Background and Aims

Methods

Results

Conclusions

Background and Aims

Dosimetry for FLASH radiotherapy, VHEE radiotherapy as well as for laser-driven beams cause significant metrological challenges due to the ultra-high dose rates and pulsed structure of these beams, in particular for real time measurements with active dosimeters. It is not possible to simply apply existing Codes of Practice available for dosimetry in conventional external radiotherapy here. However, reliable standardized dosimetry is necessary for accurate comparisons in radiobiological experiments, to compare the efficacy of these new radiotherapy techniques and to enable safe clinical application. UHDpulse aims to develop the metrological tools needed for reliable real-time absorbed dose measurements of electron and proton beams with ultra-high dose rate, ultra-high dose per pulse or ultra-short pulse duration.

Methods

Within UHDpulse, primary and secondary absorbed dose standards and reference dosimetry methods are developed, the responses of available state-of-the-art detector systems are characterised, novel and custom-built active dosimetric systems and beam monitoring systems are designed, and methods for relative dosimetry and for the characterization of stray radiation are investigated.

Results

Prototypes of different active dosimetry systems show promising results for real-time dosimetry for particle beams with ultra-high pulse dose rates. The results of the UHDpulse project will be the input data for future Codes of Practice.

Conclusions

A brief overview of the progress in the UHDpulse project and the involved institutions will be given.

Acknowledgement: This project 18HLT04 UHDpulse has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme.

Background and Aims

In our work we thought to compare the effects of conventional (CONV) vs ultra-high dose rate (UHDR) by quantifying DNA strand breaks (SB) after irradiation of plasmid-DNA (pBR322) under various oxygen concentrations.

Methods

Supercoiled pBR322 was irradiated dry or in water using a 6 MeV FLASH-validated electrons beam, with increasing doses (1-100 Gy) and dose per pulse (0.01 Gy/s (CONV), 5.0*10² to 5.6*10⁶ Gy/s (UHDR)) and at atmospheric (21%), physoxic (4%) and hypoxic (0.5%) oxygen level. The increase of relaxed (R) and linear (L) plasmid forms after irradiation was quantified by agarose gel electrophoresis and used to compute single and double SB yields.

Results

Dry, atmospheric conditions cause similar yields of SB in CONV and UHDR. Aqueous conditions shows higher SB yields as expected. Physoxia induces radioprotection compare to atmospheric condition: 50% of R at 10 Gy (4% O₂) vs 2 Gy (21% O₂), but no difference relative to dose rate. Hypoxia revealed higher SB yields than physoxia in CONV (50% of R at 6 Gy) but 2x less SB in UHDR for doses >30 Gy (see figure for L).

Conclusions

First results in dry condition suggest that direct effects are not involved in FLASH. In aqueous condition, 4% oxygen mimicking healthy tissues shows no difference between UHDR and CONV, while 0.5% oxygen mimicking tumors shows less damages in UHDR. These results are opposite to the preclinical results showing the FLASH effect. Thus, plasmid irradiation might be useful to understand DNA damage at UHDR but seems barely relevant to investigate the FLASH effect at the biological level.

Background and Aims

Future RT devices using very-high energy electrons (VHEE) (50-250MeV) may produce suitable beams to treat deep-seated tumours conformally and at ultra-high dose rates (UHDR) capable of triggering the FLASH effect. The FLASH effect has been observed for large doses delivered with overall treatment times less than 200ms. Such treatment durations do not allow the use of a movable gantry and multiple fixed beam lines (FBL) become mandatory. This treatment planning study evaluates VHEE dose distributions in patients using a varying number of FBL with different energies and source-axis-distances (SAD). The minimum requirements for delivering conformal VHEE RT comparable to conventional VMAT plans and trade-offs between plan quality and number of beam lines are assessed.

Methods

We performed VHEE and VMAT treatment planning for multiple indications (glioblastoma, mediastinum, lung, prostate) using RayStation (research version) and compared the dosimetric quality of VHEE plans to VMAT while assessing the impact of arrangement and number of FBL, beam energies, and SAD.

Results

Most substantial coverage and conformity improvement is achieved when increasing the beam energy from 50 to 100MeV. Further improvement is obtained specifically for deep-seated targets (>10-15cm) when increasing energies further to 200MeV. While VHEE plans using 16 coplanar beams outperform VMAT plans, we found that VHEE plans using only 3-5 beams have DVH metrics that are comparable to VMAT plans. Beams with SAD>1m are preferable for treatments using few beams.

Conclusions

UHDR VHEE devices with only a few FBL may provide competitive dosimetric conformity that may be additionally enhanced by the FLASH effect.

Background and Aims

FLASH radiation modalities deliver ultra-high dose rates with high dose per pulse and a low number of pulses. In this work, we investigate the impact of electron beams with different doses per pulse (from 0.01 to 40 Gy) on water radiolysis using the Geant4-DNA code.

Methods

The single-track simulation mode is extended to multiple electron tracks delivered in the same pulse to obtain the desired dose to the target volume. This extension allows us to simulate the chemical stage up to hours after radiation exposure.

Results

The G values of hydroxyl radicals (^•OH), hydrated electrons (e⁻_aq) and hydrogen radicals (H^•) decrease earlier in time as the dose per pulse increases. In oxygenated water, a shorter lifetime of the reactive oxygen species (ROS) – superoxide radical (O₂^•-) and hydroperoxyl radical (HO₂^•) – is obtained for higher doses per pulse, which reduces the level of hydrogen peroxide (H₂O₂). These observations are compared with the available experimental data.

Conclusions

We found that the significant reduction in ROS yield results from the high concentration of species generated with high doses per pulse.

Background and Aims

In this study, we investigated the effects of tumor oxygen tension on the anti-tumor efficacy of ultra-high-dose-rate (FLASH) radiotherapy (RT).

Methods

U87 glioblastoma cells were xenografted in Swiss Nude mice and irradiated using a single 20-Gy dose administered at UHDR (2 pulses, 100 Hz, 1.8 µs pulse width, 0.01 s delivery) or CONV (~ 0.1 Gy/s) dose rates with the Oriatron/eRT6 (PMB, CHUV) under normoxia, hypoxia (vascular clamp), and hyperoxia (carbogen breathing). In situ oxygen tension was measured during and following irradiation using an OxyLite probe. Tumor growth was monitored using caliper measurements and tumor were sampled for RNA and protein profiling (GIF, UNIL). Metabolic analysis and ROS measurements were performed in vitro using Seahorse XF96 Analyzer and CellROX.

Results

Surprisingly, the anti-tumor efficacy of FLASH-RT was not affected by hypoxia in this U87 xenograft model, whereas hypoxia induced radioresistance with CONV-RT. Genomic profiling revealed a decrease in hypoxia signaling in the FLASH-treated compared to the CONV-treated and control tumors 24h post-RT. Oxidative metabolism was also altered in response to FLASH-RT. Real-time tumor oxygen readout, ROS levels, and metabolic testing at different oxygen tensions and timepoints post-RT are in progress.

Conclusions

FLASH-RT anti-tumor efficacy does not seem to be affected by hypoxia supporting a differential role for oxygen signaling between FLASH and CONV-RT and opening new venues for clinical application of FLASH-RT in a subset of highly radiation resistant tumors.

Acknowledgement: The study is funded by SNF Synergia grant (FNS CRS II5_186369)