Salvage surgery following boron neutron capture therapy in a case of recurrent hypopharyngeal cancer after radiotherapy: Surgical and pathological insights.

Successful salvage surgery of the residual tumor after boron neutron capture therapy (BNCT): A case report

Simple SummaryBoron Neutron Capture Therapy (BNCT) is a treatment for cancer based on the selective accumulation in tumor of boron compounds, followed by external irradiation with neutrons. The interaction between boron-10 and a neutron gives rise to very energetic particles that travel only a very short distance (approximately the diameter of a cell) and are lethal for the cell. In this way, BNCT damages tumor tissue selectively while preserving normal tissue. BNCT has proved effective to treat certain tumors in clinical trials worldwide, with room for improvement. Our group has worked on animal models to improve the efficacy of BNCT, in particular for head and neck cancer. Herein we performed clinical veterinary BNCT studies in five terminal dog patients with head and neck cancer with no other therapeutic option. In all cases we observed partial tumor response, clinical benefit, and extension of estimated survival time at recruitment with excellent quality of life. Toxicity associated to the treatment was mild/moderate and reversible. These studies contribute towards preparation for clinical BNCT trials for head and neck cancer in Argentina and suggest a potential role for BNCT in veterinary medicine.Translational Boron Neutron Capture Therapy (BNCT) studies performed by our group and clinical BNCT studies worldwide have shown the therapeutic efficacy of BNCT for head and neck cancer. The present BNCT studies in veterinary patients with head and neck cancer were performed to optimize the therapeutic efficacy of BNCT, contribute towards exploring the role of BNCT in veterinary medicine, put in place technical aspects for an upcoming clinical trial of BNCT for head and neck cancer at the RA-6 Nuclear Reactor, and assess the feasibility of employing the existing B2 beam to treat large, deep-seated tumors. Five dogs with head and neck cancer with no other therapeutic option were treated with two applications of BNCT mediated by boronophenyl-alanine (BPA) separated by 3–5 weeks. Two to three portals per BNCT application were used to achieve a potentially therapeutic dose over the tumor without exceeding normal tissue tolerance. Clinical and Computed Tomography results evidenced partial tumor control in all cases, with slight-moderate mucositis, excellent life quality, and prolongation in the survival time estimated at recruitment. These exploratory studies show the potential value of BNCT in veterinary medicine and contribute towards initiating a clinical BNCT trial for head and neck cancer at the RA-6 clinical facility.

Background: In advanced head and neck cancer (HNC) patients, 50-60% experience loco-regional relapse and distant metastasis. Boron neutron capture therapy (BNCT) has shown remarkable therapeutic response in recurrent HNC, but there is still a 70% chance of local recurrence. This study aimed to identify a suitable liquid biomarker to assess patient response following BNCT. Myeloid-derived suppressor cells (MDSCs) are immune-suppressive cells that inhibit cytotoxic T cells. Circulating MDSC levels have been linked to the clinical stage and prognosis in HNSCC. Methods: Five patients with recurrent head and neck cancer underwent a treatment regimen that commenced with BNCT, followed by fractionated image-guided intensity-modulated radiotherapy (IG-IMRT). Liquid biopsy analysis via flow cytometry and tumor volume analysis by clinical imaging were conducted at three stages: before BNCT, before the first fraction of IG-IMRT, and one month after the last fraction of IG-IMRT. Results: Compared to other MDSC subtypes, monocytic MDSCs (M-MDSCs) exhibited a notable correlation with tumor volume. This strong correlation was observed at all testing time points except one month after BNCT treatment. Conclusions: This case series highlights a strong link between tumor size and circulating M-MDSC levels before BNCT and one month after the last IG-IMRT treatment in recurrent head and neck cancer patients. These results suggest that the level of circulating M-MDSCs could be a marker for monitoring tumor progression in recurrent HNC patients following radiation therapy, including BNCT.

