Recent studies suggest that ultrahigh-dose-rate, “FLASH,” electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection.
Methods and Materials
Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation.
Results
The double scattering and collimation apparatus was dosimetrically validated with dose rates of 78 ± 9 Gy per second and 0.9 ± 0.08 Gy per second for the FLASH and standard PRT. Whole abdominal FLASH PRT at 15 Gy significantly reduced the loss of proliferating cells in intestinal crypts compared with standard PRT. Studies with local intestinal irradiation at 18 Gy revealed a reduction to near baseline levels of intestinal fibrosis for FLASH-PRT compared with standard PRT. Despite this difference, FLASH-PRT did not demonstrate tumor radioprotection in MH641905 pancreatic cancer flank tumors after 12 or 18 Gy irradiation.
Conclusions
We have designed and dosimetrically validated a FLASH-PRT system with accurate control of beam flux on a millisecond time scale and online monitoring of the integral and dose delivery time structure. Using this system, we found that FLASH-PRT decreases acute cell loss and late fibrosis after whole-abdomen and focal intestinal RT, whereas tumor growth inhibition is preserved between the 2 modalities.
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Lead authors, Eric S. Diffenderfer, PhD, Ioannis I. Verginadis, PhD, and Michele M. Kim, PhD contributed equally to this paper. Senior authors, Costas Koumenis, PhD, James Metz, MD, and Keith A. Cengel, MD, PhD contributed equally to this paper. Statistical Analyses performed by Mary Putt, PhD.
Institutional funds were provided by the Department of Radiation Oncology, University of Pennsylvania. Additional funds were by the NIH National Center for Research ResourcesS10 RR026587.
Disclosures: L.D. reports personal fees from Varian Medical Systems Speakers Bureau and other from Varian Medical Systems (PI of Master Research Agreement between the University of Pennsylvania and Varian Medical Systems), outside the submitted work. A.L. reports personal fees from Ion Beam Applications Speakers 7Bureau, personal fees from Galera Therapeutics Advisor Board, outside the submitted work.
J.M. reports other from Varian Medical Systems Advisory Board, other from Ion Beam Associates Advisory Board, other from Provision Advisory Board, outside the submitted work.
