Development of an external beam line for radiobiology experiments and microdosimetry applications at the 18 MeV proton cyclotron facility at CNA

Abstract

Cancer is one of the leading causes of mortality world-wide, killing more than one million people per year just in Europe. Nowadays, proton therapy is one of the most promising techniques in the fight against cancer, being two the main bases of its success: (1) the physical advantages of protons with respect to conventional radiotherapy with photons, resulting in a more selective energy deposition in depth; (2) the increased biological effectiveness of protons with respect to photons and their denser pattern of energy deposition in matter, usually determining a more lethal damage to the DNA. The biological effect of protons and other ions with respect to photons is described in terms of the Relative Biological Effectiveness (RBE), i.e., the ratio between the doses of the reference and studied radiation determining the same effect. In clinical proton therapy, a RBE value of 1.1 is currently used. However, there is an increasing awareness that proton RBE is not a constant, but seems to increase linearly with the Linear Energy Transfer (LD) of the proton as it slows down in tissues, especially close to the distal region of the Bragg peak, possibly leading to toxicity in healthy tissue beyond the target. In this context, recent studies aim at including dose-averaged LET objective functions in treatment planning optimization to take full advantage of the increased RBE in protons beams. This last problem, and the characterisation of RBE, can be addressed with the formalism of microdosimetry, which, on one hand, permits the calculation of RBE from a microscopic approach by means of the microdosimetric kinetic model (MKM) and, on the other hand, provides physical concepts and computational tools to calculate macroscopic LD distributions. The rationale behind this thesis project is, therefore, given by the necessity of performing studies of proton RBE at low energies, close to the Bragg peak region of clinical proton beams (below 40MeV), which would help reaching a consensus on the variation of proton RBE with LET. To do so, two main objectives were foreseen: (1) the design and mounting of a low energy proton facility at CNA (proton kinetic energy below 18MeV) for the experimental study of RBE in mono-layer cell cultures and (2) the development of a simulation tool to study the patterns of energy deposition of protons in water at a micrometric scale, for the computation of microdosimetric quantities. This thesis is divided in four chapters. In Chapter 1, the physics foundations of proton therapy are presented, followed by a description of the relevant biological parameters. In this context, special attention is given to the formalisms of microdosimetry and its most relevant quantities. Then, an insight into Monte Carlo simulations and the main codes used in this work is presented, together with a description of the radiation dosimeters employed for the experimental measurements performed. Chapter 2 is dedicated to the description of the radiobiology beam line designed and mounted at the 18MeV proton cyclotron facility installed at the National Centre of Accelerators (CNA, Seville, Spain), focusing especially on the overall optimization of the beam parameters to define the best setup for the irradiation of mono-layer cell cultures. In this chapter, a Monte Carlo simulation of the beam line, realised with Geant4 and validated towards experimental measurements, is also presented. In Chapter 3 a Monte Carlo track structure application, which was developed for the computation of microdosimetric distributions of protons in liquid water, is described. This application, based on Geant4-DNA, provides two sampling methods, uniform and weighted, for the scoring of the quantities of interest in spherical sites. Furthermore, it is used to verify the validity range of a formula that links microdosimetric quantities to the macroscopic dose-averaged LET distribution, being a powerful tool for the development of analytical models to be used in treatment planning optimisation. Chapter 4 presents the results of the first irradiation of cell cultures at the radiobiology beam line developed at the cyclotron facility. In this context, an application of the Monte Carlo code for the computation of microdosimetric quantities is shown. With this code, a theoretical derivation of the expected RBE for the experimental irradiation and cells under study could be done, through the use of the microdosimetric kinetic model. Finally, a summary of the results obtained and a brief discussion on the future perspectives of this project conclude this work.