RESUMO
Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r > 0.87 and p-values >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.
Assuntos
Terapia por Captura de Nêutron de Boro , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/radioterapia , Melanoma/radioterapia , Neoplasias Bucais/radioterapia , Mucosite/radioterapia , Fótons , Animais , Carcinoma de Células Escamosas/radioterapia , Cricetinae , Humanos , Lesões Pré-Cancerosas/radioterapia , RadiometriaRESUMO
PURPOSE: Many types of lung tumors have a very poor prognosis due to their spread in the whole organ volume. The fact that boron neutron capture therapy (BNCT) would allow for selective targeting of all the nodules regardless of their position, prompted a preclinical feasibility study of ex situ BNCT at the thermal neutron facility of RA-3 reactor in the province of Buenos Aires, Argentina. (l)-4p-dihydroxy-borylphenylalanine fructose complex (BPA-F) biodistribution studies in an adult sheep model and computational dosimetry for a human explanted lung were performed to evaluate the feasibility and the therapeutic potential of ex situ BNCT. METHODS: Two kinds of boron biodistribution studies were carried out in the healthy sheep: a set of pharmacokinetic studies without lung excision, and a set that consisted of evaluation of boron concentration in the explanted and perfused lung. In order to assess the feasibility of the clinical application of ex situ BNCT at RA-3, a case of multiple lung metastases was analyzed. A detailed computational representation of the geometry of the lung was built based on a real collapsed human lung. Dosimetric calculations and dose limiting considerations were based on the experimental results from the adult sheep, and on the most suitable information published in the literature. In addition, a workable treatment plan was considered to assess the clinical application in a realistic scenario. RESULTS: Concentration-time profiles for the normal sheep showed that the boron kinetics in blood, lung, and skin would adequately represent the boron behavior and absolute uptake expected in human tissues. Results strongly suggest that the distribution of the boron compound is spatially homogeneous in the lung. A constant lung-to-blood ratio of 1.3 ± 0.1 was observed from 80 min after the end of BPA-F infusion. The fact that this ratio remains constant during time would allow the blood boron concentration to be used as a surrogate and indirect quantification of the estimated value in the explanted healthy lung. The proposed preclinical animal model allowed for the study of the explanted lung. As expected, the boron concentration values fell as a result of the application of the preservation protocol required to preserve the lung function. The distribution of the boron concentration retention factor was obtained for healthy lung, with a mean value of 0.46 ± 0.14 consistent with that reported for metastatic colon carcinoma model in rat perfused lung. Considering the human lung model and suitable tumor control probability for lung cancer, a promising average fraction of controlled lesions higher than 85% was obtained even for a low tumor-to-normal boron concentration ratio of 2. CONCLUSIONS: This work reports for the first time data supporting the validity of the ovine model as an adequate human surrogate in terms of boron kinetics and uptake in clinically relevant tissues. Collectively, the results and analysis presented would strongly suggest that ex situ whole lung BNCT irradiation is a feasible and highly promising technique that could greatly contribute to the treatment of metastatic lung disease in those patients without extrapulmonary spread, increasing not only the expected overall survival but also the resulting quality of life.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Pulmonares/radioterapia , Animais , Argentina , Boro/farmacocinética , Boro/uso terapêutico , Compostos de Boro/farmacocinética , Terapia por Captura de Nêutron de Boro/instrumentação , Estudos de Viabilidade , Frutose/análogos & derivados , Frutose/farmacocinética , Humanos , Pulmão/metabolismo , Pulmão/efeitos da radiação , Neoplasias Pulmonares/metabolismo , Modelos Animais , Modelos Biológicos , Fótons , Radiometria/métodos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Ovinos , Fatores de Tempo , Distribuição TecidualRESUMO
OBJECTIVES: Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and inhibit long-term tumor development from field-cancerized tissue in the hamster cheek pouch model. However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT-induced severe mucositis in field-cancerized tissue. MATERIALS AND METHODS: Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh : histamine 5 mg kg(-1) ; Hislow : histamine 1 mg kg(-1) ; and JNJ7777120: 10 mg kg(-1). RESULTS: Hislow reduced the incidence of severe mucositis in field-cancerized tissue to 17% vs CONTROL: 55%; Hishigh : 67%; JNJ7777120: 57%. Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration. CONCLUSION: Histamine reduces BNCT-induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT-induced radiotoxicity in patients with head and neck cancer.
