Arts and Sciences, Irving K. Barber School of (Okanagan)
Computer Science, Department of
DSpace
UBCO
Zhang, Xiaoying
Master of Science - MSc
University of British Columbia
Purpose: The purpose of this work is to further develop and to validate a prototype three-dimensional ultrasound (3DUS) system for permanent breast seed implant (PBSI) planning procedure. PBSI is a novel brachytherapy technique for early-stage breast cancer patients. Palladium-103 seeds are planned around the seroma cavity and implanted through the guidance of a needle implant template. Currently, PBSI plans are made based on computed tomography (CT) images, while the delivery is guided under freehand 2D ultrasound (US) images in the operating room. The difference on seroma visualization on CT and US complicates the interpretation of the plan during the delivery. A prototype PBSI 3DUS system has been developed and 3DUS images are desired for improved visualization in PBSI treatment planning. Materials and Methods: The PBSI 3DUS system includes a motorized scanner that drives a 2D US probe during scanning. An encoded mechanical arm is mounted on the scanner and tracks the location of the needle implant template, and the template can be then registered into the 3DUS imaging volume for visual guidance. A method was developed to rigidly register 3DUS images with CT images through a point-based registration. A 3D-printed model was made to provide visible landmarks in both imaging volumes. Gel breast phantoms were constructed to test the registration feasibility and accuracy. Results: A 3D-printed model with eight landmarks ranging over 6 cm in three dimensions was adopted for 3DUS-CT rigid registration process. The registration was performed on gel breast phantoms, with the 3DUS scanner oriented in a 40 range of lateral orientation. The average registration error was (1.9 ± 0.8) mm. The maximum error in 25 3DUS-CT registration trials was 4.6 mm, and 19 out of 25 (76%) trials had a registration error less than 2 mm. Conclusions: This work facilitated the clinical implementation of the PBSI 3DUS system. The 3DUS system was commissioned and a clinical quality assurance (QA) procedure with baseline data was made to monitor the system performance. A method was developed to achieve 3DUS-CT rigid registration and the registration was tested on gel breast phantoms.
Rigid Registration of 3D Ultrasound Images andComputed Tomography Images for PermanentBreast Seed Implant Brachytherapy TreatmentPlanningbyXiaoying ZhangB.Sc., Fudan University, 2017A THESIS SUBMITTED IN PARTIAL FULFILLMENTOF THE REQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCEinThe College of Graduate Studies(Medical Physics)THE UNIVERSITY OF BRITISH COLUMBIA(Okanagan)August 2019© Xiaoying Zhang, 2019The following individuals certify that they have read, and recommend to the College of GraduateStudies for acceptance, a thesis/dissertation entitled:RIGID REGISTRATION OF 3D ULTRASOUND IMAGES AND COMPUTED TOMOGRAPHY IM-AGES FOR PERMANENT BREAST SEED IMPLANT BRACHYTHERAPY TREATMENT PLANNINGsubmitted by XIAOYING ZHANG in partial fulfilment of the requirements of the degree of Masterof ScienceDr. Michelle Hilts, I. K. Barber School of Arts & SciencesSupervisorDr. Andrew Jirasek, I. K. Barber School of Arts & SciencesSupervisory Committee MemberDr. Deidre Batchelar, I. K. Barber School of Arts & SciencesSupervisory Committee MemberDr. Hadi Mohammadi, School of EngineeringUniversity ExamineriiAbstractPurpose: The purpose of this work is to further develop and to validate a prototype three-dimensionalultrasound (3DUS) system for permanent breast seed implant (PBSI) planning procedure. PBSI isa novel brachytherapy technique for early-stage breast cancer patients. Palladium-103 seeds areplanned around the seroma cavity and implanted through the guidance of a needle implant template.Currently, PBSI plans are made based on computed tomography (CT) images, while the deliveryis guided under freehand 2D ultrasound (US) images in the operating room. The difference onseroma visualization on CT and US complicates the interpretation of the plan during the delivery.A prototype PBSI 3DUS system has been developed and 3DUS images are desired for improvedvisualization in PBSI treatment planning.Materials and Methods: The PBSI 3DUS system includes a motorized scanner that drives a 2DUS probe during scanning. An encoded mechanical arm is mounted on the scanner and tracksthe location of the needle implant template, and the template can be then registered into the 3DUSimaging volume for visual guidance. A method was developed to rigidly register 3DUS images withCT images through a point-based registration. A 3D-printed model was made to provide visiblelandmarks in both imaging volumes. Gel breast phantoms