Background and Aims

Convincing evidence has been provided that lowering the mean dose rate below 30 Gy/s (Montay-Gruel et al. Radiother Oncol 124: 365-369, 2017) or increasing the oxygen tension through carbogen breathing (Montay-Gruel et al. PNAS 116: 10943-10951, 2019) can reduce (if not eliminate) the sparing effect of FLASH in the mouse brain. Three theoretical models have since been proposed to account for the dependence of FLASH on oxygen, namely, (i) Radiation-induced transient oxygen depletion (TOD), (ii) Cell-specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species, (iii) Self-annihilation of radicals by bimolecular recombination.

Methods

These theoretical models were confronted to experimental evidence relating to physical chemistry and the response of biological systems to ultrahigh dose rate irradiation in light of the chemical reactions underlying the radiosensitizing effect of O₂ from immediate, early processes to late complications.

Results

The radiosensitizing effect of oxygen has long been known to stem from peroxyl radicals (ROO^•). Peroxyl radicals areformed by the addition of O₂ in its fundamental, triplet state to short-lived carbon-centered radicals (R^•) generated upon H^• atom abstraction from aliphatic, unsaturated or conjugated substrates (RH).

Conclusions

Any attempt at deciphering the physical-chemical processes that underpin the FLASH effect must take into consideration the fate of these radicals, and in particular the probability of radical recombination. The radiation dose rate emerges as the most important factor. We propose testable procedures to investigate the mechanisms that underly the FLASH effect in normal cells, and differential tumor vs. normal cells responses.

Background and Aims

With medical linear accelerators, the dose is delivered in approximately a thousand of low-dose radiation pulses and is regulated by monitoring ionization chambers, which turn off the beam once the preset number of Monitor Units (MU) is reached. In FLASH electron beams, on the contrary, the dose-per-pulse is much higher (> 1 Gy/pulse), which, a) prevent the use of conventional monitoring systems, and b) implies that the complete treatment is delivered with a very limited number of pulses, sometimes only one. To guarantee that the planned dose is delivered as intended, new methodologies for monitoring must be elaborated for FLASH beam delivery.

Methods

In preclinical studies with ElectronFLASH4000 (SIT), we have defined FLASH-MU as a fraction of the pulse’s temporal profile integral, which is recorded with a non-destructive monitoring toroid. For the control experiments performed at conventional dose-rate, MU measured by classical monitor chambers have been cross-referenced with FLASH-MU, through calibration by film dosimetry.

Results

FLASH electron beams can be effectively monitored by toroidal current transformers, provided they have adequate performances. Prescribed doses have been translated in MU with different pulse length, pulse amplitude and/or number of pulses. Heterogeneous pulse sequences including decreasing doses-per-pulse allowed a smaller cut-off step.

Conclusions

This opens the discussion on techniques for FLASH monitoring and on beam cut-off strategies for radiotherapy treatments delivered with very few ultra-high-dose pulses. At least some of them can already be tested for dose accuracy and biological effectiveness.

Acknowledgement: This work is part of 18HLT04-UHDpulse project, which received funding from the EMPIR program.

Background and Aims

Convincing evidence has been provided that lowering the mean dose rate below 30 Gy/s (Montay-Gruel et al. Radiother Oncol 124: 365-369, 2017) or increasing the oxygen tension through carbogen breathing (Montay-Gruel et al. PNAS 116: 10943-10951, 2019) can reduce (if not eliminate) the sparing effect of FLASH in the mouse brain. Three theoretical models have since been proposed to account for the dependence of FLASH on oxygen, namely, (i) Radiation-induced transient oxygen depletion (TOD), (ii) Cell-specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species, (iii) Self-annihilation of radicals by bimolecular recombination.

Methods

These theoretical models were confronted to experimental evidence relating to physical chemistry and the response of biological systems to ultrahigh dose rate irradiation in light of the chemical reactions underlying the radiosensitizing effect of O₂ from immediate, early processes to late complications.

Results

The radiosensitizing effect of oxygen has long been known to stem from peroxyl radicals (ROO^•). Peroxyl radicals areformed by the addition of O₂ in its fundamental, triplet state to short-lived carbon-centered radicals (R^•) generated upon H^• atom abstraction from aliphatic, unsaturated or conjugated substrates (RH).

Conclusions

Any attempt at deciphering the physical-chemical processes that underpin the FLASH effect must take into consideration the fate of these radicals, and in particular the probability of radical recombination. The radiation dose rate emerges as the most important factor. We propose testable procedures to investigate the mechanisms that underly the FLASH effect in normal cells, and differential tumor vs. normal cells responses.

Background and Aims

In order to translate the FLASH effect in clinical use and to treat deep tumors, Very High Electron Energy irradiations could represent a valid technique. Here, we address the main issues in the design of a VHEE FLASH machine. We present preliminary results for a compact C-band system aiming to reach a high accelerating gradient and high current necessary to deliver a dose up to 12 Gy/pulse, with a beam pulse duration of 3

Methods

The proposed system is composed by low energy high current injector linac followed by a high acceleration gradient structure able to reach 50-100 MeV energy range. To obtain the maximum energy, an energy pulse compressor options is considered. CST code was used to define the specifications RF parameters of the linac. To optimize the accelerated current and therefore the delivered dose, beam dynamics simulations was performed using Parmela code.

Results

The VHEE parameters Linac suitable to satisfy FLASH criteria were simulated. Preliminary results allow to obtain a maximum energy of 100 MeV, with a peak current of 200 mA, which corresponds to a charge of 200 nC per μs, or equivalently to about 4 Gy in a single pulse of 1µs and >10⁶ Gy/s over a ∅10 cm irradiation surface.

Conclusions

A promising preliminary design of VHEE linac for FLASH RT has been performed. Supplementary studies are ongoing to complete the characterization of the machine and to manufacture and test the RF prototypes.

Background and Aims

Currently, many research groups are more interested in the FLASH radiotherapy characterized by irradiation with ultra-high dose rate. A first usual step is to validate the beam line for FLASH studies by reproducing published FLASH effect in animals. However, it classically requires time consuming animal studies with dedicated skills, authorizations and infrastructures. Thus, to provide alternative methods and facilitate the implementation and validation of new FLASH beams, we aimed at developing in vitro and ex vivo models that will allow rapid and pertinent evaluation of the FLASH effect.

Methods

For our studies, we are using the ElectronFLASH LINAC manufactured by SIT company. To achieve this goal, we first used an in vitro model of human lung basal stem cells obtained from patients. Cultured in specific air-liquid conditions, this model allows the monitoring of stem cells survival and their capacity to differentiate after irradiation. In parallel, we adapted organotypic lung slices model, recapitulating lung complexity, architecture and microenvironment interactions, for radiation toxicity studies.

Results

Our results indicate that organotypic lung slices enables a rapid evaluation of the FLASH effect.

Conclusions

These models developed in the lab allow to rapidly determine the impact of the various beam parameters on FLASH effect with a robust and reproducible assay. With the inclusion of tumoral cells within the organotypic lung slices, we hypothesize that this ex vivo model can assess concomitantly the FLASH sparing effect on healthy tissue as well as the antitumoral efficacy. Moreover, the model can apply for human patient samples as well as rodent tissues.