FLASH radiotherapy (FLASH-RT) is a novel radiotherapy approach based on the use of ultra-high dose radiation to treat malignant cells. Although tumours can be reduced or eradicated using radiotherapy, toxicities induced by radiation can compromise healthy tissues. The FLASH effect is the observation that treatment delivered at an ultra-high dose rate is able to reduce adverse toxicities present at conventional dose rates. While this novel technique may provide a turning point for clinical practice, the exact mechanisms underlying the causes or influences of the FLASH effect are not fully understood. The study presented here uses data collected from 41 experimental investigations (published before March 2024) of the FLASH effect. Searchable databases were constructed to contain the outcomes of the various experiments in addition to values of beam parameters that may have a bearing on the FLASH effect. An in-depth review of the impact of the key beam parameters on the results of the experiments was carried out. Correlations between parameter values and experimental outcomes were studied. Pulse Dose Rate had positive correlations with almost all end points, suggesting viability of FLASH-RT as a new modality of radiotherapy. The collective results of this systematic review study suggest that beam parameter qualities from both FLASH and conventional radiotherapy can be valuable for tissue sparing and effective tumour treatment.

UNASSIGNED: Radiotherapy increases survival in patients with glioblastoma. However, the prescribed dose is limited by unwanted side effects on normal tissue. Previous experimental studies have shown that FLASH radiotherapy (FLASH-RT) can reduce these side effects. Still, it is important to establish an equal anti-tumor efficacy comparing FLASH-RT to conventional radiotherapy (CONV-RT).
UNASSIGNED: Fully immunocompetent Fischer 344 rats with the GFP-positive NS1 intracranial glioblastoma model were irradiated with CONV-RT or FLASH-RT in one fraction of 20 Gy, 25 Gy or 30 Gy. Animals were monitored for survival and acute dermal side effects. The brains were harvested upon euthanasia and tumors were examined post mortem.
UNASSIGNED: Survival was significantly increased in animals irradiated with CONV-RT and FLASH-RT at 20 Gy and 25 Gy compared to control animals. The longest survival was reached in animals irradiated with FLASH-RT and CONV-RT at 25 Gy. Irradiation at 30 Gy did not lead to increased survival, despite smaller tumors. Tumor size correlated inversely with irradiation dose, both in animals treated with CONV-RT and FLASH-RT. Acute dermal side effects were mild, but only a small proportion of the animals were alive for evaluation of those side effects.
UNASSIGNED: The dose response was similar for CONV-RT and FLASH-RT in the present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose.

UNASSIGNED: We have previously adapted a clinical linear accelerator (Elekta Precise, Elekta AB) for ultra-high dose rate (UHDR) electron delivery. To enhance reliability in future clinical FLASH radiotherapy trials, the aim of this study was to introduce and evaluate an upgraded beam control system and beam tuning process for safe and precise UHDR delivery.
UNASSIGNED: The beam control system is designed to interrupt the beam based on 1) a preset number of monitor units (MUs) measured by a monitor detector, 2) a preset number of pulses measured by a pulse-counting diode, or 3) a preset delivery time. For UHDR delivery, an optocoupler facilitates external control of the accelerator\'s thyratron trigger pulses. A beam tuning process was established to maximize the output. We assessed the stability of the delivery, and the independent interruption capabilities of the three systems (monitor detector, pulse counter, and timer). Additionally, we explored a novel approach to enhance dosimetric precision in the delivery by synchronizing the trigger pulse with the charging cycle of the pulse forming network (PFN).
UNASSIGNED: Improved beam tuning of gun current and magnetron frequency resulted in average dose rates at the dose maximum at isocenter distance of >160 Gy/s or >200 Gy/s, with or without an external monitor chamber in the beam path, respectively. The delivery showed a good repeatability (standard deviation (SD) in total film dose of 2.2%) and reproducibility (SD in film dose of 2.6%). The estimated variation in DPP resulted in an SD of 1.7%. The output in the initial pulse depended on the PFN delay time. Over the course of 50 measurements employing PFN synchronization, the absolute percentage error between the delivered number of MUs calculated by the monitor detector and the preset MUs was 0.8 ± 0.6% (mean ± SD).
UNASSIGNED: We present an upgraded beam control system and beam tuning process for safe and stable UHDR electron delivery of hundreds of Gy/s at isocenter distance at a clinical linac. The system can interrupt the beam based on monitor units and utilize PFN synchronization for improved dosimetric precision in the dose delivery, representing an important advancement toward reliable clinical FLASH trials.