Introduction: Recently head and neck cancer has pay attention to many researchers. Its therapeutic methods include surgery, chemotherapy, radiotherapy and Boron neutron capture therapy (BNCT). BNCT is better than conventional radiotherapy because it targets the tumor cell. This method involves two steps of infusion of stable 10B and then neutron radiation with a suitable intensity and energy. The BNCT in combination with boronphenylalanine (BPA) and borocaptate sodium (BSH) that was make using the epithermal neutron. BSH and PBA are used as 10B carriers. Epithermal neutrons reach to thermal transiting through tissues of the body. When 10B absorbed thermal neutrons, the α and 7Li particles produced in the 10B (n, α) 7Li reaction are of high linear energy. Transfer radiation have a short range of one cell diameter. Materials and Methods: Monte Carlo simulations were performed with MCNPX2.6 and RO31 MIRD phantom. The neutron source was employed the surface disk with 10 diameters and the range of energy was considered from 1ev-10Kev. The results of neutron and gamma dose at various depths was calculated using tally F4 and F6 in MCNPX2.6 code. Results: Relative Dose was obtained at various depths based on energy changes for gamma, fast and thermal neutron. The results of this study have shown increases of optimum energy as the tumor get deeper respect to the skin. In addition, an analytical relation was proposed for energy optimization with the position of the tumor. Conclusion: The optimum neutron energy dependence was investigated for neck tumor in different depths. These results provide useful information to the physicians to choice best optimum energy neutron beam in BNCT method.

Boron Neutron Capture Therapy for Squamous Cell Carcinoma of the Skull Base

The element boron is not renowned among biologists, short of a few specialists who know that it is an essential nutrient for plants and an element in boromycin—an antibiotic compound produced by Streptomyces . Yet, on the whole, molecular biologists and, in particular, those in drug development seem to have little use for carbon's left‐hand neighbour in the periodic table. This is about to change. Currently, boron is largely produced in Turkey and the USA, and is used in a wide range of products, including glass, detergents, fire retardants, fibres to reinforce plane fuselages and body armour, and in superhard materials. Now, both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design. > …both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design A series of recent scientific and commercial developments indicate that boron‐based compounds are interesting drug candidates against all disease categories and might even speed up drug development. Pharmaceutical companies have already increased their boron research, particularly GlaxoSmithKline (GSK; Brentford, UK), which announced a US$2.5 billion investment in the US company Anacor (Palo Alto, CA, USA) in November 2008. Anacor was founded in 2002 to develop boron‐based antibacterial drugs, but has since expanded into antivirals and other targets with its boron‐based platform. Co‐founders Lucy Shapiro and Stephen Benkovic began collaborating in 2001 to look for novel inhibitors of several newly identified bacterial target sites that, they thought, could lead to more effective antibiotics. “They randomly inserted boron and got good activity,” said David Perry, CEO of Anacor. This serendipitous discovery led to the formation of Anacor a year later. “We were lucky,” Perry conceded. “At that stage we had no idea what the broader potential of boron …

Since June 2020, boron neutron capture therapy (BNCT) has been a health care service covered by health insurance in Japan to treat locally advanced or recurrent unresectable head and neck cancers. Therefore, we aimed to assess the clinical outcomes of BNCT as a health insurance treatment and explore its role among the standard treatment modalities for head and neck cancers. We retrospectively analyzed data from patients who were treated using BNCT at Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, between June 2020 and May 2022. We assessed objective response rates based on the Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events based on the Common Terminology Criteria for Adverse Events, version 5.0. Additionally, we conducted a survival analysis and explored the factors that contributed to the treatment results. Sixty-nine patients (72 treatments) were included in the study, with a median observation period of 15 months. The objective response rate was 80.5%, and the 1-year locoregional control, progression-free survival, and overall survival rates were 57.1% (95% confidence interval [CI]: 43.9%-68.3%), 42.2% (95% CI: 30.1%-53.8%), and 75.4% (95% CI: 62.5%-84.5%), respectively. Locoregional control was significantly longer in patients with earlier TNM staging and no history of chemotherapy. BNCT may be an effective treatment option for locally advanced or recurrent unresectable head and neck cancers with no other definitive therapies. If definitive surgery or radiation therapy are not feasible, BNCT should be considered at early disease stages.