were constructed to test the registrationfeasibility and accuracy.Results: A 3D-printed model with eight landmarks ranging over 6 cm in three dimensions wasadopted for 3DUS-CT rigid registration process. The registration was performed on gel breast phan-toms, with the 3DUS scanner oriented in a 40◦ range of lateral orientation. The average registrationerror was (1.9 ± 0.8) mm. The maximum error in 25 3DUS-CT registration trials was 4.6 mm, and19 out of 25 (76%) trials had a registration error less than 2 mm.Conclusions: This work facilitated the clinical implementation of the PBSI 3DUS system. The3DUS system was commissioned and a clinical quality assurance (QA) procedure with baseline datawas made to monitor the system performance. A method was developed to achieve 3DUS-CT rigidregistration and the registration was tested on gel breast phantoms.iiiLay SummaryThe permanent breast seed implant (PBSI) technique is a brachytherapy procedure for early stagebreast cancer patients, where radio-active seeds are implanted around the surgical cavity to deliverradiation. PBSI has shown to be effective, safe and significantly shortens the treatment time com-pared to conventional radiation therapy, thus is appealing to many patients, especially those whomust travel to receive radiation therapy. Computed tomography (CT) images are used for PBSIplanning currently but can be challenging to visualize the surgical cavity. A three-dimensionalultrasound (3DUS) system has been developed to assist the PBSI planning process. This thesisintroduces a method to incorporate 3DUS images with CT images for PBSI planning.ivPrefaceThis thesis is ultimately based on a three-dimensional ultrasound (3DUS) system developed incollaboration between the Robarts Research Institute group in London, Ontario and BC Cancer -Kelowna group. Chapter 3 was a further clinical validation based on a previous study by DanielMorton (BC Cancer, Abbotsford), except section 3.2.3 and section 3.2.4, and he was involved in theearly stages of the concept formation of 3DUS system commissioning. I was the lead investigatorfor Chapter 4, where I was responsible for all major areas of concept formation, data collectionand analysis, as well as manuscript composition, with guidance from the supervisory committeemembers, Michelle Hilts, Deidre Batchelar, and Andrew Jirasek. The apparatus, including the 3D-printed model and the clamp, were made with the help of Mark Robinson (BC Cancer - Kelowna).Nathan Orlando and Lori Gardi (Robarts Research Institute group) contributed to the 3DUS softwareupgrade and hardware diagnosis.vTable of ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiLay Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ivPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vTable of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viList of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ixList of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xList of Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiiiAcknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 Breast Cancer and Available Treatment . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Breast Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.3 Permanent Breast Seed Implant Brachytherapy . . . . . . . . . . . . . . . . . . . 41.4 Technical Challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.5 Thesis Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.1 Basics of Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.1.1 Interactions of Radiation with Matter . . . . . . . . . . . . . . . . . . . . 82.1.2 Radiation Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112.1.3 Radioactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.1.4 Types of Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 142.1.4.1 External Beam Radiation Therapy . . . . . . . . . . . . . . . . 142.1.4.2 Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 172.1.5 General Treatment Process . . . . . . . . . . . . . . . . . . . . . . . . . . 172.1.5.1 Computed Tomography Simulation . . . . . . . . . . . . . . . . 172.1.5.2 Treatment Planning . . . . . . . . . . . . . . . . . . . . . . . . 182.1.5.3 Treatment Delivery . . . . . . . . . . . . . . . . . . . . . . . . 19vi2.1.5.4 Post-Treatment Follow-up . . . . . . . . . . . . . . . . . . . . . 192.2 Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192.2.1 Task Group 43 Dose Calculation . . . . . . . . . . . . . . . . . . . . . . . 202.2.2 Types of Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 222.2.2.1 High Dose Rate Brachytherapy . . . . . . . . . . . . . . . . . . 222.2.2.2 Low Dose Rate Brachytherapy . . . . . . . . . . . . . . . . . . 232.2.3 Brachytherapy for Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . 