RESUMEN
BACKGROUND AND PURPOSE: Patients with hypopharyngeal cancer (HPC)/laryngeal cancer (LCA) with a history of head and neck irradiation are often difficult to treat with conventional radiotherapy. This study aimed to clarify the efficacy and safety of boron neutron capture therapy (BNCT) for HPC/LCA. MATERIALS AND METHODS: In this retrospective study, HPC/LCA with local lesions were analyzed, including both recurrent cases after treatment and second primary cases. The primary endpoints were tumor response and incidence of adverse events (AEs) after BNCT. The secondary endpoints were local control (LC), progression-free survival (PFS), and overall survival (OS). Evaluation of tumor response was terminated when any additional treatment was administered, and only survival data were collected. RESULTS: The analysis included 25 and 11 cases of HPC and LCA, respectively. All had a history of head and neck irradiation, and median dose of prior radiotherapy was 70 Gy. The complete response (CR) rate was 72%, overall response rate was 84%, and the 1-year LC and PFS were 63.1% and 53.7%, respectively. The median survival time was 15.5 months, and the 2-year OS was 79.8%. Of the 27 patients with CR, 11 cases recurred at a median of 6.0 months. The acute G3 AEs were oral mucositis (6%), pharyngeal mucositis (3%), and soft tissue infection (3%). Acutely, there were no G4-5 AEs, except hyperamylasemia, and in the late phase, there were no G3 or higher AEs. CONCLUSION: BNCT can be achieve good tumor response while preserving the larynx without severe AEs.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias Hipofaríngeas , Neoplasias Laríngeas , Humanos , Masculino , Neoplasias Hipofaríngeas/radioterapia , Neoplasias Hipofaríngeas/mortalidad , Neoplasias Hipofaríngeas/patología , Terapia por Captura de Neutrón de Boro/métodos , Terapia por Captura de Neutrón de Boro/efectos adversos , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Anciano , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Adulto , Anciano de 80 o más Años , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/mortalidad , Resultado del TratamientoRESUMEN
PURPOSE: Pediatric diffuse malignant glioma located in the brainstem was officially named "diffuse midline glioma" (DMG) by the World Health Organization in 2016. For this disease, radical surgery is not beneficial, and the only major treatment strategy is radiotherapy. However, the dose limitations to brainstem tissue mean that treatment by radiotherapy can only control and not eradicate the tumors, and there is no effective treatment for recurrence, resulting in short overall survival of 6-12 months. This paper reports our experience with boron neutron capture therapy (BNCT), a new treatment process, and its efficacy in treating children with recurrent DMG. METHODS: From September 2019 to July 2022, we treated 6 children affected by recurrent DMG. With the collaboration of Taipei Veteran General Hospital (TVGH) and National Tsing-Hua University (NTHU), each patient received two sessions of BNCT within 1 month. RESULTS: Among the six patients, three showed partial response and the rest had stable disease after the treatment. The overall survival and recurrence-free survival duration after treatment were 6.39 and 4.35 months, respectively. None of the patients developed severe side effects, and only one patient developed brain necrosis, which was most likely resulted from previous hypofractionated radiotherapy received. CONCLUSION: BNCT elicited sufficient tumor response with low normal tissue toxicity; it may benefit vulnerable pediatric patients with DMG.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias Encefálicas , Glioma , Humanos , Niño , Neoplasias Encefálicas/radioterapia , Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/métodos , Glioma/radioterapia , Resultado del Tratamiento , Recurrencia Local de Neoplasia/patologíaRESUMEN
Local recurrence of colorectal cancer (CRC) can occur in patients after curative resection, and additional surgical resection may therefore be required; however, this is a significant burden for patients, because additional surgical resection may necessitate the resection of other organs such as the bladder, prostate, uterus, or sacral bone. Therefore, there is a need for alternative therapeutic strategies. We focused on boron neutron capture therapy (BNCT) as a treatment modality that can selectively target tumor cells without excessive damage to normal tissues. The usefulness of BNCT to pelvic CRC remains unknown. This study investigated the anti-cancer effect of boronophenylalanine (BPA)-mediated BNCT in a previously established mouse model of pelvic recurrence of CRC. Uptake of BPA in CRC was observed both in vitro and in vivo, and the concentrations were sufficient for BNCT. Our results are the first to show that BPA-mediated BNCT prolonged the survival of experimental mice with pelvic tumors; moreover, it did not cause any obvious severe side effects in the treated animals. In conclusion, BPA-mediated BNCT could contribute to treating local recurrence of pelvic CRC.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias Colorrectales , Neoplasias de la Boca , Neoplasias Pélvicas , Animales , Compuestos de Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Colorrectales/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Neoplasias de la Boca/patología , Neoplasias Pélvicas/tratamiento farmacológico , Neoplasias Pélvicas/etiologíaRESUMEN
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.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Animales , Compuestos de Boro , Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/métodos , Eosina Amarillenta-(YS) , Femenino , Fibrosis , Proteínas Hedgehog , Hematoxilina , Cirrosis Hepática , Ratones , Ratones Endogámicos C57BL , Fenilalanina/análogos & derivados , TriglicéridosRESUMEN
