Project Summary This project will investigate spatio-temporal delivery of FLASH radiation using pencil beam scanning technology. Modern Pencil Beam Scanning (PBS) technology can deliver spatially non-uniform (Gaussian-like) pencil beam in very high instantaneous dose rate to both shallow and deep-seated tumors; however, the low dose tail of a pencil beam and the relatively slow volume scanning speed for large targets generate a variable dose rate at selected target or normal tissue locations. The impact of this spatial-temporal variation is still unknown for FLASH. Even at the same (averaged) dose rate, degeneracy exists that the FLASH treatment can be delivered by different time-dose sequences. There is a need to study the timing structure of dose delivery in the context of FLASH treatment, as well as measuring and documenting each FLASH treatment so that the outcome can be better understood. Our central hypothesis is that proton PBS can be optimized to deliver FLASH enhanced radiotherapy with existing accelerator technology. The aims of the proposal are: Aim 1 - Investigation of spatio-temporal variations and SOBP versus shoot through PBS beams. Aim 2 - Development of a spatial-temporal biological effective dose model for PBS-based FLASH proton therapy. Aim 3 - Development of fast dose recording instrumentation, image guided positional systems, quality assurance procedures, and end-to-end validation. Success of this project will demonstrate the ability to deliver FLASH to large treatment volumes using proton PBS for the first time. Combined with the ability of proton therapy to accurately deliver dose to deep targets, this will allow translation of PBS FLASH proton therapy to early stage clinical trial studies.