Feasibility of proton FLASH irradiation using a synchrocyclotron for preclinical studies

Darafsheh, Arash; Hao, Yaowu; Zwart, T.; Wagner, Miles; Catanzano, Daniel; Williamson, Jeffrey F.; Knutson, Nels C.; Sun, Baozhou; Mutic, Sasa; Zhao, Tianyu

doi:10.1002/mp.14253

Cited by 79 publications

(107 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent preclinical studies have suggested that ultra‐high‐dose‐rate (UHDR) “FLASH” irradiation may be superior to conventional radiation delivery in terms of sparing normal tissues 1–7 . In one of those studies, the incidence of lung fibrosis in mice exposed to 4.5 MeV electron beams at UHDR (40 Gy/s or higher) was lower at total doses higher than those used for irradiation at conventional dose rates (CDR).…”

Section: Introductionmentioning

confidence: 99%

“…Recent preclinical studies have suggested that ultra-highdose-rate (UHDR) "FLASH" irradiation may be superior to conventional radiation delivery in terms of sparing normal tissues. [1][2][3][4][5][6][7] In one of those studies, the incidence of lung fibrosis in mice exposed to 4.5 MeV electron beams at UHDR (40 Gy/s or higher) was lower at total doses higher than those used for irradiation at conventional dose rates (CDR). For example, irradiating mouse lungs to 17 Gy via CDR elicited fibrogenesis at 24 weeks after exposure, in contrast, at FLASH dose rates, only rare fibrotic patches were observed after exposure to 30 Gy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oxygen depletion in FLASH ultra‐high‐dose‐rate radiotherapy: A molecular dynamics simulation

2020

View full text Add to dashboard Cite

Purpose We present a first‐principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra‐high‐dose‐rate (UHDR) FLASH radiotherapy. Methods We simulated damage to a segment of DNA (also representing other biomolecules such as RNA and proteins) in a simulation box filled with H2O and O2 molecules. Attoseconds physical interactions (ionizations, electronic, and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4‐DNA. Immediately after ionization, ab initio Car–Parrinello molecular dynamics (CPMD) simulation was used to identify which H2O and O2 molecules surrounding the DNA molecule were converted into reactive oxygen species (ROS). Subsequently, the femto‐ to nanosecond reactions of ROS were simulated by using MD with reactive force field (ReaxFF), to illustrate ROS merging into new types of non‐reactive oxygen species (NROS) due to strong coupling among ROS. A coarse‐grained model was constructed to describe the relevant collective phenomenon at the macroscopic level on ROS aggregation and formation of NROS agglomerates consistent with the underlying microscopic pathways obtained from MD simulations. Results Time‐dependent molecular simulations revealed the formation of metastable and transient spaghetti‐like complexes among ROS generated at UHDR. At the higher ROS densities produced under UHDR, stranded chains (i.e., NROS) are produced, mediated through attractive electric polarity forces, hydrogen bonds, and magnetic dipole–dipole interactions among hydroxyl (.OH) radicals. NROS tend to be less mobile than cellular biomolecules as opposed to the isolated and sparsely dense ROS generated at conventional dose rates (CDR). We attribute this effect to the suppression of biomolecular damage induced per particle track. At a given oxygen level, as the dose rate increases, the size and number of NROS chains increase, and correspondingly the population of toxic ROS components decreases. Similarly, at a given high dose rate, as the oxygen level increases, so do the size and number of NROS chains until an optimum level of oxygen is reached. Beyond that level, the amount of oxygen present may be sufficient to saturate the production of NROS chains, thereby reversing the sparing effects of UHDRs. Conclusions We showed that oxygen depletion, hypothesized to lead to lower normal‐tissue toxicity at FLASH dose rates, takes place within femto‐ to nanoseconds after irradiation. The mechanism is governed by the slow dynamics of chains of ROS complexes (NROS). Under physoxic (≈ 4–5% oxygen) conditions (i.e., in normal tissues), NROS are more abundant than in hypoxic conditions (e.g., <0.3% in parts of tumors), suggesting that biomolecular damage would be reduced in an environment with physoxic oxygen levels. Hence irradiation at UHDRs would be more effective for sparing physoxic normal tissues but not tumors containing regions of hypoxia. At much higher levels of oxygen (e.g., >10–1...

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oxygen depletion in FLASH ultra‐high‐dose‐rate radiotherapy: A molecular dynamics simulation

2020

View full text Add to dashboard Cite

show abstract

“…Therefore, the beam structure might be very important in realizing a good correction strategy for recombination effects in a proton facility. The challenge in obtaining a high-precision dose monitoring with ionization chambers was highlighted by Darafsheh et al [21]. In this study, the authors could measure more than 200 Gy/s dose-rate beams produced by a clinical synchro-cyclotron with a commercially available plane-parallel ionization chamber; however, the measured value was about 5% off the expectation, an uncertainty which might be due to several reasons.…”

Section: Control and Monitoringmentioning

confidence: 89%

“…This means that the beam consists of short pulses (order of 1 µs) repeated every 1-3 ms. As such, the use of synchrocyclotrons for FLASH irradiation seems to be challenging and might require some adaptations. For instance, a clinical Mevion HYPERSCAN ® (Mevion Medical Systems, Littleton, MA, USA ) system was modified to deliver ultra-high dose rates for FLASH experiments [21]. One of the key changes was an increased pulse width to 20 µs.…”

