The lateral penumbra of a proton pencil beam scanning system (PBS) is of great importance in sparing of organs at risk and normal tissue when treating patients. The purpose of this current work is to measure the lateral penumbra of the Ion Beam Applications (Ion Beam Applications, Louvain‐la‐Neuve, Belgium) ProteusPLUS PBS Proton Therapy System and compare the measurements with the computed results from the RayStation proton treatment planning system. The lateral penumbra (80%-20%) was measured using EBT-3 Gafchromic film in the water tank. The lateral penumbra was studied for various parameters such as range, depth, and air gap. The computed lateral penumbra was found to be higher than the measured lateral penumbra by up to 2.3 mm in the case of depth dependency at 30 cm, and lower by up to 1.18 mm in the case of an air gap of 15 cm. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2019. / FAU Electronic Theses and Dissertations Collection

Charged particle beams are an increasingly common method of cancer treatment. Because of their Bragg peak dose distribution, protons are an effective way to deliver a dose to the tumor, while minimizing the dose to surrounding tissue. Charged particles with greater mass and higher charge than protons have an even sharper Bragg peak and a higher Relative Biological Effectiveness (RBE), allowing a greater dose to be delivered to the tumor and sparing healthy tissue. Since carbon ions are being implemented for treatment in Europe and Japan, this study will focus on carbon as the heavier ion of choice. Comparisons are drawn between moderated and unmoderated protons and carbon ions, all of which have a penetration depth of 10 cm in tissue. Scattering off the beam line, dose delivered in front of and behind the tumor, and overall dose mapping are examined, along with fragmentation of the carbon ions. It was found that fragmentation of the carbon ion beam introduced serious problems in terms of controlling the dose distribution. The dose to areas behind the tumor was significantly higher for carbon ions versus proton beams. For both protons and carbon ions, the use of a moderator increased the scattering off of the beam line, and slightly increased the dose behind the tumor. For carbon ions, the use of a moderator increased the degree of fragmentation throughout the beam path.

Background: In treatment planning for intensity-modulated proton therapy (IMPT), we aim to deliver the prescribed dose to the target yet minimize the dose to adjacent healthy tissue. Mixed-integer programming (MIP) has been applied in radiation therapy to generate treatment plans. However, MIP has not been used effectively for IMPT treatment planning with dose-volume constraints. In this study, we incorporated dose-volume constraints in an MIP model to generate treatment plans for IMPT. Methods: We created a new MIP model for IMPT with dose volume constraints. Two groups of IMPT treatment plans were generated for each of three patients by using MIP models for a total of six plans: one plan was derived with the Limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS) method while the other plan was derived with our MIP model with dose-volume constraints. We then compared these two plans by dose-volume histogram (DVH) indices to evaluate the performance of the new MIP model with dose-volume constraints. In addition, we developed a model to more efficiently find the best balance between tumor coverage and normal tissue protection. Results: The MIP model with dose-volume constraints generates IMPT treatment plans with comparable target dose coverage, target dose homogeneity, and the maximum dose to organs at risk (OARs) compared to treatment plans from the conventional quadratic programming method without any tedious trial-and-error process. Some notable reduction in the mean doses of OARs is observed. Conclusions: The treatment plans from our MIP model with dose-volume constraints can meetall dose-volume constraints for OARs and targets without any tedious trial-and-error process. This model has the potential to automatically generate IMPT plans with consistent plan quality among different treatment planners and across institutions and better protection for important parallel OARs in an effective way.

