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

BACKGROUND: 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. PURPOSE: We present the details of our novel algorithm and the verification results of the calculation accuracy based on the MC calculation result. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Enhancement of Radiation Response Associated With Metformin in Hepatocellular Carcinoma: Preclinical Animal and Clinical Cohort Study.

BACKGROUND/AIM: This study examined whether metformin can enhance the radiation response in a hepatocellular carcinoma (HCC) xenograft mice model and patient population. MATERIALS AND METHODS: Huh-7 human HCC-bearing xenograft mice were treated with gamma-ray, metformin, neutron therapy, and their combinations. Tumour growth and lung colonies were assessed. Overall, 145 patients who underwent radiotherapy for HCC were retrospectively analysed. RESULTS: The combinations of gamma-ray and metformin and neutron radiation and metformin inhibited tumour growth and metastatic lung nodule formation when compared to the monotherapy and gamma-ray groups, respectively. In patients who received radiotherapy for HCC, the overall survival rate was higher in the metformin-treated group than in the non-metformin group. CONCLUSION: Metformin inhibited tumour growth and metastasis in HCC by enhancing the radiation response in animal experiments. Additionally, metformin was also found to be associated with a higher survival outcome in patients with HCC.

Tumor Cell-Specific 2'-Fluoro RNA Aptamer Conjugated with Closo-Dodecaborate as A Potential Agent for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic approach to the treatment of malignant tumors, especially glioblastoma, the most frequent and incurable brain tumor. For successful BNCT, a boron-containing therapeutic agent should provide selective and effective accumulation of 10B isotope inside target cells, which are then destroyed after neutron irradiation. Nucleic acid aptamers look like very prospective candidates for carrying 10B to the tumor cells. This study represents the first example of using 2'-F-RNA aptamer GL44 specific to the human glioblastoma U-87 MG cells as a boron delivery agent for BNCT. The closo-dodecaborate residue was attached to the 5'-end of the aptamer, which was also labeled by the fluorophore at the 3'-end. The resulting bifunctional conjugate showed effective and specific internalization into U-87 MG cells and low toxicity. After incubation with the conjugate, the cells were irradiated by epithermal neutrons on the Budker Institute of Nuclear Physics neutron source. Evaluation of the cell proliferation by real-time cell monitoring and the clonogenic test revealed that boron-loaded aptamer decreased specifically the viability of U-87 MG cells to the extent comparable to that of 10B-boronophenylalanine taken as a control. Therefore, we have demonstrated a proof of principle of employing aptamers for targeted delivery of boron-10 isotope in BNCT. Considering their specificity, ease of synthesis, and large toolkit of chemical approaches for high boron-loading, aptamers provide a promising basis for engineering novel BNCT agents.

Combined Effect of Neutron and Proton Radiations on the Growth of Solid Ehrlich Ascites Carcinoma and Remote Effects in Mice.

The combined effect of the irradiation with a proton pencil scanning beam (PBS) at a total dose of 80 Gy and neutron radiation at a dose of 5 Gy on the growth of solid Ehrlich ascites carcinoma (EAC) and the remote effects in tumor-bearing mice was studied. Combined irradiation of mice with neutrons before and after irradiation with PBS, as well as irradiation only with PBS, effectively suppressed the growth of solid EAC within 1 month. In terms of the frequency and severity of radiation-induced skin reactions of mice observed 15-40 days after therapy, neutron irradiation after the irradiation with PBS showed better values of these parameters as compared to only PBS; however, exposure to neutrons before PBS was more damaging as compared to the other two options. It was also shown that the tumor relapse rate in the groups of animals with combined irradiation was higher, and the total lifespan was lower than the group of mice irradiated with PBS alone.

Physical and Biological Characteristics of Particle Therapy for Oncologists.

Particle therapy is a promising and evolving modality of radiotherapy that can be used to treat tumors that are radioresistant to conventional photon beam radiotherapy. It has unique biological and physical advantages compared with conventional radiotherapy. The characteristic feature of particle therapy is the "Bragg peak," a steep and localized peak of dose, that enables precise delivery of the radiation dose to the tumor while effectively sparing normal organs. Especially, the charged particles (e.g., proton, helium, carbon) cause a high rate of energy loss along the track, thereby leading to high biological effectiveness, which makes particle therapy attractive. Using this property, the particle beam induces more severe DNA double-strand breaks than the photon beam, which is less influenced by the oxygen level. This review describes the general biological and physical aspects of particle therapy for oncologists, including non-radiation oncologists and beginners in the field.

