Science, Faculty of
Physics and Astronomy, Department of
DSpace
UBCV
Möehle, Swantje D.
Master of Science - MSc
University of British Columbia
Quality assurance of radiation therapy devices used to treat cancer is important to assure successful treatment and prevent over- or under-dosage. For brachytherapy eye plaques, the current standard procedure involves measuring the individual seed air-kerma strengths in a well chamber and visually inspecting the plaque. This leaves room for errors to occur between seed verification, plaque assembly, and implantation. In addition, the availability of manufacturer-assembled commercial eye plaques has increased, where independent, pre-implantation verification is limited to verifying the seed strength of additional loose seeds from the same seed lot. Currently, no commercially available system or technique exists for routine quality assurance of assembled eye plaques. This thesis investigates whether a flat panel image detector can be used in combination with Monte Carlo simulations, to develop a quality assurance system for assembled I-125 and Pd-103 brachytherapy eye plaques. The detector is used in conjunction with an acrylic plaque holder to record the 2D dose distribution of the plaque perpendicular to the plaque central axis. The system is simulated in Monte Carlo to generate a 3D dose distribution. Calibrating the detector relative to the Monte Carlo results allows comparisons between simulated and measured plaques, making it possible to verify the central dose rate of the plaque and to verify the 2D dose distribution in the detector plane using gamma index analysis. Results showed good agreement between the dose distributions and central strengths of detector measured and simulated results for a variety of seed strengths and seed arrangements, enabling the detection of dead or missing seeds. A procedure was established to compare the results to TG-43 dose calculations used in treatment planning. The method was tested on BC Cancer in-house design acrylic eye plaques and a commercial Eye Physics dummy plaque. The detector showed strong attenuation for incoming radiation with large angles of incidence, limiting the applicability of this method for individually collimating plaques. Overall, this study showed that a flat panel imaging detector and Monte Carlo simulations can be combined for routine quality assurance and verification of assembled eye plaques without individual seed collimation.
Combining Monte Carlo Simulations and DetectorMeasurements for a Novel Quality Assurance System ofAssembled Brachytherapy Eye Plaques.bySwantje D. Mo¨hleA THESIS SUBMITTED IN PARTIAL FULFILLMENTOF THE REQUIREMENTS FOR THE DEGREE OFMaster of ScienceinTHE FACULTY OF GRADUATE AND POSTDOCTORALSTUDIES(Physics)The University of British Columbia(Vancouver)December 2020c© Swantje D. Mo¨hle, 2020The following individuals certify that they have read, and recommend to the Fac-ulty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled:Combining Monte Carlo Simulations and Detector Measurements fora Novel Quality Assurance System of Assembled Brachytherapy EyePlaques.submitted by Swantje D. Mo¨hle in partial fulfillment of the requirements for thedegree of Master of Science in Physics.Examining Committee:Ingrid Spadinger, Department of Surgery, Faculty of MedicineSupervisorI. Antoniu Popescu, Department of Physics and Astronomy, Faculty of ScienceAdditional ExamineriiAbstractQuality assurance of radiation therapy devices used to treat cancer is important toassure successful treatment and prevent over- or under-dosage. For brachyther-apy eye plaques, the current standard procedure involves measuring the individualseed air-kerma strengths in a well chamber and visually inspecting the plaque. Thisleaves room for errors to occur between seed verification, plaque assembly, and im-plantation. In addition, the availability of manufacturer-assembled commercial eyeplaques has increased, where independent, pre-implantation verification is limitedto verifying the seed strength of additional loose seeds from the same seed lot.Currently, no commercially available system or technique exists for routinequality assurance of assembled eye plaques. This thesis investigates whether a flatpanel image detector can be used in combination with Monte Carlo simulations, todevelop a quality assurance system for assembled I-125 and Pd-103 brachytherapyeye plaques. The detector is used in conjunction with an acrylic plaque holder torecord the 2D dose distribution of the plaque perpendicular to the plaque centralaxis. The system is simulated in Monte Carlo to generate a 3D dose distribution.Calibrating the detector relative to the Monte Carlo results allows comparisonsbetween simulated and measured plaques, making it possible to verify the centraldose rate of the plaque and to verify the 2D dose distribution in the detector planeusing gamma index analysis.Results showed good agreement between the dose distributions and centralstrengths of detector measured and simulated results for a variety of seed strengthsand seed arrangements, enabling the detection of dead or missing seeds. A pro-cedure was established to compare the results to TG-43 dose calculations used intreatment planning. The method was tested on BC Cancer in-house design acryliciiieye plaques and a commercial Eye Physics dummy plaque. The detector showedstrong attenuation for incoming radiation with large angles of incidence, limitingthe applicability of this method for individually collimating plaques.Overall, this study showed that a flat panel imaging detector and Monte Carlosimulations can be combined for routine quality assurance and verification of as-sembled eye plaques without individual seed collimation.ivLay SummaryCancer inside the eye can be treated by brachytherapy, which involves attachinga disk holding radioactive sources to the outside of the eyeball where the tumoris located. The sources emit x-ray radiation, which kills the cancer cells. At thesame time, the radiation also damages surrounding healthy cells. To make surethe cancer cells are killed but healthy cells are protected as much as possible, itis important to verify that the plaque behaves exactly as expected and delivers theright amount of radiation in the right spots. This thesis investigates if images takenwith an x-ray imaging detector can be used to verify assembled plaque properties,by comparing the detector images to computer simulations of the planned plaque.This makes it possible to check plaques directly before implantation and detecterrors, like dead sources, to increase patient safety and reduce the risk of treatmentmistakes.vPrefaceThe idea of using a detector to verify assembled brachytherapy plaques and com-pare them to Monte Carlo simulations was conceived by Dr. Ingrid Spadinger. Mycontributions include the establishment of the measurement protocol, including theholder design, all experiments and experimental designs, as well as all Monte Carlosimulations including the modeling of the different plaque types. The analysis anddiscussion is my work and I wrote all analysis code, with the exception of thegamma analysis code, which I adapted from code written by Dr. Alanah Bergmanand the 3ddose file import code that I received from Dr. Shiqin Su. Dr. IngridSpadinger expanded the in-house TG-43 code to calculate the dose distribution inthe detector plane.Throughout the thesis, sources are cited as appropriate, especially in Chapter 1where the required background knowledge and the motivation for this project areintroduced.viTable of ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiLay Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viTable of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viiList of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xList of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiiGlossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviiAcknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviii1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 Ocular Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1.1 Anatomy of the eye . . . . . . . . . . . . . . . . . . . . . 11.1.2 Medical background . . . . . . . . . . . . . . . . . . . . 31.1.3 Treatment options . . . . . . . . . . . . . . . . . . . . . 41.2 Introduction to Radiation Therapy Physics . . . . . . . . . . . . . 51.2.1 Directly and indirectly ionizing radiation . . . . . . . . . 61.2.2 Radioactive decay . . . . . . . . . . . . . . . . . . . . . 61.2.3 X-ray production . . . . . . . . . . . . . . . . . . . . . . 71.2.4 The decay equation . . . . . . . . . . . . . . . . . . . . . 8vii1.2.5 Radiation properties of brachytherapy source materials . . 91.2.6 Photon-matter interactions and attenuation . . . . . . . . 101.2.7 Air kerma strength, absorbed dose, and activity . . . . . . 131.2.8 Radiobiology: Effects of radiation on cells and tissue . . . 141.3 Brachytherapy Dose Calculations . . . . . . . . . . . . . . . . . . 161.3.1 TG-43 dosimetry formalism . . . . . . . . . . . . . . . . 171.3.2 Monte Carlo techniques . . . . . . . . . . . . . . . . . . 191.4 Eye plaque Treatment Planning and Administration . . . . . . . . 211.4.1 Eye plaque treatment recommendations . . . . . . . . . . 221.4.2 Treatment administration and follow-up . . . . . . . . . . 231.4.3 Eye plaque types and geometry . . . . . . . . . . . . . . 231.5 Eye Plaque Brachytherapy Quality Assurance . . . . . . . . . . . 241.5.1 Treatment plan quality assurance . . . . . . . . . . . . . . 241.5.2 Preoperative quality assurance . . . . . . . . . . . . . . . 251.6 Current Challenges and Thesis Outline . . . . . . . . . . . . . . . 262 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . 302.1 Eye Plaques and Brachytherapy Sources . . . . . . . . . . . . . . 302.1.1 Brachytherapy Eye Plaques . . . . . . . . . . . . . . . . 322.2 Experimental Design . . . . . . . . . . . . . . . . . . . . . . . . 352.2.1 Detector properties . . . . . . . . . . . . . . . . . . . . . 362.2.2 Eye plaque holder design . . . . . . . . . . . . . . . . . . 392.2.3 Seed strength calibration using a well chamber . . . . . . 402.2.4 Radiation safety considerations . . . . . . . . . . . . . . 402.2.5 Experimental setup and measurements . . . . . . . . . . . 422.2.6 Measurements through sterile package . . . . . . . . . . . 422.3 Monte Carlo Calculations . . . . . . . . . . . . . . . . . . . . . . 442.3.1 BC Cancer plaque geometry . . . . . . . . . . . . . . . . 452.3.2 Input and scoring options . . . . . . . . . . . . . . . . . . 452.3.3 MC simulation of Eye Physics plaques . . . . . . . . . . 472.3.4 Absolute dose calculations of the MC results . . . . . . . 482.4 Detector calibration . . . . . . . . . . . . . . . . . . . . . . . . . 492.4.1 Data input and image registration . . . . . . . . . . . . . 50viii2.4.2 Effective detector depth . . . . . . . . . . . . . . . . . . 512.4.3 Effective detector thickness . . . . . . . . . . . . . . . . 522.4.4 Calibration factors . . . . . . . . . . . . . . . . . . . . . 532.5 Analysis and Acceptance Criteria . . . . . . . . . . . . . . . . . . 532.5.1 Relationship between dose distribution and seed strength . 542.5.2 Dose comparison using Gamma-Index analysis . . . . . . 542.5.3 Central percentage difference . . . . . . . . . . . . . . . 553 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573.1 Detector calibration . . . . . . . . . . . . . . . . . . . . . . . . . 573.1.1 125I calibration . . . . . . . . . . . . . . . . . . . . . . . 573.1.2 103Pd calibration . . . . . . . . . . . . . . . . . . . . . . 593.2 Plaque Measurements . . . . . . . . . . . . . . . . . . . . . . . . 623.2.1 Symmetric 125I seed arrangements . . . . . . . . . . . . . 633.2.2 Symmetric 103Pd seed arrangements . . . . . . . . . . . . 643.2.3 Asymmetric seed configurations . . . . . . . . . . . . . . 663.2.4 Detection of dead or misplaced seeds . . . . . . . . . . . 663.3 Measurement through sterile package . . . . . . . . . . . . . . . 693.4 Uncertainty Analysis . . . . . . . . . . . . . . . . . . . . . . . . 703.4.1 Repeated measurements . . . . . . . . . . . . . . . . . . 703.4.2 Monte Carlo uncertainty . . . . . . . . . . . . . . . . . . 713.4.3 Calibration fit uncertainty . . . . . . . . . . . . . . . . . 723.4.4 Seed position influence . . . . . . . . . . . . . . . . . . . 733.4.5 Uncertainty budget . . . . . . . . . . . . . . . . . . . . . 763.5 Translation to TG-43 . . . . . . . . . . . . . . . . . . . . . . . . 773.6 Eye Physics Plaques . . . . . . . . . . . . . . . . . . . . . . . . 813.6.1 Angle based seed contribution . . . . . . . . . . . . . . . 834 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864.1 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89ixList of TablesTable 2.1 Technical data of the Dexela Complementary Metal-Oxide-Semiconductor(CMOS) flat panel detector model 151236. . . . . . . . . . . . . 38Table 3.1 Calibration factors for eye plaques using 125I seeds and an ex-posure time of 1000 ms based on three calibration plaques. . . 59Table 3.2 Calibration factors for eye plaques using 103Pd seeds and anexposure time of 300 ms based on three calibration plaques. . . 61Table 3.3 Results of 125I plaque measurements with symmetric seed ar-rangements showing the central dose-rate values for the detec-tor and MC measurements, as well as the difference betweenthe two in percent (based on the MC values) and the percentageof pixels within the dose cut-off window that comply with thegamma map acceptance criteria by having a gamma value ≤ 1. 63Table 3.4 Results of 103Pd plaque measurements with symmetric seed ar-rangements showing the central dose-rate values for the detec-tor and MC measurements, as well as the difference betweenthe two in percent (based on the MC values) and the percentageof pixels within the dose cut-off window that comply with thegamma map acceptance criteria by having a gamma value ≤ 1. 65Table 3.5 Gamma Analysis and central dose rate difference results for theplaque configurations shown in Figure 3.5 . . . . . . . . . . . 68xTable 3.6 comparison of detector measured dose distributions without ster-ile packaging (1), with the foil between the holder and the detec-tor (2) and with the plaque packed in the self-sealing envelopewith the foil between the holder and the plaque (3). The cen-tral dose difference and gamma agreement percentages use thedetector measurement of (1) as a reference dose distribution. . 70Table 3.7 Results of repeated measurements of a 103Pd seed at differentpositions within a plaque (left) where the seed positions are in-dicated in the image (right). Agreement between detector mea-sured dose and Monte Carlo (MC) calculated central dose rate,as well as gamma index agreement is better the closer the seedis to the center. . . . . . . . . . . . . . . . . . . . . . . . . . . 74Table 3.8 Uncertainty budget for 125I and 103Pd detector and Monte Carloresults. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Table 3.9 Results of measurements of an 103Pd loaded Eye Physics plaque.The measurements marked in yellow were used for the calibra-tion and the effective detector depth is 7 mm. . . . . . . . . . . 81Table 3.10 Results of comparing the superposition of the detector results oftwo plaques, that combined have the same seed configuration asthe plaque they are being compared to. . . . . . . . . . . . . . 84xiList of FiguresFigure 1.1 Schematic drawing of the anatomy of the human eye, picturedas a horizontal cross-section of the right eye. (Image takenfrom: https://en.wikipedia.org/wiki/Human eye) . . . . . . . 2Figure 1.2 Photon attenuation coefficients in water due to coherent Rayleighscattering, incoherent Compton scattering, and photoelectricabsorption at photon energies of 1-50 keV in water14. . . . . . 10Figure 1.3 Relative contributions of Rayleigh (coherent) scattering, Comp-ton (incoherent) scattering and photoelectric absorption to thetotal photon-matter interactions in water at photon energies of1-50 keV14. . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Figure 1.4 Coordinate system used to calculate dose rate at a point P ata distance r and an angle θ with respect to the center of thesource with an active length L and the longitudinal axis. TheTG-43 reference point P(ro,θo) lies along the transverse axisof the seed at a distance of 1cm from the center (not pictured). 18Figure 2.1 Schematic drawing of the cross section of an IsoAid ADVAN-TAGE Pd-103 source with dimensions given in millimeters. Itconsists of a 4.5 mm long titanium capsule with welded ends(blue), encapsulating a 1.25 mm long cylindrical silver markerin the center (purple), and two 0.5 mm diameter polystyrenespheres with uniformly adsorbed radioactive 103Pd (yellow). . 31xiiFigure 2.2 Schematic drawing of the cross section of an AgX100 125Isource with dimensions given in millimeters. It contains a3.5 mm long silver marker, coated with a 2 µm thick layer ofradioactive AgI (orange), encapsulated by a 4.5 mm long tita-nium capsule with welded ends (blue). . . . . . . . . . . . . . 31Figure 2.3 BCCA eye plaque with and without shielding before insertionof sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Figure 2.4 Three in-house design dummy plaques used in this study with-out seeds inserted into the slots, and a gold shield as used forthis plaque type. . . . . . . . . . . . . . . . . . . . . . . . . 34Figure 2.5 The Eye Physics dummy-plaque used in this study, which has30 seed slots and a notch on the side opposite of the eyelets. . 35Figure 2.6 Schematic of top and side of the Dexela CMOS flat panel de-tector model 151236. Dimensions are given in millimeters. . . 36Figure 2.7 The plaque holder, consisting of a solid Polymethyl methacry-late (PMMA) partial sphere with an 11 mm radius of curvatureand an overall height of 6 mm. The holder can be split in themiddle to obtain a 3 mm holder for small plaques. . . . . . . . 39Figure 2.8 Well chamber (top) and seed holder used to position the seed atthe center of the well chamber for seed strength measurements(bottom). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Figure 2.9 The detector setup as seen through the leaded-glass window ofthe radiation shield. It shows the detector with position mark-ings using masking tape, with the plaque holder and plaque po-sitioned in the center of the measurement window. The plaqueis attached with medical tape. . . . . . . . . . . . . . . . . . 43Figure 2.10 Measurement of a plaque with the plastic film of the sterilepackaging between the holder and detector. . . . . . . . . . . 44Figure 2.11 NNDC 2.6 spectrum used in the Monte Carlo simulation of103Pd brachytherapy seeds showing the dominating low photonenergies (left) and the small fraction of high energy gammarays (right). . . . . . . . . . . . . . . . . . . . . . . . . . . . 46xiiiFigure 2.12 NCRP spectrum used in the Monte Carlo simulation of 125Ibrachytherapy seeds. . . . . . . . . . . . . . . . . . . . . . . 46Figure 2.13 Simulated EyePhysics plaque (gold) filled with nine 103Pd seeds(cyan) as seen from two different angles. The plaque is sim-ulated in egs brachy and the image was taken using theegs view software. . . . . . . . . . . . . . . . . . . . . . . 48Figure 2.14 Monte Carlo calculated dose distribution from an 18 seed 103Pdplaque for the region below the detector surface (at z=0). Anincrease along z corresponds to an increased distance to thedetector surface. . . . . . . . . . . . . . . . . . . . . . . . . 51Figure 3.1 Average absolute difference per pixel between the detector mea-sured and MC derived dose distributions in the detector plane,plotted against effective detector thickness for an increasingnumber of 125I seeds in an eye plaque. . . . . . . . . . . . . . 58Figure 3.2 Calibration plot for 125I source plaques using three eye plaquesand a linear least-square fit to determine the calibration factorneeded to convert detector readings to absolute dose rates. . . 60Figure 3.3 Average difference per pixel between the detector measureddose and MC derived dose distribution in the detector planeplotted against an increasing detector thickness between 0.2 mmand 2.4 mm for an increasing number of 103Pd seeds in an eyeplaque. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Figure 3.4 Calibration plot for 103Pd source plaques using three eye plaquesand a linear least-square fit to determine the calibration factorneeded to convert detector readings to absolute dose rates. . . 62Figure 3.5 Detecting deviations in seed arrangements between referenceand evaluated plaque results due to a missing or additional seedin the evaluated plaque compared to the reference plaque. . . . 67xivFigure 3.6 Gamma map comparing the detector result of a plaque with-out sterile packaging to a measurement with the sterile foil be-tween the holder and the detector (left) and with the plaque inthe sterile envelope with the foil between plaque and holder(right). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Figure 3.7 Comparison of seed position influence with the source placedin the center (a) and close to the edge of the plaque (b). Theimages at the top show the dose rate map resulting from thedetector measurement. The middle images show the dose ratemap as calculated from the MC simulation. The bottom im-ages show the gamma map with a dose cut-off of 25% of themaximum dose and 3%/1mm acceptance criteria. The seedpositions a & b correspond to the results 1 & 11 in Table 3.7. . 75Figure 3.8 Plaque design used to compare TG-43 and Monte Carlo dosedistributions in a uniform water phantom. . . . . . . . . . . . 78Figure 3.9 Dose rate distributions in the detector plane for an 11 seedplaque as calculated using a uniform water phantom MonteCarlo simulation (top left), and the TG-43 algorithm (top left).In the lower row, the left image shows the gamma index mapwith a very good agreement between both results, while theright image shows the pixel-wise difference between the MCand TG-43 result. . . . . . . . . . . . . . . . . . . . . . . . . 78Figure 3.10 Flowchart of the plaque verification process. . . . . . . . . . . 80Figure 3.11 Calibration plot for the Eye Physics plaque using 4 measure-ments (left) and the pixelwise difference between MC resultand detector measurements using this calibration factor for an16 seed plaque (right). . . . . . . . . . . . . . . . . . . . . . 81Figure 3.12 Seed configurations used to determine if a plaque measurementresult can be modeled by the combination of two symmetricplaques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83xvFigure 3.13 Difference between the (reference) dose distribution of the fullplaque and the (evaluated) dose distribution of the combinedplaques, showing very good agreement. The measured plaqueis shown in Figure 3.12b. . . . . . . . . . . . . . . . . . . . . 