The purpose of this study was to outline the course and profile of adverse events specific to boron neutron capture therapy (BNCT) for head and neck cancer. This was a sub-analysis of the phase II JHN002 trial. Patients received 400 mg/kg borofalan(10B), followed by neutron irradiation. The course of adverse events after BNCT was documented in the JHN002 Look Up study. Patients were grouped into face/front (FF), face/lateral (FL) and neck (N) beam groups according to the point of skin incidence of the epithermal neutron beam axis, and the profile of adverse events dependent on beam incidence position was examined. The courses of adverse events in eight recurrent squamous cell carcinoma (R-SCC) and 13 recurrent or locally advanced non-SCC cases were analyzed. Median interval to complete recovery was 23 days (interquartile range (IQR), 14-48 days) for oral mucositis, 40 days (IQR, 24-56 days) for dermatitis, 58 days (IQR, 53-80 days) for dysgeusia and 156 days (IQR, 82-163 days) for alopecia. In the FF beam group, parotitis (P = 0.007) was less frequent, while oral mucositis (P = 0.032), fatigue (P = 0.002), conjunctivitis (P = 0.001), epistaxis (P = 0.001) and abdominal discomfort (P = 0.029) tended to be more frequent than in the FL and N beam groups. Courses and irradiation site-specific profiles of adverse events in BNCT for head and neck cancer were identified. This profile may be useful for considering interventions to prevent exacerbation of treatment-related adverse events on BNCT.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Estomatitis , Terapia por Captura de Neutrón de Boro/efectos adversos , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Recurrencia Local de Neoplasia , Estomatitis/etiologíaRESUMEN
BACKGROUND: Although boron neutron capture therapy has shown excellent survival data, previous studies have shown an increase in radiation necrosis against recurrent malignant glioma. Herein, we proposed that bevacizumab may reduce radiation injury from boron neutron capture therapy by re-irradiation. We evaluated the efficacy and safety of a boron neutron capture therapy and add-on bevacizumab combination therapy in patients with recurrent malignant glioma. METHODS: Patients with recurrent malignant glioma were treated with reactor-based boron neutron capture therapy. Treatment with bevacizumab (10 mg/kg) was initiated 1-4 weeks after boron neutron capture therapy and was administered every 2-3 weeks until disease progression. Initially diagnosed glioblastomas were categorized as primary glioblastoma, whereas other forms of malignant glioma were categorized as non-primary glioblastoma. RESULTS: Twenty-five patients (14 with primary glioblastoma and 11 with non-primary glioblastoma) were treated with boron neutron capture therapy and add-on bevacizumab. The 1-year survival rate for primary glioblastoma and non-primary glioblastoma was 63.5% (95% confidence interval: 33.1-83.0) and 81.8% (95% confidence interval: 44.7-95.1), respectively. The median overall survival was 21.4 months (95% confidence interval: 7.0-36.7) and 73.6 months (95% confidence interval: 11.4-77.2) for primary glioblastoma and non-primary glioblastoma, respectively. The median progression-free survival was 8.3 months (95% confidence interval: 4.2-12.1) and 15.6 months (95% confidence interval: 3.1-29.8) for primary glioblastoma and non-primary glioblastoma, respectively. Neither pseudoprogression nor radiation necrosis were identified during bevacizumab treatment. Alopecia occurred in all patients. Six patients experienced adverse events ≥grade 3. CONCLUSIONS: Boron neutron capture therapy and add-on bevacizumab provided a long overall survival and a long progression-free survival in recurrent malignant glioma compared with previous studies on boron neutron capture therapy alone. The add-on bevacizumab may reduce the detrimental effects of boron neutron capture therapy, including pseudoprogression and radiation necrosis. Further studies of the combination therapy with a larger sample size and a randomized controlled design are warranted.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias Encefálicas , Glioblastoma , Glioma , Traumatismos por Radiación , Bevacizumab/uso terapéutico , Terapia por Captura de Neutrón de Boro/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Glioma/tratamiento farmacológico , Glioma/radioterapia , Humanos , Necrosis/etiología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Traumatismos por Radiación/etiologíaAsunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias/radioterapia , Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/métodos , Terapia por Captura de Neutrón de Boro/normas , Toma de Decisiones Clínicas , Estudios Clínicos como Asunto , Vías Clínicas , Manejo de la Enfermedad , Humanos , Neoplasias/diagnóstico , Resultado del TratamientoRESUMEN
Boron neutron capture therapy (BNCT) is a targeted therapy, which consists of preferential accumulation of boron carriers in tumor followed by neutron irradiation. Each oral cancer patient has different risks of developing one or more carcinomas and/or oral mucositis induced after treatment. Our group proposed the hamster oral cancer model to study the efficacy of BNCT and associated mucositis. Translational studies are essential to the advancement of novel boron delivery agents and targeted strategies. Herein, we review our work in the hamster model in which we studied BNCT induced mucositis using three different cancerization protocols, mimicking three different clinical scenarios. The BNCT-induced mucositis increases with the aggressiveness of the carcinogenesis protocol employed, suggesting that the study of different oral cancer patient scenarios would help to develop personalized therapies.