Neutron Therapy for High-Grade Salivary Carcinomas in the Adjuvant and Primary Treatment Setting.

OBJECTIVES/HYPOTHESIS: Our primary objective was to compare differences in survival of patients with high-grade salivary gland carcinomas (SGCs) receiving adjuvant neutron versus photon radiotherapy using a hospital-based national cohort and restricted mean survival time (RMST) analysis. Our secondary objective was to compare survival of similar patients treated with primary neutron versus photon radiation. STUDY DESIGN: Multicenter, retrospective population-based study of patients within the National Cancer Database from 2004 to 2014. METHODS: One thousand eight hundred forty-four patients were selected on diagnosis of high-grade parotid and submandibular malignancies. One thousand seven hundred seventy-seven patients receiving photon and 67 patients receiving neutron therapy were identified who met inclusion criteria. Patients were then categorized as having primary surgery with adjuvant radiation or primary radiation without prior surgery. Bivariate analysis was performed to assess for differences between groups, and RMST analysis was performed at 1-, 2-, and 5-year timepoints with controlling for available covariate data. RESULTS: There was no significant difference in RMST for patients receiving neutrons over photons at 1, 2, and 5 years in the adjuvant setting. Among patients undergoing primary radiotherapy, there was a difference in RMST of 2.29 months at 1 year and 5.05 months at 2 years for neutrons over photons, though this benefit was not observed at 5 years post-therapy. CONCLUSIONS: For patients with high grade SGCs undergoing adjuvant photon versus neutron radiotherapy, there was no difference in RMST. There was observed to be a significant difference in RMST at 1 and 2 years among patients undergoing primary neutron therapy of up to 5 months. Given the benefit observed with primary neutron therapy, it should be considered in both the primary and adjuvant treatment setting. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:541-547, 2021.

The 20th Gray lecture 2019: health and heavy ions.

OBJECTIVE: Particle radiobiology has contributed new understanding of radiation safety and underlying mechanisms of action to radiation oncology for the treatment of cancer, and to planning of radiation protection for space travel. This manuscript will highlight the significance of precise physical and biologically effective dosimetry to this translational research for the benefit of human health.This review provides a brief snapshot of the evolving scientific basis for, and the complex current global status, and remaining challenges of hadron therapy for the treatment of cancer. The need for particle radiobiology for risk planning in return missions to the Moon, and exploratory deep-space missions to Mars and beyond are also discussed. METHODS: Key lessons learned are summarized from an impressive collective literature published by an international cadre of multidisciplinary experts in particle physics, radiation chemistry, medical physics of imaging and treatment planning, molecular, cellular, tissue radiobiology, biology of microgravity and other stressors, theoretical modeling of biophysical data, and clinical results with accelerator-produced particle beams. RESULTS: Research pioneers, many of whom were Nobel laureates, led the world in the discovery of ionizing radiations originating from the Earth and the Cosmos. Six radiation pioneers led the way to hadron therapy and the study of charged particles encountered in outer space travel. Worldwide about 250,000 patients have been treated for cancer, or other lesions such as arteriovenous malformations in the brain between 1954 and 2019 with charged particle radiotherapy, also known as hadron therapy. The majority of these patients (213,000) were treated with proton beams, but approximately 32,000 were treated with carbon ion radiotherapy. There are 3500 patients who have been treated with helium, pions, neon or other ions. There are currently 82 facilities operating to provide ion beam clinical treatments. Of these, only 13 facilities located in Asia and Europe are providing carbon ion beams for preclinical, clinical, and space research. There are also numerous particle physics accelerators worldwide capable of producing ion beams for research, but not currently focused on treating patients with ion beam therapy but are potentially available for preclinical and space research. Approximately, more than 550 individuals have traveled into Lower Earth Orbit (LEO) and beyond and returned to Earth. CONCLUSION: Charged particle therapy with controlled beams of protons and carbon ions have significantly impacted targeted cancer therapy, eradicated tumors while sparing normal tissue toxicities, and reduced human suffering. These modalities still require further optimization and technical refinements to reduce cost but should be made available to everyone in need worldwide. The exploration of our Universe in space travel poses the potential risk of exposure to uncontrolled charged particles. However, approaches to shield and provide countermeasures to these potential radiation hazards in LEO have allowed an amazing number of discoveries currently without significant life-threatening medical consequences. More basic research with components of the Galactic Cosmic Radiation field are still required to assure safety involving space radiations and combined stressors with microgravity for exploratory deep space travel. ADVANCES IN KNOWLEDGE: The collective knowledge garnered from the wealth of available published evidence obtained prior to particle radiation therapy, or to space flight, and the additional data gleaned from implementing both endeavors has provided many opportunities for heavy ions to promote human health.

