Moderator of 1 Session
Presenter of 2 Presentations
NEUROPROTECTIVE EFFECTS OF ULTRA-HIGH DOSE RATE FLASH BRAGG PEAK PROTON IRRADIATION
Abstract
Background and Aims
Advancements in the field of radiotherapy led to a development of ultra high dose-rate (uHDR) radiotherapy. It has been shown that acceleration of dose delivery to tumor sites from standard dose rates (0.02 Gy/s to 0.3 Gy/s) to so-called FLASH dose rates (≳35 Gy/s) can prevent healthy tissue toxicity. Few studies describe protective effects of uHDR in the brain tissue using electron beams. Due to the limiting depth-dose distribution of electrons, its clinical utilization is restricted to superficial tumors. Treatment of deep-seated tumors requires precise and accurate delivery of high dose to the target, which is achievable with heavier charged particles, such as protons. Therefore, we sought to investigate if pencil beam uHDR proton irradiation may also elicit similar FLASH sparing effects for the endpoint acute neurotoxicity.
Methods
Active scanning uHDR delivery was established for proton beams for investigation of dose rate effects between clinical SDR and uHDR at ∼10 Gy in the Bragg peak region (dose-averaged linear energy transfer [LETD] ranging from 4.5 to 10.2 keV/μm). Radiation- induced injury of neuronal tissue was assessed by studying the DNA double strand break repair kinetics surrogated by nuclear γH2AX staining (radiation induced foci [RIF]), microvascular density and structural integrity (MVD, CD31+ endothelium), and inflammatory microenvironmental response (CD68+ microglia/macrophages and high mobility group box protein 1[HMGB]) in healthy C57BL/6 mouse brains.
Results
Averaged dose rates achieved were 0.17 Gy/s (SDR) and 120 Gy/s (uHDR). The fraction of RIF-positive cells increased after SDR ∼10-fold, whereas a significantly lower fraction of RIF-positive cells was found after uHDR versus SDR (∼2 fold, P < .0001). Moreover, uHDR substantially preserved the microvascular architecture and reduced microglia/macrophage regulated associated inflammation as compared with SDR.
Conclusions
The feasibility of uHDR raster scanning proton irradiation is demonstrated to elicit FLASH sparing neuroprotective effects compared to SDR in a preclinical in vivo model.
High Dose Rate p, 4He and 12C Ion Therapy: Biological Investigations at Heidelberg Ion-Beam Therapy Center (HIT)
Abstract
Abstract Body
Irradiation at ultra-high dose rates (FLASH) has already shown promising potential for improving therapeutic window using electrons and protons, where multiple facilities worldwide have made efforts to modify accelerator settings to achieve FLASH relevant dose rates. At the Heidelberg Ion-Beam Therapy Center, the world’s first dedicated research and pre-clinical platform for FLASH irradiations with protons, helium and carbon ions has been established. With the aim of a future clinical translation of FLASH therapy with multiple radiation qualities, we describe the biological rationale of the FLASH effect in vitro 2D and 3D cultures and in vivo. Our team at HIT provided the first in vitro study using FLASH dose-rate helium beams, indicated decrease DNA damage signal and cell killing potential for normal and tumor lung cells exclusively in hypoxic conditions (1% O2) and at doses starting from 8 Gy. Moreover, we have demonstrated neuroprotective effect of proton FLASH radiotherapy for the spread-out Bragg peak region on healthy mouse brain in vivo. Similarly, decreased DNA damage signal was observed in human pluripotent stem cell derived brain organoids after carbon ion FLASH radiotherapy. Currently, preclinical in vivo studies using carbon ion FLASH beams on healthy and tumor tissue are ongoing. These studies altogether indicate a promising potential for higher LET particles in FLASH radiotherapy. However, more in-depth in vitro and especially in vivo investigations are necessary to further understand FLASH effect of particle radiotherapy. In order to tackle FLASH mechanistic questions, biological experiments with high LET beams such as oxygen beams are foreseen.