Ultra-high dose rate radiotherapy (FLASH-RT) is an external beam radiotherapy strategy that uses an extremely high dose rate (≥40 Gy/s). Compared with conventional dose rate radiotherapy (≤0.1 Gy/s), the main advantage of FLASH-RT is that it can reduce damage of organs at risk surrounding the cancer and retain the anti-tumor effect. An important feature of FLASH-RT is that an extremely high dose rate leads to an extremely short treatment time; therefore, in clinical applications, the steps of radiotherapy may need to be adjusted. In this review, we discuss the selection of indications, simulations, target delineation, selection of radiotherapy technologies, and treatment plan evaluation for FLASH-RT to provide a theoretical basis for future research.

OBJECTIVE: The impact of radiotherapy (RT) at ultra high vs conventional dose rate (FLASH vs CONV) on the generation and repair of DNA double strand breaks (DSBs) is an important question that remains to be investigated. Here, we tested the hypothesis as to whether FLASH-RT generates decreased chromosomal translocations compared to CONV-RT.
METHODS: We used two FLASH validated electron beams and high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), employing S. aureus and S. pyogenes Cas9 \"bait\" DNA double strand breaks (DSBs) in HEK239T cells, to measure differences in bait-proximal repair and their genome-wide translocations to \"prey\" DSBs generated after various irradiation doses, dose rates and oxygen tensions (normoxic, 21% O2; physiological, 4% O2; hypoxic, 2% and 0.5% O2). Electron irradiation was delivered using a FLASH capable Varian Trilogy and the eRT6/Oriatron at CONV (0.08-0.13 Gy/s) and FLASH (1x102-5x106 Gy/s) dose rates. Related experiments using clonogenic survival and γH2AX foci in the 293T and the U87 glioblastoma lines were also performed to discern FLASH-RT vs CONV-RT DSB effects.
RESULTS: Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Furthermore, RT dose rate modality on U87 cells did not change γH2AX foci numbers at 1- and 24-hours post-irradiation nor did this affect 293T clonogenic survival.
CONCLUSIONS: Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

UNASSIGNED: Investigating the antitumor effect and intratumor as well as local immune response in breast cancer-bearing mice after MV X-ray ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT).
UNASSIGNED: Six-week-old female C57BL/6 mice were inoculated subcutaneously with Py8119 and Py230 breast tumor cells in the inguinal mammary gland and administered 10 Gy abdominal 6 MV X-ray FLASH-RT (125 Gy/s) or CONV-RT (0.2 Gy/s) 15 days after tumor inoculation. Tumor and spleen tissues were obtained at different time points post-irradiation (PI) for analysis of immune cell infiltration using flow cytometry and immunohistochemical (IHC) staining. Intestine tissues were collected 3 days PI to evaluate normal tissue damage and immune cell infiltration.
UNASSIGNED: Both FLASH-RT and CONV-RT significantly delayed tumor growth. Flow cytometry showed increased CD8+/CD3 + and CD8+/CD4 + ratios, and IHC confirmed a similar increased CD8 + T cell infiltration at 2 weeks PI in Py8119 tumor tissues in both irradiation groups. No statistical difference was observed between the irradiation groups in terms of tumor growth and increased T cell infiltration in the tumor. Unexpectedly, significantly smaller spleen weight and substantially higher CD8+/CD3 + and lower CD4+/CD3 + ratios were observed in the spleens of the FLASH-RT group than in the spleens of the non-irradiated control and CONV-RT groups 4 weeks PI. Pathological analysis revealed severe red pulp expansion in several spleens from the CONV-RT group, but not in the spleens of the FLASH-RT group. Reduced intestinal damage, macrophage and neutrophil infiltration were observed in the FLASH-RT group compared with CONV-RT group.
UNASSIGNED: FLASH-RT and CONV-RT effectively suppressed tumor growth and promoted CD8 + T cell influx into tumors. FLASH-RT can induce different splenic immune responses and reduce radiation-induced damage in the spleen and intestine, which may potentially enhance the therapeutic ratio of FLASH-RT.