Thermal Neutron Relative Biological Effectiveness Factors for Boron Neutron Capture Therapy from In Vitro Irradiations.

The experimental determination of the relative biological effectiveness of thermal neutron factors is fundamental in Boron Neutron Capture Therapy. The present values have been obtained while using mixed beams that consist of both neutrons and photons of various energies. A common weighting factor has been used for both thermal and fast neutron doses, although such an approach has been questioned. At the nuclear reactor of the Institut Laue-Langevin a pure low-energy neutron beam has been used to determine thermal neutron relative biological effectiveness factors. Different cancer cell lines, which correspond to glioblastoma, melanoma, and head and neck squamous cell carcinoma, and non-tumor cell lines (lung fibroblast and embryonic kidney), have been irradiated while using an experimental arrangement designed to minimize neutron-induced secondary gamma radiation. Additionally, the cells were irradiated with photons at a medical linear accelerator, providing reference data for comparison with that from neutron irradiation. The survival and proliferation were studied after irradiation, yielding the Relative Biological Effectiveness that corresponds to the damage of thermal neutrons for the different tissue types.

The Unfolded Protein Response: Neutron-Induced Therapy Autophagy as a Promising Treatment Option for Osteosarcoma.

Radiotherapy using high linear energy transfer (LET) radiation results in effectively killing tumor cells while minimizing dose (biological effective) to normal tissues to block toxicity. It is well known that high LET radiation leads to lower cell survival per absorbed dose than low LET radiation. High-linear energy transfer (LET) neutron treatment induces autophagy in tumor cells, but its precise mechanisms in osteosarcoma are unknown. Here, we investigated this mechanism and the underlying signaling pathways. Autophagy induction was examined in gamma-ray-treated KHOS/NP and MG63 osteosarcoma cells along with exposure to high-LET neutrons. The relationship between radiosensitivity and autophagy was assessed by plotting the cell surviving fractions against autophagy levels. Neutron treatment increased autophagy rates in irradiated KHOS/NP and MG63 cells; neutrons with high-LETs showed more effective inhibition than those with lower LET gamma-rays. To determine whether the unfolded protein response and Akt-mTOR pathways triggered autophagy, phosphorylated eIF2α and JNK levels, and phospho-Akt, phosphor-mTOR, and phospho-p70S6 levels were, respectively, investigated. High-LET neutron exposure inhibited Akt phosphorylation and increased Beclin 1 expression during the unfolded protein response, thereby enhancing autophagy. The therapeutic efficacy of high-LET neutron radiation was also assessed in vivo using an orthotopic mouse model. Neutron-irradiated mice showed reduced tumor growth without toxicity relative to gamma-ray-treated mice. The effect of high-LET neutron exposure on the expression of signaling proteins LC3, p-elF2a, and p-JNK was investigated by immunohistochemistry. Tumors in high-LET-neutron radiation-treated mice showed higher apoptosis rates, and neutron exposure significantly elevated LC3 expression, and increased p-elF2a and p-JNK expression levels. Overall, these results demonstrate that autophagy is important in radiosensitivity, cell survival, and cellular resistance against high-LET neutron radiation. This correlation between cellular radiosensitivity and autophagy may be used to predict radiosensitivity in osteosarcoma.

Accelerator-based boron neutron capture therapy for malignant glioma: a pilot neutron irradiation study using boron phenylalanine, sodium borocaptate and liposomal borocaptate with a heterotopic U87 glioblastoma model in SCID mice.

