Redefining FLASH Radiation Therapy: The Impact of Mean Dose Rate and Dose Per Pulse in the Gastrointestinal Tract

Kevin Liu; Trey Waldrop; Edgardo Aguilar; Nefetiti Mims; Denae Neill; Abagail Delahoussaye; Ziyi Li; David Swanson; Steven H Lin; Albert C Koong; Cullen M Taniguchi; Billy W Loo Jr; Devarati Mitra; Emil Schüler

doi:10.1016/j.ijrobp.2024.10.009

Redefining FLASH Radiation Therapy: The Impact of Mean Dose Rate and Dose Per Pulse in the Gastrointestinal Tract

Int J Radiat Oncol Biol Phys. 2024 Oct 17:S0360-3016(24)03466-7. doi: 10.1016/j.ijrobp.2024.10.009. Online ahead of print.

Authors

Affiliations

¹ Department of Radiation Physics, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
² Department of Radiation Physics, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
³ Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁴ Division of Basic Sciences, Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁵ Department of Radiation Oncology & Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
⁶ Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: [email protected].
⁷ Department of Radiation Physics, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, Texas. Electronic address: [email protected].

PMID: 39424078
DOI: 10.1016/j.ijrobp.2024.10.009

Abstract

Purpose: The understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited. We sought to systematically evaluate how the magnitude of radiation-induced gastrointestinal toxicity depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP).

Methods and materials: C57BL/6J mice received total abdominal irradiation (TAI, 11-14 Gy single fraction) through either conventional (CONV) irradiation (low-DPP and low MDR, CONV) or through various combinations of DPP and MDR up to ultra-high-dose-rate beam conditions. DPPs ranging from 1 to 6 Gy were evaluated, while the total dose and MDR (>100 Gy/s) were kept constant; the effects of MDR were evaluated for the range of 0.3 to 1440 Gy/s, while the total dose and DPP were kept constant. Radiation-induced gastrointestinal toxicity was quantified in nontumor-bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay.

Results: Within each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to an increase in sparing (an increase in the number of regenerating crypts), with a more prominent effect seen at 12- and 14-Gy TAI. Interestingly, at DPPs of >4 Gy, a similar level of crypt sparing was demonstrated irrespective of the MDR used (from 0.3 to 1440 Gy/s). At a fixed high-DPP of 4.7 Gy, survival was equivalently improved relative to CONV irrespective of MDR. However, at a lower DPP of 0.93 Gy, an MDR of 104 Gy/s produced a greater survival effect compared with 0.3 Gy/s. We also confirmed that high-DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model.

Conclusions: This study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high-DPP and ultra-high-dose-rate appeared independently sufficient to produce FLASH sparing of gastrointestinal toxicity while isoeffective tumor response was maintained across all conditions.