Boron neutron capture therapy as a larynx-preserving treatment for locally recurrent laryngeal carcinoma after conventional radiation therapy: A preliminary report.

OBJECTIVE: Laryngeal preservation and a radical cure are the treatment goals for laryngeal carcinoma, and larynx-preserving therapy is generally preferred for early-stage laryngeal carcinoma. When laryngeal carcinoma recurs locally, patients are often forced to undergo total laryngectomy, resulting in loss of vocal function. However, many patients with laryngeal carcinoma who have residual or recurrent disease after radiotherapy wish to preserve their voice. The purpose of this study was to investigate the possibility of using BNCT as a larynx-preserving treatment for residual or recurrent laryngeal carcinomas following radical irradiation. PATIENTS AND METHODS: This study included 15 patients who underwent BNCT for residual or recurrent laryngeal carcinoma after radical laryngeal carcinoma irradiation. The number of treatment sessions for all patients was one irradiation. Before BNCT, the recurrent laryngeal carcinoma stage was rT1aN0, rT2N0, rT2N1, rT3N0, rT3N1, and rT4aN0 in one, six, one, three, one, and three patients, respectively. The median maximum tumor diameter before BNCT was 15 mm (8-22 mm). All patients underwent a tracheostomy before BNCT to mitigate the risk of upper airway stenosis due to laryngeal edema after BNCT. Treatment efficacy was evaluated retrospectively using monthly laryngoscopy after BNCT and contrast-enhanced CT scans at 3 months. The safety of treatment was evaluated based on examination findings and interviews with patients. RESULTS: The median hospital stay after BNCT was 2 days (1-6). The response rate at three months after BNCT in 15 patients with locally recurrent laryngeal carcinoma was 93.3 %, and the CR rate was 73.3 %. The most frequent adverse event associated with BNCT was laryngeal edema, which occurred in nine patients the day after BNCT. The average course of laryngeal edema peaked on the second day after BNCT and almost recovered after 1 week in all patients. One patient had bilateral vocal fold movement disorders. None had dyspnea because of prophylactic tracheostomy. No grade four or higher adverse events occurred. Other grade 2 adverse events included pharyngeal mucositis, diarrhea, and sore throat. Three months after BNCT, tracheostomy tubes were removed in nine patients, retinal cannulas were placed in three patients, and voice cannulas were placed in three patients. CONCLUSIONS: BNCT for locally recurrent laryngeal carcinoma can safely deliver radical irradiation to tumor tissues, even in patients undergoing radical irradiation. BNCT has shown antitumor effects against recurrent laryngeal carcinoma. However, further long-term observations of the treatment outcomes are required.

Preliminary outcomes of boron neutron capture therapy for head and neck cancers as a treatment covered by public health insurance system in Japan: Real-world experiences over a 2-year period.

PURPOSE: 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. MATERIALS AND METHODS: 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. 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. CONCLUSIONS: 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.

Safety of Boron Neutron Capture Therapy with Borofalan(10B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance.

BACKGROUND: This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). METHODS: This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. RESULTS: The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. CONCLUSIONS: This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting.

Out-of-field dosimetry using a validated PHITS model and computational phantom in clinical BNCT.

BACKGROUND: The out-of-field radiation dose for boron neutron capture therapy (BNCT), which results from both neutrons and γ-rays, has not been extensively evaluated. To safely perform BNCT, the neutron and γ-ray distributions inside the treatment room and the whole-body dose should be evaluated during commissioning. Although, certain previous studies have evaluated the whole-body dose in the clinical research phase, no institution providing BNCT covered by health insurance has yet validated the neutron distribution inside the room and the whole-body dose. PURPOSE: To validate the Monte Carlo model of the BNCT irradiation room extended for the whole-body region and evaluate organ-at-risk (OAR) doses using the validated model with a human-body phantom. METHODS: First, thermal neutron distribution inside the entire treatment room was measured by placing Au samples on the walls of the treatment room. Second, neutron and gamma-ray dose-rate distributions inside a human-body water phantom were measured. Both lying and sitting positions were considered. Bare Au, Au covered by Cd (Au+Cd), In, Al, and thermoluminescent dosimeters were arranged at 11 points corresponding to locations of the OARs inside the phantom. After the irradiation, γ-ray peaks emitted from the samples were measured by a high-purity germanium detector. The measured counts were converted to the reaction rate per unit charge of the sample. These measurements were compared with results of simulations performed with the Particle and Heavy Ion Transport code System (PHITS). A male adult mesh-type reference computational phantom was used to evaluate OAR doses in the whole-body region. The relative biological effectiveness (RBE)-weighted doses and dose-volume histograms (DVHs) for each OAR were evaluated. The median dose (D50% ) and near-maximum dose (D2% ) were evaluated for 14 OARs in a 1-h-irradiation process. The evaluated RBE-weighted doses were converted to equivalent doses in 2 Gy fractions. RESULTS: Experimental results within 60 cm from the irradiation center agreed with simulation results within the error bars except at ±20, 30 cm, and those over 70 cm corresponded within one digit. The experimental results of reaction rates or γ-ray dose rate for lying and sitting positions agreed well with the simulation results within the error bars at 8, 4, 11, 7 and 7, 4, 7, 6, 5, 6 out of 11 points, respectively, for Au, Au+Cd, In, Al, and TLD. Among the detectors, the discrepancies in reaction rates between experiment and simulation were most common for Au+Cd, but were observed randomly for measurement points (brain, lung, etc.). The experimental results of γ-ray dose rates were systematically lower than simulation results at abdomen and waist regions for both positions. Extending the PHITS model to the whole-body region resulted in higher doses for all OARs, especially 0.13 Gy-eq increase for D50% of the left salivary gland. CONCLUSION: The PHITS model for clinical BNCT for the whole-body region was validated, and the OAR doses were then evaluated. Clinicians and medical physicists should know that the out-of-field radiation increases the OAR dose in the whole-body region.