This dissertation addresses the issue of robustness in proton therapy treatment planning for cancer treatment. Proton therapy is considered to be advantageous in treating most childhood cancers and certain adult cancers, including those of the skull base, spine and head and neck. Protons, unlike X-rays, have a finite range highly dependent on the electron density of the material they are traversing, resulting in a steep dose gradient at the distal edge of the Bragg peak. These characteristics, together with advancements in computation and technology have led to the ability to plan and deliver treatments with greater conformality, sparing normal tissue and organs at risk. Radiotherapy treatment plans aim to meet set dosimetric constraints, and meet them at every fraction. Plan robustness is a measure of deviation between the delivered dose distribution and the planned dose distribution. Due to the same characteristics that make protons advantageous, conventional means of using margins to create a Planning Target Volume (PTV) to ensure plan robustness are inadequate. Additional to this, without a PTV, a new method of analysing plan quality is required in proton therapy. My original contribution to the knowledge in this area is the demonstration of how site- and centre- specific robustness constraints can be established. Robustness constraints can be used both for proton plan analysis and to identify patients that require plans of greater individualisation. I have also used the daily volumetric imaging from patients previously treated with conventional radiotherapy to quantify range uncertainty from inter- and intra-fraction motion. These new methods of both quantifying and analysing the change in proton range in the patient can aid in the choice of beam directions, provide input into a multi- criteria optimisation algorithm or can be used as criteria to determine when adaptive planning may be required. This greater understanding in range uncertainty better informs the planner on how best to balance the trade-off between plan conformality and robustness in proton therapy. This research is directly relevant to furthering the knowledge base in light of HM Government pledging £250 million to build two proton centres in England, to treat NHS patients from 2018. Use of methods described in this dissertation will aid in the establishment of clear and pre-defined protocols for treating patients in the future.

Spatially fractionated radiation therapy (or grid) using megavoltage x-rays is a relatively new method of treating bulky (>8 cm) malignant tumors. Unlike the conventional approach in which the entire tumor is targeted with a nearly uniform radiation field, in grid the incident radiation is collimated with a special grid collimator. As such, only the volume under the open areas of the grid receives direct irradiation from the incident beam; the rest only sees scattered radiation and hence receives significantly less dose. Those regions seeing less dose serve as regrowth areas for normal tissues, thus reducing the normal tissue complication probability after the treatment. Although the grid dose distribution in a tumor is non-uniform, the regression of tumor mass has exhibited uniform regression clinically. Protons have two advantages over megavoltage x-rays which are typically used for grid: (1) protons scatter less in tissue, and (2) they have a fixed range in tissue (the Bragg peak) that can be used to target a tumor. The goal of this thesis is to computationally and experimentally assess the feasibility of grid using clinical proton beams. The proton pencil beams at the Provision Cancer Center in Knoxville, Tennessee, are used to create an array of beams mimicking the arrangement of beams in grid therapy. The dose distributions at various depths in a solid-water phantom are obtained computationally by the Monte Carlo code MCNP and validated by RayStation experimental Gafchromic film EBT3. The results are compared with those of the grid using megavoltage x-rays.

<p>Scanned proton beams offer the possibility to take full advantage of the dose deposition properties of proton beams, i.e. the limited range and sharp peak at the end of the range, the Bragg peak. By actively scanning the proton beam, laterally by scanning magnets and longitudinally by shifting the energy, the position of the Bragg peak can be controlled in all three dimensions, thereby enabling high dose delivery to the target volume only. A typical scanned proton beam line consists of a pair of scanning magnets to perform the lateral beam scanning and possibly a range shifter and a multi-leaf collimator (MLC). Part of this thesis deals with the development of control, supervision and verification methods for the scanned proton beam line at the The Svedberg laboratory in Uppsala, Sweden. </p><p>Radiotherapy is preceded by treatment planning, where one of the main objectives is predicting the dose to the patient. The dose is calculated by a dose calculation engine and the accuracy of the results is of course dependent on the accuracy and sophistication of the transport and interaction models of the dose engine itself. But, for the dose distribution calculation to have any bearing on the reality, it needs to be started with relevant input in accordance with the beam that is emitted from the treatment machine. This input is provided by the beam model. As such, the beam model is the link between the reality (the treatment machine) and the treatment planning system. The beam model contains methods to characterise the treatment machine and provides the dose calculation with the reconstructed beam phase space, in some convenient representation. In order for a beam model to be applicable in a treatment planning system, its methods have to be general. </p><p>In this thesis, a beam model for a scanned proton beam is developed. The beam model contains models and descriptions of the beam modifying elements of a scanned proton beam line. Based on a