Aim and structure of this work

The aim of this thesis is to investigate ion-based transmission imaging as an innovative imaging method to tackle the uncertainties faced nowadays in ion-beam radiotherapy.

The use of ion based transmission imaging could enable full clinical exploitation of the advan-tages of ion beams for cancer treatment, since it promises to overcome several major delivery inaccuracies at different stages of the treatment work-flow. During the planning phase, the distribution of the Stopping Power Ratio (SPR) relative to water, also defined as therelative

1.2. Aim and structure of this work Water Equivalent Path Length (rWEPL), of the patient anatomy could be reconstructed and introduced as input for theTreatment Planning System (TPS). Using this information directly deduced from ion interaction in tissue, the uncertainties arising from the current use of a X-ray-based empirical calibration method could be avoided. Furthermore, at the treatment site, transmitted planar or reconstructed volumetric images can be used before and in-between the treatment to monitor the patient positioning and anatomical changes as well as forBeam’s Eye View (BEV)verification of the integralrWEPLrelative to water.

Ion-based radiographies and tomographies rely on lower doses to the patient than those usually reached with conventional X-rays diagnostic images, as shown by some of the state-of-the-art investigations(cf. Section 2.4.3). This advantage is owed to the high-energetic and low-fluence ion-beams used, which guarantee the patient to be exposed only to the reduced radiation dose at the entrance region of theBC.

To this end,ion Radiography (iRAD)andion Computed Tomography (iCT), by means of the direct measurement of the ion residual range, has started being investigated at theHeidelberg Ion Beam Therapy Center (HIT). This research was performed with various phantoms of dif-ferent complexity and tissue-equivalent composition, which were imaged using an integration-mode multi-channel detector. The range telescope, consisting of 61 air-filled Parallel-Plate Ionization Chambers (PPICs) interleaved with Polymethyl Methacrylate (PMMA) absorber slabs of 3 mm thickness, already demonstrated the transmission imaging proof-of-principle of carbon ion transmission imaging at very high doses [Rinaldi 2011;Rinaldi et al. 2013]. There-fore this thesis work addresses a comprehensive characterization of the detector performance with new electronics under low-dose irradiation conditions.

The investigations of this work revealed the sensitivity to noise of the charge signal integrated in thePPIC-stack in the low-dose regime. In consequence, part of this work aimed at proposing ad-hoc data-acquisition parameters of the transmission-imaging prototype to achieve optimal signal quality. Moreover, in order to obtain the maximum radiographic and tomographic information in lateral (spatial resolution) and longitudinal (ion range resolution) directions, signal-feature assessment strategies and advanced data pre- and post-processing techniques supported by Monte Carlo (MC) simulations [Marcelos 2014; Meyer 2015] were developed.

Making use of these dedicated data-analysis methods, reduced-dose carbon iRADs and iCTs could be experimentally demonstrated within the scope of this work.

Finally, the ultimate goal of this work is to pave the way towards the clinical application of ion-based transmission imaging, by improving the next generation of the actual prototype.

The results provided in this work demonstrate the potential to obtain reliableiRADsandiCTs with the optimal trade-off between the minimal dose to the patient and a precise retrieve of the patientWater Equivalent Thickness (WET)and rWEPL, respectively.

This thesis is divided in four parts and organized as follows: The first part contains two chap-ters. In thefirst chapter, the ion-beam therapy and the topic of this study are introduced in the context of the current situation of cancer malignancies and conventional therapy worldwide.

Thesecond chapter, establishes the physical and biological foundations of ion-beam radiother-apy and how they influence ion-based transmission imaging. Besides, the technical and clinical implementation at theHITfacility is covered in detail. The sources of uncertainties present in

the clinical application of particle therapy are discussed and the different approaches of medical imaging to overcome them are reviewed in this chapter, too. Special focus is dedicated to the historical development of ion-based transmission-imaging techniques to know the state-of-the-art of the studied topic. The second pstate-of-the-art of the thesis contains Chapter 3 and 4 and it delves into the materials and methods involved in the performed investigations. These include the experimental acquisition process (cf. Chapter 3), which requires the synchronization of the Data Acquisition (DAQ) system of the new electronics with the active scanning beam delivery available at HIT, and a comprehensive characterization of the experimental setup in the low-dose regime. Moreover, single-spot signal assessment maps are developed and implemented to visually evaluate the detector performance. The irradiated phantoms are also presented in the third chapter.

Chapter 4 describes the two-dimensional (2D)-radiographic and 3D-tomographic image re-construction strategies, as well as the underlying MC simulations. Then, the MC-based ad-vanced post-processing methods applied in this work, are also described.

Part III of this thesis is dedicated to the carbon ion-based imaging results and discussion.

It is subdivided in two chapters, whereChapter 5presents low-doseiRADsof three phantoms of different geometry and material composition. In this chapter, the WET achieved with the Residual Range Detector (RRD) under various experimental acquisition-conditions is deter-mined and compared to reference MC in-silico [Meyer 2015] and ground-truth radiographies.

The core topic of this thesis, iCT, is addressed inChapter 6, where the carbon-iCTsof two dif-ferent tissue-equivalent phantoms are shown and evaluated also in comparison to the rWEPL obtained from the geometry-based calculation (ground-truth) and the MCsimulations.

Finally, the Part IVwraps up the the final remarks of this thesis work. Chapter 7 outlines the use of proton beams for transmission imaging as future prospect of these investigations, together with the possibility to couple single-particle position-tracking detectors to the RRD for these purposes. The conclusions of this thesis work are discussed in Chapter 8, followed by the forthcoming perspectives and the identified necessary improvements to accomplish the desired clinical application ofiRAD andiCT to improve ion-beam radiotherapy in the not too distant future.

This thesis work has been pursued on the frame of the German Research Fundation (Deutsche Forschungsgemeinschaft (DFG)) project: ”A novel imaging technique for ion beam therapy:

Ion Computed Tomography”, which aims for the development of a fully integrated transmission imaging system for range monitoring and planar and volumetric medical images reconstructed from actively scanned ion beams.

The best scientist is open to experience and begins with romance: the idea that anything is possible.

Ray Bradbury

Foundations of ion-beam therapy and ion-based 2

transmission-imaging

Ion-based transmission images, similar to other imaging modalities, rely on the attainable image-quality at a given patient dose. Planar and volumetric images are reconstructed from highly-energetic, low-fluence, ion-beams traversing the patient and being detected afterwards (see Figure2.1). The detection method exploited in this work is grounded on the integration-mode detector technology. The signal revealed by this type of detector systems encodes in-formation about the energy deposition of the ion beam traversing and interacting with the material of the object being imaged and the detector. Many physical parameters influence the quality of the transmitted images, since the signal attributes depend upon the distinct Bragg curve (BC) shape, also affected by the lateral and longitudinal beam distortion.

A comprehensive understanding of the physical interactions influencing theBC profile shape is of great importance to accurately interpret the discrete experimental data points and deter-mine image-quality indicators, such as (a)the radiography spatial resolution, which relies upon the finite beam size and irradiation steps (also known asRaster Points (RPs)) and the (b)the range accuracy, which is inherently limited by the detector granularity and it is connected to the the density resolution or contrast. These metrics ultimately determine the quality of the radiography, and, together with the angular sampling of the tomographic image reconstruction, the image-quality of the tomography.

2.1 The physics of ion-beam therapy and its implications in ion-based imaging