Dose Conformation in Tumor Therapy with External Ionizing Radiation: Physical Possibilities and Limitations

The central problem in tumor irradiation is to deposit a high and spatially uniform dose in the tumor target volume while sparing the surrounding normal tissue as much as possible. The present work investigates how such an adaptation ("conformation") of the spatial dose distribution to arbitrarily shaped target volumes can be achieved, and where the physical limits lie. In particular, the specific possibilities of irradiation with different types of radiation are determined under these aspects, whereby a rough distinction is made between irradiation with charged and uncharged particles. Due to the different mechanisms of radiation-tissue interaction, a conformal dose distribution can be achieved with only one radiation field in the case of heavy charged particles; in the case of uncharged particles, several radiation fields from different directions are required. First, the possibilities and limits of dose conformation are evaluated theoretically. Analytical approximations for modeling dose distributions with uncharged and charged particles are developed. Within the framework of these approximations, the theory of the exponential Radon transform is used to determine the optimal parameters for obtaining a desired dose distribution. It is shown that for an infinite number of radiation fields in the plane, it is possible to adapt the high-dose region to arbitrarily shaped target volumes for both uncharged and charged particles. The dose in a small radiation-sensitive organ at risk in the immediate vicinity of the target volume can be reduced to small scatter contributions. In the case of charged particles, this is also possible for multiple organs at risk. Furthermore, the non-conformal "dose background" is always smaller for charged particles than for uncharged particles. In a more application-oriented chapter, an algorithm is developed for the optimization of dose distributions under practical boundary conditions, i.e. in three dimensions, with finitely many radiation fields and for finite resolutions of the beam shaping devices. To achieve optimal dose distributions, the use of fluence- and (in the case of charged particles) energy-modulated radiation fields is necessary. Especially in the case of uncharged particles, the technical prerequisites for this are not yet available in clinical practice. Therefore, newly developed approaches to fluence modulation for uncharged particles using a dynamically or quasi-dynamically driven "multileaf collimator" are presented. Furthermore, the first phantom experiment is described in which these generalized methods for achieving the best possible conformal dose distribution were realized with high-energy photons (15-MV bremsstrahlung spectrum). The high degree of practically achievable dose conformation is thus verified. Finally, a comparison of the optimized dose distributions achievable with photons and protons is performed for challenging clinical cases where conventional radiotherapy reaches its limits. The most important result is that irradiation with uncharged particles, and in particular with high-energy X-rays, can be optimized in such a way that, in all clinically relevant cases, tumor-conformal dose distributions can be achieved with relatively few (less than ten) radiation fields. The exposure of healthy tissue is naturally higher than for heavy charged particles. However, the tolerance dose values are not exceeded. Exceptions are the rare cases in which the target volume is surrounded on almost all sides by particularly radiation-sensitive risk organs. Only in these cases can a much better result be achieved with the technically more demanding heavy charged particle therapy

