重新定义FLASH放射治疗：平均剂量率与脉冲剂量对胃肠道的影响

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

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS

影响因子:6.5

分区:医学1区 Top / 肿瘤学2区核医学2区

发表日期:2025 Mar 15

作者: 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, Devarati Mitra, Emil Schüler

DOI: 10.1016/j.ijrobp.2024.10.009

摘要

关于不同辐射束参数设置如何影响FLASH效应的诱导及其强度的理解仍有限。我们旨在系统评估辐射引起的胃肠毒性大小如何依赖于平均剂量率（MDR）和脉冲剂量（DPP）之间的相互作用。C57BL/6J小鼠接受腹部总照射（TAI，11-14 Gy单次剂量），通过传统照射（CONV，低DPP和低MDR）或各种DPP与MDR组合的超高剂量率照射条件。评估DPP范围为1至6 Gy，同时保持总剂量和MDR（>100 Gy/s）不变；MDR范围从0.3到1440 Gy/s，保持总剂量和DPP不变。通过再生隐窝检测和存活率评估，量化非肿瘤小鼠的辐射引起的胃肠毒性。肿瘤反应通过肿瘤生长延迟进行评估。在每个总剂量下，MDR保持不变（>100 Gy/s），增加DPP会增强保护作用（增加再生隐窝数量），在12和14 Gy TAI表现尤为明显。有趣的是，在DPP >4 Gy时，无论MDR如何（0.3至1440 Gy/s），隐窝保护水平相似。在固定高DPP（4.7 Gy）时，存活率相较于CONV相等，无论MDR如何。然而，在DPP较低（0.93 Gy）时，104 Gy/s的MDR比0.3 Gy/s产生更显著的存活改善。我们还确认，不论MDR如何，高DPP都能在临床相关的黑色素瘤小鼠模型中实现与CONV相当的肿瘤生长延迟。本研究展示了束参数设置对FLASH效应强度的显著影响。高DPP和超高剂量率似乎能独立产生胃肠毒性保护，同时保持等效的肿瘤反应。

Abstract

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).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.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.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.