Purpose: To evaluate the efficacy of boron neutron capture therapy (BNCT) for a heterotopic U87 glioblastoma model in SCID mice using boron phenylalanine (BPA), sodium borocaptate (BSH) and liposomal BSH as boron compounds at a unique, accelerator-based neutron source.Materials and methods: Glioblastoma models were obtained by subcutaneous implantation of U87 cells in the right thighs of SCID mice before administration of 350 mg/kg of BPA (BPA-group), 100 mg/kg of BSH (BSH-group) or 100 mg/kg of BSH in PEGylated liposomes (liposomal BSH-group) into the retroorbital sinus. Liposomes were prepared by reverse-phase evaporation. Neutron irradiation was carried out at a proton accelerator with a lithium target developed for BNCT at the Budker Institute of Nuclear Physics, Novosibirsk, Russian Federation. A proton beam current integral of 3 mA/h and energy of 2.05 MeV were used for neutron generation.Results: Boron compound accumulation in tumor tissues at the beginning of irradiation was higher in the BPA group, followed by the Liposomal BSH and BSH groups. Tumor growth was significantly slower in all irradiated mice from the 7th day after BNCT compared to untreated controls (p < .05). Tumor growth in all treated groups showed no large variation, apart from the Irradiation only group and the BPA group on the 7th day after BNCT. The overall trend of tumor growth was clear and the differences between treatment groups became significant from the 50th day after BNCT. Tumor growth was significantly slower in the Liposomal BSH group compared to the Irradiation only group on the 50th (p = .012), 53rd (p = .005), and the 57th (p = .021) days after treatment. Tumor growth in the Liposomal BSH group was significantly different from that in the BPA group on the 53rd day after BNCT (p = .021) and in the BSH group on the 50th (p = .024), 53rd (p = .015), and 57th (p = .038) days after BNCT. Skin reactions in the form of erosions and ulcers in the tumor area developed in treated as well as untreated animals with further formation of fistulas and necrotic decay cavities in most irradiated mice.Conclusions: We observed a tendency of BNCT at the accelerator-based neutron source to reduce or suspend the growth of human glioblastoma in immunodeficient animals. Liposomal BSH showed better long-term results compared to BPA and non-liposomal BSH. Further modifications in liposomal boron delivery are being studied to improve treatment outcomes.

Boron neutron capture therapy (BNCT): a unique role in radiotherapy with a view to entering the accelerator-based BNCT era.

Boron neutron capture therapy (BNCT) has a unique property of tumor-cell-selective heavy-particle irradiation. BNCT can form large dose gradients between cancer cells and normal cells, even if the two types of cells are mingled at the tumor margin. This property makes it possible for BNCT to be used for pre-irradiated locally recurrent tumors. Shallow-seated, locally recurrent lesions have been treated with BNCT because of the poor penetration of neutrons in the human body. BNCT has been used in clinical studies for recurrent malignant gliomas and head and neck cancers using neutron beams derived from research reactors, although further investigation is warranted because of the small number of patients. In the latter part of this review, the development of accelerator-based neutron sources is described. BNCT for common cancers will become available at medical institutes that are equipped with an accelerator-based BNCT system. Multiple metastatic lung tumors have been investigated as one of the new treatment candidates because BNCT can deliver curative doses of radiation to the tumors while sparing normal lung tissue. Further basic and clinical studies are needed to move toward an era of accelerator-based BNCT when more patients suffering from refractory cancers will be treated.

Measurement of the contralateral breast photon and neutron dose in breast cancer radiotherapy: A Monte Carlo study.

INTRODUCTION: This study aimed to calculate the photon and neutron doses received to the contralateral breast (CB) during breast cancer radiotherapy for various field sizes in the presence of a physical wedge. MATERIALS AND METHODS: Varian 2100 C/D linear accelerator was simulated using a MCNP4C Monte Carlo code. Then, a phantom of real female chest was simulated and the treatment planning was carried out on tumoral breast (left breast). Finally, the received photon and neutron doses to CB (right breast) were calculated in the presence of a physical wedge for 18 MV photon beam energy. These calculations were performed for different field sizes including 11 cm × 13 cm, 11 cm × 17 cm, and 11 cm × 21 cm. RESULTS: The findings showed that the received doses (both of the photon and neutron) to CB in the presence of a physical wedge for 11 cm × 13 cm, 11 cm × 17 cm, and 11 cm × 21 cm field sizes were 9.87%, 12.91%, and 27.37% of the prescribed dose, respectively. In addition, the results showed that the received photon and neutron doses to CB increased with increment in the field size. CONCLUSION: From the results of this study, it is concluded that the received photon and neutron doses to CB in the presence of a physical wedge is relatively more, and therefore, they should be reduced to as low as possible. Therefore, using a dynamic wedge instead of a physical wedge or field-in-field technique is suggested.

A Monte Carlo feasibility study for neutron based real-time range verification in proton therapy.

