M.Sc. degree
Università degli studi dell'Insubria, Como, Italy, 2024

Maria Vittoria Rossi

Supervisor: Michela Prest

A novel dose delivery system for cell irradiations with conventional and FLASH dose rates at the Bern medical cyclotron

Keywords:

• Instrumentation for hadron therapy
• Radiotherapy concepts
• Dosimetry concepts and apparatus

Abstract:

In recent decades, radiation therapy has become a key technique in the fight against cancer, revolutionizing the landscape of cancer care. This therapeutic technique, which uses radiation energy to damage or destroy cancer cells, is currently used in 60% of cancer patients.
The most commonly used radiation types in radiation therapy are photons and electrons, produced by linear accelerators and focused into the volume to be treated. These radiations release their maximum dose at the patient’s surface and diminish exponentially with depth, affecting healthy tissues both before and after the target area. In the case of deep seated tumors or tumors located near critical organs, the use of heavy charged particles, such as protons, produced by circular accelerators, allows a more targeted dose distribution to be achieved. These particles deposit minimal energy until they stop, releasing all their energy at the Bragg peak. FLASH radiotherapy is an innovative technique designed to maximize the dose delivered to the target volume while sparing surrounding healthy tissues. This technique delivers high doses of radiation (> 40 Gy/s) in fractions of a second (< 500 ms), showing potential advantages in terms of efficacy and safety. Although the exact mechanisms are under investigation, it is believed that high doses and short treatment times reduce damage to healthy tissues while maintaining therapeutic effects on tumors. Numerous studies have already been conducted on cells and animals, and the first treatment on a patient was carried out in 2018, sparking growing interest in the scientific and medical community. Further studies are necessary to integrate this practice into clinical therapy. Additionally, adjusting dosimetry techniques for this radiation regime poses a research challenge, as conventional dosimeters, like ionization chambers, exhibit saturation in FLASH regimes.
This thesis was conducted under the SEMP-Erasmus+ Traineeship program, adapting the medical cyclotron at the University Hospital of Bern (Inselspital) for pre-clinical cell studies under both conventional and FLASH dose rate regimes. The Bern medical cyclotron is used daily to produce PET radioisotopes, operating with high beam currents. In contrast, significantly lower currents are required for applications in pre-clinical studies. In the first phase, it was therefore necessary to adapt the beam currents to the required values and ensure their stability throughout the irradiation process. Subsequently, the project focused on optimizing and validating a setup for cell irradiation, emphasizing beam uniformity and energy.
The optimized structure included a current measurement device with a collimator connected to a long tube sealed by a beam extraction window. To diffuse and equalize the beam, two aluminum scatterers were added to the collimator and the extraction window. The most effective solution for the thickness of the scatterers was determined by simulations of the beam scattering angle using the SRIM (Stopping and Range of Ions in Matter) program. With the optimized setup, a proton beam uniformity of 9% was achieved, meeting cell irradiation requirements. The setup also featured an ionization chamber for current measurement and a remotely controllable stand for the cell flasks. Simulations using LISE++ and Pstar programs provided beam energy and stopping power values of 7.69 MeV and 56.34 MeV·cm2/g, respectively. These simulations indicated that the plastic material of the flasks containing the cells significantly affects the beam energy and therefore will be modified for future measurements.
A real-time proton beam dose rate measurement system was developed to accurately monitor doses during irradiation. Initially, a dose analysis was performed using Gafchromic films, which were previously calibrated as part of this research at the Radio-Oncology clinic of the University Hospital of Bern, at the Swiss Metrology Institute METAS, and at the CNR Institute for Organic Synthesis and Photoreactivity in Bologna, Italy. The resulting dose was divided by the irradiation time to extract the dose rate, which was successively related to the current density recorded by the ionization chamber.
The linearity of detector response was validated across conventional and FLASH regimes, confirming accurate measurements from 0.02 Gy/s to 88.29 Gy/s. Since the error on irradiation time with the current instrument (± 0.60 s) was found to be one of the limiting factors for higher dose rate measurements, a chamber readout system with better temporal resolution will be used in future tests.
Further characterization of the proton beam dose rate involved a scintillator-based detector coupled to an optical fiber. Specifically, a fiber connected to a plastic scintillator and a fiber connected to an inorganic scintillator (GAGG) were used. Despite linear responses in repeated irradiations, single signal conversion to dose rate was not possible, suggesting further studies on radiation and temperature resistance of detector components. A fully characterized dosimeter will enable pre-clinical studies of FLASH radiation therapy.
Using the optimized setup, three cell lines with varying radiosensitivity were irradiated at 0.03 Gy/s and analyzed with the Clonogenic Cell Survival Assay. The survival curve was compared with one obtained from irradiation data of the same cell types using photons. As expected from the literature, proton irradiation caused greater biological damage, resulting in lower cell survival compared to photon irradiation. This result demonstrates the efficiency of the apparatus, built at the Bern Medical Cyclotron during this project, for conducting pre-clinical tests on cells. The next phase involves optimizing the setup for FLASH irradiation to study cell effects and compare them with conventional dose rates. Although the proton beam energy is limited to 18 MeV, well below the 250 MeV generally used in therapy, the findings suggest potential for future pre-clinical animal studies.