85xviGlossaryCMOS Complementary Metal-Oxide-SemiconductorLDR Low Dose RatePMMA Polymethyl methacrylateMC Monte CarloADCL Accredited Dosimetry Calibration LaboratoryNIST National Institute of StandardsPBRT Proton Beam RadiotherapyADC Analog to digital coverterDAQ Data acquisitionNRC National Research Council of CanadaHVL Half Value LayerTPS Treatment Planning SystemHDR High Dose RateLINAC Linear AcceleratorABS American Brachytherapy SocietyAAPM American Association of Physicists in MedicineAJCC American Joint Comittee on CancerCOMS Cooperative Ocular Melanoma StudyFPN Fixed Pattern NoisexviiAcknowledgmentsFirst and foremost I would like to thank my supervisor, Dr. Ingrid Spadinger, forall her support and guidance, her helpful answers to my many questions, and thethoughtful conversations about my work. Many thanks as well to Dr. Maral Gol-shan for helping me with the detector, and Dr. Marc Chamberland for answeringall my questions about egs brachy. I also want to express my appreciation to thestaff and students at the BC Cancer Medical Physics department in Vancouver forthe help, support, community, and for their inspiring dedication to their patients’health.My deep gratitude also goes to my parents and the friends who helped me finisha thesis in the middle of a pandemic. Especially to Lara for the tea, Kelsey, Else,and Rosie for the mountain adventures, and my partner Joe for a continuous supplyof support and coffee.Finally, I want to thank all people, past and present, who contributed to makingradiation therapy - and this type of research - safe. Especially those who sufferedradiation injuries and chose to be studied to prevent harm to others.xviiiChapter 1Introduction1.1 Ocular MelanomaCancer is a complex and common disease, one of the leading causes of death world-wide and the leading cause of death in Canada. Statistically, every second Canadianwill develop cancer during their lifetime and one in 4 Canadians will die from it1.While cancer is a heavily studied disease, its complexity makes it difficult to treatand its many forms require individual and specialized treatment solutions. Theycan generally be categorized into three main categories: surgery, chemotherapy,and radiation therapy. A rare but dangerous kind of cancer is ocular melanomawhich occurs inside the eye and often metastasizes to the liver with a very poorprognosis and without a systemic treatment option. Ocular melanoma is primarilytreated by radiation therapy, with good local control. The following section willgive an overview of the disease as well as current treatment options.1.1.1 Anatomy of the eyeThe eye is a complex organ responsible for vision. Its main component, the globe(more commonly called the eyeball) consists of three layers of tissue. The sclerais the white, tough outer layer and covers most of the globe. In the front (anterior)a circular opening is instead covered by the translucent cornea to let light insidethe eye. The uvea is the middle layer and mostly consists of the choroid, a thin,pigmented layer filled with blood vessels and capillaries, that lines the inside of the1Figure 1.1: Schematic drawing of the anatomy of the human eye, picturedas a horizontal cross-section of the right eye. (Image taken from:https://en.wikipedia.org/wiki/Human eye)sclera and supplies the vision layer (the retina) with blood. On the anterior sideof the eye behind the cornea is the iris, a colored circular muscle responsible forregulating the amount of light entering the eye by adjusting the size of the pupil,a small opening in its center. Behind the pupil sits the lens, which is held by theciliary body and is deformed by ciliary muscles to adjust the focus of the eye. Thespace between the iris and the cornea is called the anterior chamber of the eye and isfilled with aqueous humor, a fluid produced by the ciliary epithelium in the ciliarybodies. The innermost layer of the eye is the retina, which covers the back andsides of the eye and contains light sensitive photoreceptor cells that are connectedto the optic nerve. The optic nerve exits the globe on the back of the eye in theoptic disk, where all nerves coming from the photoreceptors combine. Next to the2optic disk, at the focal point on the retina is the macula, a region without bloodvessels but with a high density of cone photoreceptors, whose center, the fovea, isresponsible for high acuity vision. The inside of the eye is called the vitreous bodyand is filled with fluid.The globe sits in a pocket of tissue inside the orbit, a bony socket that is partof the skull. Six extraocular muscles are attached to the sclera on all sides and areused to move the eye in all directions. A variety of accessory structures protect,lubricate, and support the eye, including the eyelids, tear glands and the tear duct,which connects to the nasal passage and helps drain excess tears2. A schematicdrawing of the anatomy of the eye is shown in Figure 1.1.1.1.2 Medical backgroundOcular melanoma is a rare type of cancer with a worldwide incidence rate of 5per million3 but it is the second most common type of melanoma (after cutaneousmelanoma in the skin). Incidence rates are slightly higher in men than women,with a male to female ratio of 1.29, and increases with age. The median age ofpatients is 55 years at diagnosis. Similar to skin melanoma, uveal melanoma israre among People of Colour, with white people having 8 times the risk of devel-oping this disease as compared to Black people in the US4. The most commonsite of origin of ocular melanoma is the uvea, but occurrence is also possible in theiris, ciliary body, and choroid. Symptoms of uveal melanoma depend on size andlocation of the tumor and can range from asymptomatic to vision impairment orvision loss. It is diagnosed via ophthalmic examination, where it most commonlypresents as a dome or mushroom shaped subretinal mass, with color ranging fromnon-pigmented (amelanotic) to brown5. The primary ocular melanoma tumor isclassified by anatomical extent as well as ciliary body and extrascleral involvementbased on the American Joint Comittee on Cancer (AJCC) cancer staging manual6.While being a rare disease, ocular melanoma is a tumor with a high incidence ofmetastatic spread and an extremely poor prognosis after occurrence of metastases.Due to the lack of lymphatic drainage in the uvea, metastatic spread is throughblood and not through the lymphatic system. The most common site for metastasisis the liver, followed by lung and bone, with a median survival of only 2-4 months3following diagnosis of hepatic metastasis4. Currently, no systemic treatment formetastatic uveal melanoma is available, resulting in very low survival rates. 80%of patients die within one year of diagnosis of metastases and 92% within 2 years.The most important clinical features to determine prognosis are tumor size anddiameter, involvement of ciliary body or extrascleral tissue, and genetic risk fac-tors5. As risk increases with increasing tumor size and thickness, early detectionand treatment is key to reducing the risk of metastatic spread.1.1.3 Treatment optionsTreatment options for ocular melanoma encompass surgery, radiation therapy, or acombination of both. Surgical treatment is the oldest and most radical treatment,consisting of enucleation, in which the affected eye is removed. In addition, sur-rounding affected tissue can be removed during surgery. With the advancement ofmodern, more conservative treatments, the use of enucleation has decreased andtoday it is reserved for treatment of very large or diffuse tumors for which othertreatment methods would fail or have already failed. Instead, modern radiationtherapy treatment options aim to conserve eye and vision and are therefore con-sidered conservative treatments. The two categories of radiation therapy treatmentfor ocular melanomas are external beam radiotherapy and brachytherapy. Exter-nal beam therapy approaches for uveal melanoma most commonly use protonsto irradiate the tumor. However, photon based external beam stereotactic radio-surgery using a Linear Accelerator (LINAC) is less commonly used as well7. InProton Beam Radiotherapy (PBRT), a proton external beam is used to irradiate thetumor while sparing the healthy tissue surrounding it, taking advantage of the pro-ton beam property of depositing most of the dose in a specific, narrow range ofdepth within the tissue, known as the Bragg-Peak. Before the treatment, metal-lic markers are inserted surgically to mark the tumor location. During treatment,the patient remains sitting and is immobilized using an immobilization mask forthe head. Treatment is delivered in multiple fractions lasting a few minutes overmultiple (commonly four) days at a specialized particle accelerator facility8. Dueto the highly specialized equipment needed in PBRT, as well as the high costs andrequirements for operating these facilities, this treatment is only available in a few4highly specialized treatment centers and is the method of choice for large tumorsor those located very close to critical structures like the optic disk or the macula9.The most commonly used treatment option is Low Dose Rate (LDR) brachyther-apy using an episcleral eye plaque. For this, a number of small radioactive sources(seeds) is inserted into a concave disk (plaque) made of metal or plastic. A lesscommonly used type of plaque consists of a disk with a uniformly distributed ra-dioactive layer across the inner surface. The plaque is surgically attached to theouter globe on top of the tumor location and remains there for a period of 4-7 days,after which it is surgically removed. In between surgeries, the patient is free toleave the clinic and partake in their normal life as much as possible. The numberand individual strength of the seeds are determined by the size and shape of thetumor and required safety margins.The outcome of all three treatment options is similar in qualifying tumors, withvery good local control and similar long-term survival rates3, although the morbid-ity profiles differ. The most common treatment related morbidity is vision loss ordecline, due to radiation toxicity in critical structures. These include cataracts, ra-diation retinopathy, neovascular glaucoma, and optic neuropathy. While cataractcan relatively easily be corrected by lens-replacement surgery, the other morbidi-ties result in irreversible vision damage. The risk of these morbidities increaseswith the dose to critical structures, especially the macula and the optic nerve andtherefore strongly depends on the position of the tumor10.1.2 Introduction to Radiation Therapy PhysicsRadiation therapy uses the toxic effects of ionizing radiation on biological cells andtissue to treat cancer. To understand the underlying mechanisms, it is important tounderstand what radiation is and how it can be described. This includes knowingabout the properties of different kinds of radiation, and how they are generated andbehave. Another important aspect is understanding how radiation interacts withmatter, and how this interaction affects cells and tissue. The following section isintended to provide an overview of these fundamental concepts. More in-depthintroductions can be found in the literature, for example in the textbook by Johnsand Cunningham 11.51.2.1 Directly and indirectly ionizing radiationIonizing radiation consists of fast moving particles with high enough energy toionize other atoms or molecules by detaching electrons from them. There are twomain types of ionizing radiation: directly, and indirectly ionizing radiation. Di-rectly ionizing radiation consists of charged particles with mass, like electrons,atomic nuclei, or protons. When moving at large speeds, these particles directlyionize nearby atoms by fundamental interaction through the Coulomb force. α andβ particles belong to this category. Indirectly ionizing radiation does not interactstrongly with matter and consists of uncharged, electrically neutral particles likehigh-energy neutrons or photons in the ionizing range of the electromagnetic spec-trum. However, when an interaction does occur, directly ionizing particles are setinto motion. Any discussion of photon radiation or interaction in the followingonly refers to photons in the ionizing energy range.1.2.2 Radioactive decayRadioactive decay describes the process in which an unstable nucleus (the parentnuclide) emits energy by emitting radiation, decaying into a daughter nuclide oflower mass and energy. A nucleus is unstable if the forces among the particles in itare unbalanced and the nucleus has an excess of internal energy. An unstable atomwill continue to decay and emit particles and energy until the forces are balancedand the nucleus is stable. Each radioactive decay process is characterized by theemitted radiation (the type and energy of emissions), with the most common onesbeing:• α decay: A helium nucleus, known as an α particle, is emitted during thedecay process. It consists of 2 protons and 2 neutrons, so the atomic numberof the daughter nuclide is reduced by 2 and the mass number by 4 comparedto the parent nuclide.• β− decay: A neutron in the nucleus decays into a proton by emitting anelectron (β− particle) and an anti-neutrino ν¯ , increasing the atomic numberof the daughter nuclide by one.• β+ decay: A proton in the nucleus decays into a neutron, releasing a positron6(β+ particle) and a neutrino, decreasing the atomic number of the daughternuclide by one compared to its parent.• γ decay: A nucleus in an excited state (often as a result of a previous decayprocess like an α or β decay), decays to a lower energy state by emitting aphoton (γ particle).• electron capture: When the nucleus absorbs an electron from one of theinner electron shells, a proton changes into a neutron, releasing an electronneutrino νe and decreasing the atomic number of the daughter nuclide byone.• internal conversion: In an internal conversion process, an excited nucleusinteracts with one of the orbital electrons, causing the electron to be ejectedfrom the atom.Each chemical element is characterized by its atomic number, which is equal tothe number of protons in that atom’s nucleus. However, in most cases, a variety ofatoms of one element with different numbers of neutrons exist. These variants arecalled isotopes and their nuclear properties can differ from each other due to thedifferent neutron numbers. While some isotopes are stable, others, called radioiso-topes, are unstable and therefore radioactive. Isotopes are named by specifying thename of the element and the isotope’s mass number (the combined number of pro-tons and neutrons in the nucleus). Examples of radioisotopes are Palladium-103(or 103Pd ), a radioisotope of the element Palladium, consisting of 46 protons and57 neutrons, or the radioisotope Iodine-125 (or 125I ), consisting of 53 protons and72 neutrons.1.2.3 X-ray productionX-rays are high energy photons that are primarily emitted in one of two ways:as characteristic X-ray radiation, or through bremsstrahlung. Depending on theenergy of the photons, they are used in medical imaging applications and photon-based radiation therapy. The two main ways of producing X-rays can be explainedin the following way:7• characteristic X-rays: When an orbital electron in an excited energy staterelaxes to a lower energy state, it releases a photon carrying the differencein energy. Each atom’s electron energy states are discrete and depend on theatomic number of the atom. This results in the energy of the released pho-ton being characteristic of the producing element and state change, resultingin distinct lines on the electromagnetic spectrum. When the resulting char-acteristic photons have energies in the x-ray range of the electromagneticspectrum, they are called characteristic x-rays. Electron capture and inter-nal conversion processes lead to the emission of characteristic radiation. Insome cases, instead of emitting a photon, the energy released in this processis transferred onto a different shell electron which is then emitted from theatom. This is known as an Auger electron.• Bremsstrahlung: Bremsstrahlung consists of photons produced by the de-celeration of a charged particle (typically an electron) due to deflection byanother charged particle (typically a nucleus). The radiation produced hasa continuous spectrum and this effect is heavily utilized in the productionof X-ray beams used for external beam radiation therapy and radiographicimaging.1.2.4 The decay equationRadioactive decay is a Poisson process and can be modeled as an exponential de-cay. This means that while the decay behavior of each individual atom is randomand cannot be predicted deterministically, the behavior of an ensemble, consistingof a large number of atoms, will behave deterministically and can be calculatedusing the decay equation:N(t) = N0 exp(−λ t) . (1.1)The number of non-decayed atoms of a certain element N(t) at a given time tdepends on the initial number of atoms N0 and the decay constant λ , which ischaracteristic for the specific radioisotope. λ is related to the half-life T1/2, thetime it takes until a given amount of a radioactive substance has decayed to half its8initial amount, viaT1/2 = ln(2)/λ . (1.2)The activity A defines the number of decays per unit time and can be derived fromEquation 1.1 as:A=− dNdt= λN . (1.3)1.2.5 Radiation properties of brachytherapy source materialsA variety of photon emitting radioisotopes are used for brachytherapy applications,including 125I , 106Ru, 103Pd , 131Cs, 198Au and 192Ir. For eye plaque brachytherapy,125I and 103Pd are most widely used in North America12. Both have in commona relatively short half-life and, more importantly, emit low-energy photons, whichmakes them easy to shield and handle. The activities used in eye plaque appli-cations are significantly higher than in other common brachytherapy applicationsthat use these radionuclides (such as permanent prostate implants), due to the lownumber of seeds used in each plaque, as well as the limited irradiation time of a fewdays. While both 103Pd and 125I are used widely, their radiation properties differ,which must be accounted for in treatment planning.Radiation properties of 103PdPalladium-103 is a radioisotope of the element Palladium with a half-life of 17days. Its primary decay route is via electron capture to the first excited state of103Rh, which then de-excites primarily via internal conversion to the ground state.Photons emitted as characteristic x-rays from the internal conversion process haveenergies ranging from 20-23 keV with a mean energy of 21 keV. In addition, asmall fraction of photons is emitted as high-energy gamma rays13.Radiation properties of 125IIodine-125 has a half-life of 59.4 days and emits characteristic x-rays with ener-gies between 27.2 and 31.7 keV, with a mean energy of 28 keV, by decaying via9Figure 1.2: Photon attenuation coefficients in water due to coherent Rayleighscattering, incoherent Compton scattering, and photoelectric absorptionat photon energies of 1-50 keV in water14.electron capture to an excited state of 125Te, which then de-excites via internal con-version. A small amount of 35.5 keV photons is produced by gamma decay insteadof internal conversion13.1.2.6 Photon-matter interactions and attenuationWhile charged particles like α and β particles interact strongly with matter andare easily attenuated, photons interact much less frequently and are therefore muchmore penetrative. In LDR brachytherapy applications, radioisotopes are encapsu-lated in a biocompatible material, often a small capsule of titanium. The titaniumis sufficient to stop the emitted charged particles, while a large proportion of thephotons passes through.The attenuation of a non-diverging mono-energetic photon beam passing througha medium is characterized by the linear attenuation coefficient µ , which dependson the material properties, including the density ρ , and the energy of the photons,10as shown for water in Figure 1.2. It can be described by an exponential decayequation:N(x) = N0 exp(−µx) , (1.4)where N(x) is the number of photons at depth x in the material and N0 is the numberof photons entering the material (at x=0). A multi-energetic beam can be describedas a combination of multiple monoenergetic beams. Similar to the half-life forthe decay properties of a radioisotope, the Half Value Layer (HVL) defines thethickness of a material needed to reduce the intensity of a defined type of radiationby 1/2. It is related to the attenuation coefficient as:HVL= ln(2)/µ . (1.5)This property is often used in radiation shielding calculations with lead as the ref-erence material. The HVL to shield photons of encapsulated sources is 0.004 mmof lead for 103Pd and 0.025 mm of lead for 125I sources15.The beam attenuation is a result of individual photons interacting with themedium. µ is therefore related to the probability of such an interaction. Wheninteracting with matter, a photon can either be scattered (with or without energytransfer) or completely absorbed (full energy transfer). An energy transfer inter-action results in ionization of the interacting atom causing fast, high energy elec-trons to be ejected. These electrons lose their energy by exciting or ionizing otheratoms along their path. There are three relevant types of interactions for low energyphotons as used in brachytherapy applications: the photoelectric effect, Comptonscattering, and Rayleigh scattering.The photoelectric effectThe photoelectric effect is a complete energy transfer interaction, where a suffi-ciently high energy photon is absorbed and an electron (photoelectron) is ejectedfrom a bound shell of the interacting atom. The ejected photoelectron’s energyis the photon energy minus the binding energy of the electron. The resulting va-cancy in the shell is filled with an outer shell electron, emitting the excess energy11as Auger electrons or characteristic photons. The photoelectric effect is especiallypronounced in photons of low energies within the ionizing range of the electro-magnetic spectrum, and absorber materials of high atomic number Z.Compton scatteringThe Compton effect is a partial energy transfer interaction, where the incomingphoton is scattered off an outer valence electron of the atom it interacts with, eject-ing the electron in the process. The photon is deflected at an angle and transferssome of its energy to the electron in the process. Compton scattering is also knownas incoherent scattering.Rayleigh scatteringIn a Rayleigh, or coherent scattering process, the incoming photon interacts withthe electron cloud of an atom. It briefly excites the electron cloud and is deflectedby a small angle. There is no energy transfer and the photon retains its full energy.It is common at low energies and in high atomic number materials.At a photon energy of 21 keV, the average energy emitted by 103Pd , the pho-toelectric effect is the most important photon-matter interaction process in water,closely followed by Compton scattering. At 28 keV, the average energy emittedby 125I , Compton scattering and the