242.2.4 Permanent Breast Seed Implant . . . . . . . . . . . . . . . . . . . . . . . 252.2.4.1 PBSI Literature Review . . . . . . . . . . . . . . . . . . . . . . 252.2.4.2 Patient Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . 272.2.4.3 Clinical Treatment Procedure . . . . . . . . . . . . . . . . . . . 282.2.4.3.1 PBSI Delivery . . . . . . . . . . . . . . . . . . . . . . 292.2.4.3.2 Post-implant QA . . . . . . . . . . . . . . . . . . . . 302.3 Ultrasound Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312.3.1 The Physics of Ultrasound Imaging . . . . . . . . . . . . . . . . . . . . . 312.3.2 US Image Quality and Artifacts . . . . . . . . . . . . . . . . . . . . . . . 342.3.3 3-Dimentional Ultrasound Technology . . . . . . . . . . . . . . . . . . . . 362.3.4 Clinical Use of US . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 3DUS System Commissioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393.1 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393.1.1 3DUS for PBSI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393.1.2 Matrix Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413.1.3 System Commissioning Tests . . . . . . . . . . . . . . . . . . . . . . . . 423.1.3.1 Scanning System Linear Accuracy Test . . . . . . . . . . . . . . 433.1.3.2 Scanning System Volumetric Accuracy Test . . . . . . . . . . . 433.1.3.3 Orthogonal Template Registration Test . . . . . . . . . . . . . . 443.1.3.4 Clinical Template Registration Limitation Test . . . . . . . . . . 453.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463.2.1 Scanning System Linear and Volumetric Accuracy Test . . . . . . . . . . . 463.2.2 Orthogonal Template Registration Accuracy Test . . . . . . . . . . . . . . 473.2.3 Clinical Template Registration Limitations Test . . . . . . . . . . . . . . . 493.2.4 Clinical QA Procedure Worksheet . . . . . . . . . . . . . . . . . . . . . . 503.3 Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 Rigid Registration of 3DUS and CT . . . . . . . . . . . . . . . . . . . . . . . . . . . 544.1 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544.1.1 Point-based Registration . . . . . . . . . . . . . . . . . . . . . . . . . . . 544.1.2 3DUS-CT Registration Workflow . . . . . . . . . . . . . . . . . . . . . . 564.1.3 Imaging Phantoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574.1.4 Landmarks Configuration Design . . . . . . . . . . . . . . . . . . . . . . 584.1.5 3DUS-CT Registration Test . . . . . . . . . . . . . . . . . . . . . . . . . 604.1.5.1 Initial 3DUS-CT Registration Test with the Resonant Phantom . 60vii4.1.5.2 Registration Test with Gel Breast Phantoms . . . . . . . . . . . 614.1.6 3DUS Scanner Positioning Limits Test . . . . . . . . . . . . . . . . . . . 614.1.6.1 3DUS Scanner Orientation Limits . . . . . . . . . . . . . . . . . 624.1.6.2 3DUS Scanner Position Limits . . . . . . . . . . . . . . . . . . 624.1.7 DICOM Files Sagittal/Axial Writing Test . . . . . . . . . . . . . . . . . . 634.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644.2.1 Gel Breast Phantom Construction Test . . . . . . . . . . . . . . . . . . . . 644.2.2 Landmarks Configuration Test . . . . . . . . . . . . . . . . . . . . . . . . 654.2.3 Initial 3DUS-CT Registration Test with the Resonant Phantom . . . . . . . 654.2.4 3DUS-CT Registration Test with Gel Breast Phantoms . . . . . . . . . . . 664.2.5 3DUS Scanner Positioning Limits Test . . . . . . . . . . . . . . . . . . . 674.2.6 DICOM Files Sagittal/Axial Writing Test . . . . . . . . . . . . . . . . . . 684.3 Discussions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694.3.1 Landmark Configuration and 3D-printed Model Position . . . . . . . . . . 694.3.2 3DUS Scanner Positioning . . . . . . . . . . . . . . . . . . . . . . . . . . 704.3.3 DICOM Files Sagittal/Axial Writing . . . . . . . . . . . . . . . . . . . . . 715 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735.1 Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75viiiList of TablesTable 3.1 Measurements of 3DUS System Linear Accuracy . . . . . . . . . . . . . . . . 47Table 3.2 Measurements of 3DUS System Template Registration Accuracy . . . . . . . . 48Table 3.3 Measurements of Template Registration Accuracy with Different Clinical Tem-plate Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Table 4.1 Measurements of TRE (Ave ± SD) Using Different Landmark Configurations . 65Table 4.2 Measurements of Registration Accuracy on the Resonant Phantom . . . . . . . 65Table 4.3 Measurements of Registration Accuracy on Gel Breast Phantoms . . . . . . . . 66Table 4.4 Measurements of TRE (Ave ± SD) with the Scanner Placed on Different BreastQuadrants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Table 4.5 Measurements of Registration Accuracy Using Sagittal Views and Axial Viewsof 3DUS Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69ixList of FiguresFigure 1.1 Anatomy of the breast in sagittal plane. . . . . . . . . . . . . . . . . . . . . . 