Ultra-High Dose-Rate (UHDR) Proton Therapy is an area of active research due to its potential to target cancer cells while sparing healthy tissues. To deepen the knowledge of underlying biological mechanisms of FLASH effect, pre-clinical experiments are required, necessitating large uniform field achieving dose rates above 40 Gy/s. To achieve this, in the Research & Development (R&D) fixed horizontal proton beam line of HollandPTC, a fully 3D printed contoured passive scattering system has been developed. This system is designed to shape a 250 MeV proton beam into a suitable configuration for pre-clinical radiobiological experiments, achieving the necessary dose rates and uniform field distribution. The beamline configuration was initially modelled using the Monte Carlo-based Tool for Particle Therapy Simulation (TOPAS). Subsequently, the contoured passive scattering system was optimized through simulations to generate a sufficiently uniform field for future radiobiological experiments. To validate simulations, the system was fabricated using advanced 3D printing technology. A tungsten-heavy filament blend, consisting of approximately 75% tungsten by mass, was employed in a fused deposition modelling (FDM) process. Simulations were validated against experimental data. The measured dose distributions demonstrated a lateral field uniformity exceeding 95%, corresponding to a dose homogeneity within ± 3% over a field diameter of 2.8 cm. Dose rates above 40 Gy/s were achieved under experimental conditions, with measured values reaching up to approximately 60 Gy/s at the beam entrance, and 100 Gy/s within the Spread-Out Bragg Peak (SOBP). These results confirm the system’s design and performance, thus opening multiple possibilities for UHDR radiobiological experiments.

Background and purpose:
Understanding the cellular and molecular effect of proton radiation, particularly the increased DNA damage complexity at the distal end of the Bragg curve, is current topic of investigation. This work aims to study in vitro clonogenic survival and DNA damage foci kinetics of a head and neck squamous cell carcinoma cell line at various positions along a double passively scattered Bragg curve. Complementary in silico studies are conducted to gain insights into the link between cell survival variations, experimentally yielded foci and the number and complexity of double strand breaks (DSBs).

Materials and methods:
Proton irradiations are performed at the HollandPTC R&D proton beamline, using a double passively scattered setup. A custom water phantom setup is employed to accurately position the samples within the Bragg curve. FaDu cells are irradiated at the proximal 36 % point of the Bragg peak, (P36), proximal 80 % point of the Bragg peak (P80) and distal 20 % point of the Bragg peak (D20), with dose-averaged mean lineal energies (yD¯) of 1.10 keV/μm, 1.80 keV/μm and 7.25 keV/μm, respectively.

Results:
Clonogenic survival correlates strongly with yD¯, showing similar survival for P36 (D37%=3.0 Gy) and P80 (D37%=2.9 Gy), but decreased survival for D20 (D37% = 1.6 Gy). D20 irradiated samples exhibit increased 53BP1 foci shortly after irradiation, slower resolution of the foci, and larger residual 53BP1 foci after 24 h, indicating unrepaired complex breaks. These experimental observations are supported by the in silico study which demonstrates that irradiation at D20 leads to a 1.7-fold increase in complex DSBs with respect to the total number of strand breaks compared to P36 and P80.

Conclusions:
This combined approach provides valuable insights into the cellular and molecular effect of proton radiation, emphasizing the increased DNA damage complexity at the distal end of the Bragg curve, and has the potential to enhance the efficacy of proton therapy.

Objective. Bragg peak measurements play a key role in the beam quality assurance in proton therapy. Used as base data for the treatment planning softwares, the accuracy of the data is crucial when defining the range of the protons in the patient. Approach. In this paper a protocol to reconstruct a Pristine Bragg Peak exploring the direct correlation between the particle flux and the dose deposited by particles is presented. Proton flux measurements at the HollandPTC and FLUKA Monte Carlo simulations are used for this purpose. This new protocol is applicable to plastic scintillator detectors developed for Quality Assurance applications. In order to obtain the Bragg curve using a plastic fiber detector, a PMMA phantom with a decoupled and moveable stepper was designed. The step phantom allows to change the depth of material in front of the fiber detector during irradiations. The Pristine Bragg Peak reconstruction protocol uses the measured flux of particles at each position and multiplies it by the average dose obtained from the Monte Carlo simulation at each position. Main results. The results show that with this protocol it is possible to reconstruct the Bragg Peak with an accuracy of about 470 µm, which is in accordance with the tolerances set by the AAPM. Significance. It has the advantage to be able to overcome the quenching problem of scintillators in the high ionization density region of the Bragg peak.