RESUMEN
PURPOSE: Our purpose was to report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck. METHODS AND MATERIALS: This prospective first-in-human, multicenter clinical study evaluated 31 lesions in 28 patients. The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. Eligibility criteria included all patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy; 13 of 31 lesions (42%) had received prior radiation therapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. Tumor response was assessed at 30 to 45 days at a follow-up visit using the Response Evaluation Criteria in Solid Tumors, version 1.1. Median follow-up time was 6.7 months. RESULTS: Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI, 28.61%-81.35%) for complete responders. Overall survival rates at 12 months post-DaRT implantation were 75% (95% CI, 46.14%-89.99%) among all patients and 93% (95% CI, 59.08%-98.96%) among complete responders. CONCLUSIONS: Alpha-emitter brachytherapy using DaRT achieved significant tumor responses without grade 3 or higher toxicities observed. Longer follow-up observations and larger studies are underway to validate these findings.
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Braquiterapia/métodos , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Radio (Elemento)/uso terapéutico , Neoplasias Cutáneas/radioterapia , Torio/uso terapéutico , Anciano , Anciano de 80 o más Años , Partículas alfa/efectos adversos , Partículas alfa/uso terapéutico , Braquiterapia/efectos adversos , Braquiterapia/instrumentación , Carcinoma de Células Escamosas/patología , Eritema/etiología , Estudios de Factibilidad , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Dolor Asociado a Procedimientos Médicos/etiología , Fotograbar , Proyectos Piloto , Supervivencia sin Progresión , Estudios Prospectivos , Radio (Elemento)/efectos adversos , Seguridad , Neoplasias Cutáneas/patología , Úlcera Cutánea/etiología , Torio/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
A new method utilizing alpha particles to treat solid tumors is presented. Tumors are treated with interstitial radioactive sources which continually release short-lived alpha emitting atoms from their surface. The atoms disperse inside the tumor, delivering a high dose through their alpha decays. We implement this scheme using thin wire sources impregnated with (224)Ra, which release by recoil (220)Rn, (216)Po and (212)Pb atoms. This work aims to demonstrate the feasibility of our method by measuring the activity patterns of the released radionuclides in experimental tumors. Sources carrying (224)Ra activities in the range 10-130 kBq were used in experiments on murine squamous cell carcinoma tumors. These included gamma spectroscopy of the dissected tumors and major organs, Fuji-plate autoradiography of histological tumor sections and tissue damage detection by Hematoxylin-Eosin staining. The measurements focused on (212)Pb and (212)Bi. The (220)Rn/(216)Po distribution was treated theoretically using a simple diffusion model. A simplified scheme was used to convert measured (212)Pb activities to absorbed dose estimates. Both physical and histological measurements confirmed the formation of a 5-7 mm diameter necrotic region receiving a therapeutic alpha-particle dose around the source. The necrotic regions shape closely corresponded to the measured activity patterns. (212)Pb was found to leave the tumor through the blood at a rate which decreased with tumor mass. Our results suggest that the proposed method, termed DART (diffusing alpha-emitters radiation therapy), may potentially be useful for the treatment of human patients.
Asunto(s)
Partículas alfa/uso terapéutico , Braquiterapia/instrumentación , Braquiterapia/métodos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Fraccionamiento de la Dosis de Radiación , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , RatonesRESUMEN
Diffusing alpha-emitter radiation therapy (DaRT) is a proposed new form of brachytherapy using α particles to treat solid tumors. The method relies on implantable ²²4Ra-loaded sources that continually release short-lived α-particle-emitting atoms that spread inside the tumor over a few millimeters. This treatment was demonstrated to have a significant effect on tumor growth in murine and human-derived models, but the degree of tumor response varied across cell lines. Tumor response was found to correlate with the degree of radionuclide spread inside the tumor. In this work we examined the radiosensitivity of individual cells to determine its relationship to tumor response. Cells were irradiated in vitro by α particles using a ²²8Th irradiator, with the mean lethal dose, D0, estimated from survival curves generated by standard methods. The results were further analyzed by microdosimetric tools to calculate z0, the specific energy resulting in a survival probability of 1/e for a single cell, which is considered to better represent the intrinsic radiosensitivity of individual cells. The results of the study demonstrate that, as a rule, tumors that respond more favorably to the DaRT treatment are also characterized by higher intrinsic cellular radiosensitivities, with D0 ranging from 0.7 Gy to 1.5 Gy for the extreme cases and z0 following the same trend.
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Partículas alfa , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Humanos , Ratones , Probabilidad , Tolerancia a Radiación/efectos de la radiación , Radiometría , TorioRESUMEN
Diffusing alpha-emitters radiation therapy (DART) is a proposed new form of brachytherapy, allowing the treatment of solid tumors by alpha particles. DART utilizes implantable sources carrying small activities of radium-224, which continually release into the tumor radon-220, polonium-216 and lead-212 atoms, while radium-224 itself remains fixed to the source. The released atoms disperse inside the tumor by diffusive and convective processes, creating, through their alpha emissions, a high-dose region measuring several mm in diameter about each source. The efficacy of DART has been demonstrated in preclinical studies on mice-borne squamous cell carcinoma and lung tumors and the method is now being developed toward clinical trials. This work studies DART safety with respect to the dose delivered to distant organs as a result of lead-212 leakage from the tumor through the blood, relying on a biokinetic calculation coupled to internal dose assessments. It is found that the dose-limiting organs are the kidneys and red bone marrow. Assuming a typical source spacing of approximately 5 mm and a typical radium-224 activity density of 0.4-0.8 MBq g(-1) of tumor tissue, it is predicted that tumors weighing up to several hundred grams may be treated without reaching the tolerance dose in any organ.
Asunto(s)
Partículas alfa/uso terapéutico , Braquiterapia/métodos , Radioisótopos/uso terapéutico , Radio (Elemento)/uso terapéutico , Partículas alfa/efectos adversos , Animales , Médula Ósea/efectos de la radiación , Braquiterapia/efectos adversos , Carcinoma de Células Escamosas/radioterapia , Femenino , Humanos , Riñón/efectos de la radiación , Cinética , Radioisótopos de Plomo/efectos adversos , Radioisótopos de Plomo/sangre , Radioisótopos de Plomo/uso terapéutico , Neoplasias Pulmonares/radioterapia , Masculino , Ratones , Modelos Biológicos , Radiometría , Dosificación RadioterapéuticaRESUMEN
An experimental scheme for sequencing large DNA molecules is proposed where DNA strands are replicated, with all nucleotides of a given kind marked with radioactive 32P. The marked strands are affixed to an appropriate substrate and are kept until most 32P atoms decay. The local damage caused by the decay is expected to allow the identification of the sites occupied by that particular nucleotide, using atomic scale microscopy (scanning tunneling or atomic force microscopy). Quantitative aspects and methodological considerations associated with the proposed scheme are discussed.