Section: Beam Structurementioning

confidence: 99%

FLASH Irradiation with Proton Beams: Beam Characteristics and Their Implications for Beam Diagnostics

Nesteruk

Psoroulas

2021

Applied Sciences

View full text Add to dashboard Cite

FLASH irradiations use dose-rates orders of magnitude higher than commonly used in patient treatments. Such irradiations have shown interesting normal tissue sparing in cell and animal experiments, and, as such, their potential application to clinical practice is being investigated. Clinical accelerators used in proton therapy facilities can potentially provide FLASH beams; therefore, the topic is of high interest in this field. However, a clear FLASH effect has so far been observed in presence of high dose rates (>40 Gy/s), high delivered dose (tens of Gy), and very short irradiation times (<300 ms). Fulfilling these requirements poses a serious challenge to the beam diagnostics system of clinical facilities. We will review the status and proposed solutions, from the point of view of the beam definitions for FLASH and their implications for beam diagnostics. We will devote particular attention to the topics of beam monitoring and control, as well as absolute dose measurements, since finding viable solutions in these two aspects will be of utmost importance to guarantee that the technique can be adopted quickly and safely in clinical practice.

show abstract

“…5 The first application to a human was conducted on a skin tumor using a 5.6 MV electron linac 6 and experiments with protons on cells and mice, among other small animals, have been conducted or are under preparation. [7][8][9][10][11] After the HZB cyclotron was proven able to deliver FLASH proton radiation, 12 a dedicated nozzle was designed to enable Charit e to repeat its mice irradiation program under FLASH conditions. Besides the dose rate and the irradiation time, which were now aimed at 75 Gy(RBE)/s (RBE = 1.1) and 200 ms accordingly, the other specifications remained unchanged: 15 Gy(RBE) total dose with an error smaller than AE5%, 5 mm water-equivalent range with a spread-out Bragg peak (SOBP) and a distal fall-off (90%-10%) <1 mm, planning target volume (PTV) of 6 mm diameter with <10% uniformity, <5% symmetry, and <3 mm penumbra (90%-10%).…”

Section: Introductionmentioning

confidence: 99%

FLASH proton irradiation setup with a modulator wheel for a single mouse eye

et al. 2021

View full text Add to dashboard Cite

Recent studies indicate that FLASH irradiation, which involves ultra-high dose rates in a short time window (usually >40 Gy/s in <500 ms), might be equally efficient against tumors but less harmful to healthy tissues, compared to conventional irradiation with the same total dose. Aiming to verify the latter claim for ocular proton radiotherapy, in vivo experiments with mice are being carried out by Charit e-Universit€ atsmedizin Berlin. This work presents the implemented setup for delivering FLASH proton radiation to a single eye of mice at the Helmholtz-Zentrum Berlin f€ ur Materialien und Energie (HZB). Materials and methods: The HZB cyclotron is tuned to provide a high-intensity 68 MeV focused proton beam. Outside the vacuum beamline, the protons hit a single scatterer, which also serves as range shifter, and a rotating modulator wheel, which produces a flat depth-dose distribution. Two transmission ionization chambers in between, read out by fast electronics, are used as dose monitors for triggering an in-vacuum beam shutter, which blocks the beam once the desired dose has been delivered. A collimating aperture shapes the radiation field at the isocenter, which is measured by a radioluminescent screen and a CCD camera. At the same position, a parallel-plate ionization chamber of type Advanced Markus â is used for absolute dosimetry and characterization of the spread-out Bragg peak inside a water phantom. A thin-foil mirror of adjustable tilt in the beam path assists the correct alignment of the target through side illumination. Radiochromic films of type EBT3 are used to supplement the dosimetry and assist the alignment. Results: A dose rate of 75 Gy/s has been measured, delivering within 200 ms 15 Gy (RBE) with a reproducibility better than AE1%. A depth-dose curve with a range of 5.2 mm in water, 0.9 mm distal fall-off (90%-10%), and AE2.5% ripple has been demonstrated, with a PTV of 6.3 mm diameter, 1.7 mm lateral penumbra (90%-10%), 8% uniformity, and 3% symmetry. Conclusions: The implemented setup is able to accommodate ocular irradiation of narcotized mice with protons, targeting selectively the left or the right eye, under conventional and FLASH conditions. Switching between these two modes can be done within half an hour, including the calibration of the dose monitors and the verification of the dose delivery. Further upgrades are planned after the completion of the ongoing experiment.

show abstract

Feasibility of proton FLASH irradiation using a synchrocyclotron for preclinical studies

Cited by 79 publications

References 33 publications

Oxygen depletion in FLASH ultra‐high‐dose‐rate radiotherapy: A molecular dynamics simulation

Oxygen depletion in FLASH ultra‐high‐dose‐rate radiotherapy: A molecular dynamics simulation

FLASH Irradiation with Proton Beams: Beam Characteristics and Their Implications for Beam Diagnostics

FLASH proton irradiation setup with a modulator wheel for a single mouse eye

Contact Info

Product

Resources

About