Head and neck (HN) cancer is an endemic disease in Taiwan, China. Locally recurrent HN cancer after full-dose irradiation poses a therapeutic challenge, and boron neutron capture therapy (BNCT) may be a solution that could provide durable local control with tolerable toxicity. The Tsing-Hua Open Pool Reactor (THOR) at National Tsing-Hua University in Hsin-Chu, provides a high-quality epithermal neutron source for basic and clinical BNCT research. Our first clinical trial, entitled “A phase I/II trial of boron neutron capture therapy for recurrent head and neck cancer at THOR”, was carried out between 2010 and 2013. A total of 17 patients with 23 recurrent HN tumors who had received high-dose photon irradiation were enrolled in the study. The fructose complex of l-boronophenylalanine was used as a boron carrier, and a two-fraction BNCT treatment regimen at 28-day intervals was used for each patient. Toxicity was acceptable, and although the response rate was high (12/17), re-recurrence within or near the radiation site was common. To obtain better local control, another clinical trial entitled “A phase I/II trial of boron neutron capture therapy combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for locally recurrent HN cancer” was initiated in 2014. The first administration of BNCT was performed according to our previous protocol, and IG-IMRT was initiated 28 days after BNCT. As of May 2017, seven patients have been treated with this combination. The treatment-related toxicity was similar to that previously observed with two BNCT applications. Three patients had a complete response, but locoregional recurrence was the major cause of failure despite initially good responses. Future clinical trials combining BNCT with other local or systemic treatments will be carried out for recurrent HN cancer patients at THOR.

Prevention and early management of carotid blowout syndrome for patients receiving head and neck salvage boron neutron capture therapy (BNCT)

During the COVID-19 pandemic, pedicle flaps instead of free flap transfer were recommended for head and neck reconstruction to reduce infection risk. Boron neutron-capture therapy in Japan was clinically approved in 2020 as a salvage radiotherapy for recurrent head and neck cancer following chemoradiotherapy. The efficacy and safety of salvage surgery following boron neutron-capture therapy remain unclear. We describe a 57-year-old male with crT4aN0M0 oral cancer after three different forms of radiotherapy including boron neutron-capture therapy, treated by salvage partial maxillectomy with both buccal fat pad and nasoseptal flaps. His postsurgical course was successful, without tracheostomy, and he had no Clavien- Dindo grade 3 or 4 complications. The pathological diagnosis was T4a squamous cell carcinoma with a negative surgical margin. No recurrence or metastasis had occurred at 113 days postoperatively. No opioid consumption was needed postoperatively. Pathological negative margins were achieved in this case and there were no severe complications. Further accrual of cases salvage surgery following boron neutron-capture therapy is required to clarify treatment strategies for recurrent head and neck cancer.

