I. I. Verginadis1, K. Kim1, M. M. Kim1, G. Skoufos2,3, E. S. Diffenderfer1, S. A. O. Motlagh1, M. Kokkorakis1,4, I. Koliaki1,4, G. S. Morcos1, K. Shoniyozov1, J. Griffin5, A. Hatzigeorgiou2,3, J. M. Metz1, A. Lin6, S. J. Feigenberg1, K. A. Cengel1, B. Ky7, and C. Koumenis1; 1Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 2Department of Electrical & Computer Engineering, University of Thessaly, Volos, Greece, 3Hellenic Pasteur Institute, Athens, Greece, 4Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, 5Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 6Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 7Department of Medicine, University of Pennsylvania, Philadelphia, PA
Purpose/Objective(s): Research over the last 10 years indicates that delivering radiation at dose rates surpassing 40 Gy/s, referred to as "FLASH" radiotherapy, improves the therapeutic effectiveness of radiation therapy (RT) by reducing decreasing normal tissue damage while preserving tumor response, compared to conventional (or standard) RT. This study illustrates the cardioprotective advantages of FLASH proton RT (F-PRT) over standard proton RT (S-PRT), as demonstrated by reduced incidences of acute and chronic cardiac toxicities. Materials/
Methods: Mice underwent cone beam computed tomography imaging to accurately locate the apex of the heart, serving as the beams isocenter. Irradiation was performed using a shoot-through technique employing a 5mm diameter circular collimator. Bulk RNA-sequencing was performed on samples from non-irradiated (NR) mice, as well as on apexes treated with either F-PRT or S-PRT, two weeks after a single 40 Gy dose. Inflammatory responses were evaluated through multiplex cytokine/chemokine microbead assays and immunofluorescence analyses. Levels of fibrosis were quantified using Massons Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was assessed using 2D echocardiograms at 8 and 30 weeks post-PRT. Results: Radiation-induced damage was confined to the apex of the heart. RNA profiling of cardiac tissues treated with PRT revealed distinct responses between S-PRT and F-PRT. S-PRT uniquely activated pathways related to DNA damage response, induction of tumor necrosis factor superfamily, and inflammatory response, whereas F-PRT primarily affected cytoplasmic translation, mitochondrion organization, and ATP synthesis. Significantly, F-PRT resulted in a milder inflammatory response, accompanied by markedly attenuated changes in TGF-ß1 and aSMA levels. Importantly, F-PRT reduced collagen deposition and better preserved cardiac functionality compared to S-PRT. Conclusion: The findings of this study indicate that F-PRT reduces the induction of an inflammatory environment with decreased expression of inflammatory cytokines and profibrotic factors, and more effectively maintains cardiac functionality. This study lays the groundwork for further exploration into the potential of FLASH proton radiotherapy to improve the treatment of thoracic malignancies compared to conventional proton radiotherapy.