photoelectric effect contribute nearly equally.The relative contributions of the three described effects on low-energy photon in-teractions with water are shown in Figure 1.3.X-ray sources emit radiation in all directions, resulting in divergence effectsthat cause the X-ray intensity to fall off in proportion to the inverse square of thedistance traveled from the source. Due to this, the energy deposited by a radioac-tive source into the surrounding water medium is very high close to the sourceand decreases rapidly with increasing distance. This 1/r2 dependence (where r isthe distance from a point source) dominates the energy deposition surrounding abrachytherapy source.12Figure 1.3: Relative contributions of Rayleigh (coherent) scattering, Comp-ton (incoherent) scattering and photoelectric absorption to the totalphoton-matter interactions in water at photon energies of 1-50 keV14.1.2.7 Air kerma strength, absorbed dose, and activityAn important quantity in radiation dosimetry is kerma K, which stands for “KineticEnergy released per unit mass”. It is defined as the average amount of energytransferred (Etr) in a small volume from indirectly ionizing radiation to directlyionizing radiation, or in other words, the sum of the initial kinetic energies of allcharged particles produced by uncharged (photon and neutron, if present) ionizingradiation in a sample of matter, divided by the mass m of the sample:K =dEtrdm(1.6)Kerma is dependent on the sample material. In brachytherapy applications, thekerma in air, or air-kerma, is used to measure source strength. It is specified interms of air kerma strength Sk, which is defined as the product of air kerma rateK˙δ (d) due to photons of energy greater than δ in vacuo at distance d, and thesquared distance d at a point along the perpendicular bisector of the source, with d13typically being 1 meter:Sk = K˙δ (d) ·d2 (1.7)The unit of air kerma is gray (Joules/kg), whereas air kerma strength is measuredin U, where 1 U = 1 µGym2/h = 1 cGycm2/h. The d2 term is accounting for theinverse square fall-off effects with increasing distance.Absorbed dose D is another important quality in dosimetry. It is the energydeposited in matter by ionizing radiation per unit mass. Dose is given in the sameunit as kerma, in gray, defined as one Joule of energy absorbed in one kilogramof matter. For low energies, dose and kerma are nearly equal at a given point inan absorber material. However, in a radiotherapy context, dose is more commonlycalculated in water or tissue, as opposed to in air like the air-kerma. Dose is theprincipal determining factor for the effect of radiation on tissue and therefore thequantity in which prescriptions are specified in radiotherapy.1.2.8 Radiobiology: Effects of radiation on cells and tissueWhen radiation interacts with tissue, it can lead to cell damage and death if theenergy of the radiation particles is absorbed in, or close to, critical structures, mostimportantly the cell nucleus and the genetic information contained in the DNAwithin it. The DNA consists of a double-stranded helix where the genetic infor-mation is encoded in matching sets of opposing nucleic acid basepairs on eachstrand of the helix. There are two main ways in which radiation can damage oneof the DNA strands: by having the radiation particle directly interact and exciteor ionize atoms in the DNA strand, leading to a break, or indirectly by ionizingsurrounding molecules and producing radicals (atoms or molecules with at leastone free valence electron) which interact with atoms in the DNA strand and leadto a break. A break in one of the DNA strands can be quickly repaired by the celland while it can result in mutations during the repair, it in most cases doesn’t leadto further damage. However, if both strands break within a few base-pairs of eachother, the DNA helix breaks apart and it is often irreparably broken. This leads tocell mutations and often cell death, either immediately or by causing failure dur-ing cell division. Due to the stochastic nature of radiation-matter interactions, it14is impossible to predict where and when exactly the damage in any individual cellwill occur, but it is possible to predict the effects on an ensemble of cells. As ageneral rule, the cell toxic effect of radiation increases with the absorbed dose inthe tissue, but different kinds of cells exhibit different sensitivities to dose, makingthem more or less susceptible to damage. The pattern of dose deposition also influ-ences the effectiveness of different types of radiation in causing irreparable doublestrand breaks. A more detailed introduction to radiobiology can be found in theliterature16.Deterministic and stochastic effects of radiation exposureWhen discussing radiation exposure effects, we differentiate between stochasticand deterministic effects. The type of exposure determines which of these effectsis prevalent. High dose rates and events with large exposure above a critical doselimit result in deterministic effects, while low exposure events are responsible forstochastic effects. It is important to note that there is no dose threshold underwhich radiation exposure is considered harmless. Any increase in dose to tissueincreases the chance of cell damage and mutations that can lead to a long-termincrease in cancer risk. This increase in risk is only observable across a largenumber of people and is therefore considered a stochastic effect. It is the reasonwhy doctors try to minimize radiation exposure during diagnostic imaging andstrict radiation protection protocols are applied whenever possible. The stochasticeffects of radiation damage will often surface after a very long time of multipleyears or decades, making it difficult to link cause and effect. The deterministiceffects of radiation on the other hand are felt within hours to months after exposureto high amounts of radiation, as encountered in nuclear accidents and in radiationtherapy, when a large number of cells is damaged significantly, to the point ofcell death. This type of damage is considered deterministic because it is possibleto predict the risk of damage that a dose above a critical threshold will producein an organ. Exposure to such doses can be intentional, as in radiation therapy,where a threshold dose must be reached throughout the target volume to kill thetumor cells, but it can also be unavoidable when healthy tissue is irradiated anddamaged during treatment. Radiation damage occurs in both healthy and cancer15cells, making healthy tissue sparing and shielding one of the most important aspectsof radiation therapy.Different kinds of tissue also express varying levels of sensitivity to radiation.In the eye, the dose required to control uveal melanoma exceeds the dose toleranceof the retina, optic nerve, lens, eyelids and lashes as well as the lacrimal appara-tus15. Therefore, these structures, especially the optic nerve due to its functionalimportance to vision, should be spared from dose as much as possible without com-promising treatment success. The cell toxic effects of radiation on both healthy anddiseased tissue constitutes the main optimization problem in radiation therapy. Onone hand, it is important that ideally all cancer cells receive a dose high enoughto kill the tumor or establish control, to reduce the risk of metastatic spread andrecurrence. On the other hand, both the maximum dose to healthy tissue and theamount of healthy tissue irradiated should be minimized, to prevent damage andreduce the risk of causing new radiation-induced cancer in the future.1.3 Brachytherapy Dose CalculationsIn brachytherapy, dose calculation is based on the formalism outlined in the AAPMTask Group 43 (TG-43) report17. It describes an analytical solution to calculatingthe dose distribution based on a set of parameters describing the source and as-sumes a homogeneous, infinite water phantom to calculate the dose in. It does notaccount for effects like the self-attenuation of an assembly of seeds, attenuation orscattering by other components of an eye plaque, or the impact of inhomogeneoustissue composition. While some brachytherapy treatment planning systems haveevolved to include more realistic dose calculations, eye plaque brachytherapy dosecalculations are still mostly done using TG-43 calculations. A few specialized eyeplaque treatment planning systems, like the Plaque Simulator Software [Eckert andZiegler, Berlin, Germany], have tried to fill this gap and employ a small number ofcorrections. Due to its importance, a short introduction to the TG-43 formalism isprovided in the following.161.3.1 TG-43 dosimetry formalismThe TG-43 formalism17 calculates dose to water in an infinite water medium, butuses the seed strength in air at large distance, in units of air kerma strength, as aninput because the dose or air-kerma rates close to the source are subject to steepgradients due to the inverse square fall-off and are therefore extremely difficultto measure in a clinical setting. The measurement is made in air for practicalreasons, one of which is to minimize attenuation effects that would further reducethe dose or kerma rate at large distances. For each source type, a set of parametersis determined that characterizes the in-water dose distribution around the source.These parameters account for radiation properties as well as scatter, absorption,and attenuation by the source capsule. They are published as TG-43 parametersand used for treatment planning, and are determined through a combination ofexperimental measurements and Monte Carlo (MC) simulations for each type ofbrachytherapy source approved for clinical use. In the TG-43 formalism, seedscan either be treated as cylindrical sources, or approximated as point sources ifthe orientation of the seeds is difficult to determine. The dose rate at a point ofinterest P(r,θ), at a distance r from the seed center and an angle θ relative to thelongitudinal axis of the source, is calculated via:D˙(r,θ) = SkΛGL(r,θ)GL(r0,θ0gL(r)F(r,θ) (line source form) (1.8)D˙(r,θ) = SkΛGp(r,θ)Gp(r0,θ0)gp(r), φ¯an (Point source approximation) (1.9)Here, r0 = 1cm denotes the reference distance used and θ0 = 90◦ states the ref-erence angle defined by the transverse plane. Sk denotes the air kerma strengthof the seed. Λ is the dose-rate constant in water and is dependent on the sourceradionuclide and source construction. It is another important TG-43 parameterand provides the relationship between Sk and dose in water at the TG-43 referencepoint. A diagram of the seed coordinate system is shown in Figure 1.4.The next factor, GL(r,θ) or Gp(r,θ), is the geometry function for the line and17Figure 1.4: Coordinate system used to calculate dose rate at a point P at adistance r and an angle θ with respect to the center of the source withan active length L and the longitudinal axis. The TG-43 reference pointP(ro,θo) lies along the transverse axis of the seed at a distance of 1cmfrom the center (not pictured).point source approximation, respectively. For the line source, it is given by:GL(r,θ) =βLr sinθ if θ 6= 0◦1r2−L2/4 if θ = 0◦(1.10)where β is the opening angle between the point of interest P and the end points ofthe source’s active length L. The geometry function for the point source is givenby a simple inverse square equation of the distance:Gp(r,θ) =1r2(1.11)The relative dose function gX(r) (where X = L or p) accounts for dose fall-off withdistance in the transverse plane, primarily due to photon attenuation and scattering.It is defined so that g(r = r0 = 1cm) = 1. It is provided in tabulated form andinterpolated during calculations.The 2D anisotropy function F(r,θ) is used for the line source approximation18and describes the variation in dose as a function of polar angle relative to the trans-verse plane. It is defined as unity on the transverse plane (at θ = θ0 = 90◦) andtypically decreases as r decreases, θ moves away from the transverse plane, andas encapsulation thickness increases or photon energy decreases. It is also given intabulated form and can be interpolated for treatment planning. In the point sourceapproximation, the 1D anisotropy function φan(r) replaces F(r,θ). At a given dis-tance r, it is the ratio of the solid angle weighted dose rate averaged over the entire4pi steradian space, to the dose rate at the same distance on the transverse plane.For long implant times and sources with relatively short half-lives, the doserate changes over time and is therefore a function of r, θ and the time t. For theline source, it is given by:D˙(r,θ , t) = Sk exp(−λ t)Λ GL(r,θ)GL(r0,θ0)gL(r)F(r,θ) . (1.12)λ denotes the decay constant of the radioisotope. To calculate the total dose topoint P, the dose-rate needs to be integrated over the implantation time T :D(r,θ ,T ) =∫ T0D˙(r,θ , t)dt (1.13)=Skλ(1− exp(−λ t))Λ GL(r,θGL(r0,θ0)gL(r)F(r,θ) (1.14)For multiple sources, the dose contributions to a point P are individually calculatedand then summed up. The TG-43 formalism therefore doesn’t include effects likeself-attenuation and shielding and other interaction effects between sources.1.3.2 Monte Carlo techniquesMonte Carlo (MC) simulations are a class of computational methods and algo-rithms used to solve complex mathematical problems that cannot be solved byanalytical means. The technique makes use of the law of large numbers in proba-bility theory, which states that the average of the results of repeating an experimenta large number of times will converge towards the expectation value. MC sim-ulations use repeated random (or pseudo-random) sampling from the probabilitydistribution describing the problem. The name ”Monte Carlo” refers to the well-19known casino in Monaco, due to the similarities between this statistical methodand the process of gambling when rolling a dice or playing roulette. Due to thelarge number of repetitions needed to converge on a reliable result, MC simulationsare computationally expensive, but their flexibility and broad range of possible ap-plications make them the tool of choice to solve a variety of problems in physics,mathematics, business, biology, and many other fields. A detailed overview ofradiation therapy applications of MC techniques can be found in the literature18.Due to the inherent randomness of radiation interactions, MC simulations havelong been the preferred method to simulate radiation transport. In radiation therapyapplications, they have been used to both calculate dose distributions pre-treatment,as well as validate dose measurements with great success. However, they are toocomputationally expensive for routine treatment planning. The probability dis-tributions that govern the interactions of photons, particles, and matter are wellknown. Therefore, the random trajectories of photons and their interaction with themedium they are traveling through can be modeled by generating large numbers ofparticles and randomly sampling from the respective probability distributions. Thatway, the trajectory of the photon, its interaction with the medium and all secondaryparticles and their respective trajectories can be calculated by randomly samplingfrom the probability distributions for each step. Within a defined region of inter-est (the scoring region), any physical property, like the absorbed energy, can becalculated (scored). The ensemble of events, from the origin of a particle until itand all other particles resulting from its interactions have been absorbed or left themodeled region, is called a particle history or particle shower. After calculating alarge number of these particle histories, the average and standard deviation of thedeposited energy in each voxel of the medium can be calculated and the final dosedeposition is found by summing up the energy deposition of each history dividedby the mass of the voxel.EGSnrcThe EGSnrc software toolkit is a Monte Carlo codebase that can be used to sim-ulate a wide range of radiation physics experiments. It is an open-source codemaintained by the National Research Council of Canada (NRC) and can simulate20coupled electron-photon transport for particle energies between 1 keV and 10 GeVin a wide range of geometries and materials. EGSnrc contains the geometry libraryegs++, which enables the user to design geometries to be used for the simulation,as well as an extensive library of atomic scattering cross-section tables. A spe-cialized toolkit for brachytherapy applications based on EGSnrc is egs brachy,which contains a library of brachytherapy sources, material properties, and ra-dioisotope spectra and is optimized to solve brachytherapy problems in an efficientmanner19. egs brachy input files generally contain a combination of geome-tries. For brachytherapy seeds, the source geometry is a model of the seed(s). Thesource geometry is inscribed in a phantom geometry that models the region of in-terest (e.g. detailed anatomy or homogeneous water). The scoring geometry is theregion in which dose is scored. It is voxelized and the size of the voxels must bedefined when writing the model. A variety of scoring options can be defined, in-cluding whether the individual particle tracks or other properties are being saved,as well as an energy cut-off for low energy particles and other efficiency enhancingprocedures. egs brachy can also automatically produce an egsphant output fileto display the geometry and material properties of the phantom in other softwareapplications. It outputs the dose distribution and relative error in a 3ddose file thatis the common file format for these applications and can easily be used to importthe data into other programs for analysis. A detailed description of the code can befound in the user manual20.1.4 Eye plaque Treatment Planning and AdministrationTo optimize the dose distribution administered to a patient during treatment (inother words to achieve a sufficient dose to the tumor while protecting healthy tis-sue), treatment planning specialists (medical physicists or dosimetrists) generatea treatment plan. Depending on the tumor, treatment region and modality, this isdone manually using an established dose calculation formalism or via a TreatmentPlanning System (TPS), a software that implements these formalisms and may addextra correction factors not included in the original formalism. Eye plaque treat-ment planning encompasses several steps, including determining the prescriptiondose and treatment duration, selecting the type of radionuclide and plaque type21to be used, and finding the best configuration of seed numbers, activity and posi-tions in the plaque. This process requires repeated iterations and calculation of thedose distribution. Therefore, a fast dose calculation such as the TG-43 algorithmis generally used. Once the treatment plan has been made, multiple quality assur-ance procedures are completed before the treatment is administered. The followingsection focuses on the treatment planning and administration of brachytherapy eyeplaques.1.4.1 Eye plaque treatment recommendationsBecause differences in treatment practices often exist between treatment centers,professional organizations like the American Brachytherapy Society (ABS) andAmerican Association of Physicists in Medicine (AAPM) develop and publish guide-lines for plaque brachytherapy of uveal melanoma21 and other types of brachyther-apy treatments. This includes two publications by the AAPM Task-Group 129 ondose calculation methods for intraocular tumors22 and dosimetry of 125I and 103PdCooperative Ocular Melanoma Study (COMS) plaques23. Clinically, it is recom-mended that eye plaque brachytherapy is provided in a specialized medical centerby a team composed of a trained plaque surgeon, a radiation oncologist, and a med-ical physicist trained in plaque brachytherapy12. In the past it was recommended toclassify uveal melanoma based on size and location15, but current guidelines rec-ommend classification based on the AJCC eye cancer staging system6. Brachyther-apy is recommended for most stages of uveal melanoma, except for tumors withgross extraocular extension and blind painful eyes, and no light perception vision.Metastatic spread is not an exclusion criterion for brachytherapy treatment, but itmight not be the method of choice in this case. The ophthalmic oncologist assessesthe tumor and provides the treatment team with a treatment form and fundus dia-gram, containing the patient information as well as laterality of the involved eye,largest basal dimension of the tumor, treatment scheduling and tumor staging. Themedical physicist uses this information to plan the treatment. Depending on theplaque design and calculation method, dose prescriptions range from 70 to 80 Gyat the tumor apex. The prescription isodose line should encompass the entire tu-mor and dose rates should be equal to or exceed 0.60 Gy/h. To accomplish this, the22medical physicist can adjust the size of the plaque and the number and position ofseeds in the plaque, as well as their air kerma strength. The tumor diameter shouldnot exceed the diameter of the planning target volume. Instead, the plaque apertureshould be large enough to provide a safety margin around the tumor.1.4.2 Treatment administration and follow-upThe plaque is inserted surgically under local or general anesthesia of the patientafter localizing the tumor via transocular illumination of the globe, in which thetumor base casts a shadow onto the sclera. The edges of the shadow are markedusing tissue dye as well as a safety margin of 2-3 mm surrounding it, to mark thetreatment volume. The plaque is positioned to cover the treatment volume andsutured in place. If extraocular muscles interfere with the plaque placement, theycan be detached and reattached afterwards. The plaque is removed after 5-7 dayswith another surgery under general or local anesthesia and any displaced musclesare reattached to their original position. After treatment, regular follow-up every3-6 months should be conducted to check for local control, complications, andsystemic disease21.1.4.3 Eye plaque types and geometryA variety of different eye plaque designs exist and are used in clinical application.While they differ in geometry and materials, they share similar defining properties.An eye plaque typically consists of a carrier medium to hold the brachytherapysources, a shield on the backside (some plaque designs have an integrated carrierand shield), and suturing lugs with holes to stitch the plaque in place in the cor-rect position on the eye. The carrier medium and shield are of a domed shape toconform to the eye and are generally wide enough to encompass the base area ofthe tumor. Classically, eye plaques consisted of a circular disk shape, but morerecent designs include various shapes to better fit a wider variety of tumor shapesand positions or include a notch to accommodate the optic nerve.The most commonly used plaque design is the COMS plaque24, consisting ofa circular, domed, silastic carrier containing slots to accommodate