Uncertainties in the proton range in tissue during proton therapy limit the precision in treatment delivery. These uncertainties result in expanded treatment margins, thereby increasing radiation dose to healthy tissue. Real-time range verification techniques aim to reduce these uncertainties in order to take full advantage of the finite range of the primary protons. In this paper, we propose a novel concept for real-time range verification based on detection of secondary neutrons produced in nuclear interactions during proton therapy. The proposed detector concept is simple; consisting of a hydrogen-rich converter material followed by two charged particle tracking detectors, mimicking a proton recoil telescopic arrangement. Neutrons incident on the converter material are converted into protons through elastic and inelastic (n,p) interactions. The protons are subsequently detected in the tracking detectors. The information on the direction and position of these protons is then utilized in a new reconstruction algorithm to estimate the depth distribution of neutron production by the proton beam, which in turn is correlated with the primary proton range. In this paper, we present the results of a Monte Carlo feasibility study and show that the proposed concept could be used for real-time range verification with millimetric precision in proton therapy.

The efficacy of neutron radiation therapy in treating salivary gland malignancies.

OBJECTIVES: Radiation therapy is commonly used to treat head and neck malignancies. While there is abundant research regarding photon radiation therapy, literature on neutron radiotherapy (NRT) and oral complications is limited. This study aims to determine: (1) the 6-year and 10-year locoregional control and survival rates, (2) factors associated with locoregional control and survival and (3) the frequency of oral complications in patients undergoing NRT for salivary gland malignancies. MATERIALS AND METHODS: This is a retrospective cohort study. The sample was composed of patients with salivary gland malignancies treated with NRT between 1997 and 2010. Data were extracted from patient charts, telephone surveys, and social security records. Multivariate competing risk and Cox regression models were used to assess predictors of locoregional control and survival. RESULTS: The sample was composed of 545 subjects with a mean age of 54.2 years (±16). The predominant tumor and location were adenoid cystic carcinoma (47%) and the parotid (56%). Multivariate analysis indicated that positive surgical margins, biopsied/inoperable malignancies, neck involvement, and lymphovascular invasion were prognostic risk factors associated with decreased survival. The 6- and 10-year locoregional control rates were 84% and 79%. The 6- and 10-year survival rates were 72% and 62%. Osteoradionecrosis developed in 3.4% of subjects. CONCLUSIONS: The 6- and 10-year locoregional control and survival rates compare favorably to rates reported for conventional photon radiation. Osteoradionecrosis rates were comparable to that of photon radiation treatment (2-7%). Given the potential benefits of NRT, healthcare professionals should be educated regarding its indications and oral complications.

Secondary Neutron Dose From a Dynamic Collimation System During Intracranial Pencil Beam Scanning Proton Therapy: A Monte Carlo Investigation.

PURPOSE: Patients receiving pencil beam scanning (PBS) proton therapy with the addition of a dynamic collimation system (DCS) are potentially subject to an additional neutron dose from interactions between the incident proton beam and the trimmer blades. This study investigates the secondary neutron dose rates for both single-field uniform dose (SFUD) and intensity modulated proton therapy treatments. METHODS AND MATERIALS: Secondary neutron dose distributions were calculated for both a dynamically collimated and an uncollimated, dual-field chordoma treatment plan and compared with previously published neutron dose rates from other contemporary scanning treatment modalities. Monte Carlo N-Particle transport code was used to track all primary and secondary particles generated from nuclear reactions within the DCS during treatment through a model of the patient geometry acquired from the computed tomography planning data set. Secondary neutron ambient dose equivalent distributions were calculated throughout the patient using a meshgrid with a tally resolution equivalent to that of the treatment planning computed tomography. RESULTS: The median healthy-brain neutron ambient dose equivalent for a dynamically collimated intracranial chordoma treatment plan using a DCS was found to be 0.97 mSv/Gy for the right lateral SFUD field, 1.37 mSv/Gy for the apex SFUD field, and 1.24 mSv/Gy for the composite intensity modulated proton therapy distribution from 2 fields. CONCLUSIONS: These results were at least 55% lower than what has been reported for uniform scanning modalities with brass apertures. However, they still reflect an increase in the excess relative risk of secondary cancer incidence compared with an uncollimated PBS treatment using only a graphite range shifter. Regardless, the secondary neutron dose expected from the DCS for these PBS proton therapy treatments appears to be on the order of, or below, what is expected for alternative collimated proton therapy techniques.

Second primary malignancies after high-dose-rate 60Co photon or 252Cf neutron brachytherapy in conjunction with external-beam radiotherapy for endometrial cancer.