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Terapia por Captura de Neutrón de Boro/efectos adversos , Neoplasias de la Boca/radioterapia , Mucositis/diagnóstico , Neoplasias Experimentales/radioterapia , Traumatismos por Radiación/diagnóstico , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Terapia por Captura de Neutrón de Boro/métodos , Carcinógenos/toxicidad , Cricetinae , Relación Dosis-Respuesta en la Radiación , Humanos , Neoplasias de la Boca/inducido químicamente , Neoplasias de la Boca/complicaciones , Mucositis/etiología , Mucositis/prevención & control , Neoplasias Experimentales/inducido químicamente , Traumatismos por Radiación/etiología , Traumatismos por Radiación/prevención & control , Dosificación Radioterapéutica , Índice de Severidad de la EnfermedadRESUMEN
PURPOSE: Boron neutron capture therapy (BNCT) combines selective accumulation of 10B carriers in tumor tissue with subsequent neutron irradiation. BNCT has been proposed for the treatment of multiple, non-resectable, diffuse tumors in lung. The aim of the present study was to evaluate the therapeutic efficacy and toxicity of BNCT in an experimental model of lung metastases of colon carcinoma in BDIX rats and perform complementary survival studies. MATERIALS AND METHODS: We evaluated tumor control and toxicity in lung 2 weeks post-BNCT at 2 dose levels, including 5 experimental groups per dose level: T0 (euthanized pre-treatment), Boronophenylalanine-BNCT (BPA-BNCT), BPA + Sodium decahydrodecaborate-BNCT ((BPA + GB-10)-BNCT), Beam only (BO) and Sham (no treatment, same manipulation). Tumor response was assessed employing macroscopic and microscopic end-points. An additional experiment was performed to evaluate survival and oxygen saturation in blood. RESULTS AND CONCLUSIONS: No dose-limiting signs of short/medium-term toxicity were observed in lung. All end-points revealed statistically significant BNCT-induced tumor control vs Sham at both dose levels. The survival experiment showed a statistically significant 45% increase in post-treatment survival time in the BNCT group (48 days) versus Sham (33 days). These data consistently revealed growth suppression of lung metastases by BNCT with no manifest lung toxicity. Highlights Boron Neutron Capture Therapy suppresses growth of experimental lung metastases No BNCT-induced short/medium-term toxicity in lung is associated with tumor control Boron Neutron Capture Therapy increased post-treatment survival time by 45.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias Pulmonares/radioterapia , Investigación Biomédica Traslacional , Animales , Terapia por Captura de Neutrón de Boro/efectos adversos , Línea Celular Tumoral , Neoplasias del Colon/secundario , Relación Dosis-Respuesta en la Radiación , Neoplasias Pulmonares/patología , Radiometría , Ratas , Análisis de SupervivenciaRESUMEN
AIM: Determination of boron neutron capture therapy in-phantom parameters by response matrix (RM) method. MATERIALS AND METHODS: In this study, various in-phantom figures-of-merit including therapeutic gain, advantage depth dose rate, advantage depth, therapeutic depth, treatment time, skin dose rate, and skull dose rate have been analyzed using the RM method. This method is based on the division of neutron/gamma spectrum and calculation of various dose components of each energy group. Summation of these dose responses is equal to the total dose of the whole spectrum. Based on this method, in-phantom parameters could be calculated by a computer program in a very short time. RESULTS: There is a good agreement between direct calculation and RM method. The maximum allowable contaminations of the thermal and fast neutrons in a neutron beam have been calculated by RM method. It was found that these values are 17.4% and 2.6%, for thermal and fast neutron, respectively. CONCLUSION: The results confirm that the RM method is a fast method to evaluate in-phantom parameters without repeating simulations due to change in neutron spectrum and treatment conditions.
