Development and establishment of FLASH beamlines for pre-clinical and clinical translation
The availability of beam lines capable of achieving dose rates >40 Gy/s has been a large obstacle in the research community and has limited the progression of the field of FLASH RT. We have previously developed a novel FLASH irradiation platform that uses a clinical linear accelerator to produce dose rates in excess of 1000 Gy/s for mouse irradiation experiments with highly uniform dose throughout treatment volumes selectable from partial organs to whole mouse and a high degree of control over essential beam parameters. This system opened up the field of FLASH RT to the general research community. We are continuing the development of these type of systems while at the same time bringing in commercial systems such as the FLASH Mobetron (IntraOp) and the Oriatron (PMB-Alcen) for our research efforts.
Detector systems for FLASH RT
The dosimetry of FLASH beams is made complicated by the very high dose rates used, thus limiting the number of available dosimetry systems that we can use. To date, researchers have had to rely on passive dose monitoring with Gafchromic film or alanine and thermoluminescent dosimeters for dose measurements. Although accurate dosimetry independent of dose rate can be achieved with these passive dosimeters, these platforms are limited by delayed readout (up to 24h), non-linear dose response, energy dependence, and complicated calibration procedures. We propose to develop scintillation-based detectors and establish the necessary dosimetry protocols for FLASH RT. Scintillators are one of the few dosimetry platforms that can be used in FLASH RT because of their dose-rate independence, tissue equivalence, and dose linearity. Further, scintillation detectors allow measurements of integrated dose in real time, as well as allowing temporal resolution of individual LINAC pulses, which is required to elucidate the mechanisms of the FLASH effect.
Biological effects of FLASH irradiation
The biological effects of ultra-high-dose-rate irradiation hold promise for lesser normal tissue toxicity after irradiation than irradiation delivered at conventional dose rates. Our published findings show that whole-brain irradiation with FLASH led to better preservation of cognitive function in mice relative to conventional dose rate irradiation. Specifically, FLASH led to greater preservation of dendritic spine density in the hippocampal area and led to decreased inflammatory processes as compared with conventional irradiation. Similar sparing was found after total abdominal irradiation, in that the function of the GI tract was preserved and survival was increased after FLASH relative to conventional irradiation.
Optimization of the FLASH effect
Little is known of the physical or biological mechanisms underlying normal-tissue sparing (the FLASH effect). Early evidence indicated a mean dose rate threshold of ~ 40 Gy/s, but evidence is accumulating on a mean dose rate dependence, where increased dose rates induce higher sparing effects. Furthermore, there are also indications of the importance of other details, such as dose per pulse, pulse width, overall delivery time, and pulse frequency. However, as of yet, there is no consensus on which physical beam parameters are needed to achieve a FLASH effect and if there is an optimal set of parameters. In order to gain insight into the dependence of the physical beam parameters on the magnitude of the normal tissue sparing achieved through FLASH RT, we have set up a large multi-institutional collaboration. Through this collaborative effort we aim to gain insight into the dependence of the physical beam parameters on different biological endpoints, thus allowing us to optimize the effectiveness of FLASH RT treatments.
Future of research direction
The aim of our research is to develop a universal dosimetry platform for FLASH irradiation, to characterize the functional responses of FLASH irradiation on normal and tumor tissue, and to establish FLASH beams lines for the clinical translation of FLASH RT