Assuntos
Terapia por Captura de Nêutron de Boro/efeitos adversos , Histamina/uso terapêutico , Neoplasias Bucais/radioterapia , Lesões Pré-Cancerosas/radioterapia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Estomatite/prevenção & controle , Animais , Cricetinae , Modelos Animais de Doenças , Indóis/uso terapêutico , Piperazinas/uso terapêutico , Lesões Experimentais por Radiação/etiologia , Estomatite/etiologiaRESUMO
A model of multiple lung metastases in BDIX rats is under study at CNEA (Argentina) to evaluate the feasibility of BNCT for multiple, non-surgically resectable lung metastases. A practical shielding device that comfortably houses a rat, allowing delivery of a therapeutic, uniform dose in lungs while protecting the body from the neutron beam is presented. Based on the final design obtained by numerical simulations, the shield was constructed, experimentally characterized and recently used in the first in vivo experiment at RA-3.
Assuntos
Terapia por Captura de Nêutron de Boro/instrumentação , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Proteção Radiológica/instrumentação , Planejamento da Radioterapia Assistida por Computador/métodos , Animais , Desenho Assistido por Computador , Desenho de Equipamento , Análise de Falha de Equipamento , Dosagem Radioterapêutica , RatosRESUMO
BNCT was proposed for the treatment of diffuse, non-resectable tumors in the lung. We performed boron biodistribution studies with 5 administration protocols employing the boron carriers BPA and/or GB-10 in an experimental model of disseminated lung metastases in rats. All 5 protocols were non-toxic and showed preferential tumor boron uptake versus lung. Absolute tumor boron concentration values were therapeutically useful (25-76ppm) for 3 protocols. Dosimetric calculations indicate that BNCT at RA-3 would be potentially therapeutic without exceeding radiotolerance in the lung.
Assuntos
Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Fenilalanina/análogos & derivados , Animais , Linhagem Celular Tumoral , Combinação de Medicamentos , Neoplasias Pulmonares/radioterapia , Taxa de Depuração Metabólica , Especificidade de Órgãos , Fenilalanina/administração & dosagem , Fenilalanina/farmacocinética , Dosagem Radioterapêutica , Ratos , Distribuição TecidualRESUMO
OBJECTIVES: Field-cancerized tissue can give rise to second primary tumours, causing therapeutic failure. Boron neutron capture therapy (BNCT) is based on biological targeting and would serve to treat undetectable foci of malignant transformation. The aim of this study was to optimize BNCT for the integral treatment for oral cancer, with particular emphasis on the inhibitory effect on tumour development originating in precancerous conditions, and radiotoxicity of different BNCT protocols in a hamster cheek pouch oral precancer model. MATERIALS AND METHODS: Groups of cancerized hamsters were locally exposed to single or double (2 or 4 weeks apart) applications of BNCT at different dose levels, mediated by the boron compounds boronophenylalanine (BPA) or BPA and decahydrodecaborate (GB-10) administered jointly. Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumour development from field-cancerized tissue and mucositis were followed for 8 months. RESULTS: A double application (4 weeks apart) of BNCT mediated by GB-10+ BPA at a total dose of 10 Gy in two 5-Gy doses rendered the best therapeutic advantage (63-100% inhibition of tumour development from field-cancerized tissue), minimizing dose-limiting mucositis. CONCLUSION: BNCT can be optimized for the integral treatment for head and neck cancer, considering the implications for field-cancerized tissue.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias Bucais/radioterapia , Lesões Pré-Cancerosas/radioterapia , Animais , Cricetinae , Modelos Animais de DoençasRESUMO
Ex-situ BNCT for multifocal unresectable liver metastases employing whole or partial autograft techniques requires knowledge of boron concentrations in healthy liver and metastases following perfusion and immersion in Wisconsin solution (W), the procedure employed for organ preservation during ex-situ irradiation. Measurements of boron concentration in blood, liver and metastases following an intravenous infusion of BPA-F in five colorectal liver metastases patients scheduled for surgery were performed. Tissue samples were evaluated for boron content pre and post perfusion and immersion in W. Complementary histological studies were performed. The data showed a dose-dependent BPA uptake in liver, a boron concentration ratio liver/blood close to 1 and a wide spread in the metastases/liver concentration ratios in the range 0.8-3.6, partially attributable to histological variations between samples. Based on the boron concentrations and dose considerations (liver < or =15 Gy-Eq and tumor> or =40 Gy-Eq) at the RA-3 thermal neutron facility (mean flux of about (6+/-1) x 10(9) n cm(-2)s(-1)), ex-situ treatment of liver metastases at RA-3 would be feasible.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Boro/farmacocinética , Neoplasias Colorretais/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Idoso , Argentina , Boro/sangue , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro , Feminino , Humanos , Técnicas In Vitro , Infusões Intravenosas , Isótopos/sangue , Isótopos/farmacocinética , Fígado/metabolismo , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Fenilalanina/administração & dosagem , Fenilalanina/análogos & derivados , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/uso terapêutico , Distribuição Tecidual , Transplante AutólogoRESUMO