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Terapia por Captura de Neutrón de Boro/métodos , Neoplasias/radioterapia , Planificación de la Radioterapia Asistida por Computador/métodos , Terapia por Captura de Neutrón de Boro/efectos adversos , Simulación por Computador , Neutrones Rápidos , Rayos gamma , Humanos , Método de Montecarlo , Neoplasias/patología , Fantasmas de Imagen , Dosificación RadioterapéuticaRESUMEN
Boron neutron capture therapy (BNCT) is a promising modality for biochemically targeted, highly selective radiation treatment of various cancers, including malignant gliomas. Currently available results demonstrate the beneficial effect of such therapy on survival of patients with both recurrent and newly diagnosed glioblastomas. The main drawback of BNCT in cases of previously irradiated neoplasms is high rates of symptomatic pseudoprogression and radiation necrosis. For prevention of these complications, concurrent administration of bevacizumab may be helpful. Further studies are needed to establish the optimal therapeutic protocols and to define the exact role of this management option in multimodality treatment strategies. Recent technological developments of accelerator-based neutron sources may simplify placement of the device for BNCT within clinical facilities and lead to wider application of this technique in cases of various cancers.
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Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/radioterapia , Terapia Combinada/métodos , Glioma/radioterapia , Traumatismos por Radiación/prevención & control , Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/normas , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Humanos , Traumatismos por Radiación/etiologíaRESUMEN
In boron neutron capture therapy, it is important to evaluate the dose administered to a patient's body outside the tumour area. The exposure dose is evaluated by calculation; however, the calculated value must be validated using a measured value. The dose evaluations based on the measured neutron spectrum are investigated. Multi-foil activation, combined with a LiCaAlF6 scintillation detector and an imaging plate, is proposed as a measurement method. The proposed method can measure the neutron spectrum at various points quickly.
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Terapia por Captura de Neutrón de Boro/métodos , Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/estadística & datos numéricos , Calibración , Relación Dosis-Respuesta en la Radiación , Neutrones Rápidos/efectos adversos , Neutrones Rápidos/uso terapéutico , Humanos , Neoplasias/radioterapia , Fantasmas de Imagen , Dosificación Radioterapéutica , Conteo por CintilaciónRESUMEN
Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster cheek pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster cheek pouch model of oral cancer at the new "B2" configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in "B1" experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94-96%) than in control (16%) and BO groups (9-38%), and did not differ significantly from the "B1" results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control.
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Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/instrumentación , Mejilla , Neoplasias de la Boca/etiología , Neoplasias Inducidas por Radiación/etiología , Reactores Nucleares , Investigación Biomédica Traslacional , Animales , Cricetinae , Modelos Animales de Enfermedad , Histamina/farmacología , Neoplasias de la Boca/prevención & control , Neoplasias Inducidas por Radiación/prevención & control , Protectores contra Radiación/farmacologíaRESUMEN
Rheumatoid arthritis is a chronic autoimmune pathology characterized by the proliferation and inflammation of the synovium. Boron neutron capture synovectomy (BNCS), a binary treatment modality that combines the preferential incorporation of boron carriers to target tissue and neutron irradiation, was proposed to treat the pathological synovium in arthritis. In a previous biodistribution study, we showed the incorporation of therapeutically useful boron concentrations to the pathological synovium in a model of antigen-induced arthritis (AIA) in rabbits, employing two boron compounds approved for their use in humans, i.e., decahydrodecaborate (GB-10) and boronophenylalanine (BPA). The aim of the present study was to perform low-dose BNCS studies at the RA-1 Nuclear Reactor in the same model. Neutron irradiation was performed post intra-articular administration of BPA or GB-10 to deliver 2.4 or 3.9 Gy, respectively, to synovium (BNCS-AIA). AIA and healthy animals (no AIA) were used as controls. The animals were followed clinically for 2 months. At that time, biochemical, magnetic resonance imaging (MRI) and histological studies were performed. BNCS-AIA animals did not show any toxic effects, swelling or pain on palpation. In BNCS-AIA, the post-treatment levels of TNF-α decreased in four of six rabbits and IFN-γ levels decreased in five of six rabbits. In all cases, MRI images of the knee joint in BNCS-AIA resembled those of no AIA, with no necrosis or periarticular effusion. Synovial membranes of BNCS-AIA were histologically similar to no AIA. BPA-BNCS and GB-10-BNCS, even at low doses, would be therapeutically useful for the local treatment of rheumatoid arthritis.