2Figure 1.2 a. PBSI clinical template; b. Bevelled needle and fiducial needle; c. 103Pd seedsand spacers in the needle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Figure 1.3 Visualization of a slice of the same seroma in CT and US imaging. . . . . . . . 6Figure 2.1 An illustration of photoelectric effect. . . . . . . . . . . . . . . . . . . . . . . 9Figure 2.2 An illustration of Compton scattering. . . . . . . . . . . . . . . . . . . . . . . 10Figure 2.3 An illustration of pair production. . . . . . . . . . . . . . . . . . . . . . . . . 10Figure 2.4 Survival fraction curves for tissues with different α/β ratios. . . . . . . . . . . 12Figure 2.5 Clinical LINAC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Figure 2.6 The major components of a LINAC. . . . . . . . . . . . . . . . . . . . . . . . 16Figure 2.7 A general CT room with CT simulator, couch and laser system. . . . . . . . . 18Figure 2.8 TG43 dose calculation geometry. . . . . . . . . . . . . . . . . . . . . . . . . . 21Figure 2.9 The Varian GammaMedplus™ iX afterloader (Varian Medical Systems, PaloAlto, CA). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Figure 2.10 Decay scheme of 103Pd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Figure 2.11 US evaluation on seroma for PBSI. . . . . . . . . . . . . . . . . . . . . . . . 28Figure 2.12 An illustration of PBSI planning: (a) The fiducial needle insertion direction andthe seroma; (b) Several rows of seeds planned around the seroma; (c) The seedlocations on the template grid, PTV contour and 100% isodose line. . . . . . . 30Figure 2.13 An illustration of PBSI delivery: (a) PBSI mark-up procedure; (b) Patient’s setup in the OR with the implant template and the fiducial needle. . . . . . . . . . 30Figure 2.14 A slice of PBSI post-implant CT images. . . . . . . . . . . . . . . . . . . . . 31Figure 2.15 An illustration of US transmission, reflection and refraction. . . . . . . . . . . 32Figure 2.16 A single-element transducer. . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Figure 2.17 US transducer three-dimension resolution axes. . . . . . . . . . . . . . . . . . 35Figure 2.18 An LDR needle on US image. . . . . . . . . . . . . . . . . . . . . . . . . . . 36Figure 2.19 An illustration of different image acquisition methods for 3D US image recon-struction: 2D US images are acquired during a linear scan (a), a tilting scan (b),and a rotational scan (c) of the transducer. . . . . . . . . . . . . . . . . . . . . 36Figure 2.20 Clinical used (a) abdominal probe, (b) breast probe, and (c) rectal probe for USexamination (BK Medical®, Herlev, Denmark). . . . . . . . . . . . . . . . . . 38xFigure 3.1 (a) 3DUS scanner components: Part a being a housing that contains motor andelectronics; Part b being a TPX plate; Part c being an encoded mechanical arm;(b) A photo of the registration plate used for registration process. . . . . . . . 40Figure 3.2 (a) An illustration of four major coordinate systems and matrix transformationprocess; (b) A photo of visualized 3D implant template model in the software. 42Figure 3.3 (a) String phantom; (b) Needle separation measurement in reconstructed sagittalview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Figure 3.4 (a) Object contour in 3DUS software; (b) Volume segmentation in 3DUS soft-ware. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Figure 3.5 (a) Needles inserted through a needle jig for imaging; (b) The registration tem-plate fitting onto the needle jig for template registration; (c) The 3D imagingvolume and the template grid under same coordinates system, with the plannedposition of the needles marked in blue. . . . . . . . . . . . . . . . . . . . . . 45Figure 3.6 (a) The clinical template rotation and tilt direction; (b) The template registrationtest performed with a tilt angle of the template. . . . . . . . . . . . . . . . . . 46Figure 3.7 The implant template limits to perform the template registration. . . . . . . . . 49Figure 3.8 QA worksheet for PBSI 3DUS system. . . . . . . . . . . . . . . . . . . . . . 51Figure 4.1 Workflow for 3DUS-CT registration process. . . . . . . . . . . . . . . . . . . 56Figure 4.2 (a) Gel breast phantom placed on the Rando® Phantom (Alderson ResearchLaboratories Inc., Stamford, CT), and a clamp fixed on the breast board andholding the 3D-printed model; (b) An illustration showing the clamp allowingtranslation in two directions and 180◦ rotation of the 3D-printed model. . . . . 58Figure 4.3 Different landmarks configurations used for 3DUS-CT registration; (a) Con-figuration A, the red arrows showing the 3DUS image coordinate system; (b)Configuration B; (c) Configuration C. . . . . . . . . . . . . . . . . . . . . . . 