As a promising modality of binary radiation therapy, boron neutron capture therapy (BNCT) combines the advantages of boron-10 delivery agents for tumor-targeting and heavy charged particles for robust cell killing. BNCT has been approved for clinical treatment of head and neck cancer in Japan. However, the heavy ion rays generated from 10B (n, α) 7Li reactions as well as the concurrent gamma ray and thermal neutron radiation during BNCT can not only destroy cancer cells but also inevitably damage normal oral tissues, which constitutes the primary concern for head and neck cancer patients who are suitable for BNCT. Unfortunately, our knowledge about the radiobiology of BNCT-caused oral tissue damage is very limited to date. Therefore, we set out this study to explore the potential mechanisms in oral tissue reactions following BNCT. We collected various oral tissues from a mouse tumor model treated with BNCT and extracted total RNA from tongue tissues of 11 mice (4 controls without BNCT and 7 BNCT-treated samples with 2.5 mM/kg boron-10 delivery agents) for transcriptome sequencing. By comparing the gene expression profiles between the BNCT-treated group and the control group, we identified a total of 308 differentially expressed genes. Notably, these genes were enriched in cell junctions and cell membrane pathways. We further analyzed the interactome network of the 308 genes by common topological algorithms, i.e., Maximal Clique Centrality (MCC), Maximum Neighborhood Component (MNC), and Degree, where we identified a subset of 11 genes based on the shortest paths with the algorithm Stress. Among the 11 genes, both β-Catenin (CTNNB1) and Annexin A2 (ANXA2) were significantly downregulated in BNCT-treated group (P<0.05). Further RT-qPCR analyses confirmed the results, while immunohistochemistry analyses demonstrated consistent BNCT effects in protein levels of these two genes. The encoded protein from CTNNB1 constitutes adherens junctions and anchors the actin cytoskeleton for maintenance of epithelial cell layers. In addition, ANXA2 plays an important role in tissue inflammation and vascular integrity. Thus, we speculate that BNCT induces cell-cell junction disorder through CTNNB1 and ANXA2, leading to damaged cell junctions in blood vessels and normal tissue inflammation. Indeed, disrupted epithelial structure as well as increased interferon-γ expression was detected in oral tissue microenvironment following BNCT. These findings set a basis for developing strategies of normal tissue protection and improving quality of life of head and neck cancer patients that were treated with BNCT. Citation Format: Lin Ma, Yupeng Luo, Jianyue Liu, Yonghui Luo, Zhiyi Wang, Zexi He, Haotian Tang, Qi Liu. Radiation effects in normal oral tissues caused by boron neutron capture therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1836.

Simple SummaryBNCT is a biologically targeted, densely ionizing form of radiation therapy that allows for increased tumor cell kill, while reducing toxicity to surrounding normal tissues. Although BNCT has been investigated in the treatment of head and neck cancers and recurrent brain tumors, its applicability to breast cancer has not been previoulsy investigated. In this review we discuss the physical and biological properties of various boronated compounds, and advantages and challenges associated with the potential use of BNCT in the treatment of breast cancer. BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states.

<p indent="0mm">Boron neutron capture therapy (BNCT) is an emerging radiotherapeutic modality aimed at selectively concentrating boron compounds in tumor cells and then subjecting the tumor cells to neutron beam radiation. Treatment with BNCT is based on the nuclear capture and fission reactions that occur when nonradioactive boron-10 (¹⁰B) is irradiated with neutrons to yield an alpha particle (helium, ⁴He) and a recoiling lithium-7 (⁷Li) nuclei. The ⁴He particle has a range of <sc>9 μm</sc> and the ⁷Li particle <sc>5 μm</sc> in tissue. In theory, the short range of this reaction limits the damage to malignant cells while sparing adjacent normal cells. The development of BNCT is still constrained by the progress in developing boron delivery agents with a high tumor uptake, low normal tissue uptake, and optimizing the dosing paradigms and quantitative estimation of the ¹⁰B concentrations. It is widely recognized that the second generation boron-containing agents, sodium borocaptate (BSH) and boronophenylalanine (BPA), are less than ideal. New and more effective boron-containing agents are urgently required for clinical use to deliver the requisite amounts of boron to tumor cells. The delivery of boron-containing agent can also be optimized to improve cancer cell uptake and subcellular distribution. Additionally, it is crucial to design high intensity neutron sources and establish hospital-based BNCT. Compared with nuclear reactors, accelerator-based neutron sources are more realistic to be applied in clinical practice. In future, the critical issues regarding novel boron-containing agents, the appropriate delivery strategies, and neutron sources of BNCT for clinical use must be addressed. Two clinical trials with newly diagnosed glioblastoma have been reported, BNCT alone after surgery provided a mean survival time of 17.7 and <sc>19.5 months</sc> respectively. The survival outcomes were good as compared to the current standard of care which is post-operation fractionated radiotherapy with concomitant and adjuvant TMZ. Several clinical studies of BNCT in the treatment of recurrent head and neck cancer have been reported, with high response rate and acceptable toxicity. To date, BNCT has been clinically evaluated as an alternative to conventional radiotherapy for the treatment of several tumor types, including newly diagnosed glioblastoma, recurrent glioma, recurrent head and neck tumors, meningioma, malignant melanoma, and liver metastasis. Recently, accelerator-based neutron source has been used in clinical trials for recurrent malignant gliomas and head &amp; neck cancers. Although initial results with BNCT are promising, high-quality prospective clinical trials are still lacking. Well-designed phase II/III clinical research is necessary to define the efficacy and safety of BNCT in various tumor types. Meanwhile, studies comparing the outcomes of BNCT with other standards of care are needed for the further development of BNCT. Based on the previous studies, the BNCT clinical trials in glioblastoma can be initiated with newly diagnosed glioblastoma patients. For other tumor types, late-stage patients with recurrent or metastatic disease after the first-line treatment might be recruited. Last but not the least, in the era of comprehensive treatment for malignant tumor, it is necessary to explore the combined treatment mode of BNCT. For the future research, BNCT may be coupled with a variety of anti-tumor modalities, including traditional photon radiotherapy, immunotherapy, targeted therapy and chemotherapy. It is also possible to explore a variety of drug delivery methods to improve the uptake of boron-containing agents by tumor sites. Multidisciplinary model is needed to jointly promote BNCT to become a routine clinical treatment modality.