well-defined set of generally applicable characterisation measurements, ten beam model parameters are extracted, describing the basic properties of the beam, i.e. the energy spectrum, the radial and the angular distributions and the nominal direction. Optional beam modifying elements such as a range shifter and an MLC are modelled by dedicated Monte Carlo calculation algorithms. The algorithm that describes the MLC contains a parameterisation of collimator scatter, in which the rather complex phase space of collimator scattered protons has been parameterised by a set of analytical functions. </p><p>Dose calculations based on the phase space reconstructed by the beam model are in good agreement with experimental data. This holds both for the dose distribution of the elementary pencil beam, reflecting the modelling of the basic properties of the scanned beam, as well as for complete calculations of collimated scanned fields.</p>

abstract: The challenge of radiation therapy is to maximize the dose to the tumor while simultaneously minimizing the dose elsewhere. Proton therapy is well suited to this challenge due to the way protons slow down in matter. As the proton slows down, the rate of energy loss per unit path length continuously increases leading to a sharp dose near the end of range. Unlike conventional radiation therapy, protons stop inside the patient, sparing tissue beyond the tumor. Proton therapy should be superior to existing modalities, however, because protons stop inside the patient, there is uncertainty in the range. “Range uncertainty” causes doctors to take a conservative approach in treatment planning, counteracting the advantages offered by proton therapy. Range uncertainty prevents proton therapy from reaching its full potential. A new method of delivering protons, pencil-beam scanning (PBS), has become the new standard for treatment over the past few years. PBS utilizes magnets to raster scan a thin proton beam across the tumor at discrete locations and using many discrete pulses of typically 10 ms duration each. The depth is controlled by changing the beam energy. The discretization in time of the proton delivery allows for new methods of dose verification, however few devices have been developed which can meet the bandwidth demands of PBS. In this work, two devices have been developed to perform dose verification and monitoring with an emphasis placed on fast response times. Measurements were performed at the Mayo Clinic. One detector addresses range uncertainty by measuring prompt gamma-rays emitted during treatment. The range detector presented in this work is able to measure the proton range in-vivo to within 1.1 mm at depths up to 11 cm in less than 500 ms and up to 7.5 cm in less than 200 ms. A beam fluence detector presented in this work is able to measure the position and shape of each beam spot. It is hoped that this work may lead to a further maturation of detection techniques in proton therapy, helping the treatment to reach its full potential to improve the outcomes in patients. / Dissertation/Thesis / Doctoral Dissertation Physics 2019

Scanned proton beams offer the possibility to take full advantage of the dose deposition properties of proton beams, i.e. the limited range and sharp peak at the end of the range, the Bragg peak. By actively scanning the proton beam, laterally by scanning magnets and longitudinally by shifting the energy, the position of the Bragg peak can be controlled in all three dimensions, thereby enabling high dose delivery to the target volume only. A typical scanned proton beam line consists of a pair of scanning magnets to perform the lateral beam scanning and possibly a range shifter and a multi-leaf collimator (MLC). Part of this thesis deals with the development of control, supervision and verification methods for the scanned proton beam line at the The Svedberg laboratory in Uppsala, Sweden. Radiotherapy is preceded by treatment planning, where one of the main objectives is predicting the dose to the patient. The dose is calculated by a dose calculation engine and the accuracy of the results is of course dependent on the accuracy and sophistication of the transport and interaction models of the dose engine itself. But, for the dose distribution calculation to have any bearing on the reality, it needs to be started with relevant input in accordance with the beam that is emitted from the treatment machine. This input is provided by the beam model. As such, the beam model is the link between the reality (the treatment machine) and the treatment planning system. The beam model contains methods to characterise the treatment machine and provides the dose calculation with the reconstructed beam phase space, in some convenient representation. In order for a beam model to be applicable in a treatment planning system, its methods have to be general. In this thesis, a beam model for a scanned proton beam is developed. The beam model contains models and descriptions of the beam modifying elements of a scanned proton beam line. Based on a well-defined set of generally applicable characterisation measurements, ten beam model parameters are extracted, describing the basic properties of the beam, i.e. the energy spectrum, the radial and the angular distributions and the nominal direction. Optional beam modifying elements such as a range shifter and an MLC are modelled by dedicated Monte Carlo calculation algorithms. The algorithm that describes the MLC contains a parameterisation of collimator scatter, in which the rather complex phase space of collimator scattered protons has been parameterised by a set of analytical functions. Dose calculations based on the phase space reconstructed by the beam model are in good agreement with experimental data. This holds both for the dose distribution of the elementary pencil beam, reflecting the modelling of the basic properties of the scanned beam, as well as for complete calculations of collimated scanned fields.