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Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/radioterapia , Terapia por Captura de Neutrón de Boro/instrumentación , Ovalbúmina/farmacología , Sinovectomía , Animales , Terapia por Captura de Neutrón de Boro/efectos adversos , Modelos Animales de Enfermedad , Femenino , Conejos , Radiobiología , Dosificación Radioterapéutica , Seguridad , Membrana Sinovial/efectos de la radiaciónRESUMEN
A boron delivery system with high therapeutic efficiency and low adverse effects is crucial for a successful boron neutron capture therapy (BNCT). In this study, we developed boron cluster-containing redox nanoparticles (BNPs) via polyion complex (PIC) formation, using a newly synthesized poly(ethylene glycol)-polyanion (PEG-polyanion, possessing a (10)B-enriched boron cluster as a side chain of one of its segments) and PEG-polycation (possessing a reactive oxygen species (ROS) scavenger as a side chain of one of its segments). The BNPs exhibited high colloidal stability, selective uptake in tumor cells, specific accumulation, and long retention in tumor tissue and ROS scavenging ability. After thermal neutron irradiation, significant suppression of tumor growth was observed in the BNP-treated group, with only 5-ppm (10)B in tumor tissues, whereas at least 20-ppm (10)B is generally required for low molecular weight (LMW) (10)B agents. In addition, increased leukocyte levels were observed in the LMW (10)B agent-treated group after thermal neutron irradiation, and not in BNP-treated group, which might be attributed to its ROS scavenging ability. No visual metastasis of tumor cells to other organs was observed 1 month after irradiation in the BNP-treated group. These results suggest that BNPs are promising for enhancing the BNCT performance.
Asunto(s)
Terapia por Captura de Neutrón de Boro/métodos , Boro/administración & dosificación , Depuradores de Radicales Libres/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias Experimentales/radioterapia , Neoplasias Inducidas por Radiación/prevención & control , Especies Reactivas de Oxígeno/metabolismo , Animales , Boro/efectos adversos , Boro/química , Terapia por Captura de Neutrón de Boro/efectos adversos , Línea Celular Tumoral , Isótopos/administración & dosificación , Isótopos/efectos adversos , Masculino , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/patología , Neoplasias Inducidas por Radiación/etiología , Radiofármacos/administración & dosificación , Radiofármacos/efectos adversos , Radiofármacos/química , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Terapia por Captura de Neutrón de Boro/métodos , Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Adulto , Anciano , Compuestos de Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro/efectos adversos , Enfermedades de las Arterias Carótidas/etiología , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Hemorragia/etiología , Humanos , Edema Laríngeo/etiología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Fenilalanina/uso terapéutico , Fotones/uso terapéutico , Estudios Prospectivos , Estomatitis/etiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: To investigate the safety and efficacy of boron neutron capture therapy (BNCT) as a larynx-preserving treatment option for patients with recurrent laryngeal cancer. METHODS AND MATERIALS: Six patients with locally recurrent squamous cell laryngeal carcinoma and 3 patients with persistent laryngeal cancer after prior treatment were treated with BNCT at the FiR1 facility (Espoo, Finland) in 2006 to 2012. The patients had received prior radiation therapy with or without concomitant chemotherapy to a cumulative median dose of 66 Gy. The median tumor diameter was 2.9 cm (range, 1.4-10.9 cm) before BNCT. Boron neutron capture therapy was offered on a compassionate basis to patients who either refused laryngectomy (n=7) or had an inoperable tumor (n=2). Boronophenylalanine-fructose (400 mg/kg) was used as the boron carrier and was infused over 2 hours intravenously before neutron irradiation. RESULTS: Six patients received BNCT once and 3 twice. The estimated average gross tumor volume dose ranged from 22 to 38 Gy (W) (mean; 29 Gy [W]). Six of the 8 evaluable patients responded to BNCT; 2 achieved complete and 4 partial response. One patient died early and was not evaluable for response. Most common side effects were stomatitis, fatigue, and oral pain. No life-threatening or grade 4 toxicity was observed. The median time to progression within the target volume was 6.6 months, and the median overall survival time 13.3 months after BNCT. One patient with complete response is alive and disease-free with a functioning larynx 60 months after BNCT. CONCLUSIONS: Boron neutron capture therapy given after prior external beam radiation therapy is well tolerated. Most patients responded to BNCT, but long-term survival with larynx preservation was infrequent owing to cancer progression. Selected patients with recurrent laryngeal cancer may benefit from BNCT.