59Figure 4.4 The landmarks contours in MIM Symphony. . . . . . . . . . . . . . . . . . . 60Figure 4.5 (a) The 3DUS-CT registration test setup on the Resonant phantom; (b) The3DUS-CT registration test setup on gel breast phantom, with the 3DUS scannerable to be rotated laterally within 0◦ < θ < 40◦. . . . . . . . . . . . . . . . . . 61Figure 4.6 3DUS scanner orientation limits . . . . . . . . . . . . . . . . . . . . . . . . . 62Figure 4.7 Four quadrants of the gel breast phantom. . . . . . . . . . . . . . . . . . . . . 63Figure 4.8 Top View of 3DUS and CT Imaging Volume . . . . . . . . . . . . . . . . . . 63Figure 4.9 (a) US image of an olive (with pit) embedded in gel; (b) US image of a water-filled balloon embedded in gel; (c) CT image of an olive with pit in gel; (d) CTimage of a water-filled balloon in gel. . . . . . . . . . . . . . . . . . . . . . . 64Figure 4.10 An axial view of CT(red) and 3DUS(grey) registered images of the Resonantphantom in MIM Symphony fusion mode, the pink contour being the sphere in3DUS images, and the blue contour being the sphere in CT images. . . . . . . 66Figure 4.11 Axial view (a), sagittal view (b), and coronal view (c) of the CT (red) and 3DUS(grey) registered images of a gel breast phantom with a water-filled balloon in-side, the blue contours being the balloon in CT images, and the almond contoursbeing the balloon in 3DUS images. . . . . . . . . . . . . . . . . . . . . . . . 67xiFigure 4.12 (a) An illustration when the 3D-printed model is placed orthogonal to the 3DUScoordinate system; (b) An illustration when the 3D-printed model is not placedorthogonal to the 3DUS image coordinate system. . . . . . . . . . . . . . . . . 70xiiList of Acronyms3DUS Three-dimensional ultrasoundAAPM American Association of Physicists in MedicineACS Arm coordinate systemAPBI Accelerated partial breast irradiationBCS Breast-conserving surgeryCT Computed tomographyCTV Clinical target volumeDSB Double strand breakEBRT External beam radiation therapyEC Electron CaptureFRE Fiducial registration errorHDR High-dose-rateIC Internal ConversionICS Imaging coordinate systemIMRT Intensity Modulated Radiation TherapyLDR Low-dose-rateLINAC Linear acceleratorLQ Linear-quadraticMLC Multiple-leaf collimatorMRI Magnetic resonance imagingOARs Organs at riskOR Operating roomxiiiOS Overall survivalPBSI Permanent breast seed implantPET Positron emission tomographyPTV Planning target volumeQA Quality assuranceREB Research Ethics BoardSCS Scanner coordinate systemTCS Template coordinate systemTG43 Task Group 43TPS Treatment planning systemTPX Polymethylpentene plasticTRE Target registration errorUS UltrasoundVMAT Volumetric Modulated Arc TherapyWBI Whole breast irradiationxivAcknowledgmentsI would like to thank my supervisors Dr. Michelle Hilts and Dr. Deidre Batchelar of the I.K. Barber School of Arts & Sciences at the University of British Columbia. They’ve always beenavailable to offer me guidance and help throughout my whole project. It is their continuous input thathelped me better understand my project from both academic and clinical perspectives and eventuallypush it forward. Their patient guidance on my thesis writing helped me tremendously as a foreignstudent. I would also like to thank my committee member Dr. Andrew Jirasek, who has beenalways approachable throughout my study and has given me great suggestions from his specializedperspective. Their help has benifited me both professionally and personally.I must acknowledge the contribution of Dr. Daniel Morton, who has previously worked on thisproject, but still happy to get involved and always willing to help me with any problems I encoun-tered. His research was the foundation of this project.I would like to thank all the staff from BC Cancer - Kelowna. I would like to thank Dr. JuanitaCrook, who has always been willing to help me with any clinical-relevant questions I had. I alsowant to express my special thanks to Mark Robinson, who helped me greatly with the design,engineering, and manufacturing during my project. I wouldn’t have been able to make my idea areality without him.I would also like to thank Nathan Orlando, Lori Gardi, and the rest of the team from RobartsResearch Institute (London, Ontario). Their continuous support has helped me greatly throughoutmy project.As well, I want to thank my fellow-students Michael Kudla and Ramie Ali-Adeeb. We have spentlots of time working together during the course work and became good friends. I want to thank myfriend Yuhao Huang, whose company was appreciated during my study in a foreign country. I alsowant to thank Cortlan Jolley, who helped me refine the wording in my thesis and never complainedthat I made him read