The aim of this study is the clinical derivation of the dose-response relations of bladder and prostate regarding PSA progression and urinary complications using patients treated for prostate cancer with both photon and proton beams. Such data are necessary for a prospective estimation of the clinical effectiveness of radiation therapy using combinations of different radiation modalities. Material During the period from 2002 until 2006, at the Academic Hospital in Uppsala, Sweden 189 patients underwent radiotherapy for prostate cancer, which combined photon and proton beams therapy. Of these patients, 100 have been included in this study and have been analysed for the prostate. The analyses for urinary complications were made for 72 patients who didn’t have final clinical urinary outcome equal to one . The dose distribution delivered to the prostate, the two regions of the bladder and the clinical treatment outcome, were available for each patient. The patients were given a proton boost of 20 Gy in 4 fractions of 5 Gy in addition to a conventional photon beam treatment, which was prescribed to a dose of 50 Gy in 25 fractions of 2 Gy. In this analysis, the delineated regions of interest were the prostate, the whole urinary bladder and the lower 3 cm part of the bladder. It is known that most urinary complications come from the lower 3cm part of bladder due to its anatomical position near to urethra and prostate. The photon and proton doses were calculated using the BED (biologically effective dose) concept. Furthermore, for the calculation of the proton dose an RBE value of 1.1 was considered. Finally, the combined effective dose was chosen to be the sum of the maximum dose of protons and the mean dose of photons for the whole bladder and the bladder-3cm, while for the prostate, the effective dose was considered as the sum of the mean dose for photons and the minimum dose for protons. The radiobiological parameter acquisition was performed for the Poisson Binomial and Probit models using the Maximum Likelihood method. Results Of the 100 patients, 94 had tumor control (94 %), whereas 6 patients had treatment failure (6 %). Of the 72 patients, 15 (21%) showed urinary complications, whereas 57 (79%) were complication-free.. The estimated values of the parameters for tumour are D50= 49.4 Gy (68% CI = 47.90-52.80 Gy) and γ = 2.25 (68% CI = 1.95-2.80) for the Poisson , D50= 49.55Gy (68% CI= 47.56-51.45Gy) and γ = 2.25 (68% CI = 1.95-2.80) for Binomial, whereas for the Probit model the values of D50 and γ50 are 47,27Gy (68% CI = 45.25-50.01 Gy) and 1,33 (68% CI = 1.20-1.37), respectively. The estimated values of the parameters for the whole bladder are D50= 104 Gy (68% CI = 103.12-105.01 Gy) and γ = 0.7 (68% CI = 0.67-0.72) for the Poisson , D50= 108 Gy (68% CI= 106-108.8 Gy) and γ = 0.6 (68% CI = 0.58-0.70) for Binomial, whereas for the Probit model the values of D50 and γ50 are 97 Gy (68% CI = 95.30-97.56 Gy) and 1 (68% CI = 0.94-1.12), respectively. Finally, the estimated values of the parameters for bladder 3cm are D50= 88.4 Gy (68% CI = 85.4-89.5 Gy) and γ = 1.30 (68% CI = 1.18-1.45) for the Poisson , D50= 88.58 Gy (68% CI= 86.21-89.85 Gy) and γ = 1.28 (68% CI = 1.12-1.51) for Binomial, whereas for the Probit model the values of D50 and γ50 are 85.58 Gy (68% CI = 83.23-89.21Gy) and 1.78 (68% CI = 1.56-1.83), respectively. From