brachytherapyseeds, which is inserted into a lipped gold shield with suturing holes. Another pop-23ular type of eye plaques are Eye Physics plaques [Eye Physics LLC, Los Alamitos,USA], a combined carrier and shield consisting of gold, with slots to fit brachyther-apy seeds that are glued in place. Eye Physics plaques come in a variety of shapes,sizes, and designs and can be purchased pre-loaded or self-assembled. In additionto this, a variety of in-house plaque designs are used in many centers with greatsuccess.In our clinic, an in-house design is used, consisting of a 1.1 mm thick Poly-methyl methacrylate (PMMA) domed disk, with cut-out slots on the outside to holdseeds arranged in one or more concentric polygons. It features 3 suturing holesand can contain a notch to accommodate the optic nerve for posterior tumors or beshaped to accommodate the cornea for anterior tumors. Each plaque is individuallydesigned for each patient. The seeds are fixed in their respective slots using dentalwax and a 0.25 mm thick spherical gold shield is glued onto the outside, coveringthe seeds and wax.1.5 Eye Plaque Brachytherapy Quality AssuranceRadiation therapy is a treatment with a significant amount of side effects and alarge potential for harm to both patient and personnel if executed poorly. There-fore, quality assurance plays an important role in treatment planning, administra-tion as well as post-treatment care. The TG-129 report23 describes the minimumrequirements of a brachytherapy quality assurance system. This often consists oftwo major components: Quality assurance of the treatment plan, and preoperativequality assurance of the plaque.1.5.1 Treatment plan quality assuranceAs a first step, quality assurance of the treatment plan is important to reduce therisk that planning errors make it into the treatment and to make sure that a treat-ment executed as planned has the biggest possible benefit with the lowest amountof harm caused to the patient. This includes commissioning checks of the TPS 23,calculation of dose to the prescription point as well as critical structures (e.g. fovea,optic nerve, lens, and opposite eyewall), and documentation of all treatment infor-mation. The plan should be checked by a second medical physicist and the dose24distribution should be verified by an independent dose calculation method, like acommercial software, spreadsheet calculation, or by a MC simulation which is thestandard in many other radiation therapy applications.1.5.2 Preoperative quality assuranceThe other important aspect of quality assurance in radiation therapy is the physicalverification of the treatment execution, to ascertain that it agrees with the plannedtreatment. This can include routine measurements of the equipment used for treat-ment (such as in external beam therapy or High Dose Rate (HDR) brachytherapy)to verify that the equipment behaves as assumed and rule out any equipment fail-ures over time. It can also include dose measurements after or during treatment(as done in LINAC external beam therapy, where the dose rate is measured usingion chambers) to validate the equipment behavior during the specific treatment.LDR brachytherapy provides a unique set of challenges when it comes to qualityassurance of the treatment. While the previous treatment modalities use the samehardware and control systems for a multitude of patients, which remain relativelystable over time, the sources used in LDR brachytherapy are specific to each pa-tient and only used once. LDR sources have a low dose rate and are implanted intothe patient, making any measurements of the treatment post-implantation unfea-sible. Therefore, LDR brachytherapy quality assurance has to focus on validatingthe strength and behavior of the sources pre-insertion and the positioning of thesources during/after insertion.Seed strength verificationWhile manufacturers provide seed strength measurements with their sources, theTG-129 report23 requires the independent verification of seed strengths prior toassembly using a well chamber with a traceable calibration to a national metrol-ogy institute like the National Institute of Standards (NIST)25, which should bere-calibrated every two years by an Accredited Dosimetry Calibration Labora-tory (ADCL)26. Independent verification of seed strengths is needed to reduce therisk of mix-ups, mislabeling, and other sources of error between manufacturingand assembly. The low number of seeds used in eye plaque brachytherapy means25that each seed contributes significantly to the total dose. While ideally each seed ismeasured, at least 10 randomly selected seeds from each source strength grouping(or all seeds for batches with less than 10 seeds) must be measured.In addition, seed positions and loading pattern should be verified post-assemblyby visual inspection, photography, or autoradiography23. While this is possible forself assembled plaques, multiple vendors offer pre-assembled plaques in sterilepackaging, making independent measurements of the seeds impossible. In thiscase, the current recommendation is to acquire one loose, non-sterile seed from thesame batch as used in the plaque for independent seed strength verification. Whilethis should detect strong variations in the mean source strength (i.e. if the wholebatch has a too low or too high activity), it can not find individual dead seeds. Italso requires that the measured seed is indeed representative of the whole batch.Experience has shown that this is not always the case when measuring a batchof seeds. This problem could only be solved by using a post-assembly qualityassurance and source strength verification system for eye plaques, which couldverify the plaque dosimetric properties directly prior to insertion, ruling out anyproblems in the assembly process.1.6 Current Challenges and Thesis OutlineA significant gap in the quality assurance process of eye plaque brachytherapytreatment is the unavailability of a clinically feasible post-assembly dose distri-bution and seed strength validation system, especially for pre-assembled plaques.The goal of this thesis is to present a proof of concept for a new detector-basedsystem to close that gap. Various approaches to measure the dosimetric propertiesof assembled plaques have been developed in the past using different techniquesand designed for a variety of applications. Some developments were intended tobe used for the development of plaque designs and the experimental verificationof dose calculation algorithms for these plaques. They are often complex and timeconsuming and are focused on research applications. Others are intended as pre-insertion quality assurance for everyday clinical usage. Beiki-Ardakani et al. 27used a pinhole camera and a computer radiography unit to verify the positioningof seeds in a plaque and measure relative seed strength, combined with a survey26meter to estimate the total strength of the seeds in the plaque. Its primary use isto distinguish seeds in a non-uniformly loaded plaque. A different approach is tomeasure the central axis dose at various distances from the plaque. Carrara et al. 28use a spectroscopic semiconductor probe and a measurement jig in a water phan-tom, with the plaque fixed in a plastic capsule holder to maintain sterility. Kejdaet al. 29 use a similar approach but use a silicone diode to measure central axisdose rate at various distances. Eichmann et al. 30 use a precision measuring tablein which the plaque is fixed, to move the plaque with respect to a plastic scintil-lator detector in a water phantom, to produce a 2D or 3D dose rate distributionof a 106Ru plaque. Morrison 31 used radiographic film to measure a 2D dose dis-tribution perpendicular to the central axis of the plaque and compared the resultsto Monte Carlo generated simulations of the dose distribution. Zimmermann andWilkinson 32 use a Styrofoam holder to hold the plaque and a dose calibrator setupto measure the total air-kerma strength of the plaque at a fixed distance along thecentral plaque axis and compare the results to calibration plaque measurements ofthe same type.All these methods have their own strengths and weaknesses. Measuring thedose along one or more spots on the central axis is the easiest approach to verifyplaque integrity to some degree, but only having information along one dimensionrequires precise measurements to pick up on subtle problems like a weak or mispo-sitioned seed. It also heavily relies on the accuracy of the distance measurement.While a lot of seed or loading errors are most pronounced close to the surface,the uncertainties resulting from errors of the distance measurements increase dra-matically at small distances due to the inverse square relation between dose anddistance. Measurements in a water phantom are useful due to their compatibilitywith TG-43 calculations. However, water phantoms are much more difficult tohandle than solid phantoms or measurements in air. It is more difficult to maintainsterility in a wet environment, and water phantoms need regular maintenance andhave an inherent risk of spilling accidents.In comparison to probe-based techniques, the use of radiographic film results ina 2D map of the dose rate instead of a single position or series of positions, whereall pixels are irradiated at the same time. This reduces uncertainty due to position-ing of measurement points and unequal irradiation times. However, radiographic27film requires careful calibration and handling. The calibration needs to be doneusing the same photon energies as the intended measurements, due to the energydependence of the film. While it is successfully used in external beam application,where energies and dose rates are high, the irradiation times for LDR brachyther-apy applications have to be long and the film is not intended for such low energies.In addition to long irradiation times, radiochromic films continue to darken post-exposure and require a minimum of 24h between exposure and readout. They alsorequire careful storage protected from light and need to be scanned to convert theinformation into a digital format, introducing further sources of uncertainty andrequiring a significant amount of work and time, making it unfeasible for routinechecks during clinical practice.This work aims to provide a new approach to quality assurance of assembledplaques, combining detector measurements and Monte Carlo derived dosimetry, inthe hopes of combining the benefits of both. The system is intended to possess thefollowing properties:• Sensitivity: The system must be able to detect a dead, missing, or displacedseed. It should also detect a seed that differs from its expected strengthenough to change the resulting dose distribution.• Comparability: The detector measurements should be comparable to treat-ment planning calculated dose distributions.• Versatility: The system should be able to be used for a variety of plaquedesigns and source isotopes with minimal adjustments.• Speed and ease of use: Measurements should be fast enough to allow inte-gration into the clinical pre-insertion workflow. It should also require a mini-mum of maintenance and if possible, avoid the use of liquid water phantoms.• Sterility management: It should be possible to maintain the sterility of apre-assembled plaque.• Ease of interpretation: Results should be easily understandable with a clearindication of any possible problems with the plaque.28With these goals in mind, a workflow to ascertain plaque integrity was developed.It is based on two components: A Monte Carlo simulation of the expected doserate distribution, and a 2D measurement of the dose rate distribution of the plaqueperpendicular to the central axis, using a digital flat panel X-ray detector, whichcan be compared to find inconsistencies.29Chapter 2Materials and Methods2.1 Eye Plaques and Brachytherapy SourcesBrachytherapy eye plaques generally consist of three main components: the ra-dioactive sources, the plaque body, and the shield, which can also be combined.The following section describes the types of sources and eye plaques used in thisstudy.The most commonly used brachytherapy sources for LDR eye plaque brachyther-apy are encapsulated 103Pd and 125I sources. They have a near-identical outer ge-ometry, making the handling process very similar. As brachytherapy sources wereoriginally designed for interstitial brachytherapy applications, both sources have aradioopaque marker incorporated into their design. Sources of both radionuclidesare used in this study.103Pd SourcesSeveral commercial 103Pd source models are available for use in eye plaques. Weuse the IsoAid ADVANTAGE Pd-103 source [IsoAid LLC, Port Richey, FL]. Itconsists of a 1.25 mm long and 0.5 mm diameter cylindrical radio-opaque silvermarker and four 0.5 mm diameter spherical polystyrene pellets with uniformly ad-sorbed 103Pd , two positioned on each side of the marker. The source is enclosed bya 4.5 mm long titanium capsule with a 0.8 mm outer diameter and a wall thicknessof 0.05 mm. The end welds on both sides have a maximum thickness of 0.35 mm33.30Figure 2.1: Schematic drawing of the cross section of an IsoAid ADVAN-TAGE Pd-103 source with dimensions given in millimeters. It consistsof a 4.5 mm long titanium capsule with welded ends (blue), encapsu-lating a 1.25 mm long cylindrical silver marker in the center (purple),and two 0.5 mm diameter polystyrene spheres with uniformly adsorbedradioactive 103Pd (yellow).Figure 2.2: Schematic drawing of the cross section of an AgX100 125I sourcewith dimensions given in millimeters. It contains a 3.5 mm long silvermarker, coated with a 2 µm thick layer of radioactive AgI (orange), en-capsulated by a 4.5 mm long titanium capsule with welded ends (blue).A schematic drawing is shown in Figure 2.1.125I SourcesThe AgX100 125I source manufactured by Theragenics Co. [Buford, GA] containsa radio-opaque, 3.5 mm long cylindrical silver marker with a diameter of 0.59 mm,coated with a 2 µm thick layer of radioactive AgI with a density of 5.675 gcm−3.It is encapsulated by a 4.5 mm long titanium capsule with an outer diameter of0.79 mm. The capsule space is filled with air and it is welded closed on both endswith a maximum weld thickness of 0.4 mm34. A schematic drawing is shown inFigure 2.2.31In our center, eye plaque brachytherapy is performed using 103Pd sources ex-clusively. For the 103Pd measurements, the seeds used in this study were seedsthat have been ordered for eye plaque brachytherapy treatments and the measure-ments were taken before the seeds were inserted into the treatment plaques andlater used for treatment. They therefore have very high activities of 3.5 U to 6.1U, dependent on the treatment plan for the patient. The 125I seeds in this study arecalibration seeds and leftover seeds from permanent prostate implant brachyther-apy treatments, which uses much lower activity seeds due to the higher number ofsources used and because the seeds remain in the patient permanently (as opposedto a week for eye plaque brachytherapy), where they emit radiation until fully de-cayed. Therefore the seed activity of the 125I seeds used for these measurements isbetween 0.35 U and 0.49 U, approximately 1/10th of the 103Pd source strength.2.1.1 Brachytherapy Eye PlaquesA variety of eye plaques are used successfully in different centers worldwide.Some are commercially available, like the COMS plaque, which was designed for astandardized study on the effectiveness of eye plaque brachytherapy24, or the EyePhysics plaques, while others are individually produced in-house designs. Thisstudy was primarily conducted on in-house designed plaques that have been usedwith great success at the BC Cancer Vancouver Center. In addition to that, mea-surements were conducted on a dummy plaque of a commercially available EyePhysics plaque to test the adaptability of the system.BC Cancer plaquesAt the Vancouver Cancer Center, an in-house design for brachytherapy eye plaqueshas been used sucessfully for a long time. The eye plaque body is manufacturedfrom a 1.2 mm thick, spherical PMMA shell which conforms to a 22 mm diameternominal spherical globe. The inner surface has a radius of Ri = 11 mm, the outerradius is Ro = 12.2 mm. The size of the plaque depends on the size and anatomy ofthe tumor and varies with each patient. Each plaque has three suturing eyelets forattachment of the plaque to the eye and can be manufactured with a notch along theedge to accommodate the optic nerve for posteriorly situated tumors or the edge32Figure 2.3: BCCA eye plaque with and without shielding before insertion ofsources.of the cornea for anterior tumors. To hold the seeds, slots are cut into the upperside of the plaque. For 103Pd and 125I sources, each slot is 5.05 mm long and 1.02mm wide with a nominal depth equivalent to the seed diameter. Seed positions areindividually determined for each patient during treatment planning and are gener-ally planned as a series of parallel seeds and concentric polygons around the centerpoint. To accommodate a notch or other requirements, incomplete polygons canbe used in the design. If a plaque does not contain a seed at the center, a marker(either a lead shot or a dummy seed) is inserted at the plaque center to assist inplaque localization post insertion. The sources are inserted into the slots and fixedin position using dental wax. Afterwards, a 0.25 mm thick spherical domed goldshield consisting of 99.9% gold, is glued onto the outer side of the plaque in theoperating room. The shield has to be big enough to cover all seeds but does notextend beyond the outer dimensions of the plaque and does not cover the eyelets.It is cut to conform to the plaque edge, especially if a notch is present. The plaqueis produced in an in-house machine shop and filed down and polished at the endof manufacturing to prevent any damage to the eye. An example of an eye plaque(without seeds) with and without the shield is shown in Figure 2.3.For consistency, four standard plaques without eyelets were used in this study.Various seed arrangements were measured and modeled, with some slots filled andothers left empty. Seeds were generally used loose and not fixed with wax in theslots. Photographs of the four used slot designs are shown in Figure 2.4.33Figure 2.4: Three in-house design dummy plaques used in this study withoutseeds inserted into the slots, and a gold shield as used for this plaquetype.Eye Physics plaquesA common type of commercially available eye plaques are Eye Physics plaques.They are available in various designs and eye diameters and consist of a solidgold body with seed slots on the plaque inside. They can be bought or rentedeither empty or pre-assembled with seeds in sterile packaging. The slot dimensionschange with the positions of the slots and are intended to collimate the radiationemitted from the seed, which helps reduce the dose delivered to uninvolved tissueclose to the inner plaque surface. In this study, an Eye Physics dummy plaque wasused to investigate whether the dose measurement system can be used on otherplaque designs. It consists of a brass body covered in a thin layer of gold. Theplaque used has a notch, two eyelets for suturing, and 30 slots to accommodateseeds. The plaque layout is shown in Figure 2.5.34Figure 2.5: The Eye Physics dummy-plaque used in this study, which has 30seed slots and a notch on the side opposite of the eyelets.2.2 Experimental DesignDuring the planning of the measurement setup, several guiding principles wereused. Any measurements had to be easy and fast to do, not require a water phantom,and it had to be possible to maintain plaque sterility during measurement if needed.While other approaches have tried to make measurement conditions as similar aspossible to TG-43 conditions, often resulting in complicated measurement setups,we aimed to design an easy measurement setup and use a Monte Carlo calcula-tion to accurately simulate the dose distribution for this experimental setup. Wedo this by calculating which dose distribution is expected from the known plaqueproperties, as defined during treatment planning, in the measurement environment.The versatility of MC calculations means that the same plaque can be simulated inthis artificial environment as well as in a water phantom or simulated patient, todetermine the dose distribution in water and validate the treatment planning. Themeasurement system consists of three simple parts: a holder for the eye plaque, adetector to measure the dose distribution, and a computer to operate the detectorand save the measured data. The details of the setup are described in the following.35Figure 2.6: Schematic of top and side of the Dexela Complementary Metal-Oxide-Semiconductor (CMOS) flat panel detector model 151236. Di-mensions are given in millimeters.2.2.1 Detector propertiesDigital flat panel x-ray detectors have replaced film measurements in many med-ical imaging applications and offer a variety of advantages. They provide near-instant, digital read-out, require lower doses, and have a linear dose-response. Pre-vious works by Golshan et al. have shown that a suitable detector can be usedfor dosimetry of low-energy 125I brachytherapy sources in needles for interstitialprostate brachytherapy. Therefore there is reason to believe that it is also a suitabletool for quality assurance of brachytherapy eye plaques35.Digital detectors collect photons and convert them to a digital signal. In thecase of x-ray detectors, they consist of a scintillating layer commonly made ofgadolinium oxysulphide (GOS) or cesium iodide (CsI), in which incoming x-rayphotons are converted to photons in the visible light spectrum. This increases the36sensitivity of the detector, as the layer of active pixel sensors that are opticallycoupled to the scintillating layer are more sensitive to visible light than x-rays. Ina CMOS detector, the active pixel sensors that convert the incoming photons fromthe scintillating layer to electric signals, are made of complementary metal-oxidesemiconductors. This results in fast image acquisition and low read-out noise. Alayer of read-out electronics then collects the signal from the individual sensors.We use the same detector model as the one used by Golshan et al., the DexelaModel 1512 CMOS flat panel detector. The low energy range of photons emittedby 125I and 103Pd poses a challenge for most technologies developed for imagingapplications, which are designed to focus on higher energy x-rays, with the excep-tion of mammography x-ray detectors like the one used. The Dexela Model 1512contains a high resolution caesium iodide scintillator, designed to convert x-raysin the range of 30-250 keV to light photons. CsI scintillators like the one usedin this study have an inherent columnar structure and a thickness of up to a fewhundred µm. High resolution CsI scintillators in addition often consist of columnsof scintillating material surrounded by light guides (often consisting of aluminum),which are transparent