Probabilistic Treatment Planning for Carbon Ion Therapy

Intensity-modulated scanned particle therapy in combination with the characteristic depth dose deposition of carbon ions entail a higher sensitivity to physical changes of the patient geometry as compared to photons. As a result, carbon ions may stop at different spatial locations than predicted during treatment planning. But also the patient's response to radiation is uncertain thereby further compromising the quality of the radiation treatment plan. The unknown level of uncertainty in the carbon ion dose requires a patient specific uncertainty analysis and uncertainty mitigation. For this reason the thesis at hand presents a novel method to assess and quantify carbon ion treatment plan uncertainties considering physical uncertainties, biological uncertainties as well as fractionation effects. Second, the manuscript demonstrated how uncertainties were in a subsequent probabilistic optimization mitigated. The proposed methodology was applied to multiple clinical scenarios and its advantageous impact on the carbon ion treatment plan robustness was demonstrated. Unlike protons, carbon ion treatment planning needs to account for the increased nonlinear cell killing of carbon ions in a mixed radiation field which increases the treatment planning complexity. With respect to uncertainties, not only the location of dose deposition is uncertain for carbon ions but also their effectiveness which consequently introduces biological uncertainties to treatment planning. Different to scenario based approaches, this work presents exact and approximated nonlinear closed-form calculations of the expectation value and covariance of the RBE weighted dose accounting for setup-, range- and biological-uncertainties in fractionated carbon ion therapy. The developed analytical pipeline allows propagating linearly correlated Gaussian input uncertainties through the carbon ion pencil beam dose calculation algorithm to obtain uncertainties in dose. With I and J being the number of voxels and pencil beams, respectively, low-rank tensor approximations were derived for the expectation value and standard deviation reducing the computational complexity from O(I x J^2) to O(I x J) and from O(I x J^4) to O(I x J^2) with minimal loss in accuracy. The consideration of biological errors introduces a new uncertainty structure in the analytical pipeline without increasing the computational complexity. The calculation of expected dose and variance influence information via APM allows performing a subsequent probabilistic optimization. A proof of concept and several aspects such as accuracy, fractionation and the impact of different probability densities to model input uncertainties were studied in detail on a one-dimensional phantom case. Further, basic three-dimensional dose calculation and optimization functionalities were implemented in the open-source treatment planning system matRad. A subsequent validation against a clinical reference system revealed excellent agreement for elementary pencil beams and patient cases as indicated by γ-pass rates above 99.67%. Theoretical APM derivations were implemented on top and were then applied to clinical carbon ion patient cases. The expectation value and standard deviation of the RBE weighted dose were compared to estimated analogs stemming from 5000 random samples. The γ-pass rate exceeded 94.95% in all patient cases thereby proving the validity of the proposed analytical pipeline. A subsequent probabilistic optimization avoided underdosage of the target volume, reduced the integral dose and resulted in carbon ion treatment plans with a minimized standard deviation of RBE weighted dose. Thus the developed Analytical Probabilistic Model facilitates a flexible, effective and accurate probabilistic description of the radiation treatment plan and generalizes to probabilistic optimization. In conclusion, the manuscript presents an analytical method to quantify and minimize the uncertainty in the delivery of carbon ion treatment plans. As a result, treatment plans became more robust against the involved uncertainties as demonstrated for a number of clinical scenarios

Theoretical methods for the calculation of Bragg curves and 3D distributions of proton beams

The well-known Bragg-Kleeman rule RCSDA = A dot E0p has become a pioneer work in radiation physics of charged particles and is still a useful tool to estimate the range RCSDA of approximately monoenergetic protons with initial energy E0 in a homogeneous medium. The rule is based on the continuous-slowing-down-approximation (CSDA). It results from a generalized (nonrelativistic) Langevin equation and a modification of the phenomenological friction term. The complete integration of this equation provides information about the residual energy E(z) and dE(z)/dz at each position z (0 <= z <= RCSDA). A relativistic extension of the generalized Langevin equation yields the formula RCSDA = A dot (E0 +E02/2M dot c2)p. The initial energy of therapeutic protons satisfies E0 << 2M dot c2 (M dot c2 = 938.276 MeV), which enables us to consider the relativistic contributions as correction terms. Besides this phenomenological starting-point, a complete integration of the Bethe-Bloch equation (BBE) is developed, which also provides the determination of RCSDA, E(z) and dE(z)/dz and uses only those parameters given by the BBE itself (i.e., without further empirical parameters like modification of friction). The results obtained in the context of the aforementioned methods are compared with Monte-Carlo calculations (GEANT4); this Monte-Carlo code is also used with regard to further topics such as lateral scatter, nuclear interactions, and buildup effects. In the framework of the CSDA, the energy transfer from protons to environmental atomic electrons does not account for local fluctuations.Comment: 97 pages review pape

Comprehensive quality control process for high precision intensity modulated adaptive proton therapy