KORTUC, a novel hydrogen peroxide­based radiosensitizer for the enhancement of brachytherapy in patients with unresectable recurrent uterine cervical cancer.

Kochi Oxydol Radiation Therapy for Unresectable Carcinoma (KORTUC) is a novel radiosensitizer invented by Professor Ogawa at Kochi University (Japan) in 2006. The current study aimed to report the experience of the present authors with the use of KORTUC treatment in combination with interstitial brachytherapy (ISBT), with or without external beam (EB) radiotherapy (RT), in patients with locally recurrent cervical cancer (LRCC), who were likely to have a high risk of poor prognosis. Between April 2012 and January 2020, 14 female patients (15 tumoral lesions) with LRCC underwent KORTUC with ISBT. Their previous treatments included surgery (n=4), radiation therapy (n=8) and surgery plus RT (n=3). The primary lesions were located in the vaginal stump (n=5), pelvic wall (n=3), cervix (n=3), vaginal wall (n=2) and lymph nodes (n=2). At 2 h before RT, KORTUC was injected intratumorally via direct colposcopy. The dose of KORTUC ranged from 4-12 ml, adjusted for the tumor size. For patients who underwent ISBT, KORTUC was administered before and after insertion of the applicator before irradiation. Intratumoral injection of KORTUC was completed without any technical or safety issues in all 15 patients; it was well tolerated with no adverse events observed. KORTUC also showed preferable efficacy; a clinical complete response was observed in 87% of patients and the initial response rate was 100%. The 2-year local control rate in patients who underwent ISBT + KORTUC was 79%, whereas it was 63% in the re-irradiation group which was significantly lower (P=0.02) than that in the non-irradiation group (100%). Based on this finding, KORTUC with external irradiation is considered to be an optimal treatment strategy for patients with newly diagnosed LRCC this disease. Additionally, KORTUC may be an effective radiation response enhancer in multiple cancer types in which locoregional control after RT alone remains poor.

The effects of BPA-BNCT on normal bone: determination of the CBE value in mice‡.

Boron neutron capture therapy (BNCT) with p-boronophenylalanine (BPA) is expected to have less effect on the decrease in normal bone strength than X-ray therapy. However, the compound biological effectiveness (CBE) value necessary to convert the boron neutron capture reaction (BNCR) dose into a bioequivalent X-ray dose has not been determined yet. The purpose of this study was to evaluate the influence of BNCT on normal bone in mice and to elucidate the CBE factor. We first searched the distribution of BPA in the normal bone of C3H/He mice and then measured the changes in bone strength after irradiation. The CBE value was determined when the decrease in bone strength was set as an index of the BNCT effect. The 10B concentrations in the tibia after subcutaneous injection of 125, 250 and 500 mg/kg BPA were measured by prompt gamma-ray spectroscopy and inductively coupled plasma (ICP)-atomic emission spectrometry. The 10B mapping in the tibia was examined by alpha-track autoradiography and laser ablation-ICP-mass spectrometry. The 10B concentration increased dose-dependently; moreover, the concentrations were maintained until 120 min after BPA administration. The administered 10B in the tibia was abundantly accumulated in the growth cartilage, trabecular bone and bone marrow. The bone strength was analyzed by a three-point bending test 12 weeks after irradiation. The bending strength of the tibia decreased dose-dependently after the irradiation of X-ray, neutron and BNCR. The CBE factor was obtained as 2.27 by comparing these dose-effect curves; the value determined in this study will enable an accurate dosimetry of normal bone.

Analysis of boron neutron capture reaction sensitivity using Monte Carlo simulation and proposal of a new dosimetry index in boron neutron capture therapy.