for x-ray photons, but reflect light photons, to increase thesensitivity of the detector37. While detailed information about this could not beobtained for the detector model used, this structure is present in the closely relateddetector model 2923 from the same series of detectors38. The scintillator is pressedto a fibreoptic faceplate that optically couples it to the CMOS sensors and shieldsthe sensors from excessive x-ray radiation. An Analog to digital coverter (ADC)circuit board is connected to the sensors and digitizes the read-out signals andsends the timing signals to the sensors. A Data acquisition (DAQ) communicationsboard converts the signal from the ADC to a Camera Link interface. The detector ishoused in a fan-less aluminum body, which provides protection and cooling. Theinput side of the detector consists of a carbon-fiber composite panel, which coversand protects the detector while providing a radio-transparent imaging window. TheDexela Model 1521 has an active image area of 145x115 mm with a resolution of1536x1944 pixels and a pixel pitch of 74.8 µm.Technical data for the detector are given in Table 2.1 and a schematic of thedetector dimensions is shown in Figure 2.6.Via a connection cable, the detector is connected to an EPIX E4 screen grab-37Table 2.1: Technical data of the Dexela CMOS flat panel detector model151236.ber that is installed into a PCI Express slot in a computer. Another cable connectsthe power supply unit of the detector to a power outlet. All necessary drivers areinstalled on the computer. Images are acquired using the SCap image acquisitionsoftware designed to be used with this detector. Images are acquired in an unbinned16 bit fixed point format and the software can do a variety of post-acquisition im-age corrections, of which the following are applied: The descramble option con-verts the detector raw image into a legible format, Auto-contrast automatically setsbrightness and contrast. The dark correction uses a collection of previously ac-quired dark images to correct for dark noise. Linearization is used to correct for theslight non-linear light response of the pixels. The final used correction suppresseszingers, which are white, overexposed pixels resulting from direct conversion ofx-ray photons in the CMOS sensor.38Figure 2.7: The plaque holder, consisting of a solid PMMA partial sphere withan 11 mm radius of curvature and an overall height of 6 mm. The holdercan be split in the middle to obtain a 3 mm holder for small plaques.2.2.2 Eye plaque holder designWhen designing an experimental measurement setup for eye plaque dosimetry, sev-eral challenges need to be considered: Due to the small dimensions of the eyeplaque, the sharp dose fall off with distance, and the small dimensions of the areaof interest, exact positioning is important. The low energy of LDR brachytherapysources results in high attenuation through most materials, making the materialcomposition of the setup very important. Also, eye plaques come in various shapesand sizes, and an experimental setup designed to be compatible with multiple dif-ferent plaque designs has to be very adaptable. Finally, the setup has to be easyto use, so that integration into the clinical QA procedure is feasible. Ideally, it isalso able to maintain the sterility of the plaque, if it is to be used directly beforeimplantation into the patient’s eye.While eye plaques come in various shapes and sizes, they have a defining com-mon property. They all are designed to conform to the outside of the globe of amodel eye. For eye plaque dosimetry, the main region of interest for the dose dis-tribution is the inside of the globe on the concave side of the plaque, where thetumor is positioned in a patient’s eye. This must be considered in the design of asuitable holder.We chose a simple partial sphere made from PMMA with a radius of curva-ture of 11 mm, to match the inner radius of curvature of the BC Cancer in-house39plaques, as a holder. PMMA has water-like radiation properties for low energy pho-tons39. Its easy handling when machining, cost-effectiveness, and known materialproperties (which make it easy to simulate in Monte Carlo calculations), make itwell suited as a holder material. The minimal height for the phantom must allowthe plaque edge (including the eyelets) to clear the flat surface of the detector. Toaccount for this while being able to investigate different depths, the holder was de-signed as a 6 mm partial sphere consisting of 2 parallel PMMA slices perpendicularto the axis of symmetry, with a thickness of 3 mm each. They can be combined to aholder of 6 mm height, which accommodates most eye plaques used at our institu-tion. For very small plaques, the smaller holder consisting of only the 3 mm upperslice could be used in the future, while another slice at the bottom could be used toextend the holder for even larger plaques, up to a total holder height of 11 mm. Animage of the holder is shown in Figure 2.7.2.2.3 Seed strength calibration using a well chamberThe current gold standard to verify seed strength in a clinical setting is by measur-ing source air kerma strength using a well chamber. In this study, each source airkerma strength was independently measured using an ADCL calibrated HDR 1000PLUS well chamber [Standard Imaging, Middleton, USA] before insertion into aplaque. A collection time of 30 s was used and the measurement is corrected fortemperature, air pressure, and leakage. A calibrated seed holder insert positionsthe seed at the center of the cylindrical chamber as shown in Figure 2.8.2.2.4 Radiation safety considerationsDue to the high activity of eye plaque brachytherapy sources, special considerationshould be given to radiation safety procedures. The guiding ALARA principle- Any radiation exposure should be As Low As Reasonably Achievable - shouldbe employed. This includes following all legislative and regulatory proceduressurrounding radiation safety, including the use of dosimeters for anyone handlingthe sources and spending time in the hot lab. All sources should be stored in ashielded lead container when not in active use and any handling should be donebehind a suitable radiation shield. In our case, a shielded radiation workplace40Figure 2.8: Well chamber (top) and seed holder used to position the seed atthe center of the well chamber for seed strength measurements (bottom).consisting of an L-shaped lead shield with a leaded-glass window was used for allmeasurements. The well chamber is shielded by a thick lead shield as well. Toreduce exposure of the hands during handling, lead-lined gloves are recommendedand were used during these experiments. Prior to and after all measurements andhandling of sources, an extensive survey of the workplace and surrounding area, aswell as repeated counting of the sources, is necessary to verify that no sources havebeen lost and to ascertain that all sources are securely contained in lead shieldedcontainers to avoid any accidental exposure.412.2.5 Experimental setup and measurementsThe flat panel detector is placed behind the lead-shield and connected to a computerto record the measurements. A test image is taken to verify that the connectionis correct and the system works as expected. Next, a set of 10 dark images istaken with the same exposure time as will be used during measurements. Thenthe holder is placed at a marked position at the center of the active image windowof the detector. For fully-loaded plaques, the plaque is positioned on top of theholder and fixed in position using medical tape as shown in Figure 2.9. For thecalibration plaques and plaques without fixed seeds, where multiple images withseeds in different positions are required, the empty plaque is secured in place ontop of the holder using medical tape. Afterwards, seeds are added and multipleimages are taken. The exposure time is 300 ms for 103Pd seed measurements and1000 ms for 125I measurements, due to the difference in activity ranges betweenthe different source types. In all cases, attention should be paid to make sure thatthe plaque orientation is the same as during the Monte Carlo modeling. To verifythat the modeled and measured plaque are not rotated with respect to each other,a correct orientation of the plaque was assured by defining a ’north’ point of theplaque, which was aligned with markings on the detector. It is also important thatthe plaque is not tilted, especially when there is space between the plaque edge andthe detector when the plaque is positioned on the holder. This is important becausetilting changes the distance between the seeds and the measurement plane, whichhas a profound effect due to the steep dose fall-off with distance. Tilting effects arestronger, the further the seeds and measurement points are from the center of theplaque. To align the plaque center with the holder center, the holder has a smallmarking at the center point, made with a permanent marker. This marking can bealigned with the center of the transparent plaque. When adding seeds to a plaquefor a measurement series, it is also important to not move the plaque, so as to notchange the alignment for later analysis.2.2.6 Measurements through sterile packageAn important aspect of pre-insertion quality assurance procedures is the questionof whether sterility can be maintained. Pre-assembled plaques are commonly de-42Figure 2.9: The detector setup as seen through the leaded-glass window ofthe radiation shield. It shows the detector with position markings usingmasking tape, with the plaque holder and plaque positioned in the centerof the measurement window. The plaque is attached with medical tape.livered sterile and in sterile packaging. Ideally, any measurement could be donethrough this packaging, without the need to unwrap the plaque. IsoAid is ship-ping pre-assembled plaques in self-sealing sterilization pouches, consisting of amedical-grade paper backing and a transparent thin plastic laminate in the front.Two different methods of measuring the plaque through the packaging were at-tempted. For the first method, the plaque was facing with the inner surface pointingtoward the transparent foil of the pouch. The holder was positioned on the detec-tor and the plaque positioned on the holder, with the plastic layer of the pouch inbetween. Due to the stiffness of the plastic and the curvature of the plaque andholder, pressure had to be applied to get the plaque in contact with the holder.This was done using a pillow conforming to the shape of the plaque, consisting43Figure 2.10: Measurement of a plaque with the plastic film of the sterile pack-aging between the holder and detector.of a textile bag filled with grains, and a lead weight on top of it. The stiff mate-rial made the positioning of the plaque very difficult. The second method requiresa sterilized acrylic holder to be placed inside the pouch. While it is not suitablefor heat and steam sterilization, PMMA can be sterilized using Ethylene Oxide gassterilization40 41. To investigate the impact of the added plastic film between thedetector and holder, the film of a sterilization pouch was positioned on the detec-tor. The holder and plaque were then positioned on top of the film and the detectormeasurements acquired as can be seen in Figure 2.10.2.3 Monte Carlo CalculationsThe MC simulations were done using egs brachy19, a specialized brachyther-apy extension of the EGSnrc42 MC radiation transport code that is widely usedin a variety of medical physics applications. It contains geometric models for theAgX100 125I -125 and IsoAid ADVANTAGE Pd-103 sources as well as a varietyof radionuclide spectra, material properties, and cross-sections. The following sec-tions describe the parameters used for the simulations, starting with the geometricmodel of the eye plaques and the simulation model input for both types of plaques.44The process of scaling scored dose to absolute dose is also described.2.3.1 BC Cancer plaque geometryThe BC Cancer eye plaques are simulated in egs brachy using the egs++ ge-ometry library. The body of the plaque consists of a 1.2 mm thick partial sphericalshell with an 11 mm radius of curvature of the inner surface. The plaque size isidentical to that of the plaque being simulated. Like the plaques used in these mea-surements, the simulated plaque does not have any eyelets or suturing holes, asthese would be outside of the measured radiation field and would not be expectedto alter the dose distribution. The material properties of PMMA are defined in theegs brachy standard library material file. The plaque symmetry axis is alignedwith the z axis, which goes through plaque center. The plaque holder is simulatedfrom PMMA as well and the seeds are inscribed in the plaque at the correct po-sitions. The flat base of the plaque holder is positioned in the xy-plane at z = 0,defined as the detector surface. Everything below is considered to be inside thedetector.While the real plaque has air-filled slots cut into the PMMA to accommodate theseeds, the model plaque does not have these slots. Instead, the seeds are inscribeddirectly into the material. This is done to reduce the complexity of the simulationand speed up the simulation process. As the seeds are sitting on the bottom of theslots in contact with the plaque material, the small amount of air-filled space onthe sides of the slots should have a negligible impact on the results of the dosedistribution in the detector plane.2.3.2 Input and scoring optionsLoaded eye plaque configurations are simulated in egs brachy in a large airfilled cube with dimensions of 50 cm×50 cm×50 cm. Dose is scored in a vox-elized 4 cm×4 cm×5 cm box with voxel sizes of 0.2 mm×0.2 mm×0.2 mm en-compassing the plaque. For each MC run, 109 histories are simulated to obtain avery accurate result and a high signal to noise ratio. Volume correction around thesources is activated.For the isotope spectra of the sources, the files of the Pd103 NNDC 2.6 line45(a) low photon energies (b) high photon energiesFigure 2.11: NNDC 2.6 spectrum used in the Monte Carlo simulation of103Pd brachytherapy seeds showing the dominating low photon ener-gies (left) and the small fraction of high energy gamma rays (right).Figure 2.12: NCRP spectrum used in the Monte Carlo simulation of 125Ibrachytherapy seeds.spectrum (shown in Figure 2.11) and the I125 NCRP line spectrum (shown in Fig-ure 2.12), from the egs brachy library are used respectively. It is possible toassign a weighting factor to the sources if they have different strengths or differ-ent irradiation times. For eye plaques, all sources remain for the same duration,but differences in seed strengths are possible. For this study, some simulationswere performed with weighted seeds, where the individual seed strengths weremeasured before filling the plaque and a corresponding weight was assigned in the46simulation, and others with unweighted seeds, where each seed was given the sameweight and the average of their measured air kerma strengths was used. For ma-terial properties in the scoring options, the xcom 1.5 MeV eye egsphant.muendatmass-energy absorption data file from the standard library is used. egs brachyis able to do the radiation transport in air, while scoring in a different medium at thesame time, enabling modeling of the correct setup while scoring dose in a mediumthat is commonly used in brachytherapy applications. To simulate the experimen-tal environment as best as possible, the transport medium for the scoring phantomis air (AIR TG43), but to obtain a better signal to noise ratio, speed up simulationtime and obtain more familiar dose rate results to TG 43, water (WATER 0.998) isused as the scoring medium. This is justified by the fact that this Monte Carlo resultdoes not aim to simulate the dose distribution in a phantom or patient. Instead, itis supposed to produce a reference value to simulate the detector setup. However,the same plaque can easily be simulated in a TG-43 conforming water phantom, bychanging the transport medium to water and removing the holder from the geome-try, to verify the treatment plan, or in a patient phantom to obtain realistic treatmentdose distributions. Finally, the transport parameter file used is the low energy de-fault as provided in the transport library, resulting in an electron cut-off energy of1.5 MeV and a photon cut-off energy of 1 keV.2.3.3 MC simulation of Eye Physics plaquesTo simulate the Eye Physics plaque in egs brachy, the dimensions of the plaquewere extracted from the Plaque Simulator software. As each plaque has manydifferent types of slots, which all vary slightly in their size, length, depth, andthe opening angles of the slot walls, each type of slot was individually modeledas an air filled rectangle with slanted sides. The plaque was modeled as a partialspherical shell of gold with two attached eyelets and a notch on the side. The slotswere inserted into the plaque at the correct positions. The PMMA plaque holderis simulated as a solid partial sphere. For each simulation run, the sources arepositioned at the center of the slots in various combinations, according to the seedarrangements in the measured plaques. An example plaque without the holder andwith a seed arrangement consisting of nine sources positioned in the outer slots of47Figure 2.13: Simulated EyePhysics plaque (gold) filled with nine 103Pd seeds(cyan) as seen from two different angles. The plaque is simulated inegs brachy and the image was taken using the egs view soft-ware.the plaque is shown in Figure 2.13.All other simulation parameters including positioning of the plaque and holder,scoring and transport media, scoring phantom size and resolution as well as his-tories simulated are identical to the simulation runs of the acrylic in-house designplaques.2.3.4 Absolute dose calculations of the MC resultsThe dose value output produced by egs brachy needs to be scaled by the air-kerma strength of the seeds in order to obtain absolute dose or absolute dose ratevalues. A detailed description of the output and the scaling process is given in theegs brachy user manual20. If the sources are weighted to account for differ-ences in seed strength, the scored doses are weighted by the statistical weight ofthe photons from the particular source. To scale the output dose D¯ j in a voxel jto an absolute dose D j, the air-kerma strength [Sk]max of the strongest seed (forweighted seeds) or the mean air-kerma strength for unweighted seeds and the air-kerma strength per history Shistk are needed. Shistk is given in units of Gy cm2/historyand depends on the source radionuclide and geometry. The dose rate D˙ j is then48calculated via:D˙ j = [Sk]maxD¯ jShistk. (2.1)The absolute dose D j over the treatment time t, with the radionuclide mean lifetimeτ = 1/λ , where λ is the decay constant, can be calculated asD j = D˙ j τ (1− e−λ t) . (2.2)For the AgX100 I-125 seeds, Shistk = 3.94658±0.00034 ·10−4 Gy cm2/history andfor the IsoAid ADVANTAGE Pd-103 source, the air-kerma strength per history isShistk = 8.1498±0.0001 ·10−4 Gy cm2/history43.2.4 Detector calibrationModeling the experimental setup in a MC simulation comes with a variety of chal-lenges. Most importantly the lack of information about the inner dimensions, ma-terials, and construction of the detector, as the detector properties could not beobtained from published data or the manufacturer directly. These unknown detec-tor properties have a large influence on the detected dose distribution, especiallyfor low energy photons, where attenuation is strongly dependent on material com-position but could not be modeled in the MC simulation. Instead, the detector hasto be treated as a black box and any unknown properties are included in the de-tector system response during calibration. Instead of modeling the detector, wedefine theoretical detector properties that characterize the detector response: theeffective detector depth, the effective detector thickness, and the calibration factor.These effective detector properties are determined by aligning and comparing the2D measured dose distribution to the 3D dose distribution from the Monte Carlosimulation. All analysis is done in MATLAB and the process is described in thefollowing. For each source type, the full calibration process is done using threecalibration eye plaques, each loaded with an increasing number of seeds. Outof each set of the three calibration plaques, 1 set is modeled in MC using indi-vidually weighted seeds based on the seed calibration measurements, while 2 useunweighted seeds where the seed strength is the average of the seed strength mea-49surements.2.4.1 Data input and image registrationThe detector results are saved as 16 bit uncompressed gray-scale TIF files and im-ported into MATLAB . The MC results are saved as 3ddose files by egs brachy,a widely used file type for these applications, and read into MATLAB using a coderoutine based on the description of the file format found in the user manual20. First,a number of data cleaning steps are applied to the detector image. This includesremoving the background offset by averaging over a 50x50 pixel area on the edgeof the image and subtracting this value from all pixels. The detector has severaltwo pixel wide fault lines across it, which are corrected by interpolating betweenthe neighboring pixels. Then the detector image is rescaled so that the detectorimage pixel sizes are the same as the lower resolution Monte Carlo voxels. Thissmoothing reduces the influence of noise and makes the images comparable.For the Monte Carlo results, the 3D dose distribution is treated as a stack of2D slices, each 200 x 200 voxels large, with a voxel size of 0.2 x 0.2 x 0.2 mm.Each slice is perpendicular to the z-axis and oriented parallel to the 2d dose mapof the detector measurement. As an important step, the detector image and thecorresponding MC slice have to be registered with each other. Figure 2.14 showshow the dose distribution changes with increasing distance from the plaque. Itshows the dose distribution in the region below the detector surface (at z=0).Image registration is done using the MATLAB image registration functionimregtform in translation and multi-modality mode. It means the algorithmis only allowed to translate the images against each other but is not allowed tostretch, magnify, or rotate them to find the position of best alignment. This is doneto avoid overcorrecting for any actual discrepancies which could be masked bythis. Using this image registration, the effective detector depth and thickness aredetermined and the calibration factor is calculated. After aligning the images, thedetector image is cropped to the same size as the MC image.50Figure 2.14: Monte Carlo calculated dose distribution from an 18 seed 103Pdplaque for the region below the detector surface (at z=0). An increasealong z corresponds to an increased distance to the detector surface.2.4.2 Effective detector depthFlat-panel detectors are