Asunto(s)
Terapia por Captura de Neutrón de Boro/métodos , Carcinoma de Células Escamosas/radioterapia , Neoplasias Laríngeas/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Tratamientos Conservadores del Órgano/métodos , Anciano , Anciano de 80 o más Años , Compuestos de Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro/efectos adversos , Carcinoma de Células Escamosas/patología , Ensayos de Uso Compasivo , Progresión de la Enfermedad , Femenino , Glotis , Humanos , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Tratamientos Conservadores del Órgano/efectos adversos , Fenilalanina/uso terapéutico , Dosificación Radioterapéutica , Reirradiación/efectos adversos , Reirradiación/métodos , Factores de Tiempo , Carga TumoralRESUMEN
Boron neutron capture therapy (BNCT) is a particle radiation therapy that involves the use of a thermal or epithermal neutron beam in combination with a boron ((10)B)-containing compound that specifically accumulates in tumor. (10)B captures neutrons and the resultant fission reaction produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of high linear energy transfer (LET) radiation and therefore have marked biological effects. High-LET radiation is a potent inducer of DNA damage, specifically of DNA double-strand breaks (DSBs). The aim of the present study was to clarify the role of DNA ligase IV, a key player in the non-homologous end-joining repair pathway, in the repair of BNCT-induced DSBs. We analyzed the cellular sensitivity of the mouse embryonic fibroblast cell lines Lig4-/- p53-/- and Lig4+/+ p53-/- to irradiation using a thermal neutron beam in the presence or absence of (10)B-para-boronophenylalanine (BPA). The Lig4-/- p53-/- cell line had a higher sensitivity than the Lig4+/+ p53-/-cell line to irradiation with the beam alone or the beam in combination with BPA. In BNCT (with BPA), both cell lines exhibited a reduction of the 50 % survival dose (D 50) by a factor of 1.4 compared with gamma-ray and neutron mixed beam (without BPA). Although it was found that (10)B uptake was higher in the Lig4+/+ p53-/- than in the Lig4-/- p53-/- cell line, the latter showed higher sensitivity than the former, even when compared at an equivalent (10)B concentration. These results indicate that BNCT-induced DNA damage is partially repaired using DNA ligase IV.
Asunto(s)
Terapia por Captura de Neutrón de Boro/efectos adversos , Daño del ADN , ADN Ligasa (ATP)/metabolismo , Reparación del ADN/efectos de la radiación , Animales , Línea Celular , Relación Dosis-Respuesta en la Radiación , Ratones , Factores de TiempoRESUMEN
Localized dose delivery techniques to establish a brain radiation necrosis model are described. An irradiation field was designed by using accelerated protons or helium ions with a spread-out Bragg peak. Measurement of the designed field confirmed that a high dose can be confined to a local volume of an animal brain. The irradiation techniques described here are very useful for establishing a necrosis model without existence of extraneous complications.
Asunto(s)
Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Traumatismos Experimentales por Radiación/patología , Animales , Terapia por Captura de Neutrón de Boro/efectos adversos , Neoplasias Encefálicas/radioterapia , Relación Dosis-Respuesta en la Radiación , Helio/efectos adversos , Humanos , Ratones , Necrosis , Protones/efectos adversos , RatasRESUMEN
Boron neutron capture therapy (BNCT) is high linear energy transfer (LET) radiation and tumor-selective radiation that does not cause serious damage to the surrounding normal tissues. BNCT might be effective and safe in patients with inoperable, locally advanced head and neck cancers, even those that recur at previously irradiated sites. However, carotid blowout syndrome (CBS) is a lethal complication resulting from malignant invasion of the carotid artery (CA); thus, the risk of CBS should be carefully assessed in patients with risk factors for CBS after BNCT. Thirty-three patients in our institution who underwent BNCT were analyzed. Two patients developed CBS and experienced widespread skin invasion and recurrence close to the carotid artery after irradiation. Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion from recurrent lesions after irradiation is an ominous sign of CBS onset and lethal consequences.