FLASH radiation therapy—the use of dose rates exceeding 40 Gy/s—has shown potential for improving the way we treat cancer. The effects observed at these extreme dose rates are still cause for debate in radiation oncology, sparking more than 3,000 papers on the subject since it was first described in 1966 by Hornsey and Alper. Despite the recent resurgence in interest and a flurry of activity after decades of lying dormant, the FLASH community lacks consensus on many different topics related to high dose rate treatments. Still, the potential for FLASH is extraordinary, as it could revolutionize the way we treat cancer. In a previous blog post, we took a deep dive into the radiobiology and mechanics of FLASH RT. Still, there are other questions to be answered about FLASH before we fully understand how it fits within our radiation therapy toolbox.
FLASH radiotherapy presents a few issues that need to be addressed before it is ready for more intense clinical trials. The first is the method in which we deliver FLASH. Without significant modifications, conventional linacs do not produce the dose rates required for FLASH. In terms of generating FLASH capable beams, charged particle solutions seem to be the easiest choice at this juncture via cyclotron or synchrotron-generated proton beams, specialized electron linear accelerators, and conversion of clinical linacs to produce higher dose rates.
Proton FLASH: Implementation and Animal Trials
In a presentation at the 2021 AAPM FLASH Symposium, Dr. Michele Kim of the University of Pennsylvania Radiation Oncology outlined the implementation and design of a proton FLASH system for the first canine clinical trial. The presentation spoke to the design and validation of the Penn Medicine Proton FLASH Radiation Therapy System and shared results from a small animal clinical trial and preliminary results of a canine clinical trial. The team used a cyclotron-generated 230 MeV proton beam with a double scattering collimation system to produce a sufficiently large field size. On the dosimetry front, a Markus chamber fitted with a Faraday cup to remove dose rate dependence was used to obtain a dose-rate independent ion collection efficiency using an ion chamber. A linear relationship between the proton current and dose rate—as well as dose rate and monitor units—was validated.
In their small animal clinical trial, mouse abdomen were irradiated with FLASH (78±9 Gy/s) or standard (0.9±0.08 Gy/s) dose rates, with all other treatment parameters kept constant. It was shown that after delivering 15 Gy to the whole abdomen, FLASH dose rates better preserved the proliferation of intestinal crypts and inhibited long-term fibrosis formation after irradiation. More information regarding their proton FLASH implementation and small animal clinical trial can be found here.
In a 2020 paper on FLASH RT dosimetry, Ashraf et al. reports that luminescent detectors can play a crucial role in FLASH RT’s development. Luminescent detectors tend to be superior to chemical and charge-based detectors due to their dose rate independence and sub-millimeter spatial resolution. Their research shows promising results for FLASH applications using scintillators and Cherenkov detectors. Scintillation detectors may be ideal for the new modality, considering their dose rate independence, spatial resolution of less than 1 millimeter, nanosecond time-resolution, and tissue-equivalent energy dependence.
Table 1: Dosimeters and their capabilities rated for potential FLASH dose measurement of key parameters. (Ashraf et. al.)
Linac Conversion to Achieve Ultra-High Dose Rates
Ashraf et al. also worked on a solution to the delivery of FLASH-RT through the conversion of a standard linac. A Varian Clinac 2100 C/D was modified to deliver electron beams through its service mode and by retracting the x-ray target, positioning the carousel on an empty port, and selecting a 10 MV photon beam energy. The resulting surface dose rates were 238 ± 5 Gy/s for a 1 cm circular field, 262 ± 5 Gy/s for a 1.5 circular field, and 290 ± 5 Gy/s for an open field. This provides a unique solution to FLASH delivery, as it is an ultra-high dose rate beam delivered with conventional geometry to the treatment room isocenter. These FLASH modifications don’t require permanent alterations to the linac, as the process is entirely reversible within minutes.
First Human Clinical Trial
Until promising human clinical trials are thoroughly conducted, FLASH will remain a theoretical possibility instead of a clinical reality. One such clinical trial, the first on humans, began in 2020 at Cincinnati’s Children’s/UC Health Proton Therapy Center. The study set out to assess the feasibility of FLASH radiotherapy for the palliative treatment of painful bone metastases. The trial consists of 10 patients and evaluates a variety of measures related to the treatment. The primary measures consist of workflow feasibility (targeting on-table treatment time of <1hr), assessment of radiation-related toxicities associated with FLASH, and secondary outcome measures of pain relief and use of pain medication. The trial has an estimated completion date of December 2022.
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