designed for medical imaging. As such, they are intendedto record a two-dimensional dose distribution of perpendicular or nearly perpen-dicular incoming radiation from a source that is far away (typically around 60 cm)from the detector. They are not designed for dose distributions with steep dosegradients in the z direction resulting in a strong variation of the dose distributionwith varying depth, as is present in brachytherapy source autoradiographs. To findthe effective detector depth, the detector image must be related to the best fittingz slice of the MC results. This is done by individually looping over all physicallypossible MC slices (all slices situated below the detector surface) for each seed con-figuration and detector measurement. For each slice, a scaling factor is calculatedto scale the detector values to the Monte Carlo values, by finding the average valueof a 10 voxel×10 voxel square in the center of both the MC and detector image.51Assuming a linear dose-response, the scaling factor is calculated as the quotientof the central average value of the MC and detector images. Using this, the de-tector image is scaled to obtain measurements of the absolute dose rate. Then,the scaled detector image is subtracted from the MC slice, to obtain a differenceimage, and the sum of the absolute pixel differences is calculated. For each seedconfiguration, the z slice for which this is minimal is found. Finally, the averageof this value over multiple measurements and plaque calibrations is taken to findthe effective detector depth. This is done for both 103Pd and 125I measurements, asthe different photon energies cause different absorption and penetration behaviors,resulting in different effective detector depths. The effective detector depth is de-fined as the distance between the center of the effective detector thickness to thedetector surface.2.4.3 Effective detector thicknessAnother unknown property is the thickness of the active layer of the detector. Thisis important because the detector registers photon-matter interactions in the wholedepth of the active layer. To account for this and the detector response, an effec-tive water-equivalent detector thickness is determined. When comparing detectorimage and MC slices, a thicker detector would result in an image that is the meanof multiple MC slices, due to the steep dose gradient in z. This produces a differentshape of the dose distribution as the resulting dose for each pixel is the integrateddose over the detector thickness along the z axis. To determine the effective detec-tor thickness, the average of an increasing number of one to twelve detector slicesis found by adding the slices and then dividing the result by the number of slicesfor each pixel, corresponding to detector thicknesses of 0.2 mm to 2.4 mm. Withthis, the whole detector depth finding process is repeated for all calibration mea-surements. For each seed arrangement and detector thickness, the detector depthfor which the difference between detector and Monte Carlo image is minimized isrecorded. The difference is recorded as well. By comparing the absolute differ-ences for all detector thicknesses and depths, the effective depth and thickness forwhich the differences are minimized is found. The resulting depth and thicknessare different for 125I and 103Pd sources and are used for all further analysis.522.4.4 Calibration factorsTo obtain the calibration factor, the weighted average of the central 10 x 10 voxelsquare is taken for both MC and detector images of all calibration seed configura-tions. Because the MC results are considered our reference values and have muchsmaller uncertainties that can be neglected, the MC values are considered the in-dependent variable x while the detector results are the dependent variable y. Thecentral dose rate values are plotted against each other and are fitted with a weightedlinear least-squares fit of the form y= mx+b, where the slope m is the calibrationfactor and the intercept b the remaining offset. For each radionuclide, this is donefor three sets of calibration plaques which are individually filled with an increasingnumber of seeds.The linear fit equation can be inverted with the calibration factors b and m toscale the detector reading to a Monte Carlo equivalent absolute dose via:x=y−bm(2.3)which is applied to each detector pixel.2.5 Analysis and Acceptance CriteriaWhen using the system to verify the dosimetry of an assembled plaque with un-known individual seed strengths, there are two main objectives: The first is toidentify any misplaced, dead, or out-of-specification seeds, meaning any that aretoo hot or too cold as compared to the treatment plan and manufacturer’s assay andany inhomogeneities caused by this in the dose distribution. The second objectiveis to verify the overall strength of the plaque as compared to the planned plaque.To evaluate these different properties, two techniques are used. To evaluate anydifferences between the 2D dose distribution maps from the Monte Carlo and de-tector measurements, a gamma index analysis is performed on them. To evaluatethe overall plaque strength agreement, the central values of the dose distributionsare compared.532.5.1 Relationship between dose distribution and seed strengthThe dose distribution of an assembled plaque is complicated because all seedscontribute to the dose at any given point. While our method measures the dosedistribution, we would ideally also be able to relate it to the seed strengths. Whilethe TG-43 Algorithm does not encompass all processes that contribute to the dosedistribution, it can be used as a tool to determine how seed strength and dose at apoint in the geometry relate. When comparing two dose distributions D1(r,θ) andD2(r,θ), we are always comparing the dose at the same point in both distributions.Hence, neither the distance ro nor the angle θo between sources and evaluationpoint change between the distributions. According to Equation 1.12, the air kermastrengths Sk1 and Sk2 of the seeds producing the dose distributions at the commonreference point are related as:D1(ro,θo)D2(ro,θo)=Sk1Sk2. (2.4)Hence, when considering the overall plaque strength, any difference between thedoses directly reflects a difference in source strength. In the case of multiple seeds,the dose at a given point is a function of all contributing seeds.2.5.2 Dose comparison using Gamma-Index analysisA widely used tool to evaluate and compare dose distributions in radiation therapyis the Gamma-Index analysis44. It incorporates two evaluation criteria: dose differ-ence ∆D and distance-to-agreement ∆d. For each known point re in an evaluationdose matrix De, the gamma index γ is a way to determine if the evaluated dose dis-tribution is similar enough to the reference dose matrix Dr, given the acceptancecriteria ∆D and ∆d. The dimension of the reference dose distribution must be equalto or larger than the evaluated dose. For each point re of the evaluated dose matrix,the gamma function Γ is calculated in relation to the dose value Dr at all positionsrr of the reference dose matrix:Γ(~re,~rr) =√r2(~re,~rr)∆d2+δ 2(~re,~rr)∆D2(2.5)54∆D is the dose difference criterion and is set to be the maximum acceptable differ-ence between the evaluated and the reference dose. ∆d is the distance-to-agreementcriterion and is set to the maximum acceptable distance from the evaluation pointre, in which the evaluation dose De(~re) has to agree with the reference dose Dr(~rr).r(~re,~rr) = |~re−~rr| (2.6)δ (~re,~rr) = De(~re)−Dr(~rr) (2.7)The gamma index γ(~rr) is defined as the minimum of the generalized gamma func-tion Γ(~re,~rr) at the reference point ~rr:γ(~rr) = min |Γ(~re,~rr)| ∀~re . (2.8)If the gamma index is below 1, the voxel fulfills the acceptance criterion, with alower value corresponding to better agreement. This way it is possible to calculate agamma index for each reference point, which, given sufficient reference points canresult in a 2D or 3D gamma index map to visualize the dose difference. It is alsopossible to calculate the percentage of points that fulfill the acceptance criterion,either over the full range, or any specific region of interest.2.5.3 Central percentage differenceThe second acceptance criterion to take into account is the dose difference in thecenter of the plaque. This can be used as a comparison metric in plaque treatmentplanning quality assurance. Due to the number of seeds used, small deviations inseed strengths will often cancel each other out at this point. It therefore describesthe overall strength of the plaque. It is also important because the apex of the tumorfor which the dose has been planned is generally located at the center of the plaquewhere the distance between plaque and tumor is largest. In the TG-129 report23it is recommended that a batch reading of the seed strength used in the plaqueshould not deviate by more than 3% from the manufacturer’s certificate. Due to theaveraging effect of individual seed contributions to the dose at the center point, anacceptance criterion of 3% deviation of the reference center value was chosen forour analysis. The center values are calculated by averaging over a 5x5 pixel area55at the center of the plaque. It is important to note that this is not necessarily thecenter of the dose distribution for some asymmetrically loaded plaques, but ratherthe center as defined according to the geometry used in the Monte Carlo simulation.56Chapter 3Results3.1 Detector calibration3.1.1 125I calibrationTo calibrate the detector for use with 125I plaques, three calibration plaques wereused. An 11 seed plaque, consisting of a 4 seed and a 7 seed polygon, a 7 seedplaque consisting of a 7 seed polygon, and a 29 seed plaque consisting of a centralseed slot, as well as a 4 seed, 6 seed, 8 seed, and 10 seed polygon, filled with up to21 seeds. Each plaque is filled with an increasing number of seeds, starting fromthe center and filling up outwards. The calibrations were performed as describedin Section 2.4.Effective detector depth and thicknessTo find the effective detector thickness, the absolute pixel difference between theMC calculated dose and the detector measured dose is plotted against the detec-tor thickness at the best fitting detector depth. For one plaque, this is exemplarilyshown in Figure 3.1. For all three plaques, the difference is largest for the smallestdetector thickness of 0.2 mm and afterwards decreases with increasing thickness.At about 1 mm and greater thicknesses, this difference stays near constant withsmall variations and only decreases marginally with further increased thickness.57Figure 3.1: Average absolute difference per pixel between the detector mea-sured and MC derived dose distributions in the detector plane, plottedagainst effective detector thickness for an increasing number of 125Iseeds in an eye plaque.With an increase of detector thickness comes a loss of spatial resolution along thez axis. As there is little gain in increasing the detector size above 1 mm in termsof detector modeling, this thickness is chosen as the effective detector thickness tobalance resolution and detector response accuracy. The effective detector depth,defined as the difference between the surface of the detector and the center of theeffective detector thickness, stays nearly constant independent of detector thick-ness. This indicates a consistent detector response. By considering the effectivedetector depth for all seed configurations and thicknesses, we can calculate themean and standard deviations of the depth to determine the detector depth. Theeffective detector depth for each plaque over all slice thicknesses was calculated as4.4±0.2 mm, 4.8±0.3 mm, and 4.5±0.2 mm respectively. From this, the over-all detector depth of 4.6±0.2 mm below the detector surface was determined andused for the 125I seed plaque calibration.58Table 3.1: Calibration factors for eye plaques using 125I seeds and an expo-sure time of 1000 ms based on three calibration plaques.125I calibration factorAfter finding the effective detector depth and thickness, the same calibration plaqueswere used to find the calibration factor for 125I plaques as described in Section 2.4.The resulting calibration plot showing central dose values as measured with thedetector vs MC derived is shown in Figure 3.2.The calibration factor is found via a linear least-squares fit over all measuredvalues. The calibration factor values are given in Table 3.1 for the individualplaques and for the overall calibration fit obtained with all 3 calibration plaquemeasurements.3.1.2 103Pd calibrationThe calibration of the detector for use with 103Pd seed plaques is equivalent to thecalibration with 125I seeds. Three calibration plaques are used: A 19 seed plaque,consisting of a central seed slot, as well as a 4 seed, 6 seed, and 8 seed polygon,filled with an increasing number of one to nineteen seeds. The second calibrationplaque has a central seed and a six seed polygon. The final calibration plaqueconsists of a central seed slot and a 4 seed polygon. All plaques are filled with anincreasing number of seeds, starting from the center outwards.Effective detector depth and thicknessThe effective detector thickness and depth are found using the same method as forthe 125I plaques. When determining the effective detector depth, the results aresimilar to the 125I plaques, where the average absolute pixel difference betweenthe detector measured dose distribution and the MC derived dose distribution de-59Figure 3.2: Calibration plot for 125I source plaques using three eye plaquesand a linear least-square fit to determine the calibration factor needed toconvert detector readings to absolute dose rates.creases with increasing detector thickness for a thickness <1 mm and stays mostlyconstant from there on as can be seen in Figure 3.3. Due to this, 1 mm was cho-sen as the effective detector thickness to balance spatial resolution and accuraterepresentation.The effective detector depth for the individual plaques over all slice thicknesseswas 4.0± 0.2 mm, 4.2± 0.1 mm, and 3.9± 0.1 mm respectively, resulting in anoverall depth of 4.0± 0.2 mm below the detector surface, which was used for theanalysis.103Pd calibration factorThe calibration factor for the 103Pd plaques is calculated as described in Sec-tion 2.4. The linear least-squares fit plot is shown in Figure 3.4 and the resulting60Figure 3.3: Average difference per pixel between the detector measured doseand MC derived dose distribution in the detector plane plotted againstan increasing detector thickness between 0.2 mm and 2.4 mm for anincreasing number of 103Pd seeds in an eye plaque.Table 3.2: Calibration factors for eye plaques using 103Pd seeds and an expo-sure time of 300 ms based on three calibration plaques.values for the calibration factor are given in Table 3.2. As with the 125I plaques,the detector shows a linear dose-response both for the individual plaques and theoverall response using all plaque measurements.61Figure 3.4: Calibration plot for 103Pd source plaques using three eye plaquesand a linear least-square fit to determine the calibration factor needed toconvert detector readings to absolute dose rates.3.2 Plaque MeasurementsTo test the capabilities of the system, multiple 125I and 103Pd filled plaques weremeasured. Six 125I seed plaques were tested in addition to the three calibrationplaques. All resulting dose distributions were scaled and then compared to theirrespective Monte Carlo derived dose distributions by comparing the central doserates and using gamma index analysis as described in Section 2.5.For the 103Pd sources, in addition to the calibration plaques, 19 eye plaque setswere measured on multiple days and with different seed batches and plaque types.In most cases, the plaques were filled from the center outwards with an increasingnumber of seeds, to model both symmetric and asymmetric plaques.A few additional measurements were obtained for supplementary investiga-tions like determining the influence of individual seed positions on the results and62Table 3.3: Results of 125I plaque measurements with symmetric seed arrange-ments showing the central dose-rate values for the detector and MC mea-surements, as well as the difference between the two in percent (basedon the MC values) and the percentage of pixels within the dose cut-offwindow that comply with the gamma map acceptance criteria by havinga gamma value ≤ 1.determining the measurement repeatability. In the following, a number of specialcases are individually discussed.3.2.1 Symmetric 125I seed arrangementsThe majority of plaques used in clinical applications are symmetric. Therefore,special attention was given to these arrangements which contain fully populatedpolygons and may contain a central seed. Plaques containing only a central seedhave been included in this as well, even though the dose distribution is not fullysymmetric due to the elongated shape of the seed. When considering symmetricseed arrangements with one or more polygons completely filled, the measured cen-tral dose-rate value agrees very well with the one predicted by the MC calculations.For all seven plaque measurements, the results of the symmetric arrangements areshown in Table 3.3. It shows the measurement number, the maximum numberof seeds measured during the set, the seed batch number, where measurementswith the same seed batch number are using the same set of seeds, the plaque typenumber, referring to the type of plaque used and whether the MC simulation uses63individually weighted seeds or the mean seed strength. The next column indicateshow many seeds were used in the specific measurement of the set, followed bythe central dose rate values for the detector and the MC result. This is followedby a column giving the percentage difference between the detector and MC de-rived central dose-rate, based on the value expected from the MC calculations. Foreasy identification, dose-rate differences within the acceptance criteria of ±3% forbatch measurements are colored in green, while differences >+3% are red andthose <−3% are colored yellow. A positive value indicates that the detector resultis higher than the MC result, a negative value means the opposite. The last columngives the percentage of pixels within the area of interest (where the dose is at least25% of the maximum dose) for which the calculated gamma index value is ≤ 1,indicating an agreement within the acceptance criteria. Out of all measurements,the central dose difference is outside of the acceptance level of±3% twice. For themeasurement in row 9 with 4 seeds, it is just above 3%, but with a good agreementof the gamma maps. For the measurement in row 13, the central difference is above6% with a low gamma index agreement percentage. Single seed measurements likethis are more susceptible to errors in positioning and seed strengths because thereis no influence of multiple seeds on the measurement.3.2.2 Symmetric 103Pd seed arrangementsThe results of all symmetrical 103Pd data sets are given in Table 3.4.In the majority of cases, both the central dose difference is less than 3% andthe gamma map agreement rate is well above 90%. However, there are severalcases where this was not the case and which warrant a closer look. The first entry(Pd.1.4) consists of a sparsely filled plaque containing 4 seeds evenly spaced outin an 8 slot polygon. It was used to judge the detector resolution and is not aplaque that would be used in the clinic due to the uneven dose distribution. Thelow agreement in the gamma map is a result of the different resolutions of the MCand the detector images. For seeds placed close to the edge, the Monte Carlo imagehas a better resolution, leading to a difference between the inside and outside of theholder regions. This effect is not visible in the detector measurements. The setsPd.3, and Pd.5 and Pd.17 (with the last two having the same source arrangement)64Table 3.4: Results of 103Pd plaque measurements with symmetric seed ar-rangements showing the central dose-rate values for the detector andMC measurements, as well as the difference between the two in percent(based on the MC values) and the percentage of pixels within the dosecut-off window that comply with the gamma map acceptance criteria byhaving a gamma value ≤ 1.65are all plaques without a center seed and with the seeds situated in a larger polygoncloser to the edge, with 7 (Pd.3) and 9 seeds respectively.Another noteworthy discrepancy concern are the sets based on seed batch 4(Pd.11 to Pd.13), which all show a significant difference of the center dose rate,with a measured dose lower than what is expected from the MC calculations. Giventhe magnitude of the differences, and the fact that they span all measurements ofthis seed batch, it appears that there was an error in the data handling, which couldnot be reconstructed. This is especially likely, as the same source arrangements asin Pd.11 (a single central seed and a central seed as well as a filled 4 seed polygon)have been used in multiple sets (Pd.6, 7, 18) where the results agree very well.3.2.3 Asymmetric seed configurationsAsymmetric and irregular seed configurations in these plaques are less common inclinical practice. If they are being used, it is most often to accommodate a notch,with one seed of the outermost polygon moved out of the way of the notch, orfully removed. Asymmetric plaque measurements are more sensitive to errors, asrotational errors, as well as any tilting of the plaque, have a larger influence on theresults than for symmetric plaques, where any of these changes are more likely tobe averaged out by their opposing seed and the combination of all other seeds. Dueto this, the results for asymmetric and partially filled plaques are often not as goodas they are for symmetric ones. Nonetheless, they are a useful tool to determinethe importance of seed positioning and also as a step-by-step increase of seeds inthe plaque to determine the detector response.3.2.4 Detection of dead or misplaced seedsTo test the system’s ability to detect dead or missing sources, as well as additionalor mispositioned seeds, several similar but slightly differing seed arrangementswere compared. All sources are treated as having the same strength, given by themean air-kerma strength of the seed batch, as would be the case in an assembledplaque where individual seed strength measurements are not possible. The seedconfigurations in the respective 125I plaques, as well as the resulting gamma indexmap, are given in Figure 3.5, with the corresponding numerical results shown in66(a) Missing central seed (b) Missing central seed(c) Additional seed (d) Missing outer seedFigure 3.5: Detecting deviations in seed arrangements between reference andevaluated plaque results due to a missing or additional seed in the eval-uated plaque compared to the reference plaque.Table 3.5.Due to their importance in clinical applications, symmetric plaques were