Ultrahigh dose-rate radiotherapy (RT), or ‘FLASH’ therapy, has gained significant momentum following various in vivo studies published since 2014 which have demonstrated a reduction in normal tissue toxicity and similar tumor control for FLASH-RT when compared with conventional dose-rate RT. Subsequent studies have sought to investigate the potential for FLASH normal tissue protection and the literature has been since been inundated with publications on FLASH therapies. Today, FLASH-RT is considered by some as having the potential to ‘revolutionize radiotherapy’. FLASH-RT is considered by some as having the potential to ‘revolutionize radiotherapy’. The goal of this review article is to present the current state of this intriguing RT technique and to review existing publications on FLASH-RT in terms of its physical and biological aspects. In the physics section, the current landscape of ultrahigh dose-rate radiation delivery and dosimetry is presented. Specifically, electron, photon and proton radiation sources capable of delivering ultrahigh dose-rates along with their beam delivery parameters are thoroughly discussed. Additionally, the benefits and drawbacks of radiation detectors suitable for dosimetry in FLASH-RT are presented. The biology section comprises a summary of pioneering in vitro ultrahigh dose-rate studies performed in the 1960s and early 1970s and continues with a summary of the recent literature investigating normal and tumor tissue responses in electron, photon and proton beams. The section is concluded with possible mechanistic explanations of the FLASH normal-tissue protection effect (FLASH effect). Finally, challenges associated with clinical translation of FLASH-RT and its future prospects are critically discussed; specifically, proposed treatment machines and publications on treatment planning for FLASH-RT are reviewed.

Purpose By means of Monte Carlo (MC) simulations and indirect measurements, we have evaluated the maximum dose rates achievable with conventional x‐ray tubes and related them to FLASH therapy dose rates of >40 Gy/s. Methods Monte Carlo models of two 160 kV x‐ray tubes, the 3‐kW MXR‐160/22 and the 6‐kW MXR‐165, were built in the EGSnrc/BEAMnrc code. The dose rate in a water phantom placed against the x‐ray tube surface, located at 3.7 and 3.5 cm from the focal spot for the MXR‐160/22 and MXR‐165 x‐ray tube, respectively, was calculated with DOSXYZnrc. Dose delivered with the 120‐kV beam in a plastic water phantom for the MXR‐160/22 was measured and calculated. Gafchromic EBT3 films were placed at 15 and 18 mm depths in the plastic water phantom that was irradiated with a low tube current of 0.2 mA for 30 s. Results The maximum 160‐kV phantom surface dose rate was determined to be FLASH capable, calculated as (114.3 ± 0.6) Gy/s and (160.0 ± 0.8) Gy/s for the MXR‐160/22 and MXR‐165 x‐ray tubes, respectively. The dose rate in a 1‐cm diameter region was found to be (110.6 ± 2.8) Gy/s and (151.9 ± 2.6) Gy/s and remained FLASH capable to depths of 1.4 and 2.0 mm for the MXR‐160/22 and MXR‐165 x‐ray tube, respectively. The 120‐kV dose profiles measured with EBT3 films agreed with MC simulations to within 3.6% for regions outside of heel effect and at both measurement depths; this presented a good validation data set for the simulations of phantom surface dose rate using the 160‐kV beam. Conclusions We have indirectly determined that, with a careful experimental design, conventional x‐ray tubes can be made suitable for use in FLASH radiotherapy and dosimetry experiments.

Objective: To develop a bremsstrahlung target and megavoltage (MV) x-ray irradiation platform for ultrahigh dose-rate (UHDR) irradiation of small-animals for the Advanced Rare Isotope Laboratory (ARIEL) electron linac (e-linac) at TRIUMF. Approach: An electron-to-photon converter design for UHDR radiotherapy (RT) was centered around optimization of a tantalum-aluminum (Ta-Al) explosion-bonded target. Energy deposition within a homogeneous water-phantom and the target itself were evaluated using EGSnrc and FLUKA MC codes, respectively, for various target thicknesses (0.5-1.5 mm), beam energies (Ee-=8,10 MeV) and electron (gaussian) beam sizes (2σ=2-10 mm). Depth dose-rates in a 3D-printed mouse phantom were also calculated to infer the compatibility of the 10 MV dose distributions for FLASH-RT in small-animal models. Coupled thermo-mechanical FEA simulations in ANSYS were subsequently used to inform the stress-strain conditions and fatigue life (N) of the target assembly. Main Results: Dose-rates of up to 128 Gy s-1 at the phantom surface, or 85 Gy s-1 at 1-cm depth, were obtained for a 1x1 cm2 field size, 1-mm thick Ta target and 7.5 cm source-to-surface distance using the nominal treatment-beam configuration (Ee-=10 MeV,2σ=5 mm,P=1 kW); furthermore, removal of the collimation assembly and using a shorter (3.5 cm) SSD afforded dose-rates >600 Gy s-1, albeit at the expense of field conformality. Target temperatures were maintained below the tantalum, aluminum and cooling-water thresholds of 2000, 300 and 100 °C, respectively, while the aluminum strain behavior remained everywhere elastic and helped ensure N>3000 thermal cycles could be tolerated over the prescribed 5 yr life of the target. Significance: Effective design iteration, target cooling and failure mitigation have thus culminated in a robust target compatible with intensive transient (FLASH) and steady-state (diagnostic) applications. The ARIEL UHDR photon source will facilitate FLASH-RT experiments concerned with sub-second, pulsed or continuous beam irradiations at dose rates in excess of 40 Gy s-1.