my chapters over and over again.Finally, I would like to thank my Mom and Dad. They have always respected my choice on whatI wanted to pursue and have been supportive and encouraging during my studies.xvChapter 1Introduction1.1 Breast Cancer and Available TreatmentAccording to the Canadian Cancer Society, approximately 26,500 breast cancer cases were diag-nosed in Canada in 2017, with an estimated 5,000 deaths recorded by the Canadian Cancer Statisticspublication. Breast cancer is a quarter of new cancer cases in women and the incidence rate ranksNo.1 in all female cancers [2]. Statistically, one out of eight women will develop breast cancerin Canada. Being the most common cancer for women worldwide, the incidence rates vary withregions and ethnicities [3]. Although it is estimated to have a higher incidence in developed coun-tries, evidence has shown that the mortality rate is higher in less developed countries due to limitedresources for screening and early detection [18].The breast is composed of varying tissue types, including fat tissue, connective tissue, glands andducts, shown in Figure 1.1. Most breast cancers are adenocarcinomas and originate in glandularcells, either starting in the milk ducts or in the glands that produce milk. These can be diagnosed asinvasive or non-invasive. One possible form of breast cancer is ductal carcinoma in situ, which isdifficult to detect on physical exam, but which can be found by screening mammography. Invasiveductal carcinoma is the most common type of breast cancer, accounting for about 80% of breastcancers. Invasive lobular breast cancer, which starts in the lobules, accounts for about 10% ofbreast cancers, and can be hard to diagnose using mammography, sometimes requiring magneticresonance imaging (MRI). Other types of uncommon breast cancers include inflammatory breastcancer, Paget’s disease of the nipple, etc [2].1Figure 1.1: Anatomy of the breast in sagittal plane.Common treatments for breast cancer are surgery, radiation therapy, hormonal therapy, and chemother-apy. Surgery used to be the only effective option for breast cancer patients until advanced radiationtechniques and chemotherapy medications evolved in the mid-twentieth century. Most patients gothrough mastectomy or lumpectomy as a first surgical step, and a choice between them can bemade depending on individual tumour size, nodal status, and patient preference, etc. A twenty-yearfollow-up of a randomized study has reported that there is no significant difference on long-termsurvival between radical mastectomy and breast-conserving surgery (BCS) with adjuvant radiationtherapy, and for many early-stage patients BCS has been preferred for quality of life [60]. However,over time, literature has shown that BCS alone is inadequate for breast cancer local control anddistant metastasis [51]. It is possible that lumpectomy may fail to remove the disease completelybecause of the ambiguous boundaries of breast tissue [29].Multiple trials that include whole breast radiation as adjuvant breast cancer treatment have beenconducted since the 1970s [1]. Conventional whole breast radiation treatment delivers approxi-mately 50 Gy in 2Gy daily fractions, given five days per week over 5-7 weeks, sometimes followedby 10-16 Gy boost dose to the lumpectomy site [30]. Multiple clinical trials have shown that radia-tion after lumpectomy decreases the risk of recurrence in breast. Cross-centre randomized clinicaltrials have reported improvement on local control with radiation after lumpectomy compared tolumpectomy alone [10, 15, 55]. Specifically, a meta-analysis across 17 randomized trials pointedout that radiotherapy after lumpectomy halves recurrence rates and reduces breast cancer death rate2by about a sixth [1]. Consequently, BCS combined with post-operative radiotherapy has become thestandard practice for early-stage breast cancer treatment [54]. Other than external beam radiationtherapy (EBRT), brachytherapy, where the radiation dose is delivered using radioactive isotopes,is used as alternative treatment for inoperable tumours or as an additional boost following BCS orwhole breast irradiation (WBI) [38].Systemic therapy is also offered as an option for breast cancer treatment. Chemotherapy is oftencombined with surgery to either shrink the tumour size before surgery or to lower the recurrencerisk after surgery. Hormonal therapy is used in breast cancer treatment for patients with hormonereceptor positive status, aiming to change the hormone levels and slow down the growth and spreadof breast cancer. Early Breast Cancer Trialists’ Collaborative Group has shown in a 15-year trialfollow-up that chemotherapy and adjuvant hormonal therapy using drug Tamoxifen substantiallyreduced 5-year recurrence rates and 15-year