Background and Aims

The goal of this work was to demonstrate the feasibility of in vitro studies with multicellular spheroids using a conventional 80kVp x-ray tube capable of both ultrahigh (UHDR, >40Gy/s) and conventional (0.1Gy/s) dose rate delivery.

Methods

In order to achieve UHDR delivery with <1s irradiation times, a motorized rotating shutter system was designed and installed on a conventional MXR22/160 x-ray tube. 80kVp X-ray dose was measured using a plastic scintillation detector (PSD) system, Hyperscint. Signal from lead-loaded (0.5-5%Pb) and polystyrene (BCF-10) 3-mm long PSDs with a 3-mm cap placed at 2.2 cm from the focal spot was measured and validated with Monte Carlo (MC) simulations. To achieve conventional irradiations, measurements at extended source-to-detector distances (SDD) of 10-20cm were conducted. Dose rate to a 500-µm diameter spheroid was calculated (with 120kVp x-rays).

Results

Measurements with lead-loaded and BCF-10 PSDs agreed with simulations and showed maximum dose rates of 61.1 and 9.0Gy/s, respectively. Dose was linear with shutter speeds ranging from 1-200ms (R²>0.999 for all probes). The inverse square law dose rate fall-off was confirmed by PSD measurements and conventional dose rates were achieved by reducing the tube current and extending SDD to 6.7cm for the BCF-10 PSD (which mimics soft tissue). The maximum dose rate to the cell spheroid placed in the shutter was determined to be 243.1Gy/s.

Conclusions

Ultrahigh and conventional dose rates were attainable using a conventional x-ray tube equipped with a shutter system by varying tube current and SDD. This cost-effective x-ray source provides convenient access to UHDR in vitro studies.

Background and Aims

Pre-clinical laboratory research to elucidate biological effects of FLASH irradiation is imperative to support its clinical translation. At present, FLASH research employs complex accelerator technologies of limited accessibilities. Here, we introduce a novel self-shielded FLASH x-ray cabinet system to support preclinical research.

Methods

The proposed system employs two commercially available high-capacity 150 kVp x-ray sources with rotating anode technology in a parallel-opposed arrangement. X-ray sources are supported by independent bidirectional computer-controlled vertical and rotational motions for conformal and angled irradiation (Figure 1). A radiochromic film validated Monte-Carlo simulation platform (Geant4) was used to characterize the dosimetry of the system.

Results

This system delivers doses up to 67 Gy to a 20-mm thick water equivalent medium at both FLASH and conventional dose-rates of 40-240 Gy/s and <0.1 Gy/s, respectively. Depth dose-rate uniformity (±5%) is achieved over 8-12 mm in the central region of the medium. The mirrored beams minimize heel effect of the source and achieve cross-beam uniformity within ±3%. Field dimension is adjustable, ranging from 0.1–5.5 cm and 0.1–20 cm for FLASH and conventional irradiation, respectively, suitable for small animal and cell culture irradiations. Angling the two beams minimizes entrance and exit beams overlap, and reduces surface doses up to 39%.

Conclusions

This system greatly enhances FLASH radiation research in regular laboratory setting. In-vivo studies are being conducted to demonstrate kVp x-rays induced FLASH effects on superficial murine models. Results will be presented.

Background and Aims

The research at the ID17-Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF) is focused on the development of innovative biomedical applications.

Microbeam and FLASH Radiation Therapy (RT) are currently performed in preclinical experiments and the start of veterinary trials is imminent. How is this facility working?

Methods

X-ray radiation is generated from an electron beam traversing a periodic magnetic array, a so-called wiggler. The raw spectrum is altered by different attenuators, and ionization chambers are used to monitor the beam intensity. If required, positioning of a multislit collimator along the beam allows the spatial fractionation of the radiation.

The use of a motorized stage combined with radiography image acquisition allows the target placement with sub-millimetric precision. Also, a system for patient positioning is under realization to fulfil the requirements for human trials.

Results

Polychromatic beam spectra with mean energies in the 80-150 keV range are produced with dose-rates up to 14000 Gy/s. Therefore, irradiations of hundreds of Gy can be delivered in a few milliseconds. The horizontal beam divergence of 1 mrad generates quasi-parallel beams, and the definition of beamlets only few tens of microns wide is possible.

Cellular biology, tumour response studies, multi-scale dosimetry and complex irradiation geometries experiments are all successfully conducted by international teams.

Conclusions

The ESRF ID17-Biomedical Beamline represents a unique facility in the RT panorama.

It offers the possibility to investigate the mechanisms undergoing Microbeam and FLASH RT and to develop the necessary technology to make future human trials a concrete reality.