cho-sen as the reference plaques. The MC calculated dose rate distributions of thesesymmetric plaques were used as the reference dose distributions, while the detectorderived dose rate maps are used as the evaluated dose distributions for the gammaindex analysis. The first set, shown in Figure 3.5a examines a four seed plaquewith a missing seed. As shown, only 0.6% of pixels have a Γ ≤ 1, indicating avery poor spatial agreement between the two 2D dose rates. The measured centerdose rate is 24.83% lower than the MC dose rate of the reference plaque. As onemissing seed out of four should result in an overall decrease of 25% in the plaquestrength, this corresponds well to what would be expected. The second plaque con-figuration in Figure 3.5b is an 18 seed plaque, with a single seed missing close tothe center. In this case, the gamma map agreement is better, but still poor, with67Table 3.5: Gamma Analysis and central dose rate difference results for theplaque configurations shown in Figure 3.568.63% of pixels agreeing. The central dose is 5.69% lower than expected fromthe MC result. As this plaque has many seeds, a single missing seed has a muchsmaller impact on the dose distribution. However, it is strong enough to result ina clinically relevant change, and the impact is visible in these results. The nextset shown in Figure 3.5c deals with a 12 seed plaque with seeds arranged in tworings, and an additional seed in between the rings in the measured plaque. Thegamma map shows a large area in the center where the gamma values are above1, and an overall agreement percentage of 77.43%, with the measured central doserate being 11.61% larger than expected. The shape of the gamma map, with thetwo distributions being shifted slightly from each other, with a disagreeing regionin the left-center and better agreement towards the edges indicates a problem withthe plaque. The last set shown in Figure 3.5d shows a 12 seed plaque with a seedmissing in the outer ring. The central dose rate is 5.50% lower than expected. Thegamma map agreement is only 37.20%, a very low value, and the map shows asuspicious pattern, indicating a problem with the plaque.While seeds missing from a plaque could be spotted by visual inspection, amissing seed has the same effect on the dose distribution as a dead seed wouldhave. Because a dead seed looks identical to an active seed, it is impossible todetect during visual inspection. Therefore the main intention of this section wasto determine whether the detection of a dead seed would be possible. In all testedcases, our method is able to detect this.68Figure 3.6: Gamma map comparing the detector result of a plaque withoutsterile packaging to a measurement with the sterile foil between theholder and the detector (left) and with the plaque in the sterile envelopewith the foil between plaque and holder (right).3.3 Measurement through sterile packageAn 11 seed 103Pd plaque with a central seed, a 4 seed polygon, and a six seedpolygon was measured multiple times with and without sterile packaging. The firstmeasurement was done without any sterile packaging, and the second one had thelaminate foil of the sterile packaging between the holder and the detector. The thirdmeasurement had the plaque packaged inside of the self-sealing sterile envelope,with the laminate foil side of the envelope between the plaque and the holder. In Ta-ble 3.6, the results of comparing the detector dose distributions with each other aregiven. Each measurement is compared to the dose distribution of measurement 1to investigate the influence of the packaging. Measuring with the foil in betweenholder and detector decreases the central dose by 2.82%, while the gamma indexagreement remains good. The slight increase in distance between the plaque andthe detector, as well as attenuation by the foil probably causes in this. In the sec-ond case, where the foil is positioned between plaque and holder and the plaquewas fully packaged, the difference is significantly higher, with the central dose ratedecreasing by 8.35% and the gamma index agreement decreasing to 88.63%. Thegamma maps for these two measurements are shown in Figure 3.6. The stiff foilresults in an increased distance between the plaque and the detector, due to it wrin-kling when trying to conform to the curved detector surface. The full packaging69Table 3.6: comparison of detector measured dose distributions without sterilepackaging (1), with the foil between the holder and the detector (2) andwith the plaque packed in the self-sealing envelope with the foil betweenthe holder and the plaque (3). The central dose difference and gammaagreement percentages use the detector measurement of (1) as a referencedose distribution.also makes it difficult to position the plaque, potentially resulting in a non-idealalignment. This method, therefore, is not suitable for measurements through ster-ile packaging. However, including a thin layer like the sterile foil between holderand detector is a viable option if sterility needs to be maintained.In the future, the result can likely be improved by including the sterile layerinto the calibrations. It is also possible to produce a better holder with a thin, flatbase extending past the current partial sphere, that can be sterilized and act as asterile barrier.3.4 Uncertainty AnalysisThe uncertainty of the detector results is based on several factors that are discussedin the following. Some, like the repeatability of the detector measurements or theinfluence of the seed positioning, mostly affect the detector measurements, whileothers, like the well chamber measured air-kerma strength of the seeds, affect boththe Monte Carlo and the detector results. At the end of this section, the uncertaintybudget is calculated based on these factors.3.4.1 Repeated measurementsAn 125I seed at the center of dummy plaque 1 was repeatedly inserted and mea-sured to judge the uncertainty on individual measurements as well as the seed po-sition inside the plaque. Because the position of the radioactive sources inside70the seeds as well as the capsule thickness of a seed is not uniform on all sides ofthe seed, the seed orientation, as well as the seed’s rotational orientation and itsposition in the seed slot, influence the measured dose. The seed was inserted 3times, and each time, five images and an automatically averaged image over fiveshots were recorded. The mean of the individual measurements agreed, to within0.8%, 1.9%, and 0.1% respectively, with the value resulting from the averaged im-age. The standard deviation of the individual measurements was 1.0%, 1.6%, and2.2% respectively. When combining all three measurements to account for posi-tioning and rotation influences, we obtain a standard deviation of 2.7% of the meanvalue. Orientation and positioning as well as noise therefore have an impact on themeasured value and the resulting calculated seed strength. However, this effect de-creases with increasing seeds in the plaque, as these small differences are partiallycanceled out between multiple seeds.3.4.2 Monte Carlo uncertaintyWhen scaling the Monte Carlo voxel dose DMC to absolute dose D, the equationD= [Sk]max ·DMCShistk(3.1)is being used. The uncertainty of the absolute dose σD,is found via uncertaintypropagation and is calculated via:σ2D =(DMCShistk)2·σ2[Sk]max +([Sk]maxShistk)2·σ2DMC +([Sk]max · DMCShist 2k)2·σ2Shistk . (3.2)The statistical error on the dose σDMC is given as an output of the Monte Carlosimulation as part of the 3ddose file. The error on the air-kerma per history σShistkis taken from literature. For the error on the air-kerma strength of the seeds, thestandard deviation of the air kerma strength measurements is used for unweightedseed simulations, where [Sk]max is the mean of the seed strengths. For weightedsimulation runs, [Sk]max is the measured air kerma strength of the strongest seedbeing simulated. In this case, the error on the maximum air kerma strength is thatof the individual seed measurement. Repeated measurements of the same seed in71the well chamber resulted in a standard error uncertainty of 0.3%. Hence, this istaken as the uncertainty on this value. In addition to that, the calibration certificateof the well chamber states an uncertainty in the air-kerma strength measurementsof 2.4% for both 103Pd and 125I seeds. However, this will not be included in theuncertainty budget, as the aim of the analysis is to determine the uncertainty withrespect to the well chamber readings, rather than the uncertainty with respect toabsolute seed strength.3.4.3 Calibration fit uncertaintyFor the calibration fit, a weighted linear least-squares fit is used. The fit uses alinear equation of the form y = mx+b and assumes uncertainties on the y values.The x values are considered absolute values without uncertainty. We use the MCcentral strength as the independent x values and the detector central strength mea-surements as the dependent y values. The decision to neglect the MC errors for thefit was done due to their small size and good control over the simulation parame-ters. For the detector central uncertainties σ , the standard deviation of the centralarea of 10x10 pixels is taken. The estimators for mˆ and bˆ are calculated via:mˆ=(∑ yiσ2i)(∑ xiσ2i)−(∑ 1σ2i)(∑ xiyiσ2i)(∑ xiσ2i)2−(∑ x2iσ2i)(∑ 1σ2i) (3.3)bˆ=(∑ yiσ2i)− mˆ(∑ xiσ2i)(∑ 1σ2i) . (3.4)The uncertainties σmˆ and σbˆ are calculated as:σ2mˆ2 =1∑1/σ2i1〈x2〉−〈x〉2 , (3.5)σ2bˆ =1∑1/σ2i〈x2〉〈x2〉−〈x〉2 (3.6)72where 〈x〉 and 〈x2〉 are given as〈x〉= ∑xi/σ2i∑1/σ2iand 〈x2〉= ∑x2i /σ2i∑1/σ2i. (3.7)In addition, the correlation coefficient ρmˆ,bˆ is calculated asρmˆ,bˆ =−〈x〉√〈x2〉 . (3.8)The resulting fit equation y=mx+b, where y is the measured dose in detectorunits and x is the absolute dose, can be inverted to calculate the absolute dose fromthe detector units via f (m,b) = y−bm = x. The uncertainty on this value resultingfrom the fit is calculated via:σ2x =(∂ f∂b)2σ2b +(∂ f∂m)2σ2m+2ρσmσb(∂ f∂b)(∂ f∂m)(3.9)where ∂ f/∂b = −1/m and ∂ f/∂m = (b− y)/m2. The last term is important,because m and b are not independent, and corrects for an overestimation of theuncertainty at large y values.3.4.4 Seed position influenceThe position of a seed plays an important role in how well the measured and MCcalculated central dose rate agree, and on the gamma index results. In Table 3.7and the accompanying image, the results of inserting a single seed into differentslots of the plaque is shown.When the seed is closer to the center of the plaque, both the central dose rateagreement and the percentage of pixels where Γ ≤ 1 is very good between simu-lated and measured plaque. However, the further the seed is positioned towards theplaque edge, the more this agreement decreases. This is also visible when com-paring the dose rate maps and the gamma index map between these measurementsas shown in Figure 3.7. For the seed positioned close to the edge, the measureddetector dose is lower than the MC dose, both in the center of the plaque, as wellas overall. The calibration factor is calculated at the center of the plaque, which73Table 3.7: Results of repeated measurements of a 103Pd seed at different po-sitions within a plaque (left) where the seed positions are indicated in theimage (right). Agreement between detector measured dose and MC cal-culated central dose rate, as well as gamma index agreement is better thecloser the seed is to the center.explains the good agreement for central seeds. Towards the edge, the distancebetween the detector plane and the seed decreases as the thickness of the holderdecreases. This changes the ratio between the distance a photon travels throughPMMA and the unknown detector material below. In addition to that, a smaller dis-tance results in a higher sensitivity to positioning errors. As the dose decrease withdistance follows an inverse square law relationship, small position changes havea larger influence here. The same holds true for rotational position changes. Ifthe modeled and measured plaque aren’t perfectly aligned but are slightly rotatedagainst each other, the effect is negligible for centrally positioned seeds and sym-metrical arrangements. For asymmetric configurations and seeds towards the edge,this effect is larger. A tilted plaque on the holder also has a greater influence onperipheral seeds, than it does on central seeds.A contributing factor to this effect might be found in the internal structure ofthe scintillator and our inability to model the internal composition of the detectorin MC. If the active layer consists of thin columns of scintillator (one for eachpixel), encased by aluminum or a different light reflective material, it means thatlight generated in one column can not travel to a neighboring column and is in-stead registered in the pixel belonging to the column in which it was generated.However, x-ray photons can potentially travel through these ”walls”. Thus, x-ray74(a) (b)Figure 3.7: Comparison of seed position influence with the source placed inthe center (a) and close to the edge of the plaque (b). The images at thetop show the dose rate map resulting from the detector measurement.The middle images show the dose rate map as calculated from the MCsimulation. The bottom images show the gamma map with a dose cut-off of 25% of the maximum dose and 3%/1mm acceptance criteria. Theseed positions a & b correspond to the results 1 & 11 in Table 3.7.75photons coming in at an angle, could travel through one or more columns, poten-tially generating light in any of the several neighboring columns. This would resultin the signal generated from these angled photons to spread out over multiple sen-sor pixels. This may cause some of the signal to spill out of the region used todetermine the central dose. For more peripheral regions, this would also result inthe signal of oblique incoming x-ray photons being ”smeared” out over a largerarea, compromising the agreement between the dose maps.Another interesting effect is the honeycomb-like structure that is visible inmany detector images, and especially prominent in the Gamma maps and differ-ence images between detector and MC results. This Fixed Pattern Noise (FPN) (asseen in the bottom right image of Figure 3.7) also seems to be a result of the detec-tor structure, and could potentially be corrected by a employing a gain correctionusing a flood image, where the whole detector is uniformly exposed38. However,as this would have to be done with the same photon energies as the seeds, thismight be difficult to accomplish and instead, this is corrected by always averagingover multiple pixels.3.4.5 Uncertainty budgetAs discussed in this section, a multitude of factors contribute to the uncertainty ofthe central dose rate value. In addition to the uncertainty resulting from the cali-bration factors and the resulting conversion from detector reading to dose rate, theuncertainty of the positioning of the seeds along the z-direction has to be consid-ered. The manufacturing process results in an uncertainty of±0.2 mm on the verti-cal seed placements within the plaque, and a resulting equally large uncertainty onthe detector-seed distance. The uncertainty on the mean central reading is foundby taking the standard deviation of the pixels that are being averaged and the per-centage difference of this value decreases with increasing seed number, from 2%at 1 seed to 1% for an 18 seed plaque. Another factor that needs to be consideredis the repeatability of the measurements, which were found to contribute a 2.7%uncertainty to the resulting central dose rate.Table 3.8 shows the uncertainty budget with uncertainties split into Type A sta-tistical uncertainties, and Type B systematic and other uncertainties. Mainly due76Table 3.8: Uncertainty budget for 125I and 103Pd detector and Monte Carloresults.to the larger influence of noise on the lower seed strength measurements of 125Iseeds, the combined total uncertainty is 5.4% for 125I plaque measurements, higherthan the 4.9% for the 103Pd seed measurements. It is important to note, that theuncertainty decreases with increasing number of seeds in the plaque, hence the ob-served uncertainties are generally lower than this, especially for large seed numberplaques. The combined uncertainties on the MC results are 2.5% for both 103Pdand 125I plaques and are mostly driven by the statistical uncertainty produced bythe simulation, and the standard deviation of the central area of the dose distribu-tion for the central dose-rate.3.5 Translation to TG-43As the measurements are done in air and the corresponding Monte Carlo calcu-lation is based on simulating the measurement setup, the resulting output can notdirectly be compared to the output from the TG-43 based treatment planning dosecalculations. However, it is possible to run the same plaque in a uniform water MCphantom and compare the resulting output to the treatment planning calculations.To do this, our in-house TG-43 calculation code was expanded to obtain TG-43values for each point in the detector plane. The plaque designs used for this areshown in Figure 3.8.The dose rate in the detector plane was calculated by multiple means: using the77Figure 3.8: Plaque design used to compare TG-43 and Monte Carlo dose dis-tributions in a uniform water phantom.Figure 3.9: Dose rate distributions in the detector plane for an 11 seed plaqueas calculated using a uniform water phantom Monte Carlo simulation(top left), and the TG-43 algorithm (top left). In the lower row, theleft image shows the gamma index map with a very good agreementbetween both results, while the right image shows the pixel-wise differ-ence between the MC and TG-43 result.78TG-43 algorithm, by MC simulation in a TG-43 conforming environment of a large,uniform water phantom, by measuring it with the detector and by simulating thedetector response in MC. For the 11 seed plaque, the detector measurements andcorresponding Monte Carlo values for the detector agree well, with a central doserate difference of 0.4 % and a gamma map agreement value of 100 %. When thesame plaque is simulated in the TG-43 environment of a uniform water phantom, acentral dose rate of D˙MC,water =0.2275 Gy/h is calculated. The same seed arrange-ment results in a central dose rate of D˙tg=0.2271 Gy/h in the TG-43 calculation,which is 0.19% lower than the value calculated by the TG-43 equivalent MonteCarlo calculation. The dose distributions also agree spatially, with a Gamma indexagreement value of 100% of all pixels with a dose rate of ≥ 25% of the maximaldose rate.Figure 3.9 shows the dose rate distribution in the detector plane as calculatedvia MC simulation in a uniform water phantom and via TG-43 algorithm. It alsoshows the Gamma index map with the excellent agreement between the two resultsas well as the pixel-wise difference between the two distributions. In the differenceimage, the center shows a region where the MC dose rates are larger than the TG-43 calculations (shown in red), with a dark-blue ring-shaped region surroundingthe center region, where the TG-43 results are larger, followed by a large regionwhere the results are more similar again, with the TG-43 result being slightly larger.One can assume that these differences are due to the fact that the MC simulationincludes the plaque material, and a more accurate radiation transport modeling thanthe TG-43 calculation.The good agreement between the water based MC results and the TG-43 resultsshows that simulating a plaque in a uniform water phantom is a good way to com-pare the plaque to the currently existing treatment planning process. This can beused in the final plaque verification process, as the same plaque can be simulatedonce in the detector environment, and once in the TG-43 equivalent environment.Figure 3.10 shows a flow-chart of the proposed plaque verification process.During treatment planning, the 3d dose distribution for the planned plaque is cal-culated using the TG-43 formalism. The plaque is then simulated in Monte Carlo,once in a TG-43 equivalent water phantom, and once in the detector phantom in-cluding the plaque holder. Then the plaque is measured using the detector. The79Figure 3.10: Flowchart of the plaque verification process.resulting detector result is compared to the detector simulating MC result. Thisverifies that the measured plaque agrees with the MC simulated plaque. To verify,that the modeled plaque agrees with the planned plaque during treatment, the TG-43 calculation and the TG-43 equivalent MC result are compared. If both of thesecomparisons agree, the plaque is accepted.A significant part of this process can be automated, including the generation ofthe MC simulation input files and the comparisons. Furthermore, as the MC resultsare scaled for the seed’s air-kerma strength after the simulation, it is possible togenerate a library of regularly used plaque designs to avoid having to individuallysimulate each plaque, as long as unweighted seeds are used in the MC simulation.80Figure 3.11: Calibration plot for the Eye Physics plaque using 4 measure-ments (left) and the pixelwise difference between MC result and de-tector measurements using this calibration factor for an 16 seed plaque(right).Table 3.9: Results of measurements of an 103Pd loaded Eye Physics plaque.The measurements marked in yellow were used for the calibration andthe effective detector depth is 7 mm.3.6 Eye Physics PlaquesA 30 seed Eye Physics dummy plaque was used to investigate if it is possible to eas-ily expand the functionality of the system to be used with other plaque types. Themeasurements of an Eye Physics plaque filled with a varying number of 103Pd seedswere at first scaled using the 103Pd calibration from the acrylic plaques. However,this method gives very poor results, with central dose differences between 66%and 92% and a correspondingly poor gamma map agreement, showing that thecalibration is not transferable between significantly different plaque types. Whenconsidering the distinctly different plaque properties, this isn’t unexpected.81To investigate whether these results can be improved by using a calibrationfactor specific to the Eye Physics plaque, the calibration is repeated using four ofthe measurements, as shown in Figure 3.11. The resulting effective detector depthis 7 mm, where the MC registered dose is much lower (and the dose gradient lesssteep). Using this calibration, and applying it to scale and analyze all detector mea-surements, we can see that both the central dose rate agreement and the gammamap agreement values improve, as shown in Table 3.9. In it, the measurementsused for the calibration are marked in yellow. While the results improve with theplaque specific calibration, the significant central dose differences for most mea-surements show the increased uncertainty in these measurements. This might bepartially due to increased positioning uncertainties, but also due to the angle de-pendence for the detector registration and the resolution of