Background and Aims

Normal tissue preservation is the dose-limiting factor in clinical radiation therapy where late pathological changes, such as fibrosis, are the major normal tissue complications that dictate dose prescription. Microbeam radiation therapy (MRT) is a novel radiation modality that shows exceptional normal tissue sparing while delivering high-dose beamlets at ultra-high, FLASH dose rates from synchrotron sources. Explored primarily in the brain and skin, the tissue-sparing effects of MRT have never been investigated in the liver, the second most common site of metastasis and organ at risk for abdominal irradiations. We therefore investigated the effects liver exposure to FLASH MRT following irradiation of the lower right lung.

Methods

C57BL/6J mice were irradiated with two, cross-fired arrays of 50 µm wide microbeams spaced 400 µm apart with peak doses of 400 Gy (dose-rate 991.7 Gy/s). Livers were collected for histological analysis at 12, 24, and 48 hours and 6 months post-irradiation.

Results

Livers did not exhibit any signs of fibrosis 6 months after MRT. Investigation of cell death mechanisms revealed scarce apoptotic cells and the absence of necrosis at earlier time points. Within 48 hours, macrophages were organized into the beam path accompanied by infiltration of hematopoietic and immune cell populations.

Conclusions

We have demonstrated that radiation doses exceeding clinical thresholds can be delivered to the liver via a high dose-rate, spatially-fractionated MRT modality. The absence of pathological changes, such as fibrosis, in normal liver tissues at 6 months post-irradiation suggests that MRT could be used for the safe treatment of liver metastases and primary hepatocellular carcinomas.

Background and Aims

In hypofractionated proton therapy of eye melanoma (4x15 Gy(RBE)) the eyelid should be shifted from the treatment field to avoid strong skin reactions. It is usually painful for the patient and sometimes even not possible for anatomical reasons. The aim of these studies was to demonstrate the dosimetric feasibility of spatially fractionated proton therapy (SFPT) of eye with the closed eyelid. The proton beam is formed using a mesh collimators. The potential benefit of SFPT is better regeneration of microvascular structures of the irradiated eyelid.

Methods

Within the work the mesh-grid brass collimator and the dedicated range modulator were designed to obtain uniform Spread-Out Bragg Peak (SOBP) within the target volume. The system was verified at the proton eye therapy facility at IFJ PAN. The dose depth distributions was measured using Markus ionization chamber in the water phantom. Lateral profile has been determined in PMMA slab phantom using 2-D (LiF:Mg,Cu,P) thermoluminescent foils and the ProBImS scintillator system with a CCD camera.

Results

Peak-to-Valley-Dose-Ratio (PVDR) at the region of collimator was varying between 3 to 5 but due to the proton scattering the dose distribution at the depth of the tumor (15-29 mm) was practically uniform.

Conclusions

The studies demonstrated that it is possible to form the proton beam to perform the SFTP treatment of eye melanoma through the closed eyelid.

The study was partially supported by the Horizon 2020 project INSPIRE Grant No. 730983.

Background and Aims

Synchrotron Microbeam Radiation Therapy (S-MRT) consists of Synchrotron X-rays fractionated into an array of quasi-parallel beamlets delivered in FLASH mode. S-MRT achieves excellent tumour control and normal tissue sparing. This study aimed to evaluate S-MRT efficacy in a preclinical mouse lung carcinoma model.

Methods

Lewis-lung carcinoma implanted C57BL/6J mice were treated with two cross-fired arrays of S-MRT or Synchrotron-Broad Beam (S-BB) at 11 days after implantation. An array composed of seventeen microbeams 50 µm wide, spaced 400 µm apart was employed. S-MRT peak-dose was 400 Gy with a valley-dose of 4.76 Gy (delivery 361 ms, dose-rate 991.7 Gy/s). S-BB delivered a homogeneous dose of 5.16 Gy (delivery 129 ms, dose-rate 37.0 Gy/s). In addition, mouse lungs without tumours were irradiated with S-MRT, and radiation-related effects were assessed up to 6 months post-treatment.

Results

Mice in the S-MRT group had notably smaller tumour volumes compared to the S-BB group however, there was no difference in animal survival. This was attributed to pulmonary oedema found around the S-MRT-treated tumours. A mild transient form of fluid effusion was also observed in the S-MRT-treated normal lungs. Six months after S-MRT, the lungs of healthy mice were completely absent of radiation-induced pulmonary fibrosis.

Conclusions

Our study indicates that FLASH S-MRT is a promising tool for treating mouse lung carcinoma, i.e. reducing tumour size compared to mice treated with FLASH S-BB and sparing healthy lung from pulmonary fibrosis. Future experiments should focus on optimizing S-MRT parameters to minimize pulmonary oedema and maximize its therapeutic ratio.