the derived mean DVHs of the prostate it is concluded that photon and proton therapies contribute the same in the toxicity of the patients and both proton and photon therapy provide the patients with the prescribed dose in the target – prostate gland. From the derived mean DVHs of the bladder and the bladder 3cm, it is observed that photon therapy provides the patients with more dose than the proton therapy, thus it can be assumed that the urinary complications were mainly due to the photon treatment. Bladder 3cm receives more dose both during photon and proton therapy in comparison with the whole bladder for patients with and without complications. Thus, the lower 3cm part of the bladder contributes more in the possibility of urinary complications. In ROC analysis, for the prostate the area under the ROC curve is 0.71. This indicates that the model distinguishes quite well the group of the patients with and without PSA progression. For the whole bladder and the lower 3cm of the bladder, the results are 0.61 and 0.65 respectively; the model does not separate well the two groups (with and without the complications). These results suggest that other factors may also be important for urinary toxicity. Conclusions The dose-response relations of bladder and prostate appear to be described well by the estimated parameters of the Poisson, Poisson and Probit models. Future studies incorporating more radiobiological models and more detailed factors describing the combined treatment and endpoint registration will be needed until an accurate prospective estimation of the expected urinary complications is reached. / Ο σκοπός αυτής της μελέτης είναι ο προσδιορισμός των παραμέτρων δόσης απόκρισης αναφορικά με το κλινικό αποτέλεσμα της εξέλιξης της PSA και των ουροποιητικών επιπλοκών μετά από ακτινοθεραπεία προστάτη με φωτόνια και πρωτόνια. Αυτά τα δεδομμένα είναι πού χρήσιμα στην κλινική πράξη για την εκτίμηση και σύγκριση των πλάνων ακτινοθεραπείας. Υλικά και μέθοδοι Κατά την περίοδο 2002 με 2006, στο Ακαδημαϊκό Νοσοκομείο της Ουψάλα, Σουηδίας, 189 ασθενείς υποβλήθηκαν σε ακτινοθεραπεία φωτονίων και πρωτονίων για προστάτη. Από το σύνολο των ασθενών, 100 μελετήθηκαν και συμπεριλήφθηκαν στην παρούσα εργασία. Ειδικότερα για τις ουροποιητικές επιπλοκές, η ανάλυση πραγματοποιήθηκε για 72 ασθενείς χωρίς κλινικό αποτέλεσμα ίσο με 1. Το κλινικό αποτέλεσμα και οι κατανομές δόσεις της ουροδόχου κύστης και του προστάτη ήταν διαθέσιμα για κάθε ασθενή. Οι ασθενείς δέχθηκαν θεραπεία πρωτονίων των 20 Gy σε 4 συνεδρίες των 5 Gy καθώς και θεραπεία φωτονίων των 50 Gy σε 25 συνεδρίες των 2 Gy. Οι περιοχές ενδιαφέροντος που απεικονίστηκαν είναι ο προστάτης, ολόκληρη η ουροδόχος κύστη και τα χαμηλότερα 3 cm από την βάση της ουροδόχου κύστης (κύστη 3εκ.). Είναι γνωστό ότι οι περισσότερες επιπλοκές προέρχονται από το τμήμα που περιλαμβάνει τα χαμηλότερα 3 cm από την βάση της ουροδόχου κύστης εξαιτίας της ανατομικής του θέσης κοντά στην ουρήθρα και στον προστάτη. Οι δόσεις φωτονίων και πρωτονίων υπολογίστηκαν χρησιμοποιώντας την BED. Επίσης, στον υπολογισμό της δόσης πρωτονίων χρησιμοποιήθηκε η RBE ίση με 1.1. Τέλος, η ισοδύναμη δόση για την κύστη και τα 3 εκ. της κύστης είναι το άθροισμα της μέγιστης δόσης πρωτονίων και της μέσης δόσης φωτονίων. Ενώ για τον προστάτη, είναι το άθροισμα της μέσης δόσης φωτονίων και της ελάχιστης δόσης των