Purpose The goal of this work was to design a realistic mouse phantom as a useful tool for accurate dosimetry in radiobiology experiments. Methods A subcutaneous tumor‐bearing mouse was scanned in a microCT scanner, its organs manually segmented and contoured. The resulting geometries were converted into a stereolithographic file format (STL) and sent to a multimaterial 3D printer. The phantom was split into two parts to allow for lung excavation and 3D‐printed with an acrylic‐like material and consisted of the main body (mass density ρ=1.18 g/cm3) and bone (ρ=1.20 g/cm3). The excavated lungs were filled with polystyrene (ρ=0.32 g/cm3). Three cavities were excavated to allow the placement of a 1‐mm diameter plastic scintillator dosimeter (PSD) in the brain, the center of the body and a subcutaneous tumor. Additionally, a laser‐cut Gafchromic film can be placed in between the two phantom parts for 2D dosimetric evaluation. The expected differences in dose deposition between mouse tissues and the mouse phantom for a 220‐kVp beam delivered by the small animal radiation research platform (SARRP) were calculated by Monte Carlo (MC). Results MicroCT scans of the phantom showed excellent material uniformity and confirmed the material densities given by the manufacturer. MC dose calculations revealed that the dose measured by tissue‐equivalent dosimeters inserted into the phantom in the brain, abdomen, and subcutaneous tumor would be underestimated by 3–5%, which is deemed to be an acceptable error assuming the proposed 5% accuracy of radiobiological experiments. Conclusions The low‐cost mouse phantom can be easily manufactured and, after a careful dosimetric characterization, may serve as a useful tool for dose verification in a range of radiobiology experiments.

Microbeam radiation therapy (MRT) is a pre-clinical, spatially-fractionated treatment modality noted for its ability to achieve a large differential response between normal and tumoral tissues. In the present study, TOPAS Monte Carlo (MC) simulations were used to optimize the design of a compact, affordable multi-slit collimator (MSC) suitable for use with the small animal radiation research platform (SARRP). MRT dose distributions in a (1  ×  1  ×  3)cm water phantom were simulated for a tungsten MSC using different focal spot sizes (0.4, 3 mm), beam energies (40, 80, 220 kVp), slit widths (100, 125, 150, 175, 200 µm), collimator thicknesses (1.5, 2.5, 3 cm) and collimator-to-surface distances (CSD of 1 and 3 cm). Key MRT figures of merit, namely the peak-to-valley dose ratio (PVDR), full-width at half-maximum and peak dose rate were determined. Use of the small focal spot maximized the PVDR (~40 at surface) and reduced the system's sensitivity to changes in CSD, but decreased the collimated beam output to 55.2 cGy min. The large focal spot was ill-suited for large CSD irradiations, but increased the beam output by a factor of 2.8, to 153.0 cGy min, and decreased the sensitivity to changes in slit width. A modular MSC, using divergent plastic spacer materials in place of excavated slits, was also investigated. Polypropylene and polyethylene terephthalate material spacers were considered and while neither reduced the PVDR compared to air slits, the dose rate was reduced by 37% and 47%, respectively. Lastly, a steel parallel-slit MSC was used in a preliminary test of MRT delivery using the SARRP. Discrepancies between the results of film dosimetry and the corresponding MC simulations highlight the need to fabricate a more well-defined collimator for use in future validation and radiobiological work. The simulated results of this study are being used to inform the design of such a collimator, which will additionally boast a high degree of modularity at reasonable cost.