Background and Aims

In a recent experiment at the HZDR research electron accelerator ELBE the influence of dose rate and partial oxygen pressure on the Flash effect was studied in a zebrafish embryo model. High mean electron dose rates of 10⁵ Gy/s (max regime) and partial oxygen pressure below 5 mmHg were found to protect zebrafish embryo from radiation damage compared to continuous reference irradiation (0.11 Gy/s) and higher oxygen pressure (Pawelke et al. Radiother Oncol 2021). However, the influence of beam pulse structure remains unanswered in this experiment.

Methods

In addition to the above mentioned two pulse regimes, the ELBE accelerator was used to mimic the pulse structure of a clinical electron linac delivering a dose of 28 Gy by 5 pulses at a frequency of 250 Hz. For comparison, a fourth regime of similar mean dose rate, but continuous beam (280 Gy/s) mimicking Flash irradiation at a proton isochronous cyclotron (Beyreuther et al. Radiother Oncol 2019) was applied.

Results

First results indicate a clear difference between the "max regime" and the other three electron pulse regimes. Further analysis is under way and the results for different endpoints will be presented.

Conclusions

The ELBE electron accelerator can be applied to study the influence of beam dose rate and pulse structure on the Flash effect by varying both parameters over several orders of magnitude. Hence, it is the ideal tool for systematic studies on optimal electron beam parameters for Flash.

This work was supported by EMPIR 18HLT04UHDpulse project.

Background and Aims

The recent rediscovery of the “Flash-effect” revived the interest in high dose-rate radiation effects throughout the radiobiology community, promising protection of normal tissue, while simultaneously not altering tumour control. Systematic preclinical studies resulted in a “recipe” of necessary beam parameters for inducing an electron Flash effect (https://doi.org/10.3389/fonc.2019.01563). For protons, the Flash effect was confirmed in a few animal experiments using the beam parameters available at clinical cyclotrons. Extending the clinical parameter range, the “Dresden platform for high-dose rate radiobiology” enables proton experiments with dose-rates of up to 10⁹ Gy/s.

Methods

The general applicability of the different proton beams for radiobiological studies was proven using biological models of increasing complexity, from cellular models to zebrafish embryo to mouse, at the Draco laser accelerator and, for comparison, at the University Proton Therapy Dresden (UPTD).

Results

A proof-of-principle irradiation campaign was performed using a mouse ear tumour model (https://doi.org/10.1371/journal.pone.0177428) to study the effects of the continuous beam delivery at UPTD and the pulsed beam delivery at Draco with peak dose-rates of 10⁸ Gy/s. Moreover, to investigate the interplay of oxygen consumption and proton dose-rate up to 300 Gy/s and 10⁹ Gy/s, respectively, were applied at UPTD and Draco to study the radiation response of zebrafish embryos.

Conclusions

The successful performance of comparison experiments at Draco laser accelerator and UPTD cyclotron paves the way for upcoming in vivo experiments at both machines. At the conference, we will provide an overview of our radiobiological experiments and the obtained results.

Background and Aims

In FLASH radiotherapy (RT), a protective effect of healthy tissue was observed, while tumor control remains comparable to conventional RT. One possible explanation is the oxygen depletion hypothesis, in which radiolysis of water/cytoplasma causes the production of radicals that then react with O2 dissolved in water. This would cause a reduction in O2, which results in a hypoxic target and thus a radio-protective effect. In a previous study (Jansen et al. 2021), we measured O2 depletion using an optical sensor in sealed water phantoms during irradiation at high dose rates (<300 Gy/s) for protons, carbon ions and photons.

Methods

In the study presented here, this experiment was conducted further to ultra-high dose rates (10^9 Gy/s) with protons at DRACO and electrons at ELBE, where also the impact of different pulse structures on O2 depletion in water was tested. In addition, various settings were tested in order to irradiate zebrafish embryos with FLASH while simultaneously measuring O2.

Results

We were able to confirm the results of our previous study even at ultra-high dose rates and with electrons. Furthermore, it was possible to measure O2 depletion during zebrafish embryo irradiation making a simultaneous study of biological response and O2 depletion possible.

Conclusions

Not enough O2 was depleted at clinical doses to explain a FLASH effect based on radiation-induced hypoxia. The amount of O2 depleted per dose depends on dose rate, and higher dose rates deplete slightly less O2. The experimental set up allows for future joint experiments of biological samples and oxygen monitoring.

Background and Aims

After the rediscovery of the normal tissue sparing FLASH effect of high dose rate radiation, research activities on this topic have been revived. But especially for protons, the portfolio of accelerators capable of performing studies at ultra-high dose rates is limited. Laser-plasma accelerators (LPA) can generate extremely intense proton bunches of many 10 MeV kinetic energy. In combination with dedicated dose delivery systems, LPA proton sources facilitate peak dose rates well above 10⁸ Gy/s in a pulse structure regime complementary to conventional accelerators.

Methods

The reliable generation of proton spectra beyond 60 MeV at DRACO-PW [Ziegler et al, SciRep2021], combined with a dedicated energy selective pulsed magnet beam transport system [Brack et al, SciRep2020], allows tailored sample-specific dose distributions. Adapted on-shot dosimetry enables the required spectral monitoring of every proton bunch. Two irradiation series on volumetric biological samples were performed at DRACO-PW, accompanied by reference irradiations at the University Proton Therapy Dresden.

Results

The first small animal pilot study at a laser-driven proton source was conducted successfully. The mouse-ear tumor model’s requirements [Beyreuther et al, PLoS One2018] were fulfilled and verified at high precision (+/- 5%) concerning predefined dose value and conformity. Complementary, a study investigating dose-rate effects such as FLASH was performed irradiating zebrafish embryos with above 10⁹ Gy/s.

Conclusions

We present a laser-based irradiation platform at the DRACO-PW facility that enables systematic radiobiological studies, laying the foundations for further studies at LPA sources exploring ultra-high dose-rate effects, such as FLASH, over previously unreachable parameter space.