πρωτονίων. Τα δεδομένα χρησιμοποιήθηκαν σε μια διαδικασία προσαρμογής μέγιστης πιθανοφάνειας (maximum likelihood fitting) ώστε να υπολογιστούν οι βέλτιστες τιμές των παραμέτρων που χρησιμοποιούνται από τα μοντέλα Poisson, Binomial και Probit. Αποτελέσματα Από τους 100 ασθενείς , 94 ήταν ασυμπτωματικοί ασθενείς και 6 εμφάνισαν επιπλοκή όσο αφορά την εξέλιξης της PSA . Από τους 72 ασθενείς, 15 (21%) παρουσίασαν ουροποιητικές επιπλοκές ενώ, 57 (79%) δεν παρουσίασαν. Οι βέλτιστες εκτιμήσεις των παραμέτρων δόσης απόκρισης για τον όγκο είναι are D50= 49.4 Gy (68% CI = 47.90-52.80 Gy) και γ = 2.25 (68% CI = 1.95-2.80)για το Poisson, για το Binomial μοντέλο D50= 49.55Gy (68% CI= 47.56-51.45Gy) and γ = 2.25 (68% CI = 1.95-2.80), ενώ για το Probit μοντέλο οι τιμές για τα D50 και γ50 είναι 47,27Gy (68% CI = 45.25-50.01 Gy) και 1,33 (68% CI = 1.20-1.37) αντίστοιχα. . Οι βέλτιστες εκτιμήσεις των παραμέτρων δόσης απόκρισης για την κύστη είναι D50= 104 Gy (68% CI = 103.12-105.01 Gy) και γ = 0.7 (68% CI = 0.67-0.72) για το Poisson , D50= 108 Gy (68% CI= 106-108.8 Gy) και γ = 0.6 (68% CI = 0.58-0.70) για το Binomial, ενώ για το Probit μοντέλο οι τιμές για τα D50 και γ50 είναι 97 Gy (68% CI = 95.30-97.56 Gy) και 1 (68% CI = 0.94-1.12), αντίστοιχα. Τέλος, οι βέλτιστες εκτιμήσεις των παραμέτρων δόσης απόκρισης για την κύστη 3cm είναι D50= 88.4 Gy (68% CI = 85.4-89.5 Gy) και γ = 1.30 (68% CI = 1.18-1.45) για το Poisson, D50= 88.58 Gy (68% CI= 86.21-89.85 Gy) and γ = 1.28 (68% CI = 1.12-1.51) για το Binomial μοντέλο, , ενώ για το Probit μοντέλο οι τιμές είναι 85.58 Gy (68% CI = 83.23-89.21Gy) and 1.78 (68% CI = 1.56-1.83). Από τα μέσα αθροιστικά διαγράμματα του προστάτη προκύπτει ότι και η θεραπεία φωτονίων και πρωτονίων συνεισφέρουν το ίδιο στην τοξικότητα των ασθενών, αλλά και ότι και οι δυο θεραπείες δίνουν στον στόχο την καθορισμένη δόση. Από τα μέσα αθροιστικά διαγράμματα της κύστης και της κύστης 3cm, παρατηρείται ότι η θεραπεία φωτονίων προσφέρει στους ασθενείς με επιπλοκές μεγαλύτερη δόση από την θεραπεία πρωτονίων, με αποτέλεσμα να μπορεί να υποτεθεί ότι οι ουροποιητικές επιπλοκές οφείλονται κυρίως στην θεραπεία φωτονίων. Επίσης, παρατηρείται ότι η κύστη 3cm λαμβάνει περισσότερη δόση και στην θεραπεία φωτονίων και στην θεραπεία πρωτονίων συγκριτικά με ολόκληρη την κύστη για όλους τους ασθενείς με ή χωρίς επιπλοκές. Έτσι, συμπεραίνεται ότι αυτό το μέρος της κύστης συμβάλλει περισσότερο στην εμφάνιση επιπλοκών. Επιπλέον, στην ROC ανάλυση, για τον προστάτη η περιοχή κάτω από τη ROC καμπύλη είναι 0.71, δηλαδή τα μοντέλα φαίνονται να διαφοροποιούν καλά τις ομάδες ασθενών με και χωρίς επιπλοκή της PSA. Για την ουροδόχο κύστη και την κύστη 3cm , τα αποτελέσματα είναι 0.61 και 0.65 αντίστοιχα. Τα μοντέλα δεν διαφοροποιούν καλά τις ομάδες με ή χωρίς. Συμπεραίνεται ότι υπάρχουν και άλλοι παράγοντες που επηρεάζουν την ουροποιητική τοξικότητα. Συμπεράσματα Οι σχέσεις δόσης απόκρισης για την κύστη και τον προστάτη φαίνεται να περιγράφονται αρκετά καλά από τις εκτιμημένες παραμέτρους δόσης απόκρισης για τα Poisson, Poisson και Probit μοντέλα. Μελλοντικές μελέτες με περισσότερα ακτινοβιολογικά μοντέλα και λεπτομερέστερους παράγοντες, που θα περιγράφουν την συνδυασμένη θεραπεία και το κλινικό αποτέλεσμα είναι απαραίτητες για μια ακριβή πρόβλεψη των επιπλοκών.

Thesis (MScEng)--Stellenbosch University, 2012. / Please refer to full text for abstract.