Background and Aims

The University Medical Center Groningen has established in September 2020 its Particle Therapy Research Center (PARTREC) for research on physics, radiobiology and instrumentation for particle therapy. PARTREC uses the AGOR cyclotron to produce proton (upto 190 MeV) and heavy ion (helium/carbon) beams (upto 90 MeV/u). This facility builds upon expertise in accelerator physics, instrumentation and radiobiology of the former KVI-CART [1]. A major addition to the facility is a dedicated setup for the 3D-image-guided radiotherapy for particles or x-rays of small animals which should become operational in 2024. We are developing for this setup the capability to irradiate with dose rates in the range 40Gy/s-1000Gy/s at which the FLASH effect is expected to occur.

Methods

Using the flexibility of the AGOR cyclotron we can reproduce different beam delivery modes ranging from ~10-990μs pulses with repetition frequencies upto 1kHz to CW dose delivery. This allows us to generate TWIN FLASH BEAMS for FLASH proton beams available at clinical proton centers, facilitating fast translation of technical developments and pre-clinical radiobiology research to the clinic.

Results

In this work we report on several methods to monitor the beam intensity at very high dose rates and on the implementation and validation of a dose delivery control system capable of accurate dose delivery at these high dose rates. Part of the validation will be connecting the dosimetry at low dose rate with that at high dose rate.

Conclusions

The aim is to have the facility available for radiobiology experiments using shoot through irradiations by the end of 2022. A further upgrade is going to extend the irradiation capability with SOBP irradiations is planned for 2023.

Background and Aims

Advancements in the field of radiotherapy led to a development of ultra high dose-rate (uHDR) radiotherapy. It has been shown that acceleration of dose delivery to tumor sites from standard dose rates (0.02 Gy/s to 0.3 Gy/s) to so-called FLASH dose rates (≳35 Gy/s) can prevent healthy tissue toxicity. Few studies describe protective effects of uHDR in the brain tissue using electron beams. Due to the limiting depth-dose distribution of electrons, its clinical utilization is restricted to superficial tumors. Treatment of deep-seated tumors requires precise and accurate delivery of high dose to the target, which is achievable with heavier charged particles, such as protons. Therefore, we sought to investigate if pencil beam uHDR proton irradiation may also elicit similar FLASH sparing effects for the endpoint acute neurotoxicity.

Methods

Active scanning uHDR delivery was established for proton beams for investigation of dose rate effects between clinical SDR and uHDR at ∼10 Gy in the Bragg peak region (dose-averaged linear energy transfer [LET_D] ranging from 4.5 to 10.2 keV/μm). Radiation- induced injury of neuronal tissue was assessed by studying the DNA double strand break repair kinetics surrogated by nuclear γH2AX staining (radiation induced foci [RIF]), microvascular density and structural integrity (MVD, CD31+ endothelium), and inflammatory microenvironmental response (CD68+ microglia/macrophages and high mobility group box protein 1[HMGB]) in healthy C57BL/6 mouse brains.

Results

Averaged dose rates achieved were 0.17 Gy/s (SDR) and 120 Gy/s (uHDR). The fraction of RIF-positive cells increased after SDR ∼10-fold, whereas a significantly lower fraction of RIF-positive cells was found after uHDR versus SDR (∼2 fold, P < .0001). Moreover, uHDR substantially preserved the microvascular architecture and reduced microglia/macrophage regulated associated inflammation as compared with SDR.

Conclusions

The feasibility of uHDR raster scanning proton irradiation is demonstrated to elicit FLASH sparing neuroprotective effects compared to SDR in a preclinical in vivo model.

Background and Aims

Ultra-high dose rate (FLASH) particle irradiation has been vigorously investigated because an ultra-high-dose rate beam is now possible for clinical treatment systems, most of which are cyclotron-based or synchrocyclotron-based. Synchrotron-based treatment systems are energy-variable and are suitable for FLASH irradiation to various depths, but there have been only a few studies conducting FLASH experiments using a synchrotron-based system.

We tuned the beam-delivery designs of Hitachi's synchrotron-based proton/carbon-ion scanning-treatment systems to enable investigation on FLASH with particle beams.

Methods

The beam-delivery designs of a proton system at Nagoya Proton Therapy Center and carbon-ion system at Osaka Heavy Ion Therapy Center were tuned for proton and carbon-ion FLASH irradiation, respectively. Beam-extraction parameters were modulated to generate a shorter, flat, and higher-current spill.

