M Dos Santos1, R Delorme2,3, R Salmon2,3, Y Prezado2,3. 1. Department of Radiobiology and regenerative medicine (SERAMED), Laboratory of Radiobiology of Accidental exposures (LRAcc), IRSN, F-92260, Fontenay-aux-Roses, France. 2. Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC), CNRS, Univ Paris-Sud, Université Paris-Saclay, F-91400, Orsay, France. 3. Université de Paris, IMNC, F-91400, Orsay, France.
Abstract
PURPOSE: Minibeam radiation therapy (MBRT) is an innovative strategy based on a distinct dose delivery method that is administered using a series of narrow (submillimetric) parallel beams. To shed light on the biological effects of MBRT irradiation, we explored the micro- and nanodosimetric characteristics of three promising MBRT modalities (photon, electron, and proton) using Monte Carlo (MC) calculations. METHODS: Irradiation with proton (100 MeV), electron (300 MeV), and photon (effective energy of 69 keV) minibeams were simulated using Geant4 MC code and the Geant4-DNA extension, which allows the simulation of energy transfer points with nanometric accuracy. As the target of the simulations, cells containing spherical nuclei with or without a detailed description of the DNA (deoxyribonucleic acid) geometry were placed at different depths in peak and valley regions in a water phantom. The energy deposition and number of events in the cell nuclei were recorded in the microdosimetry study, and the number of DNA breaks and their complexity were determined in the nanodosimetric study, where a multi-scale simulation approach was used for the latter. For DNA damage assessment, an adapted DBSCAN clustering algorithm was used. To compare the photon MBRT (xMBRT), electron MBRT (eMBRT), and proton MBRT (pMBRT) approaches, we considered the treatment of a brain tumor located at a depth of 75 mm. RESULTS: Both mean energy deposition at micrometric scale and DNA damage in the "valley" cell nuclei were very low as compared with these parameters in the peak region at all depths for xMBRT and at depths of 0 to 30 mm and 0 to 50 mm for eMBRT and pMBRT, respectively. Only the charged minibeams were favorable for tumor control by producing similar effects in peak and valley cells after 70 mm. At the micrometer scale, the energy deposited per event pointed to a potential advantage of proton beams for tumor control, as more aggressive events could be expected at the end of their tracks. At the nanometer scale, all three MBRT modalities produced direct clustered DNA breaks, although the majority of damage (>93%) was composed of isolated single strand breaks. The pMBRT led to a significant increase in the proportion of clustered single strand breaks and double-strand breaks at the end of its range as compared to the entrance (7% at 75 mm vs 3% at 10 mm) in contrast to eMBRT and xMBRT. In the latter cases, the proportions of complex breaks remained constant, irrespective of the depth and region (peak or valley). CONCLUSIONS: Enhanced normal tissue sparing can be expected with these three MBRT techniques. Among the three modalities, pMBRT offers an additional gain for radioresistant tumors, as it resulted in a higher number of complex DNA damage clusters in the tumor region. These results can aid understanding of the biological mechanisms of MBRT.
PURPOSE: Minibeam radiation therapy (MBRT) is an innovative strategy based on a distinct dose delivery method that is administered using a series of narrow (submillimetric) parallel beams. To shed light on the biological effects of MBRT irradiation, we explored the micro- and nanodosimetric characteristics of three promising MBRT modalities (photon, electron, and proton) using Monte Carlo (MC) calculations. METHODS: Irradiation with proton (100 MeV), electron (300 MeV), and photon (effective energy of 69 keV) minibeams were simulated using Geant4 MC code and the Geant4-DNA extension, which allows the simulation of energy transfer points with nanometric accuracy. As the target of the simulations, cells containing spherical nuclei with or without a detailed description of the DNA (deoxyribonucleic acid) geometry were placed at different depths in peak and valley regions in a water phantom. The energy deposition and number of events in the cell nuclei were recorded in the microdosimetry study, and the number of DNA breaks and their complexity were determined in the nanodosimetric study, where a multi-scale simulation approach was used for the latter. For DNA damage assessment, an adapted DBSCAN clustering algorithm was used. To compare the photon MBRT (xMBRT), electron MBRT (eMBRT), and proton MBRT (pMBRT) approaches, we considered the treatment of a brain tumor located at a depth of 75 mm. RESULTS: Both mean energy deposition at micrometric scale and DNA damage in the "valley" cell nuclei were very low as compared with these parameters in the peak region at all depths for xMBRT and at depths of 0 to 30 mm and 0 to 50 mm for eMBRT and pMBRT, respectively. Only the charged minibeams were favorable for tumor control by producing similar effects in peak and valley cells after 70 mm. At the micrometer scale, the energy deposited per event pointed to a potential advantage of proton beams for tumor control, as more aggressive events could be expected at the end of their tracks. At the nanometer scale, all three MBRT modalities produced direct clustered DNA breaks, although the majority of damage (>93%) was composed of isolated single strand breaks. The pMBRT led to a significant increase in the proportion of clustered single strand breaks and double-strand breaks at the end of its range as compared to the entrance (7% at 75 mm vs 3% at 10 mm) in contrast to eMBRT and xMBRT. In the latter cases, the proportions of complex breaks remained constant, irrespective of the depth and region (peak or valley). CONCLUSIONS: Enhanced normal tissue sparing can be expected with these three MBRT techniques. Among the three modalities, pMBRT offers an additional gain for radioresistant tumors, as it resulted in a higher number of complex DNA damage clusters in the tumor region. These results can aid understanding of the biological mechanisms of MBRT.
Authors: Alejandro Mazal; Juan Antonio Vera Sanchez; Daniel Sanchez-Parcerisa; Jose Manuel Udias; Samuel España; Victor Sanchez-Tembleque; Luis Mario Fraile; Paloma Bragado; Alvaro Gutierrez-Uzquiza; Nuria Gordillo; Gaston Garcia; Juan Castro Novais; Juan Maria Perez Moreno; Lina Mayorga Ortiz; Amaia Ilundain Idoate; Marta Cremades Sendino; Carme Ares; Raymond Miralbell; Niek Schreuder Journal: Front Oncol Date: 2021-01-21 Impact factor: 6.244