the detector. This isespecially noticeable when looking at the differences between the 2D dose distri-butions of the detector and MC results. As seen in the right image of Figure 3.11,which shows the pixel-wise percentage differences for measurement 6, the detectormeasurement is relatively accurate for the center of the plaque. With increased dis-tance from the center, where high-angle incoming radiation contributes the most,the detector measurement is significantly lower than the MC predicted values. Thedose map difference in Figure 3.11 shows that the MC derived dose map is muchbetter defined (with a near-rectangular dose distribution), than the detector deriveddose distribution, which is much more rounded and oval. This, in combination withthe effective detector depth of 7 mm, a region where the dose gradient across theimaging area is a lot less steep than at smaller distances, is another indicator thatthe detector structure (especially the scintillator structure) has to be better modeledin order to predict the detector results for high-angle incoming photons. It suggeststhat the signal is indeed smeared out over all regions these angled photons passthrough.Further studies will have to show if the results can be improved by a betterplaque specific calibration process that employs correction factors for high angleincoming radiation, better modeling of the inner detector structure, and improvedplaque positioning, or whether the detector is not suitable for individually colli-mating plaques which contribute a significant part of their radiation at a large anglewith respect to the z-axis.82(a) (b) (c)Figure 3.12: Seed configurations used to determine if a plaque measurementresult can be modeled by the combination of two symmetric plaques3.6.1 Angle based seed contributionOne possible way to correct for the dependence between seed position in the plaqueand central seed strength is to use different calibration factors depending on theposition of the seeds. A possible way of doing this would entail finding a correctionfactor to correct the reduced impact of radiation coming in at a greater angle. Forsymmetric seed arrangements, this would entail finding the calibration factor foreach seed polygon. A necessary requirement for this to work is the assumptionthat the dose distribution of a plaque containing multiple source rings is the sameas adding the dose distributions of multiple plaques with one ring each, whichcombined give the same seed arrangement. This assumption is used in the TG-43 calculations. To see if this is the case for the detector measurements, severalmeasurements were done with two symmetric plaques, whose detector measureddose distributions were combined and compared to the results of a measurement ofa plaque containing the combined seed arrangements.The seed configurations used are shown in Figure 3.12. For the first seed con-figuration shown in Figure 3.12a, individual measurements of a plaque containingthe 5 seeds in the center, and a plaque containing the 8 outer seeds, were combinedand compared to a measurement of a plaque with the full 13 seeds. For the othertwo plaques, measurement results of measuring the inner and outer seed ring indi-vidually were compared to measurements of the full plaque with both rings. Theresults are given in Table 3.10, where the reference dose for the gamma analysisis the dose distribution of the full plaque, and the evaluated dose is the combined83Table 3.10: Results of comparing the superposition of the detector results oftwo plaques, that combined have the same seed configuration as theplaque they are being compared to.dose distribution of the measurements of the partially filled plaques. In all cases,the combined central dose is slightly lower than the central dose determined fromthe measurement of the full plaque, with a minimum difference of -0.27% for thefirst, and a maximum difference of -1.73% for the last measurement. This is wellwithin the measurement uncertainty for repeated measurements. As shown in Fig-ure 3.13, which shows the pixel-wise difference between the two dose distributionsin percent of the reference dose of the full plaque, the agreement between the dis-tributions is very good and uniform across the whole region.This indicates that it could indeed be possible to improve the results by intro-ducing a correction factor depending on the seed position. One possible way todo this could be to apply a weighting factor on the seeds based on their positionsin the Monte Carlo modeling of the detector response. This can be addressed infuture work.84Figure 3.13: Difference between the (reference) dose distribution of the fullplaque and the (evaluated) dose distribution of the combined plaques,showing very good agreement. The measured plaque is shown in Fig-ure 3.12b.85Chapter 4DiscussionThe use of a detector and Monte Carlo based system for brachytherapy eye plaquesworks well for the tested in-house plaques. With a cumulative uncertainty of 4.9%for 103Pd and 5.4% for 125I plaques on the central dose rate, it is above the 3% thatwould be ideal for batch measurements of multiple seeds. However, it is smallerthan the 6% tolerance for individual seed measurements. In addition, the uncer-tainty decreases with an increase of seeds as minor differences average out.The technique has been shown to be useful to detect displaced, as well as ad-ditional or missing/dead seeds and can detect an overall change in the dose distri-bution resulting from this. It is especially useful for the clinically important groupof symmetrical seed arrangements, which are less sensitive to rotational misalign-ment between the detector measurements and MC simulations. It is also especiallysuited to plaques with a central seed and seeds not too distant from the center.When this is not the case and the seeds are situated closer to the edge, multiple fac-tors increase the uncertainty of the results. The decrease in seed-detector distance,in this case, leads to an increased impact of any errors due to the inverse squarelaw decrease in dose with distance from the seeds. Any tilting or rotation errors ofthe plaque are also more prominent when seeds are more distant from the center ofthe plaque.In addition, insufficient modeling of the inner structure of the scintillating layerresults in poor agreement between simulated and measured dose for plaques thatproduce a lot of incoming photons with a large angle against the z-axis, whose86signal gets smeared out over a large area. For this reason, the detector seems bet-ter suited to uncollimated plaques like our in-house design, or the commerciallyavailable COMS plaques, which were not tested in this work. It is less suitable forplaques with individually collimating seed slots that produce a higher proportionof narrow angled, diagonally incoming radiation from peripheral seed locations. Inthe future, a more accurate modeling of the scintillating layer and the inner compo-sition of the detector might improve the results of individually collimating plaques.We consider this a successful proof of concept to show that a combination ofdetector measurements and MC calculations can successfully be used to validateassembled suitable plaques. In the future, the method can be improved in multipleways:As the calibration factors depend on the isotope used in the sources, as wellas the seed and plaque design, a plaque specific calibration for frequently usedplaque configurations might improve the accuracy of the results, especially for thecentral plaque strength. It should also be investigated whether the method can becalibrated for use with COMS plaques, which have a geometry similar to the in-house plaques but could not be obtained by us as they are not used in the clinicalpractice at this center.The most common sources of errors in brachytherapy are positioning errorsand this technique is not exempt from that. Due to the variability in plaque sizesand designs used in our center, the emphasis of this system was put on flexibilityto make sure that all plaques can be measured in this way. This necessarily comesat a cost to the precision of plaque positioning. To change this, a more plaque spe-cific positioning and plaque fixation holder could be designed to reduce the errorresulting from this. When the detector is permanently positioned in a spot, otherpositioning tools, like laser positioning beams could be used as well to maintainthe flexibility of the system while increasing accuracy.When considering sterility management, a measurement setup in air instead ofwater has many inherent advantages. While it is difficult to measure the plaqueswhile they are packaged into the sterile envelope due to the geometry of the holderand plaque, with the foil wedged in between the two, further studies could investi-gate if a different calibration set-up would make this approach feasible. However,the other method of inserting a sterile layer between the detector and the (steril-87ized) holder, seems promising. In the future, this could be replaced by a sterilizableholder with a large, thin base extending past the holder sphere, that acts as a sterilebarrier. It can be accounted for by a change in the calibration factor to include theincreased seed-detector distance.4.1 ConclusionThis study shows that a detector and Monte Carlo based measurement system foreye plaque brachytherapy quality assurance can be used for dosimetric verificationof assembled eye plaques. The use of MC simulations enables the comparison toTG-43 and Monte Carlo derived dose distributions in a flexible environment. Toexpand this to other types of plaques, an individual calibration for the plaque typemust be done.Limitations of this technique include the nature and resolution of the detector,which may not be suited for radiation coming in at a large angle. Otherwise, themeasurement of a plaque is quick and easy and results are consistent over multipleseed arrangements, different days and seed batches as well as number of seeds.While the Monte Carlo simulation of the plaques is computationally expensive, alibrary containing the MC calculated dose distributions of plaques with commonseed types and arrangements, built over time, could be reused to reduce this burden.Future studies will have to be done in order to confirm whether this techniqueis expandable to other plaque designs. Together with other recent developmentsin eye plaque brachytherapy, this will hopefully result in improvements in qualityassurance of eye plaques, to make sure that patients receive the optimal treatmentto maximize their chance of beating cancer, while also keeping them safe fromexcessive radiation.88Bibliography[1] Canadian Cancer Statistics Advisory Committee. Canadian Cancer Statistics2019, 2019. URL https://www.cancer.ca/∼/media/cancer.ca/CW/cancerinformation/cancer101/Canadiancancerstatistics/Canadian-Cancer-Statistics-2019-EN.pdf?la=en.→ page 1[2] Donald C. Rizzo. Fundamentals of Anatomy and Physiology. CengageLearning, February 2015. → page 3[3] Arun D. Singh, Mary E. Turell, and Allan K. Topham. Uveal Melanoma:Trends in Incidence, Treatment, and Survival. Ophthalmology, 118(9):1881–1885, September 2011. → pages 3, 5[4] Kathleen M. Egan, Johanna M. Seddon, Robert J. Glynn, Evangelos S.Gragoudas, and Daniel M. Albert. Epidemiologic aspects of uvealmelanoma. Survey of Ophthalmology, 32(4):239–251, January 1988. →pages 3, 4[5] Predrag Jovanovic, Marija Mihajlovic, Jasmina Djordjevic-Jocic, SlobodanVlajkovic, Sonja Cekic, and Vladisav Stefanovic. Ocular melanoma: anoverview of the current status. International Journal of Clinical andExperimental Pathology, 6(7):1230–1244, June 2013. → pages 3, 4[6] Stephen B. Edge and American Joint Committee on Cancer, editors. AJCCcancer staging manual. Springer, New York, 7th ed edition, 2010. → pages3, 22[7] Sati Akbaba, Robert Foerster, Nils Henrik Nicolay, Nathalie Arians, TilmanBostel, Juergen Debus, and Henrik Hauswald. Linear accelerator-basedstereotactic fractionated photon radiotherapy as an eye-conserving treatmentfor uveal melanoma. Radiation Oncology, 13(1):140, August 2018. → page489[8] Emmanuel Egger, Ann Schalenbourg, Leonidas Zografos, Ludmila Bercher,Terence Boehringer, Line Chamot, and Gudrun Goitein. Maximizing localtumor control and survival after proton beam radiotherapy of uvealmelanoma. International Journal of Radiation Oncology*Biology*Physics,51(1):138–147, September 2001. → page 4[9] Emmanuel Egger, Leonidas Zografos, Ann Schalenbourg, Donata Beati,Terence Bhringer, Line Chamot, and Gudrun Goitein. Eye retention afterproton beam radiotherapy for uveal melanoma. International Journal ofRadiation Oncology*Biology*Physics, 55(4):867–880, March 2003. →page 5[10] Robert Jones, Elizabeth Gore, William Mieler, Kevin Murray, MichaelGillin, Katherine Albano, and Beth Erickson. Posttreatment visual acuity inpatients treated with episcleral plaque therapy for choroidal melanomas:dose and dose rate effects. International Journal of RadiationOncology*Biology*Physics, 52(4):989–995, March 2002. → page 5[11] Harold Elford Johns and John Robert Cunningham. Physics of Radiology,Fourth Edition. Charles C Thomas Pub Ltd, Springfield, Ill., U.S.A, 4thedition edition, February 1983. → page 5[12] L. Sim. Novel application of 3D printing in brachytherapy using MED6103D printed insert for I-125 ROPES eye plaque. Australasian Physical &Engineering Sciences in Medicine, 39(4):863–870, December 2016. →pages 9, 22[13] Jean Pouliot and Luc Beaulieu. 13 - Modern Principles of BrachytherapyPhysics: From 2-D to 3-D to Dynamic Planning and Delivery. In Richard T.Hoppe, Theodore Locke Phillips, and Mack Roach, editors, Leibel andPhillips Textbook of Radiation Oncology (Third Edition), pages 224–244.W.B. Saunders, Philadelphia, January 2010. → pages 9, 10[14] NIST XCOM. URLhttps://physics.nist.gov/PhysRefData/Xcom/html/xcom1.html. Accessed:2020-10-14 11:59:03. → pages xii, 10, 13[15] Subir Nag, Jeanne M Quivey, John D Earle, David Followill, JamesFontanesi, and Paul T Finger. The American Brachytherapy Societyrecommendations for brachytherapy of uveal melanomas. InternationalJournal of Radiation Oncology*Biology*Physics, 56(2):544–555, June2003. → pages 11, 16, 2290[16] Eric J. Hall and Amato J. Giaccia. Radiobiology for the Radiologist.Lippincott Williams & Wilkins, 2006. → page 15[17] Mark J. Rivard, Bert M. Coursey, Larry A. DeWerd, William F. Hanson,M. Saiful Huq, Geoffrey S. Ibbott, Michael G. Mitch, Ravinder Nath, andJeffrey F. Williamson. Update of AAPM Task Group No. 43 Report: Arevised AAPM protocol for brachytherapy dose calculations. MedicalPhysics, 31(3):633–674, 2004. → pages 16, 17[18] Joao Seco and Frank Verhaegen. Monte Carlo Techniques in RadiationTherapy. CRC Press, March 2013. → page 20[19] Marc J. P. Chamberland, Randle E. P. Taylor, D. W. O. Rogers, andRowan M. Thomson. egs brachy: a versatile and fast Monte Carlo code forbrachytherapy. Physics in Medicine and Biology, 61(23):8214–8231,November 2016. → pages 21, 44[20] Rowan M Thomson, Randle E P Taylor, Marc J P Chamberland, and D W ORogers. User manual for egs brachy. URLhttps://clrp-code.github.io/egs brachy/. → pages 21, 48, 50[21] E. Rand Simpson, Brenda Gallie, Normand Laperrierre, AkbarBeiki-Ardakani, Tero Kivela¨, Virpi Raivio, Jorma Heikkonen, LaurenceDesjardins, Remi Dendale, Alexandro Mazal, Norbert Bornfeld, WolfgangSauerwein, Dirk Flu¨ehs, Lorenzo Brualla, Santosh G. Honavar, VijayAnand P. Reddy, Shigenobu Suzuki, Naoya Murakami, Svetlana Saakyan,Vladimir Valskiy, Anush Amiryan, Stefan Seregard, Charlotta All-Eriksson,Lars Hjelmqvist, Go¨ran Lundell, Georges Sinclair, Marie Lundell, BertilDamato, R Doug Errington, Philip Mayles, Helen Mayles, Chris Bergstrom,Hans Grossniklaus, Ian Crocker, Elizabeth Butker, Matthew Wilson, BarrettHaik, Holger Geischen, Pradeep Patra, Jay Duker, John Mignano, MarkRivard, Paul T. Finger, Ekaterina Semenova, Walter Choi, and Nina I.Kalach. The American Brachytherapy Society consensus guidelines forplaque brachytherapy of uveal melanoma and retinoblastoma.Brachytherapy, 13(1):1–14, January 2014. → pages 22, 23[22] Mark J. Rivard, Sou-Tung Chiu-Tsao, Paul T. Finger, Ali S. Meigooni,Christopher S. Melhus, Firas Mourtada, Mary E. Napolitano, D. W. O.Rogers, Rowan M. Thomson, and Ravinder Nath. Comparison of dosecalculation methods for brachytherapy of intraocular tumors: Comparison ofeye plaque dose calculation methods. Medical Physics, 38(1):306–316,December 2010. → page 2291[23] Sou-Tung Chiu-Tsao, Melvin A. Astrahan, Paul T. Finger, David S.Followill, Ali S. Meigooni, Christopher S. Melhus, Firas Mourtada, Mary E.Napolitano, Ravinder Nath, Mark J. Rivard, D. W. O. Rogers, and Rowan M.Thomson. Dosimetry of 125I and 103Pd COMS eye plaques for intraoculartumors: Report of Task Group 129 by the AAPM and ABS. MedicalPhysics, 39(10):6161–6184, 2012. → pages 22, 24, 25, 26, 55[24] The Collaborative Ocular Melanoma Study Group. Design and methods of aclinical trial for a rare condition: The collaborative ocular melanoma study:COMS Report No. 3. Controlled Clinical Trials, 14(5):362–391, October1993. → pages 23, 32[25] Wayne M. Butler, William S. Bice, Larry A. DeWerd, James M. Hevezi,M. Saiful Huq, Geoffrey S. Ibbott, Jatinder R. Palta, Mark J. Rivard, Jan P.Seuntjens, and Bruce R. Thomadsen. Third-party brachytherapy sourcecalibrations and physicist responsibilities: Report of the AAPM Low EnergyBrachytherapy Source Calibration Working Group. Medical Physics, 35(9):3860–3865, 2008. → page 25[26] Gerald J. Kutcher, Lawrence Coia, Michael Gillin, William F. Hanson,Steven Leibel, Robert J. Morton, Jatinder R. Palta, James A. Purdy,Lawrence E. Reinstein, Goran K. Svensson, Mona Weller, and LindaWingfield. Comprehensive QA for radiation oncology: Report of AAPMRadiation Therapy Committee Task Group 40. Medical Physics, 21(4):581–618, 1994. → page 25[27] Akbar Beiki-Ardakani, John Jezioranski, David A. Jaffray, and Ivan Yeung.Improving quality assurance for assembled COMS eye plaques using apinhole gamma camera. Medical Physics, 35(10):4318–4323, 2008. → page26[28] Mauro Carrara, Dean Cutajar, Saree Alnaghy, Anthony Espinoza, AnnaRomanyukha, Stefano Presilla, Chiara Tenconi, Annamaria Cerrotta, CarloFallai, Mitra Safavi-Naeini, Marco Petasecca, Alannah Kejda, MichaelLerch, Ste´phanie Corde, Michael Jackson, Andrew Howie, Joseph Bucci,and Anatoly B. Rosenfeld. Semiconductor real-time quality assurancedosimetry in brachytherapy. Brachytherapy, 17(1):133–145, January 2018.→ page 27[29] Alannah Kejda, Dean Cutajar, Michael Weaver, Marco Petasecca, andAnatoly Rosenfeld. A novel quality assurance system for eye plaque92brachytherapy. Australasian Physical & Engineering Sciences in Medicine,42(4):1109–1115, December 2019. → page 27[30] Marion Eichmann, Dirk Flu¨hs, and Bernhard Spaan. Development of a highprecision dosimetry system for the measurement of surface dose ratedistribution for eye applicators. Medical Physics, 36(10):4634–4643, 2009.→ page 27[31] Hali A. E. K. Morrison. Accurate Dosimetry for Ocular Brachytherapy:Measurement, Delivery Uncertainty, and Dose Calculation Studies, 2017.Library Catalog: era.library.ualberta.ca DOI: 10.7939/R3SB3XC4M. →page 27[32] L. W. Zimmermann and D. Allan Wilkinson. Method for verifying the airkerma strength of I-125 plaques for the treatment of ocular melanoma.Journal of Applied Clinical Medical Physics, 15(4):297–305, 2014. → page27[33] Ali S. Meigooni, Sharifeh A. Dini, Shahid B. Awan, Kai Dou, and Rafiq A.Koona. Theoretical and experimental determination of dosimetriccharacteristics for ADVANTAGETM Pd-103 brachytherapy source. AppliedRadiation and Isotopes, 64(8):881–887, August 2006. → page 30[34] Firas Mourtada, Justin Mikell, and Geoffrey Ibbott. Monte Carlocalculations of AAPM Task Group Report No. 43 dosimetry parameters forthe 125I I-Seed AgX100 source model. Brachytherapy, 11(3):237–244, May2012. → page 31[35] Maryam Golshan, Ingrid Spadinger, and Nick Chng. Source strengthverification and quality assurance of preloaded brachytherapy needles usinga CMOS flat panel detector: Strength verification and quality assurance ofbrachytherapy needles. Medical Physics, 43(6Part1):3008–3018, May 2016.→ pages 36, 37[36] Dexella Ltd. Technical manual - Dexella X-Ray Detector Panels: 2923,2315, 1512, 1207, Version 2.0, 2010. → pages x, xiii, 36, 38[37] Jose G. Rocha and Senentxu Lanceros-Mendez. Review on X-ray DetectorsBased on Scintillators and CMOS Technology. Recent Patents on ElectricalEngineeringe, 4(1):16–41, January 2011. → page 37[38] Anastasios C. Konstantinidis, Magdalena B. Szafraniec, Robert D. Speller,and Alessandro Olivo. The Dexela 2923 CMOS X-ray detector: A flat panel93detector based on CMOS active pixel sensors for medical imagingapplications. Nuclear Instruments and Methods in Physics Research SectionA: Accelerators, Spectrometers, Detectors and Associated Equipment, 689:12–21, October 2012. → pages 37, 76[39] M. Hermida-Lo´pez, L. Lu¨demann, A. Flu¨hs, and L. Brualla. Technical Note:Influence of the phantom material on the absorbed-dose energy dependenceof the EBT3 radiochromic film for photons in the energy range 3 keV–18MeV. Medical Physics, 41(11):112103, 2014. → page 40[40] T. J. A. G. Mu¨nker, S. E. C. M. van de Vijfeijken, C. S. Mulder,V. Vespasiano, A. G. Becking, C. J. Kleverlaan, A. G. Becking, L. Dubois,L. H. E. Karssemakers, D. M. J. Milstein, S. E. C. M. van de Vijfeijken, P. R.A. M. Depauw, F. W. A. Hoefnagels, W. P. Vandertop, C. J. Kleverlaan, T. J.A. G. Mu¨nker, T. J. J. Maal, E. Nout, M. Riool, and S. A. J. Zaat. Effects ofsterilization on the mechanical properties of poly(methyl methacrylate)based personalized medical devices. Journal of the Mechanical Behavior ofBiomedical Materials, 81:168–172, May 2018. → page 44[41] Cansu Yavuz, Samad Nadimi Bavil Oliaei, Barbaros Cetin, and OzlemYesil-Celiktas. Sterilization of PMMA microfluidic chips by varioustechniques and investigation of material characteristics. The Journal ofSupercritical Fluids, 107:114–121, January 2016. → page 44[42] I. Kawrakow, E. Mainegra-Hing, D. W. O. Rogers, F. Tessier, and B. R. B.Walters. The EGSnrc code system: Monte Carlo simulation of electron andphoton transport. Technical Report PIRS-701, National Research CouncilCanada, 2017. URLhttp://nrc-cnrc.github.io/EGSnrc/doc/pirs701-egsnrc.pdf. → page 44[43] Habib Safigholi, Marc J. P. Chamberland, Randle E. P. Taylor, Christian H.Allen, Martin P. Martinov, D. W. O. Rogers, and Rowan M. Thomson.Update of the CLRP TG-43 parameter database for low-energybrachytherapy sources. Medical Physics, 47(9):4656–4669, 2020. → page49[44] Daniel A. Low and James F. Dempsey. Evaluation of the gamma dosedistribution comparison method. Medical Physics, 30(9):2455–2464,August 2003. → page 5494
Thesis/Dissertation
eng
Physics
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Combining Monte Carlo simulations and detector measurements for a novel quality assurance system of assembled brachytherapy eye plaques.
Text