The thesis focuses on development and clinical implementation of comprehensive and overlaying quality control process aimed at supporting introduction of high precision adaptive IMPT workflows. The thesis consists of seven chapters, covering topics on quality control for proton range accuracy, reconstruction, and accumulation of delivered dose distributions longitudinally throughout the proton therapy course and independent dose recalculation/predictive outcome-based patient specific quality assurance procedures. A proton range probing method as a quality control tool for range accuracy validation has been proposed and applied for range accuracy assessments in animal tissue samples covering a broad range of tissue types. A fraction-wise 4D dose reconstruction and accumulation procedure utilizing treatment delivery log files and patient-specific daily breathing patterns has been proposed and implemented in clinical practice. Validation of the procedure in controlled conditions with a 4D phantom revealed ability to spatially reconstruct the dose distributions with submillimeter accuracy. Eventually, an alternative approach for in-beam measurement-based patient specific quality assurance (PSQA) procedure has been investigated, developed, and introduced in clinical practice. By incorporating the developed range probing QC procedure as a validation tool for synthetic CTs and utilizing developed dose reconstruction and accumulation workflow, it enables possibility to establish a comprehensive longitudinal patient specific quality control process to monitor the treatment delivery in an environment of adaptive proton therapy. Introduction of more adaptive treatment procedures and availability of online adaptive workflows in proton therapy might be the next major advancement needed to take full advantage of the physical characteristics of the proton beam

Applications of Monte Carlo Methods in Biology, Medicine and Other Fields of Science

This volume is an eclectic mix of applications of Monte Carlo methods in many fields of research should not be surprising, because of the ubiquitous use of these methods in many fields of human endeavor. In an attempt to focus attention on a manageable set of applications, the main thrust of this book is to emphasize applications of Monte Carlo simulation methods in biology and medicine

Deciphering the untranslated message in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) patients currently present with an overall favorable prognosis achieved through intense chemotherapy regimens. Additional challenges that are still posed today concern those patients that present with therapy resistance or relapse. In this per-spective it will be crucial to further unravel the molecular basis of T-ALL biology and identify novel targets for development of innovative therapy protocols. Technological advances in the field have opened new possibilities to dissect the T-ALL transcriptome and recent findings un-derscore the importance of noncoding RNA molecules, such as miRNAs and lncRNAs, next to protein coding genes in various cancer entities and also T-ALL. In this thesis, my aim was to landscape the expression of these noncoding RNAs in T-ALL to complement the previously published protein coding gene expression profiles. In this way, nov-el oncogenic aspects in T-ALL could be unraveled, for example when an lncRNA or miRNA is de-tected in a known T-ALL oncogenic pathway or when it could point at complete novel oncogen-ic mechanisms

The investigation of alanine/EPR dosimetry, dose enhancement caused by AuNPs and the novel synthesis of bimetallic-nanoparticles via neutron capture

