Biological Effects of Scattered Versus Scanned Proton Beams on Normal Tissues in Total Body Irradiated Mice: Survival, Genotoxicity, Oxidative Stress and Inflammation

Abstract

Side effects of proton therapy are poorly studied. Moreover, the differences in the method of dose delivery on normal tissues are not taken into account when proton beams are scanned instead of being scattered. We proposed here to study the effects of both modalities of proton beam delivery on blood; skin; lung and heart in a murine model. In that purpose; C57BL/6 mice were total body irradiated by 190.6 MeV proton beams either by Double Scattering (DS) or by Pencil Beam Scanning (PBS) in the plateau phase before the Bragg Peak. Mouse survival was evaluated. Blood and organs were removed three months after irradiation. Biomarkers of genotoxicity; oxidative stress and inflammation were measured. Proton irradiation was shown to increase lymphocyte micronucleus frequency; lung superoxide dismutase activity; erythrocyte and skin glutathione peroxidase activity; erythrocyte catalase activity; lung; heart and skin oxidized glutathione level; erythrocyte and lung lipid peroxidation and erythrocyte protein carbonylation even 3 months post-irradiation. When comparing both methods of proton beam delivery; mouse survival was not different. However, PBS significantly increased lymphocyte micronucleus frequency; erythrocyte glutathione peroxidase activity and heart oxidized glutathione level compared to DS. These results point out the necessity to take into account the way of delivering dose in PT as it could influence late side effects.

Differential normal skin transcriptomic response in total body irradiated mice exposed to scattered versus scanned proton beams

“…Future investigations are strongly needed to explain the differences in biological responses observed between PBS and DS. Indeed, differences were also recently shown in terms of genotoxicity, oxidative stress and inflammation in various organs in total body irradiated C57BL/6 mice exposed to scattered versus scanned proton beams 52 . These findings pointed out the absolute need to adapt the PT protocols according to the type of scanning.…”

Back to the Future: Very High-Energy Electrons (VHEEs) and Their Potential Application in Radiation Therapy

“…Indeed, on the one hand, there is some recent experimental evidence that large doses and dose rate variations may play a significant role in determining the response of some organs and tissues to irradiation (see Section 2.1 about the FLASH effect). On the other hand, major differences have recently been observed between scattered or scanned beams (in particular for protons), such as in late skin gene expression or according to the organs considered in terms of genotoxicity, antioxidant capacity, or inflammatory cytokines [ 68 , 69 ], which could also be related to the dose rate even if we are not in the application range of the FLASH effect. The role of the immune system and the microenvironment in the response to radiation exposure is also mentioned as a possible explanation of the FLASH effect [ 44 ].…”

Development and Implementation of Proton Therapy for Hodgkin Lymphoma: Challenges and Perspectives

“…Troeller et al [24] unambiguously demonstrated that 3D-RT-based NTCP models imperfectly work for IMRT. The validity of applying NTCP models that have been based on photon techniques for IMPT irradiation is uncertain; DNA damage with proton therapy is not fully understood but is different from classical photon beam radiobiological effects and might differ between passive scattering and pencil beam scanning proton beams [25]. Mee et al [26] stressed that NTCP models should theoretically be adjusted with the acquisition of new clinical data and updating of existing databases (which poses the problem of observation delay); finally, ∆NTCP thresholds could be prospectively adjusted based on clinical feedback and on increasing proton therapy treatment capacity.…”