Background and Aims

Experimental synchrotron X-ray-generated microbeam radiation therapy (MRT) represents an innovative mode of cancer radiotherapy with an excellent therapeutic ratio, but optimization of the irradiation protocol is an essential step toward clinical implementation.

Methods

We irradiated B16-F10 melanoma-bearing C57BL/6J female mice with one or two 396-Gy peak-dose fractions of MRT.

Results

The second MRT fraction remarkably attenuated tumour growth. Both single dose MRT and broad beam irradiation quickly accelerated the formation of metastasis in superficial cervical lymph nodes. Remarkably, the second MRT fraction triggered a very pronounced regression of locoregional metastasis that lasted for 5 weeks. This reduction cannot be explained by direct exposure of melanoma cells to low-dose scattered radiation, therefore an abscopal effect is a legitimate explanation. In search for factors that generated this anti-tumor/anti-metastatic response, we measured plasma concentrations of 34 pro-inflammatory and anti-inflammatory cytokines in cohorts of mice that received one or two MRT fractions. Neutrophil and T cell-attracting chemokines CXCL5, CXCL12 and CCL22 were significantly increased two days after the second MRT irradiation, indicating that alleviated melanoma growth and progression in animals treated with two MRT fractions could be a consequence of increased recruitment of anti-tumor neutrophils and T cells.

Conclusions

Our study indicates the approach for an optimal MRT regimen. Alone or in combination with immunotherapy, MRT may be able to not only enhance the local and locoregional control, but also boost abscopal effects. Therefore, MRT may be able to decrease the incidence of metastatic disease, the most common cause of death, even after successful treatment of the primary tumor.

Background and Aims

In this work, we present the results of first in vitro and in vivo studies for carbon ion beams irradiation that aim to investigate the biological effects delivered at ultra-high dose rate (FLASH).

Methods

The Heidelberg Ion-Beam Therapy Center (HIT) synchrotron, after technical adaptions, can reliably extract 5×10^{8 12}C ions within approximately 150 ms. This yields a dose of 7.5 Gy (homogeneity of ±5%) in a volume of at least 8 mm in diameter and a corresponding dose rate of 40-70 Gy s^-1. Additionally, similar beam application but at 8 times higher beam intensity could be recently performed at GSI for carbon FLASH irradiations in mice models (Dose: 12-18 Gy, Dose-rate 60-100 Gy s^-1).

Results

For the in vitro experiments a clonogenic survival assay and residual γH2AX foci analysis have been performed. The results of the survival assay demonstrate a significant FLASH sparing effect which is strongly oxygenation-dependent and is mostly pronounced at the concentration of 0.5% O₂ but absent at 0% and 21% O₂ (fig 1). The γH2AX results shows reduction in the residual foci signal at 1% O₂.

The GSI in vivo irradiations of mice models could be successfully performed in the plateau and in the SOBP region (fig 2). The SIS18 synchrotron enables treatment of target volumes of typically 20 cm³ with 15 Gy in 150 ms. Larger volumes seem to be possible.

Conclusions

The in vitro experiments confirm FLASH sparing effect at low oxygen concentrations. The pre-clinical results from the very recent mice model experiments are currently under evaluation.

Background and Aims

In order to translate the FLASH effect in clinical use and to treat deep tumors, Very High Electron Energy irradiations could represent a valid technique. Here, we address the main issues in the design of a VHEE FLASH machine. We present preliminary results for a compact C-band system aiming to reach a high accelerating gradient and high current necessary to deliver a dose up to 12 Gy/pulse, with a beam pulse duration of 3

Methods

The proposed system is composed by low energy high current injector linac followed by a high acceleration gradient structure able to reach 50-100 MeV energy range. To obtain the maximum energy, an energy pulse compressor options is considered. CST code was used to define the specifications RF parameters of the linac. To optimize the accelerated current and therefore the delivered dose, beam dynamics simulations was performed using Parmela code.

Results

The VHEE parameters Linac suitable to satisfy FLASH criteria were simulated. Preliminary results allow to obtain a maximum energy of 100 MeV, with a peak current of 200 mA, which corresponds to a charge of 200 nC per μs, or equivalently to about 4 Gy in a single pulse of 1µs and >10⁶ Gy/s over a ∅10 cm irradiation surface.

Conclusions

A promising preliminary design of VHEE linac for FLASH RT has been performed. Supplementary studies are ongoing to complete the characterization of the machine and to manufacture and test the RF prototypes.

Background and Aims

At the Photo Injector Test facility at DESY in Zeuthen (PITZ, near Berlin, Germany), the realization of an R&D platform for electron FLASH radiation therapy, VHEE radiation therapy and radiation biology is under preparation. The name of the new platform is HP²eFLASH-RT@PITZ, which stands for high power, high performance electron FLASH radiation therapy at PITZ.

Methods

The beam parameters that PITZ can provide are unique in the world: ps scale electron bunches with up to 5nC bunch charge at MHz repetition rate in bunch trains of up to 1 ms in length.

Results

The individual bunches can produce dose rates up to 10¹⁴ Gy/s and dose deposition up to 1000 Gy. Upon demand, each bunch of the bunch train can be guided to a different transverse location on the tumor, so that either a “painting” with micro beams, or a cumulative increase of absorbed dose using a wide beam distribution can be realized at the tumor. Full tumor treatment can hence be finished in a time interval of 1 ms, mitigating organ movement issues. Together with 20 years of operational experience at PITZ, and availability of detailed beam characterization and extremely flexible beam manipulation capabilities, this R&D platform will cover current parameter range of successfully demonstrated FLASH effects and extend the parameter range towards yet unexplored and unexploited short treatment times and high dose rates.

Conclusions

A summary of the plans for HP²eFLASH-RT@PITZ and the status of the preparations will be presented, with as goal to stimulate interest and broaden out our cooperation.

Background and Aims

In the process of establishing calorimetry as a primary standard for Very High Energy Electrons (VHEEs), measurements were performed in an ultra-high-dose-rate (UHDR) VHEE beam using the CLEAR facility at CERN. VHEEs with energies up-to 200 MeV could provide various benefits over standard clinical energy electron beams including increased conformity, deep-seated and complex tumour treatment as well as beam scanning and focusing.

Methods

The National Physical Laboratory graphite calorimeter, designed for Intensity Modulated Radiotherapy (IMRT), measured dose-to-graphite up-to approximately 5 Gy/pulse with dose-to-water calculated by application of a preliminary graphite-to-water conversion factor determined using the Geant4 Monte Carlo code. The CLEAR beamline allowed for investigation of both clinical dose-rate and UHDR regimes through tuning of the number of electron bunches per-pulse and the charge-per-bunch.

Results

As a result, the instantaneous dose-rate ranged between 5x10⁶ Gy/s and 3.1x10⁸ Gy/s whilst pulse widths ranged from 666 ps (1 bunch-per-pulse) to 133.2 ns (200 bunches-per-pulse). The dose-per-pulse ranging from 0.03 Gy/pulse to 5.26 Gy/pulse was found to increase linearly with increasing charge-per-pulse with R²=0.98 .

Conclusions

These calorimetry measurements allowed for absolute determination of ionisation chamber correction factors applicable to clinical dosimetry protocols. Moreover, a full uncertainty budget including calorimeter vacuum gap correction and perturbation factors is currently being developed such that the translation of UHDR VHEE beams to the clinical setting can be accelerated.

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

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.