Decrease in dose per fraction impairs the FLASH sparing effect in murine intestine model

  1. A. Sesink
  2. R. Geyer
  3. P. Devanand
  4. T. T. Böhlen
  5. L. Soutter
  6. R. Moeckli
  7. C. Bailat
  8. F. G. Herrera
  9. V. Grilj
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Abstract

Purpose

FLASH radiotherapy (FLASH) can ease radiation-induced normal tissue toxicities; however, its benefit in clinically relevant fractionation protocols remains insufficiently explored. This study investigated the FLASH sparing effect under two fractionated regimens using a murine model of acute gastrointestinal toxicity.

Methods and Materials

Tumor-free C57BL/6 mice received abdominal irradiation with either conventional radiotherapy (CONV) or FLASH using a 9 MeV electron beam. Three dose delivery protocols were assessed: single-fraction delivery, two equal fractions over two consecutive days, and ten equal daily fractions over two weeks. Dose escalation was performed within each protocol, while overall survival was used to monitor normal tissue sparing. The FLASH dose modifying factor (FDMF) was derived from normal tissue toxicity probability (NTCP) curves to quantify the relative protective effect of FLASH.

Results

The single-fraction irradiation demonstrated a significant FLASH sparing effect, with an FDMF of 1.14. In contrast, this protective effect was diminished in the fractionated protocols, with the two-fraction regimen yielding an FDMF of 1.03, while the ten-fraction regimen showed no measurable sparing (FDMF = 1.00).

Conclusions

In an acute responding model of radiation-induced abdominal toxicity, the FLASH sparing effect was substantially reduced with a two-fraction regimen and completely absent with a ten-fraction regimen. These findings suggest that the benefit of FLASH may be limited at lower doses per fraction and highlight the need for further studies in other clinically relevant models to better define the boundaries of its therapeutic applicability.

Highlights

  • FLASH-RT spares mice intestine from acute toxicity for single-dose delivery.

  • FLASH effect declines in mice intestine with more fractions and less dose/fraction.

  • FLASH sparing in mice intestine is lost with ten equal fractions over two weeks.

Article activity feed

  1. Version published to 10.1101/2025.08.27.672569 on bioRxiv