROM AUTHOR]

Simple Summary: Although boron neutron capture therapy (BNCT) is a promising therapeutic approach for malignant brain tumors, the optimal BNCT parameters for patients with life-threatening, end-stage brain tumors remain unclear. The results of this study show that for life-threatening, end-stage brain tumor patients, BNCT is a promising therapeutic modality that is associated with an overall survival time of 7.25 months and no severe adverse events (grade ≥ 3). Remarkably, patients who achieved a complete response had overall survival times and cancer-specific survival times of up to 17.66 and 22.5 months, respectively. In addition, since these patients are usually physically weak and already on the verge of life-threatening conditions, reducing the BNCT dose still has good therapeutic outcomes. Statistical analysis revealed the optimal BNCT parameters and tumor characteristics, including a tumor-to-normal tissue (T/N) uptake ratio of ≥4, a tumor volume of <20 mL, a mean tumor dose of ≥25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. The results of this study provide a reference for other clinicians or radiation oncologists conducting BNCT treatment for such patients. Although boron neutron capture therapy (BNCT) is a promising treatment option for malignant brain tumors, the optimal BNCT parameters for patients with immediately life-threatening, end-stage brain tumors remain unclear. We performed BNCT on 34 patients with life-threatening, end-stage brain tumors and analyzed the relationship between survival outcomes and BNCT parameters. Before BNCT, MRI and 18F-BPA-PET analyses were conducted to identify the tumor location/distribution and the tumor-to-normal tissue uptake ratio (T/N ratio) of 18F-BPA. No severe adverse events were observed (grade ≥ 3). The objective response rate and disease control rate were 50.0% and 85.3%, respectively. The mean overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) times were 7.25, 7.80, and 4.18 months, respectively. Remarkably, the mean OS, CSS, and RFS of patients who achieved a complete response were 17.66, 22.5, and 7.50 months, respectively. Kaplan–Meier analysis identified the optimal BNCT parameters and tumor characteristics of these patients, including a T/N ratio ≥ 4, tumor volume < 20 mL, mean tumor dose ≥ 25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. In conclusion, for malignant brain tumor patients who have exhausted all available treatment options and who are in an immediately life-threatening condition, BNCT may be considered as a therapeutic approach to prolong survival. [ABSTRACT FROM AUTHOR]

Hepatoma is the second leading cause of cancer death worldwide. Due to the poor outcomes of patients with late diagnosis, newer treatments for hepatoma are still needed. As an emerging therapy, boron neutron capture therapy (BNCT) may be an effective solution in hepatoma management. In this study, boric acid (BA) was used as the boron drug for in vivo analysis of action mechanism. The N1S1 single liver tumor-bearing rat and the VX2 multifocal liver tumor-bearing rabbit models were used to investigate the retention status of BA in the tumor regions during BNCT. The autoradiographic examination showed BA can localize specifically not only in the hepatoma cells but also in tumor blood vessels. Our findings indicate that superior hepatoma targeting could be achieved in BA-mediated BNCT, which supports BA to be a suitable boron drug for BNCT for hepatoma. • Boric acid (BA) was used as the boron drug for BNCT for hepatoma. • BA can be specifically retained in the tumor cells and tumor vasculature in the liver tumor-bearing animal models. • A high boron dose could be selectively achieved in the hepatoma regions during BA-mediated BNCT. [ABSTRACT FROM AUTHOR]

Abstract: The GAFCHROMIC® EBT2 dosimetry film has been studied as a rapid QC/QA tool for 2D dose profile mapping in the BNCT beam at THOR. The pixel values of the EBT2 film image were converted to the 2D dose profile using a dose calibration curve obtained by 6-MV X-ray. The reproducibility of the 2D dose profile measured using the EBT2 film in the PMMA phantom was preliminarily found to be acceptable with uncertainties within about ±2 to ±3.5%. It is found that the EBT2 measured dose profile consisted of both gamma-ray components and neutron contributions. Therefore, the dose profile measured using the EBT2 film is significantly different from the neutron flux profile measured using the indirect neutron radiography method. Further study of the influence of neutrons to the response of the EBT2 film is indispensible for the absolute dose profile determination in a BNCT beam. [Copyright &y& Elsevier]

Abstract: This paper aims to measure the spectra of HB11 (high flux reactor, HFR) and the Tsing Hua open-pool reactor (THOR) boron neutron capture therapy (BNCT) beams by multiple activation foils. The self-shielding corrections were made with the aid of MCNP calculations. The initial spectra were adjusted by a sophisticated process named coarse-scaling adjustment using SAND-EX, which can adjust a given coarse-group spectrum into a fine-group structure, i.e. 640 groups, with excellent continuity. The epithermal neutron flux of the THOR beam is about three times of HB11. The thermal neutron flux, boron and gold reaction rates along the central axis of a PMMA phantom are calculated for both adjusted spectra for comparison. [Copyright &y& Elsevier]