This thesis investigated five key areas, which are each presented as a chapter, with the major aims and findings summarized below: 1.The dose enhancement (DE) levels caused by secondary electron emissions from gold nanoparticles (AuNPs) were investigated by impregnating spherical AuNPs of varying sizes (1.9, 5 &amp; 15 nm) and concentrations (3, 2 and 1 %) within the dosimeter alanine. The AuNP/alanine composites were irradiated alongside control pellets (alanine) with different quality beams (kV and MV X-rays, electrons and protons) and the yield of alanine radicals quantified by Electron Paramagnetic Resonance (EPR) spectroscopy. For X-rays (kV and MV) increasing AuNP concentration yielded increased DE, and was greatest for kV X-rays overall (55 % DE for 3 %, 5nm AuNP /alanine composites, which decreased to 15 % DE for the 1 %-composites). Similarly, the effects of AuNP size on DE levels was clearer for kV X-ray irradiations with a preference for the smaller 1.9 nm sized AuNPs. Whilst MV X-ray irradiations did show the same AuNP size preference, the effects of concentration were more noticeable on DE, which was consistent with the literature. Irradiations with charged particles; electrons (6 MeV) and protons (150 MeV) showed no such dependence on either AuNP concentration or size and consistently yielded DE levels of ≤ 9 % (electrons) and ≤ 5 % (protons). These results agree well with recent Monte Carlo simulations, (which report little to no secondary electron production) and support cell and animal studies for AuNPs irradiated with protons that suggest the higher DE seen (ca.15 to 20 %) is due to other processes, such as; the production of reactive oxygen species (ROS) generated from the aqueous media in cells. 2.The suitability of IRGANOX®1076 as a near-tissue equivalent radiation dosimeter was investigated for various radiotherapy beam types; kV and MV X-rays, electrons and protons over clinically-relevant doses. Pellets consisting of solid solutions of IRGANOX®1076 in wax (IWSS) were manufactured, which yielded a single EPR peak after exposure to ionising radiations, and was attributed to the phenoxyl radical obtained by net loss of H•. Whilst, irradiation of solid IRGANOX®1076 produced a doublet signal, consistent with the formation of the phenol cation radical, obtained by electron loss. The IWSS pellets gave reliable dose measurements for exposures as low as 2 Gy, and a linear dose response for all types of radiations examined. Post- measurements for proton irradiations (up to 77 days) indicate good signal stability with minimal signal fading (between 1.6 to 3.8 %), and no significant change with the orientation of the sample. Overall, IWSS pellets are ideal for applications in radiotherapy dosimetry, and can easily be prepared in wax and moulded to different shapes. 3.Alanine is well known to have an EPR angular dependant response which alters its peak amplitudes. It is understood that water bound within alanine affects the EPR cavities resonance and promotes radical transformations causing signal variation. Means to overcome this include; averaging several measurements at different angles within the cavity, and using an internal EPR standard. This work examined an alternative method using alanine pellets manufactured with the binder (paraffin wax) as the bulk material (approximately 90 %) with alanine dispersed within (approximately 10 %). The sensitivity of the amplitude EPR signal when rotated within the cylindrical axis of the EPR cavity was investigated, with alanine-wax pellets showing a deviation range of; 1.14 to 2.06 % (3 days post-irradiation), which was comparable to commercial alanine pellets; 0.95 to 1.91 %. After approximately 30 days post-irradiation, the wax-alanine pellets remained stable, without being stored in a controlled environment; 1.56 to 1.93 %, whilst the commercial pellets deviation range had increased; 2.04 to 3.18 % despite being kept in a controlled environment. This simple method offers an alternative means to overcome EPR signal variation, without having to store the wax-samples in a highly controlled environment. 4.Currently alanine dosimeters are limited in their potential use in radiotherapy, mainly by poor sensitivity at low radiation doses (&lt; 5 Gy), which was addressed in this work by implementation of a new protocol called ‘spiking’. A set of alanine dosimeters were ‘spiked’ with a large dose of radiation, (approximately 30 Gy of 6 MV X-rays) then subjected to additional doses ranging between 0.5 and 10 Gy. The radical yield obtained following exposure to ionising radiation was measured by EPR spectroscopy and quantified using the central peak of the alanine radical species. After subtraction of the contribution from the &quot;spike&quot; dose, a linear correlation between both the dose and the area of the central EPR signal was obtained for doses of 0.5 Gy (regression value of 0.9890), and for the central peak’s amplitude (regression value of 0.9895). Overall, this method allowed quantification of doses as low as 0.5 Gy, and offers many advantages as a technique; it is easy to perform, requires no complex EPR signal analysis, and (by the addition of a large spike dose) is not susceptible to baseline distortions at low doses (&lt;10 Gy), and may extend the current usage of alanine dosimeters in radiotherapy. 5.Finally, the novel formation of the bimetallic nanoparticle (BiMetNP); AuHgNP by neutron capture was investigated. Neutron bombardment of AuNPs was completed at ANSTO, with gamma spectrum analysis confirming the formation of the unstable 198Au isotope. After a sufficient decay time, inductively coupled plasma mass spectroscopy (ICP-MS) positively identified the stable 198Hg isotope, thus confirming the formation of the BiMetNP product. Analysis of the γ-decay of the unstable 198Au isotope was perfumed and quantified over time (1 to 10 hours) using thermo luminescent dosimeters (TLD100s), OSL (optically stimulated luminescence) nanoDots® and Gafchromic films (EBT3 and RTQA2-1010), with good agreement between all techniques. These confirm that neutron bombardment of a mono-metallic-nanoparticle offers an alternative means to synthesize alloy-type BiMetNP products, which are not readily formed using current wet-chemistry methods (which favour a core and layer BiMetNP product). Furthermore, the γ- decay of the 198Au isotope has potential as a theranostics agent, capable of emitting a localised radiation dose at a tumour site, whilst simultaneously allowing real time imaging