Boron neutron capture therapy is a cellular-scale heavy-particle therapy. The factor determining the biological effects in the boron neutron capture reaction (BNCR) is the value of ${\alpha}_{boron}$, which is the alpha component in the Linear Quadratic (LQ) model. Recently, the factor determining the value of ${\alpha}_{boron}$ has been revealed to correspond to the structural features of the tumor tissue. However, the relationship and mechanism have yet to be thoroughly studied. In this study, we simulated BNCR in tissues using the Monte Carlo simulation technique and examined the factors that determine the value of ${\alpha}_{boron}$. According to this simulation, the nuclear-cytoplasmic (N/C) ratio, nuclear diameter and heterogeneity of the distribution of boron in the tissue have been suggested to determine the value of ${\alpha}_{boron}$. Moreover, we proposed Biological Effectivity (BE) as a new dosimetry index based on the surviving fraction (SF), extending the concept of absolute biological effectiveness (ABE) in a previous report.

Influence of Boron Neutron Capture Therapy on Normal Liver Tissue.

Radiation-induced liver diseases, including liver fibrosis, occurs when radiation damages the liver. Basic research on hepatic fibrosis, which is a late radiation injury, is necessary for evaluating adverse liver events occurring after boron neutron capture therapy. This study was conducted to establish a method for analyzing the negative effect such as fibrosis in the liver tissue after boron neutron capture therapy. Female C57BL6 mice were injected with p-boronophenylalanine solution subcutaneously at 2 h before neutron irradiation. Masson trichrome staining was performed to determine the degree of liver fibrosis. The degree of fat accumulation in mouse normal liver tissue after boron neutron capture therapy was evaluated using hematoxylin and eosin staining and triglyceride quantification. Western blotting was performed to determine the expression level of Sonic Hedgehog. Liver fat accumulation and fibrosis were significantly increased in the neutron irradiation group injected with p-boronophenylalanine compared with control group. In addition, Sonic Hedgehog expression was increased in response to boron neutron capture therapy-induced liver injury and was involved in liver fibrosis. Hepatocellular fat accumulation and Hedgehog signaling activation may be indicators of adverse events related to boron neutron capture therapy associated with liver fibrosis.

Quantitative autoradiography in boron neutron capture therapy considering the particle ranges in the samples.

PURPOSE: Boron neutron capture therapy is a cellular-scale particle therapy exploiting boron neutron capture reactions in boron compounds distributed in tumour cells. Its therapeutic effect depends on both the accumulation of boron in tumour cells and the neutron fluence. Autoradiography is used to visualise the micro-distribution of boron compounds. METHODS: Here, we present an equation for the relationship between boron concentration and pit density on the solid-state nuclear track detector, taking into consideration the particle ranges in the samples. This equation is validated using liver-tissue sections and boron standard solutions. Moreover, we present a simple co-localisation system for pit and tissue-section images that requires no special equipment. RESULTS: The equation reproduces the experimentally observed trends between boron concentration and pit density. This equation provides a theoretical explanation for the widely used calibration curve between pit density and boron concentration; it also provides a method to correct for differences of tissue-section thickness in quantitative autoradiography. CONCLUSIONS: Using the equation together with this co-localisation system could improve micro-scale quantitative estimation in tissue sections.

Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine.

As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5-9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2-4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT.

Effect of nicotine on the pelvic afferent nerve activity and bladder pressure in rats.

OBJECTIVES: To record afferent nerve activity and bladder pressure in anesthetized male rats and to investigate whether increased afferent nerve activity induced by nicotine is able to evoke reflex bladder contractions. METHODS: Using continuous infusion cystometrography, bladder pressure was measured via a bladder cannula. Afferent activity was recorded in the uncut L6 dorsal root. Nicotine was injected intra-arterially through a cannula placed near the bifurcation of the internal iliac artery a few minutes after micturition. RESULTS: Nicotine (0.15-1.5 micromol) evoked a marked elevation of afferent discharge without a simultaneous increase in bladder pressure. Bladder contractions appeared about 43 and 19 s after bolus injection of nicotine at 0.45 and 1.5 micromol, respectively. Firing rates of afferent nerves were reduced when the contraction appeared. Continuous infusion of nicotine at 0.75 micromol/min for 20 min evoked marked elevation of afferent discharge, which was maintained during infusion of nicotine and after it had been withdrawn. Repetitive contractions were observed thereafter and disappeared when the L6 dorsal roots were bilaterally resected. CONCLUSIONS: A transient increase in afferent discharges induced by bolus injection of nicotine was unable to evoke reflex bladder contraction. Repetitive bladder contractions after withdrawal of continuous nicotine infusion were induced in a reflex manner by the increased afferent activity.