PhD Thesis Defense: Jacob Sunnerberg

"Mechanistic Insights into the FLASH Effect: The role of oxygen and radiation chemistry in ultra-high dose rate radiation therapy"

Abstract

The development of new cancer therapies focuses on widening the therapeutic window between tumor control and normal tissue toxicity. Over the last decade, ultra-high dose rate (UHDR) radiation therapy, commonly known as FLASH radiotherapy (FLASH-RT), has shown promising potential to reduce normal tissue toxicity while maintaining tumor control. However, the underlying mechanisms of the FLASH effect remain poorly understood. This thesis explores the radiation-chemical basis of FLASH-RT, focusing on the role of oxygen and reactive oxygen species in modulating biological outcomes.

A comprehensive set of in vitro studies demonstrated that UHDR delivery significantly alters radiation chemistry compared to conventional dose rates. Specifically, both hydrogen peroxide production and oxygen consumption per unit dose were reduced in protein-rich environments, with mean dose rate emerging as a more predictive parameter than instantaneous dose rate. Additionally, comparison between proton and electron UHDR beams revealed beam-specific differences in reactive oxygen species yields, suggesting that UHDR radiation chemistry is not uniform across modalities.

These chemical insights were translated in vivo using murine skin models with real-time phosphorescence oximetry. Oxygen consumption during irradiation was found to be highly dependent on baseline tissue oxygenation, plateauing above 20 mmHg. This dependency proved critical in subsequent biological studies, where mice with higher pre-irradiation pO2 and greater radiation-induced oxygen consumption were more likely to develop skin ulceration. Notably, the FLASH effect, characterized by reduced skin damage at UHDR, was significant under normoxic conditions but diminished under hyperoxic conditions, indicating a saturable relationship between oxygen tension and tissue sparing.

Further investigations into UHDR temporal dose delivery structures revealed that the timing of dose delivery modulates both oxygen consumption and biological response. Shorter beam interruptions preserved the FLASH effect, while longer gaps led to reduced sparing, emphasizing the temporal dynamics of oxygen recovery as a key factor.

Together, these findings establish oxygen as a central factor in both the chemistry and biology of FLASH-RT. By linking tissue oxygenation, radiation-induced oxygen consumption, and normal tissue toxicity, this work provides a mechanistic framework to guide optimization of UHDR delivery in preclinical and future clinical applications.

Thesis Committee

• Brian Pogue (Chair)
• David Gladstone
• Petr Bruza
• P. Jack Hoopes
• Jennifer Wei Zou (U Penn)

Contact

For more information, contact Thayer Registrar at thayer.registrar@dartmouth.edu.