Background and Aims

Microbeam Radiation Therapy (MRT) is an innovative radiotherapeutic approach by which synchrotron-generated X-rays are spatially fractionated resulting in periodic, alternating dose distribution in the tissue. In parallel to the excellent tumour control, normal tissues show remarkably high resistance. However, the biggest challenge in translating MRT to the clinic are the high peak doses (300-600Gy) delivered at ultra-fast dose-rates, achievable currently only by synchrotron facilities. Therefore, to advance the clinical translation of MRT, new treatment strategies have been explored.

Methods

Microbeam Radiation Therapy, single 400Gy, fractionated (3x133Gy), combination with Au-NP and cisplatin

Results

We have demonstrated that temporally fractionated MRT (3x 133Gy) ablated 50% of murine melanomas, preventing organ metastases and local recurrence for 18 months post-treatment. In the remaining animals, the median survival increased by 2.5-fold compared to single MRT-irradiated mice and by 4.1-fold relative to untreated mice. In a double treatment, 150Gy MRT combined with Au-NP increased the median survival by more than 2-fold compared to a single MRT irradiation, and 6.6-fold compared to untreated mice. Furthermore, 150Gy MRT, when combined with cisplatin, reduced the glioblastoma tumour volume by 6-fold compared to cisplatin alone and 60-fold relative to untreated mice.
Temporally fractionated MRT and low dose MRT combined with Au-NP or cisplatin increased the efficacy of MRT in the case of radioresistant melanoma and glioblastoma, reaching the best reported treatment ratio for complete tumour remission.

Conclusions

Our results demonstrate that MRT administration could be adapted for clinical use by employing multiple fractions with lower peak doses using intersecting arrays or with combined treatment strategies.

Background and Aims

Microbeam radiotherapy (MRT) and FLASH can widen the therapeutic window in radiotherapy. For x-ray MRT and FLASH, most research was performed at synchrotrons that are, however, unsuitable for clinical application. A promising compact source for hospitals is the line-focus x-ray tube (LFxT). We present simulations for a preclinical LFxT prototype that we are currently constructing.

Methods

To examine the dose distribution, we performed Monte Carlo simulations in TOPAS of an electron beam (300 keV, 90 kW) hitting a target made of tungsten. The phase space from electron accelerator simulations exhibited a full width at half maximum of 0.05 x 20 mm². The produced photons traveled through a model of a custom-made, divergent multi-slit collimator (tungsten) into a water phantom. With finite element methods in COMSOL, we simulated the temperature increase at the focal spot.

Results

The microbeam dose distribution showed a divergent peak-valley profile with a peak-to-valley dose ratio of 23 and a peak dose rate of 10 Gy/s in 15 mm water depth, 200 mm from the target. The temperature increase at the focal spot was 480 K when the target surface moved at 200 m/s. Due to the narrow and fast beam, the main heat dissipation mechanism was heat capacity, contrary to heat conduction for conventional x-ray tubes.

Conclusions

Our simulations showed that the LFxT prototype produces a microbeam dose distribution suitable for preclinical MRT research. The LFxT utilizes the heat capacity limit in which the source can be scaled to a more powerful clinical source for concurrent MRT and FLASH.

Background and Aims

Access to robust high-energy sources of ultrahigh dose-rate x-rays for FLASH research remains severely limited. To help fill this unmet need, a FLASH-capable small-animal irradiation station is being developed around a 1kW, 10MeV electron-to-photon converter on the ARIEL e-linac at TRIUMF (Figure1).

Methods

Development of the ARIEL FLASH electron-to-photon converter has been predicated on achieving specific performance thresholds. Monte Carlo (MC) simulations (FLUKA,EGSnrc) of a water-cooled tantalum-aluminum target were performed to maximize dose-rates, evaluate activation and meet shielding requirements. Finite-element-analysis (ANSYS) simulations facilitated thermo-mechanical optimization of the target to withstand both continuous and pulsed beam irradiations for several months (Figure 1c). Offline tests are being performed to validate thermal and water erosion behavior using an arc-welding torch which provides a kilowatt heat source to replicate the thermal conditions found under e-beam irradiation.

Results

The simulated dose-rate to lung in a realistic mouse phantom is 85±3Gy/s for 10MV photons at 1kW (Figure 2). These results will be validated through film dosimetry in realistic 3D-printed mouse phantoms. Results of thermal benchmarking and stress-testing beyond threshold specifications will confirm the design robustness of the target, which has been optimized to withstand frequent thermal cycling and the resulting fatigue.

Conclusions

An ultrahigh dose-rate 10 MV x-ray source has been successfully designed for the FLASH irradiation station at the ARIEL e-linac. The experimental end-station will facilitate reproducible delivery of high-dose, single fractions to small-animal models once testing and beam characterization are completed ahead of planned treatments in Fall 2021.