Abstract Body

Toward single dose radiotherapy: Dream or reality?

Radiation oncology has been entrenched and remains dependent on advancements in technology. The capability to safely generate high energy beam modalities, characterize beam time signatures, perform accurate dosimetry and deliver image-guided treatment plans has been the cornerstone of the field. Over the years, the ultimate success of radiotherapy has been reliant on interdisciplinary contributions from physics, chemistry and biology, but has moved forward conservatively, constrained by the very technologies that have now ushered in precision driven stereotactic approaches such as SBRT/SABR and SRS. However, ultra-high dose rate FLASH radiotherapy (FLASH-RT), overlooked for over 40 years, has now triggered a renaissance in the field, aimed at evaluating if/how dose rate modifications can be garnered for therapeutic gain. This so called “FLASH effect” has been defined and validated in vivo, and provides a heretofore unforeseen capability to minimize normal tissue complications while maintaining isoefficient tumor control. The potential promise of affording curative, dose escalation via FLASH-RT was immediately recognized, as dose limiting toxicities have and always will dictate the maximum tolerated dose that can be applied to any given tissue bed.

In this regard, photon and particle FLASH radiotherapy have the potential to transform healthcare, and dovetail nicely into current trends toward hypofractionation and possibly single dose therapy. This talk will highlight unpublished data regarding the response of the adult and juvenile rodent brain to fractionated FLASH-RT, and try to link the known and possible physico-chemical and biological mechanisms that might help us translate these findings to the clinic. If/how that laudable goal can be accelerated or even achieved through forthcoming advancements in FLASH-RT remains to be seen, but this intriguing technology has certainly captured the imagination of the radiation sciences and holds appeal at several levels, except perhaps for clinical profit margins.

Abstract Body

Toward single dose radiotherapy: Dream or reality?

Radiation oncology has been entrenched and remains dependent on advancements in technology. The capability to safely generate high energy beam modalities, characterize beam time signatures, perform accurate dosimetry and deliver image-guided treatment plans has been the cornerstone of the field. Over the years, the ultimate success of radiotherapy has been reliant on interdisciplinary contributions from physics, chemistry and biology, but has moved forward conservatively, constrained by the very technologies that have now ushered in precision driven stereotactic approaches such as SBRT/SABR and SRS. However, ultra-high dose rate FLASH radiotherapy (FLASH-RT), overlooked for over 40 years, has now triggered a renaissance in the field, aimed at evaluating if/how dose rate modifications can be garnered for therapeutic gain. This so called “FLASH effect” has been defined and validated in vivo, and provides a heretofore unforeseen capability to minimize normal tissue complications while maintaining isoefficient tumor control. The potential promise of affording curative, dose escalation via FLASH-RT was immediately recognized, as dose limiting toxicities have and always will dictate the maximum tolerated dose that can be applied to any given tissue bed.

In this regard, photon and particle FLASH radiotherapy have the potential to transform healthcare, and dovetail nicely into current trends toward hypofractionation and possibly single dose therapy. This talk will highlight unpublished data regarding the response of the adult and juvenile rodent brain to fractionated FLASH-RT, and try to link the known and possible physico-chemical and biological mechanisms that might help us translate these findings to the clinic. If/how that laudable goal can be accelerated or even achieved through forthcoming advancements in FLASH-RT remains to be seen, but this intriguing technology has certainly captured the imagination of the radiation sciences and holds appeal at several levels, except perhaps for clinical profit margins.

Background and Aims

Convincing evidence has been provided that lowering the mean dose rate below 30 Gy/s (Montay-Gruel et al. Radiother Oncol 124: 365-369, 2017) or increasing the oxygen tension through carbogen breathing (Montay-Gruel et al. PNAS 116: 10943-10951, 2019) can reduce (if not eliminate) the sparing effect of FLASH in the mouse brain. Three theoretical models have since been proposed to account for the dependence of FLASH on oxygen, namely, (i) Radiation-induced transient oxygen depletion (TOD), (ii) Cell-specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species, (iii) Self-annihilation of radicals by bimolecular recombination.

Methods

These theoretical models were confronted to experimental evidence relating to physical chemistry and the response of biological systems to ultrahigh dose rate irradiation in light of the chemical reactions underlying the radiosensitizing effect of O₂ from immediate, early processes to late complications.

Results

The radiosensitizing effect of oxygen has long been known to stem from peroxyl radicals (ROO^•). Peroxyl radicals areformed by the addition of O₂ in its fundamental, triplet state to short-lived carbon-centered radicals (R^•) generated upon H^• atom abstraction from aliphatic, unsaturated or conjugated substrates (RH).

Conclusions

Any attempt at deciphering the physical-chemical processes that underpin the FLASH effect must take into consideration the fate of these radicals, and in particular the probability of radical recombination. The radiation dose rate emerges as the most important factor. We propose testable procedures to investigate the mechanisms that underly the FLASH effect in normal cells, and differential tumor vs. normal cells responses.