Background and Aims

Proton minibeam radiotherapy (pMBRT) is an external beam radiotherapy method with reduced side effects by taking advantage of spatial fractionation in the normal tissue. Due to scattering, the delivered small beams widen in the tissue ensuring a homogeneous dose distribution in the tumor. In the last decade, several preclinical studies have been conducted addressing normal tissue sparing and tumor control in-vitro and in-vivo, using human skin tissue and mouse or rat models. In some of the studies due to application requirements the dose-rates are high such that additionally the FLASH effect comes into play. The aim is to investigate how the two effects of spatial and temporal focussing can interact and further widen the therapeutic window.

Methods

This study sumarizes the knowledge gathered in the experimental studies performed on pMBRT. Furthermore biological and physical effects of this therapy method are explained. Additionally, technical feasibility and limitations will be discussed by looking at simulations as well as preclinical studies.

Results

With pMBRT, higher radiation tolerance of tissue can be achieved resulting in the possibility of using higher doses per fraction. Some of the studies shown, already used FLASH dose rates and the results are all positive.

Conclusions

This opens the possibility of hypofractionation, reducing costs as well as physical and mental stress for the patient. Additionally, pMB FLASH radiotherapy seems to be an even more promising therapeutic approach. Finally, the technology for producing such beams is already existing, but must be adapted to the special requirements of minibeam fractionation, interlacing and FLASH pMBRT.

Background and Aims

A diamond-based detector is being developed to solve the limitation of online monitoring in Microbeam Radiation Therapy (MRT), a synchrotron-based technique using a micro-beam matrix of low energy photons (100 keV range) at very high dose rates (kGy/s range). Stripped diamond detectors are used for portal monitoring.

Methods

Bulk diamond-based detectors (4.5x4.5 mm² area) have been tested under a single 50x800 µm² MRT micro-beam to test the linearity of the diamond detector response for dose rates ranging between 1 and 12000 Gy/s at European Synchrotron Radiation Facility. Recently, a first stripped diamond detector (eight 238 µm-wide strips) prototype was tested under synchrotron micro-beam array. The variation between each strip in terms of detection efficiency has been investigated together with the charge collection distribution in the 60 µm inter-strip area.

Results

The bulk diamond detectors exhibit an almost perfect linear response with respect to the dose rate (the response of four diamond detectors is presented on next figure).

The first characterization of the stripped detector prototype has shown a signal variation lower than 2% between each strip. No charge collection loss is observed in the inter-strip area.

Conclusions

Linearity and reproducibility of the measured signals demonstrate the potential of diamond-based stripped detectors for MRT real-time portal beam monitoring. A multi-stripped diamond detector coupled with multi-channel charge integrator developed at LPSC is being tested to monitor simultaneously the micro-beam and inter-beam fluxes.

Acknowledgements: Work supported by the LabEx PRIME and the Idex Université Grenoble Alpes

Background and Aims

Accurate methods for monitoring the efficacy of treatments are key in radiooncology, where the quest for imaging techniques providing in three-dimensions (3D) both high spatial and contrast resolutions is incessant. X-ray Phase Contrast-Computed Tomography (XPCI-CT) is here proposed as a label-free, full-organ, multi-scale and 3D approach to study irradiated tissues with high sensitivity.

The aim is to visualize and characterize the effects of FLASH irradiations using broad beam (BB) and spatially-fractionated microbeams (MRT) with ex-vivo XPCI-CT for virtual 3D histology.

Methods

We delivered X-ray BB and MRT on healthy lungs or on healthy and glioblastoma-bearing brains of Fisher rats; irradiations were performed at the ID17 station of the European Synchrotron Radiation Facility using a dose rate of ~14000 Gy/s. After sacrificing the animals, target organs were removed, fixed and imaged by XPCI-CT using voxel sizes down to 0.7³ µm³. Afterwards samples were analysed by histology, X-ray wide-angle scattering and fluorescence.

Results

XPCI-CT allowed the depiction of brain and lungs anatomical details down to the cellular level, the identification of tumour tissue, necrosis, calcifications and micrometric MRT-transections within brains and of radiation induced fibrosis in lungs. BB irradiations produced the largest amount of fibrotic tissue while MRT caused isolated scars with small iron accumulations and calcium deposits in damaged blood vessels. A complementary structural/chemical characterization of the detected structures was also achieved.

Conclusions

The proposed approach provides a supportive technique for 3D imaging-based virtual histology and for an accurate description of post-treatment conditions of biological tissues supplementing the capabilities of standard lab-based techniques.