mortality rates for early breast cancer patients [19].1.2 Breast RadiotherapyAmong women diagnosed with early-stage (stage I or II) breast cancer 61% undergo BCS and84% of those that have BCS receive radiation therapy as adjuvant treatment [36]. WBI after BCShas been shown to improve local control and to reduce ipsilateral tumour recurrence risk to a levelcomparable to mastectomy. Clinical trials suggest the optimal radiation treatment to be 5 weeks ofdaily therapy sometimes followed by 1 to 1.5 weeks of additional daily therapy to the tumour-bedregion [63]. This means, radiation therapy can add an additional 6 or 7 weeks after surgery. Thisis a concern for patients, particularly those who must travel for radiation therapy, who then maychoose mastectomy over breast-conserving therapy. Correspondingly, the idea of accelerated breastradiotherapy has been explored to shorten the treatment delivery time. A Canadian clinical trial,conducted by Whelan et al., showed equivalent effectiveness for a 3-week hypo-fractionated WBIcompared to the 5-week conventional fractionation [64]. Treatment time can be further reducedin cases where accelerated partial breast irradiation (APBI) is appropriate. APBI, where only thetumour bed is irradiated, has been the subject of several clinical trials since the early 1990s. TrialRadiation Therapy Oncology Group 0319 was conducted to evaluate the efficacy of APBI in 3D-conformal RT treatment by delivering 38.5 Gy in 10 fractions, given twice daily. 4-year overallsurvival (OS) was 96% and only 4% patients suffered grade 3 toxicities [61]. Another trial con-3ducted in Italy showed that 5-year OS was 96.6% for the WBI group and 99.4% for APBI group,and patients in APBI group reported less toxicities and better cosmetic outcomes [31].With the potential to offer equivalent efficacy and safety as a conventional radiation treatmentschedule and more convenience to the patients, researchers have been focusing on developing vari-ous techniques for APBI treatment globally. Currently, APBI can be delivered using 3D-conformalEBRT, intraoperative electrons or orthovoltage irradiation, and high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy.1.3 Permanent Breast Seed Implant BrachytherapyA new technique for APBI, permanent breast seed implant (PBSI) brachytherapy, was first re-ported in 2006 by Sunnybrook and Women’s Health Sciences Centre. The preliminary clinicalresults of the first PBSI trial showed that this technique was feasible and well tolerated [44]. Theprocedure was performed in a single 1-2 hour session, and permanent radioactive palladium-103(103Pd) seeds were implanted for early-stage breast cancer patients. Because of the rapid dose fall-off around radio-active seeds, PBSI can deliver a lower dose to skin and surrounding normal tissuethan conventional EBRT. As a single session procedure, it also significantly reduces the treatmenttime and greatly improves the convenience of radiation therapy in adjuvant breast cancer treatment.With promising results from early trials, PBSI showed great potential for early-stage breast cancertreatment. In 2012, BC Cancer - Kelowna became the second institution worldwide to offer PBSIas a treatment option for early-stage breast cancer patients [11].Patients who meet specific criteria are given the option to receive PBSI treatment. Similar toprostate brachytherapy, shown in Figure 1.2, a template is used for guidance during the implanta-tion procedure. The grid points on the template are 0.5 cm apart, and allows fiducial needles andbevelled needles going through them. Strands of 103Pd seeds are stored in the bevelled needles andare permanently implanted at the seroma cavity. Spacers are used between the radio-active seeds.The whole procedure is performed under 2D freehand ultrasound (US) guidance for verification ofneedle placement while the patient is anesthetized.4Figure 1.2: a. PBSI clinical template; b. Bevelled needle and fiducial needle; c. 103Pd seedsand spacers in the needle.1.4 Technical ChallengeThe clinical target volume (CTV) for PBSI treatment is defined as the surgical cavity and thesurrounding fibrosis [38]. It is contoured by the implanting oncologist, and informs the seed positionand dose distribution planning by the physicists. Therefore, accurate visualization and delineationof the seroma is significantly important for PBSI treatment planning.As the first step for PBSI treatment planning, computed tomography (CT) images and US imagesof the seroma are acquired to assess the technical feasibility of PBSI and to make the final determi-nation of eligibility. If the patient is eligible, a treatment plan will be developed based on the CTscans, because the CTV for post-lumpectomy partial breast irradiation is defined on CT under cur-rent