ABSTRACT
Significant improvement in the effectiveness of radiation therapy (RT) now seems possible because of recent
exciting research results using ultra-high dose rates (UHDR), indicating that normal tissue damage can be
reduced (the `FLASH' effect), compared to conventional radiation for the same total dose. FLASH RT delivery
has shown reduced morphological and functional damage to normal tissues such as brain, colon, lung, and skin.
Although significant research remains, early indications are that the normal tissue sparing effect may as high
50% at some dose levels. If proven in translation, this effect would be the most significant improvement in RT
therapeutic ratio since the advent of treatment planning. While intriguing mechanisms for this result have been
postulated, they remain only well-reasoned speculations because of a lack of direct in vivo data on the physico-
chemical mechanisms including oxygen depletion and free radical species alterations. Dartmouth has created
the first reversible MeV FLASH beam on a clinically commissioned linac with >100 Gy/s at the patient treatment
bed, and prototyped an open-source treatment planning system, expanding research access. Additionally, the
team has invented unique technological capabilities to directly measure the highest dose rates and in vivo tissue
oxygen transients. The key technological barriers solved in the proposed research with preliminary data are: 1)
demonstration of conversion to a UHDR irradiator within a clinically commissioned linac, 2) verification of per-
pulse and per-fraction dose rates, 3) direct in vivo observation of oxygen transients, 4) direct measurements of
free radical species changes in vitro, and 5) access to functional tissue assays and genetic and proteomic
assays. Single-pulse and single-fraction dose rates will be quantified by high frame rate imaging. Additionally,
the in vivo oxygen changes will be quantified by two independent methods for co-validation, including electron
paramagnetic resonance oximetry and optical luminescence oximetry. Free radical species changes produced
from transient hypoxia will also be assessed through systematic in vitro analyses, and the potential linkages to
functional, proteomic and DNA damage examined. The FLASH beam conditions that minimize normal tissue
damage for a fixed dose will be established with this baseline data. The work is pre-clinical but can be readily
adapted to ongoing NIH sponsored spontaneous canine cancer studies has relevance to future large animal and
first-in-human translation. Multiple Dartmouth centers partnered to initiate and support this FLASH program.
Taken altogether, this bioengineering research project will advance the state of the art in high dose rate radiation
therapy using tools that have been uniquely developed by our 3 research groups, and the project results will
build the basic science needed to support proposed human translation of this ground-breaking field. The team
has leading expertise in radiation physics, in vivo molecular measurement, and radiation genetics and
immunomolecular biology and pathology. The work is supported by an External Advisory Board of international
expert FLASH consultants, as well as an internal Radiation Oncology Advisory Group.