Results

The mean current of the tuned proton beam was approximately 160 nA in a 50-ms spill at the beam energy of 139 MeV. The doses at the beam’s center measured using a float-glass dosimetry system were 53 Gy at 1-cm-SOBP (spread-out Bragg peak) and 22 Gy at plateau, corresponding to the dose rates of 1060 and 440 Gy/s, respectively. In the case of carbon-ion beams, the mean current was ≥ 18 nA in a 100-ms spill at 208.3 MeV/n. The doses and dose rates estimated from this current were 80 Gy (800 Gy/s) at entrance and 200 Gy (2,000 Gy/s) at 1-cm-SOBP. In both modalities, the dose rates were much higher than 40 Gy/s.

Conclusions

These results indicate Hitachi's synchrotron-based scanning-treatment systems can execute particle FLASH irradiation at least with a single pencil beam. In-vitro and in-vivo experiments are currently being conducted at several sites with the scanned FLASH beams tuned in this study.

Background and Aims

FLASH protontherapy seems, nowadays, a promising modality in treating cancer patients, however, the radiobiological mechanisms which cells undergo during FLASH irradiations are still unknown. Therefore R&D pre-clinical experiments need to be carried out.

Main goal of this work was to build a passive scattering system with Spread-Out-Bragg peak suitable for FLASH radiobiological experiments in the R&D proton beam line of HollandPTC. A FLASH passive field has the advantage of delivering the dose uniformly at the same time, overcoming the scanning pattern which occur in the gantry.

Methods

In the R&D proton beam line of HollandPTC, FLASH beams are reached with a beam energy of 250MeV, with a maximum beam current up to 350nA at target for pencil beam. The pencil beam characterization of 250 MeV proton beam has been carried out and the base data helped to build a passive scattering system which would allow the production of small field with dose uniformity suitable for radiobiological experiments. Moreover, 2D energy modulators have been tested to produce Spread-Out-Bragg peaks (setup Fig.1).

Results

Pencil beam characterization has shown that ultra-high dose rate can be reached in 2 mm² field size with uniformity of 98%. A Spread-Out-Bragg peak of 20 mm and 30 mm has been produced with 2D range modulators with uniformity of 97% in the spread-out region (Fig.2). The passive scattering system provides a field size of 17 mm² with 97% uniformity suitable for different type of radiobiological experiments. The latter was tested in a radiobiological experiment delivering doses from 2 up to 8Gy into head and neck cancer cells. Two sets of cells have been irradiated using dose rate of 0.1Gy/sec versus 57Gy/sec.

Conclusions

Using the passive scattering technique and the 2D range energy modulator, we have been able to produce a collimated uniform field to perform radiobiological experiment in the SOBP.

Background and Aims

The FLASH effect has been validated in preclinical experiments with electrons (e-FLASH) and protons (p-FLASH) operating at a mean dose rate above 40 Gy/s. However, no systematic comparison of the FLASH effect produced by e- vs p-FLASH has been performed and constituted the aim of the present study.

Methods

The electron eRT6/Oriatron/CHUV/5 MeV and proton beam Gantry1/PSI/170 MeV were used to deliver conventional (0.1 Gy/s e-CONV and p-CONV) and UHDR (>100 Gy/s e-FLASH and p-FLASH). Protons were delivered in transmission. Dosimetry was performed with a system validated for e-FLASH beams and composed of alanine, TLD and gafchromic films (Jorge, 22). The FLASH effect was investigated using validated in vivo normal brain/GBM models in C57Bl6 mice. Neurocognitive sparing was evaluated 2/6 months post-WBI at 10 Gy and anti-tumor effect on GL261 subcutaneous tumors after local irradiation at 20 Gy with a follow-up > 3 months post-RT. The exact same geometry (17mm applicator) and experimental conditions were used in both sites.

Results

Doses measured at eRT6/Oriatron and at Gantry 1 were in agreement (± 2%) with reference dosimeters calibrated at CHUV/IRA.The neurocognitive capacity of e-/p-FLASH irradiated mice were indistinguishable from the controls whereas the e-/p-CONV showed irreversible cognitive decrements. Complete tumor response was obtained and similar between e-/p-FLASH vs e-/p-CONV.

Conclusions

Despite major structural differences between electron and proton beams, this study shows that dosimetric standards can be established. More importantly, the e-/p-FLASH effect (for neuro-toxicity and GBM response) is similar, suggesting that the most important physical parameter is the overall time of exposure in the range of the milliseconds, at least when small volumes are irradiated. It also suggests that the definition of a common profile will likely identify the molecular determinant of the FLASH effect.