Boron neutron capture therapy (BNCT) is a type of radiation therapy and a new modality for cancer treatment. The radiation used in BNCT is a very low energy neutron called a "thermal neutron", and unlike other radiation, it has no effect on treating cancer on its own. However, when this neutron collides with boron-10 (10B), which is a stable isotope of boron, fission occurs into a high-energy helium nucleus (α-particle) and a lithium nucleus. Moreover, the effect of this fission reaction is limited to a range of about 10 μm, which corresponds to the approximate size of one cell. Therefore, the basic principle of BNCT is "cell-selective" radiation therapy that only damages cells that have taken up 10B present in the area irradiated with thermal neutrons. For the practical application of BNCT, it is indispensable to generate a boron drug capable of selectively accumulating 10B in cancer cells. We have successfully developed a boron drug for BNCT targeting amino acid transporters. We have obtained manufacturing and marketing approval for the world's first boron drug for BNCT, Steboronine® intravenous drip bag 9000 mg/300 mL (March 25, 2020), for indications of locally unresectable recurrent or advanced unresectable head and neck cancer. This uses Borofalan (10B), which is 10B introduced into l-phenylalanine, as a drug substance. This review describes the progress of drug development and future prospects of boron drugs for BNCT.

We evaluate the clinical results of a form of tumor selective particle radiation known as boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma (NDGB) patients, especially in combination with X-ray treatment (XRT). Between 2002 and 2006, we treated 21 patients of NDGB with BNCT utilizing sodium borocaptate and boronophenylalanine simultaneously. The first 10 were treated with only BNCT (protocol 1), and the last 11 were treated with BNCT followed by XRT of 20 to 30 Gy (protocol 2) to reduce the possibility of local tumor recurrence. No chemotherapy was applied until tumor progression was observed. The patients treated with BNCT (protocol 1 plus 2) showed a significant survival prolongation compared with the institutional historical controls. BNCT also showed favorable results in correspondence with the RTOG- and EORTC-RPA subclasses. The median survival time (MST) was 15.6 months for protocols 1 and 2 together. For protocol 2, the MST was 23.5 months. The main causes of death were cerebrospinal fluid dissemination as well as local recurrence. Our modified BNCT protocol showed favorable results of patients with NDGB not only for those with good prognoses but also for those with poor prognoses.