PURPOSE: Second primary malignancies (SPMs) may occur in organs after radiotherapy (RT). This study aimed to determine the rate and distribution of SPMs for photon- or neutron-emitting radiotherapy sources for patients treated for primary endometrial cancer. METHODS AND MATERIALS: The cohort comprised 426 patients with 5334 patient-years of observation. Patients were treated by different methods of RT from 1990 to 2000. Patients received postoperative 60Co external-beam radiotherapy (43.4%), external-beam radiotherapy + high-dose-rate (HDR) intracavitary brachytherapy with 60Co or 252Cf (42.3%), or HDR intracavitary brachytherapy alone with 60Co or 252Cf (14.3%). RESULTS: Over a 25-year period, 47 SPMs were observed (21 for HDR 60Co and 26 for HDR 252Cf). SPMs were observed for 13 patients in the high-intermediate risk group for each radiation source. Patients treated with 60Co developed SPMs in the urinary tract (1.2%) and in lymphoid/hematopoietic tissues (1.2%). Only three SPM cases (0.7%) were observed in digestive tract. In comparison, the patient group treated with 252Cf developed SPMs in the digestive tract (1.4%) with the majority in the colon (1.2%), urinary tract (0.9%) primarily the kidneys, and vulva (0.7%). All other SPMs (4.9%) were in the low-risk group. Of these, SPMs in the skin were most prevalent (1.6%) for 60Co, and breast (1.6%) for 252Cf, but believed to be caused by factors other than treatment. SPM incidence in the digestive and urinary tracts were similar (2.1%), regardless of radiation source. CONCLUSIONS: For followup at 25 years, 47 SPMs were observed with no differences in the high-intermediate risk group depending on the RT source.

Boron delivery agents for neutron capture therapy of cancer.

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.

A realistic appraisal of boron neutron capture therapy as a cancer treatment modality.

Boron neutron capture therapy (BNCT) is a binary therapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope boron-10 is irradiated with neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. In this Commentary we will focus on a number of papers that were presented at a Symposium entitled "Current Clinical Status of Boron Neutron Capture Therapy and Paths to the Future", which was held in September 2017 at the China National Convention Center in Beijing. Results were presented by clinicians from Japan, Finland, the United States, the China mainland and Taiwan, China who have been working in the multiple disciplines that are required for carrying out clinical BNCT. The main focus was on the treatment of patients with malignant brain tumors, recurrent tumors of the head and neck region, and cutaneous melanomas. The results obtained in treating these patients were reported in detail and, although most of the patients with brain tumors and head and neck cancer were not cured, there was evidence of some clinical efficacy. Although there are a number of problems that must be addressed, further clinical studies to evaluate the efficacy of BNCT are warranted. First, despite considerable effort by numerous investigators over the past 40 years, there still are only two boron-containing drugs in clinical use, L-boronophenylalanine (BPA) and sodium borocaptate (BSH). Therefore, until new and more effective boron delivery agents are developed, efforts should be directed to improving the dosing and delivery of BPA and BSH. Second, due to a variety of reasons, nuclear reactor-based BNCT has ended except for its use in the China mainland and Taiwan. Therefore, the future of BNCT depends upon the results of the ongoing Phase II clinical trials that are being carried out in Japan and the soon to be initiated trials that will be carried out in Finland. If the results obtained from these clinical trials are sufficiently promising, then BNCT will have a clear path to the future, especially for patients with the therapeutically challenging malignancies that in the past have been treated with reactor-based BNCT.

Neutron track length estimator for GATE Monte Carlo dose calculation in radiotherapy.

The out-of-field dose in radiation therapy is a growing concern in regards to the late side-effects and secondary cancer induction. In high-energy x-ray therapy, the secondary neutrons generated through photonuclear reactions in the accelerator are part of this secondary dose. The neutron dose is currently not estimated by the treatment planning system while it appears to be preponderant for distances greater than 50 cm from the isocenter. Monte Carlo simulation has become the gold standard for accurately calculating the neutron dose under specific treatment conditions but the method is also known for having a slow statistical convergence, which makes it difficult to be used on a clinical basis. The neutron track length estimator, a neutron variance reduction technique inspired by the track length estimator method has thus been developped for the first time in the Monte Carlo code GATE to allow a fast computation of the neutron dose in radiotherapy. The details of its implementation, as well as the comparison of its performances against the analog MC method, are presented here. A gain of time from 15 to 400 can be obtained by our method, with a mean difference in the dose calculation of about 1% in comparison with the analog MC method.