FLASH radiotherapy (FLASH-RT) is an emerging ultra-high dose (>40 Gy/s) delivery that promises to improve the therapeutic potential by limiting toxicities compared to conventional RT while maintaining similar tumor eradication efficacy. Image guidance is an essential component of modern RT that should be harnessed to meet the special emerging needs of FLASH-RT and its associated high risks in planning and delivering of such ultra-high doses in short period of times. Hence, this contribution will elaborate on the imaging requirements and possible solutions in the entire chain of FLASH-RT treatment, from the planning, through the setup and delivery with online in vivo imaging and dosimetry, up to the assessment of biological mechanisms and treatment response. In patient setup and delivery, higher temporal sampling than in conventional RT should ensure that the short treatment is delivered precisely to the targeted region. Additionally, conventional imaging tools such as cone-beam computed tomography will continue to play an important role in improving patient setup prior to delivery, while techniques based on magnetic resonance imaging or positron emission tomography may be extremely valuable for either linear accelerator (Linac) or particle FLASH therapy, to monitor and track anatomical changes during delivery. In either planning or assessing outcomes, quantitative functional imaging could supplement conventional imaging for more accurate utilization of the biological window of the FLASH effect, selecting for or verifying things such as tissue oxygen and existing or transient hypoxia on the relevant timescales of FLASH-RT delivery. Perhaps most importantly at this time, these tools might help improve the understanding of the biological mechanisms of FLASH-RT response in tumor and normal tissues. The high dose deposition of FLASH provides an opportunity to utilize pulse-to-pulse imaging tools such as Cherenkov or radiation acoustic emission imaging. These could provide individual pulse mapping or assessing the 3D dose delivery superficially or at tissue depth, respectively. In summary, the most promising components of modern RT should be used for safer application of FLASH-RT, and new promising developments could be advanced to cope with its novel demands but also exploit new opportunities in connection with the unique nature of pulsed delivery at unprecedented dose rates, opening a new era of biological image guidance and ultrafast, pulse-based in vivo dosimetry.

OBJECTIVE: Due to their finite range, electrons are typically ignored when calculating shielding requirements in megavoltage energy linear accelerator vaults. However, the assumption that 16 MeV electrons need not be considered does not hold when operated at FLASH-RT dose rates (~200× clinical dose rate), where dose rate from bremsstrahlung photons is an order of magnitude higher than that from an 18 MV beam for which shielding was designed. We investigate the shielding and radiation protection impact of converting a Varian 21EX linac to FLASH-RT dose rates.
METHODS: We performed a radiation survey in all occupied areas using a Fluke Biomedical Inovision 451P survey meter and a Wide Energy Neutron Detection Instrument (Wendi)-2 FHT 762 neutron detector. The dose rate from activated linac components following a 1.8-min FLASH-RT delivery was also measured.
RESULTS: When operated at a gantry angle of 180° such as during biology experiments, the 16 MeV FLASH-RT electrons deliver ~10 µSv/h in the controlled areas and 780 µSv/h in the uncontrolled areas, which is above the 20 µSv in any 1-h USNRC limit. However, to exceed 20 µSv, the unit must be operated continuously for 92 s, which corresponds in this bunker and FLASH-RT beam to a 3180 Gy workload at isocenter, which would be unfeasible to deliver within that timeframe due to experimental logistics. While beam steering and dosimetry activities can require workloads of that magnitude, during these activities, the gantry is positioned at 0° and the dose rate in the uncontrolled area becomes undetectable. Likewise, neutron activation of linac components can reach 25 µSv/h near the isocenter following FLASH-RT delivery, but dissipates within minutes, and total doses within an hour are below 20 µSv.
CONCLUSIONS: Bremsstrahlung photons created by a 16 MeV FLASH-RT electron beam resulted in consequential dose rates in controlled and uncontrolled areas, and from activated linac components in the vault. While our linac vault shielding proved sufficient, other investigators would be prudent to confirm the adequacy of their radiation safety program, particularly if operating in vaults designed for 6 MV.

Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.

A recent addition to the treatment options in external beam therapy, so-called FLASH radiotherapy, shows remarkable healthy-tissue-sparing properties in a number of pre-clinical studies without impacting the overall treatment efficacy. Its potential in clinical applications is attracting a great deal of interest in the medical community. The use of ultra-high dose rates at extremely short irradiation times has been shown to significantly enhance the differential effects between normal and tumor tissue. This makes it possible to increase treatment doses without further harming the surrounding healthy tissue. While most studies to date have focused on the use of electron beams, X-ray and proton FLASH radiotherapy have also shown beneficial effects, although for these latter two the results still need to be independently confirmed. Furthermore, the mechanisms underlying the biological effects remain to be elucidated. Very recently, the FLASH effect has been demonstrated in the first human patient, with promising results, supporting further clinical studies. This review will present an overview of the investigations into FLASH radiotherapy to date.