Abstract
Ultra-high dose rate radiotherapy with electrons and protons has shown potential for cancer treatment by effectively targeting tumors while sparing healthy tissues (FLASH effect). This study aimed to investigate the potential FLASH sparing effect of ultra-high-dose rate helium ion irradiation, focusing on acute brain injury and subcutaneous tumor response in a preclinical in vivo setting. Raster-scanned helium ion beams were used to compare the effects of standard dose rate (SDR at 0.2 Gy/s) and FLASH (at 141 Gy/s) radiotherapy on healthy brain tissue. Irradiation-induced brain injury was studied in C57BL/6 mice via DNA damage response, using nuclear γH2AX as a marker for double-strand breaks (DSB). The integrity of neurovascular and immune compartments was assessed through CD31+ microvascular density and activation of microglia/macrophages. Iba1+ ramified and CD68+ phagocytic microglia/macrophages were quantified, along with the expression of inducible nitric oxide synthetase (iNOS). Tumor response to SDR (0.2 Gy/s) and FLASH (250 Gy/s) radiotherapy was evaluated in A549 carcinoma model, using tumor volume and Kaplan-Meier survival as endpoints. The results showed that helium FLASH radiotherapy significantly reduced acute brain tissue injury compared to SDR, evidenced by lower levels of DSB and preserved neurovascular endothelium. Additionally, FLASH radiotherapy reduced neuroinflammatory signals compared to SDR, as indicated by fewer CD68+ iNOS+ microglia/macrophages. FLASH radiotherapy achieved tumor control comparable to that of SDR radiotherapy. This study is the first to report the FLASH sparing effect of raster scanning helium ion radiotherapy in vivo, highlighting its potential for neuroprotection and effective tumor control.
Competing Interest Statement
JD reports grants from CRI The Clinical Research Institue GmbH grants from View Ray Inc., grants from Accuray International Sarl, grants from Accuray Incorposrated, grants from RaySearch Laboratories AB, grants from Vision RT limited, grants from Merck Serono GmbH, grants from Astellas Pharma GmbH, grants from Astra Zeneca GmbH, grants from Siemens Healthcare GmbH, grants from Merck KGaA Accounts Payable, grants from Solution Akademie GmbH, grants from Ergomed PLC Surrey Research Park, grants from Siemens Healthcare GmbH, grants from Quintiles GmbH, grants from Pharmaceutecal Research Associates GmbH, grants from Boehringer Ingelheim Pharma GmbH Co, grants from PTW Freiburg Dr. Pychlau GmbH. AA report grants and other from Merck and EMD, grants and other from Fibrogen, other from BMS, other from BioMedX, other from Roche, outside the submitted work.
Footnotes
Figure 1 and Figure 2 have been revised. New Figure 6 included, accordingly Results section was updated. Discussion was updated to include new data on tumor response to radiotherapy introduced in the new figure 6. Table has been removed and information is now contained in material and methods section. Material and methods section has been expanded. An additional co-author included. Manuscript title has been changed.