We previously demonstrated the efficacy of boron neutron capture therapy (BNCT) mediated by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and (GB-10+BPA) to control tumors, with no normal tissue radiotoxicity, in the hamster cheek pouch oral cancer model. Herein we developed a novel experimental model of field-cancerization and precancerous lesions (globally termed herein precancerous tissue) in the hamster cheek pouch to explore the long-term potential inhibitory effect of the same BNCT protocols on the development of second primary tumors from precancerous tissue. Clinically, second primary tumor recurrences occur in field-cancerized tissue, causing therapeutic failure. We performed boron biodistribution studies followed by in vivo BNCT studies, with 8 months follow-up. All 3 BNCT protocols induced a statistically significant reduction in tumor development from precancerous tissue, reaching a maximum inhibition of 77-100%. The inhibitory effect of BPA-BNCT and (GB-10+BPA)-BNCT persisted at 51% at the end of follow-up (8 months), whereas for GB-10-BNCT it faded after 2 months. Likewise, beam-only elicited a significant but transient reduction in tumor development. No normal tissue radiotoxicity was observed. At 8 months post-treatment with BPA-BNCT or (GB-10+BPA)-BNCT, the precancerous pouches that did not develop tumors had regained the macroscopic and histological appearance of normal (non-cancerized) pouches. A potential new clinical application of BNCT would lie in its capacity to inhibit local regional recurrences.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Lesões Pré-Cancerosas/radioterapia , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Boroidretos/farmacocinética , Boroidretos/uso terapêutico , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Cricetinae , Neoplasias Bucais/radioterapia , Recidiva Local de Neoplasia/radioterapia , Segunda Neoplasia Primária/radioterapia , Fenilalanina/análogos & derivados , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/uso terapêutico , Compostos de Sulfidrila/farmacocinética , Compostos de Sulfidrila/uso terapêutico , Distribuição TecidualRESUMO
The National Atomic Energy Commission of Argentina (CNEA) constructed a novel thermal neutron source for use in boron neutron capture therapy (BNCT) applications at the RA-3 research reactor facility located in Buenos Aires. The aim of the present study was to perform a dosimetric characterization of the facility and undertake radiobiological studies of BNCT in an experimental model of oral cancer in the hamster cheek pouch. The free-field thermal flux was 7.1 x 10(9) n cm(-2)s(-1) and the fast neutron flux was 2.5 x 10(6) n cm(-2)s(-1), indicating a very well-thermalized neutron field with negligible fast neutron dose. For radiobiological studies it was necessary to shield the body of the hamster from the neutron flux while exposing the everted cheek pouch bearing the tumors. To that end we developed a lithium (enriched to 95% in (6)Li) carbonate enclosure. Groups of tumor-bearing hamsters were submitted to BPA-BNCT, GB-10-BNCT, (GB-10+BPA)-BNCT or beam only treatments. Normal (non-cancerized) hamsters were treated similarly to evaluate normal tissue radiotoxicity. The total physical dose delivered to tumor with the BNCT treatments ranged from 6 to 8.5 Gy. Tumor control at 30 days ranged from 73% to 85%, with no normal tissue radiotoxicity. Significant but reversible mucositis in precancerous tissue surrounding tumors was associated to BPA-BNCT. The therapeutic success of different BNCT protocols in treating experimental oral cancer at this novel facility was unequivocally demonstrated.
Assuntos
Terapia por Captura de Nêutron de Boro/instrumentação , Neoplasias Bucais/radioterapia , Reatores Nucleares , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Argentina , Terapia por Captura de Nêutron de Boro/efeitos adversos , Terapia por Captura de Nêutron de Boro/métodos , Carcinógenos/toxicidade , Cricetinae , Mesocricetus , Neoplasias Bucais/induzido quimicamente , Radiometria/métodosRESUMO
Microdistributions of the prospective BNCT-compound CuTCPH, a carborane-containing tetraphenylporphyrin with one Cu atom in its molecular structure, have been obtained in tissue sections of different organs of tumor-bearing and normal Syrian hamsters injected with the boron compound by employing a heavy ion microbeam. High resolution X-ray spectroscopy following micro-PIXE (Particle Induced X-ray Emission with micrometer-sized beams) with a focused (16)O ion beam was used. Focusing was performed with a heavy-ion scanning high-precision magnetic quadrupole triplet microprobe. Squamous Cell Carcinomas were induced on the right Cheek Pouch of Syrian Hamsters (HCP), sampled, cryo-sectioned and freeze-dried. Two-dimensional maps of elemental concentration were obtained by scanning the beam over the samples. Very non-uniform Cu concentrations were found in all sections.