Abstract Body

A re-emergence of research implementing radiation delivery at ultra-high dose rates (UHDR) has triggered intense interest in the radiation sciences and has opened a new field of investigation in radiobiology. Much of the promise of UHDR irradiation involves the FLASH effect, an in vivo biological response observed to maintain anti-tumor efficacy without the normal tissue complications associated with standard dose rates. The FLASH effect has been validated primarily, using intermediate energy electron beams able to deliver high doses in a very short period of time (<200 ms), but has also been found with photon and proton beams. The clinical implications of this new area of research are highly significant, as FLASH radiotherapy (FLASH-RT) has the potential to enhance the therapeutic index, opening new possibilities for eradicating radio-resistant tumors without toxicity. As pioneers in this field, my group has developed a multidisciplinary research team focused on investigating the mechanisms and clinical translation of the FLASH effect. I will tell the story of the recent discovery of the FLASH effect and will review the recent results obtained with electron beams at ultra-high dose rate.

Abstract Body

FLASH radiotherapy (FLASH-RT) has come at the center of the attention in the radiobiology and radiation oncology fields. Taking into consideration the current literature, a possible definition for FLASH-RT could be: “A radiotherapy technique delivered at ultra-high dose rate with specific beam parameters able to treat tumors without inducing drastic toxicities on the surrounding normal tissues.” Nevertheless, there has been no consensus on a definition for FLASH-RT yet, and intensive work is currently ongoing to understand and decipher the mechanisms underlying the so-called “FLASH effect.”

The antitumor effect associated to an absence of normal tissue injury has caught the field by surprise, questioning the most basic concepts or radiobiology. But even if more and more studies describe a normal tissue protection following exposures to ultra-high dose rate irradiation, few biological mechanisms differentiating conventional dose rate RT to FLASH-RT responses have been described so far. This lecture aims at reviewing the most recent FLASH-RT literature to analyze the normal tissue and tumor response after FLASH RT at the molecular, cellular and tissular levels. A comprehensive approach of the different models and endpoints used in these studies will be provided to build up hypotheses on biological mechanisms explaining the FLASH effect.

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

As the development of suitable detectors in ultra high Dose Per Pulse (DPP) beams is on-going, temporary protocols solving limitations with standard tools are required for the acceptance of new dedicated machines. We present a protocol for system commissioning using clinically available dosimeters, optimizing the use of the detectors. Extra attention was given to beam characterization when varying the DPP.

Methods

Measurements were performed on the ELF, a dedicated research linac for Flash radiotherapy with electrons (ElectronFlash, SIT, Italy) at 7 and 9 MeV using standard dosimetric tools: a PTW Advanced Markus (AM) plane-parallel ion chamber, Gafchromic EBT-XD films, and alanine pellets. The system is highly tunable for pulse length, pulse repetition frequency and number of pulses. Collaboration with the developer allowed further tuning. The DPP was varied using pulse length, distance from the linac and e-gun current.

Results

Performance tests assessing dose, dose stability, PDD, profiles, and output linearity to system settings were measured cross-referencing at least two detectors (comparable within 5%). Energy and dose outputs, monitored with films and AM, were stable within 5% in several months. The AM was used for daily QA for doses up to 0.5 Gy/pulse (model proposed in abstract #211). Changing the DPP using the above-mentioned parameters resulted in a linear output change and minimal variation (<1 MeV) of the spectrum.

Conclusions

We characterized the ELF using standard dosimetric tools. We propose the combination of alanine and Gafchromic films as absolute dosimetric standard. The AM can be employed as real-time tool for daily QA.

Background and Aims

The radiobiological study of the FLASH effect requires accurate and reliable dosimetry. As scintillators are promising candidates, this work presents a first characterization of their response at UHDR, suggesting solutions to account for possible saturating effects.

Methods

Five scintillating fibers, one clinical and two experimental Y₂O₃:Eu-based scintillators (DoseVue N.V., Belgium) and two experimental Al₂O₃:C-based scintillators (SCK CEN, Belgium), were irradiated using the ElectronFlash system (SIT, Italy). Linearity with dose was validated by varying the number of pulses for both experimental Y₂O₃:Eu-based scintillators. Dose per pulse (DPP) linearity was investigated in all scintillators by varying pulse duration and the distance from the linac exit window (SSD). Pulse scheme stability was investigated by changing of the pulse repetition frequency (PRF).

Results

Good linearity with dose (R²>0.99) was observed in both experimental Y₂O₃:Eu-based scintillators. Linearity with increasing pulse duration (R²>0.95) and an inverse squared relation between DPP and SSD (R²>0.95) were observed in 4 out of 5 scintillators. However, a concave curvature in response, suggesting saturation, was observed for all scintillators. This effect was more pronounced for the smaller applicator diameter. Our results showed reduced saturation effects when increasing integration time as well as when reducing signal intensity. All scintillators showed a decreasing response with increasing PRF.

Conclusions

The promising characteristics of scintillators as on-line dosimeters for UHDR were validated and possible solutions to reduce saturation effects have been evaluated. Further research on the response by varying PRF is needed.

This work is part of the 18HLT04 UHDpulse project which received funding from the EMPIR programme.

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

FLASH sources lack dose rate independent dosimeters and dose feedback systems. We developed an ultra-high dose rate beam monitoring system for FLASH-RT, including dose-rate independent scintillating detector and fast electronics.

Methods

A commercially available plastic scintillator and a liquid fluorescein solution were coupled to a gated integrating amplifier and a field programmable gate array (FPGA) for dose monitoring and feedback control. The FPGA was programmed to integrate dose and measure pulse width for each radiation pulse. The detectors were characterized in terms of the radiation stability, mean dose-rate (Ḋ_m), and dose per pulse (D_p) linearity.

Results

The D_p and the pulse width showed a consistent ramp-up period of ~4-5 pulse. The plastic scintillator was shown to be linear with Ḋ_m (40-380 Gy/s) and D_p (0.3-1.3 Gy/Pulse) to within ± 3%. However, the plastic scintillator was subject to significant radiation damage for the first 2 kGy (24%/kGy). The fluorescein solution was also tested to be linear with Ḋ_m (± 3%) and exhibited minimal radiation damage for an initial cumulative dose of 400 Gy. In-vivo dosimetry with a 1 cm circular cut-out revealed that the for the linac ramp-up period of 4 pulses, the average D_p was 0.043 ± 0.002 Gy/pulse, whereas after the ramp-up it stabilized at 0.65 ± 0.01 Gy/Pulse.

Conclusions

The tools presented in this study can be used to determine the temporal beam parameter space pertinent to the FLASH effect. Additionally, the hardware can be used to provide real-time feedback to the linac in terms of direct measurement of dose.