clinical standards [66]. However, because of the implant geometry, needle insertion and seedlocations are extremely difficult to verify with fluorescent x-ray images in the operating room (OR)during the procedure. Currently, PBSI procedure is performed under 2D free-hand US guidance.5The fibrotic rim around the fluid-filled surgical cavity cannot be visualized on US images, thusmaking seroma visualization different on two image modalities [38]. As shown in Figure 1.3, thesize and shape of seroma have substantial differences on CT and US. In a recent study by D. Mortonet al, on average the CTV on CT (CTVCT) is 29.8% larger than on US (CTVUS) and a centroid shiftfrom CTVCT to CTVUS was noticed in all the cases reported, ranging from 3.3 mm to 11.2 mm.Further dosimetry analysis on both CTVs showed under-dose in CTVUS with a CT-based treatmentplan [41].(a) Seroma Contour on CT. (b) Seroma Contour on US.Figure 1.3: Visualization of a slice of the same seroma in CT and US imaging.Currently, the target is contoured on CT images and the plan might be slightly shifted in the ORto match the view from US, based on the oncologist’s experience. However, there is no quantitativeassessment of how seroma varies on CT and US in the same coordinate system. Accordingly, aclinical tool to rigidly register 3D US images with CT images is desired for PBSI treatment planning.1.5 Thesis ScopeThe purpose of this work is to commission and develop quality assurance (QA) tests for a novelprototype PBSI three-dimensional ultrasound (3DUS) system, and to develop and test a method touse the 3DUS system in CT to achieve rigid registration of 3DUS images with CT scans. The 3DUSsystem for PBSI was developed as a collaboration between the BC Cancer - Kelowna group andthe Robarts Research Institute group in London, Ontario, and showed great potential to offer visualguidance during PBSI planning and delivery [40]. This project is based on the previous work byformer University of Victoria (UVic) doctoral student Daniel Morton.Chapter 1 offers a brief introduction on the common treatment options for breast cancer and6current technical challenges in PBSI. Chapter 2 discusses the basic physics, biology, and a generalclinical workflow in radiation therapy, with brachytherapy techniques, dose calculation and USimaging elaborated. Chapter 3 introduces 3DUS for PBSI in detail with system commissioningresults, and establishes a regular QA procedure. Chapter 4 discusses the methodology and testresults of 3DUS-CT rigid registration on phantoms. Chapter 5 summarizes the conclusions anddiscusses some potential directions for future work.7Chapter 2Background2.1 Basics of Radiation TherapyRadiation therapy is one of the major cancer treatments for multiple tumour sites, either deliveredalone or combined with surgery or chemotherapy. Over half of all cancer patients undergo radiationtherapy, specifically, 83% of breast cancer patients receive radiation therapy [24]. Radiation therapycan be delivered in two forms clinically, EBRT or brachytherapy. An EBRT treatment generallylast for 4 to 7 weeks, with one treatment fraction per day and 5 fractions per week from Monday toFriday. Brachytherapy can be delivered through several HDR treatment fractions or a one-day LDRsurgery. In this chapter, some basics of radiation physics and biology will be explained, two formsof radiation therapy will be introduced, and current clinical treatment process will be discussed indetail.2.1.1 Interactions of Radiation with MatterRadiation describes the energy transfer process in the form of electromagnetic waves or high-speed subatomic particles traveling through media, which has been broadly applied in medical andindustrial areas. The science of radiology started with Roentgen’s discovery of x-ray in 1895, andwas gradually established after Becquerel found the evidence of radioactivity in 1896 and the Curiesdiscovered the first natural radioactive substance, radium, in 1898.Radiation was found to cause harm to human tissues, and then was gradually adapted into cancer8treatment. Common clinical radiation types include gamma-rays, x-rays, electrons, neutrons andheavy charged particles. For charged particles, direct ionizing radiation occurs, where the energyis transferred to the medium directly through Coulomb force interactions. For uncharged particleslike photons or neutrons, the ionizing radiation is indirect where the energy is transferred to chargedparticles first then transferred from secondary charged particles to the medium [6].The photon interactions that occur as the first step of indirect ionizing include: photo-electriceffect, Rayleigh scattering, Compton scattering and pair production. No energy is transferred duringRayleigh scattering, while the other three processes all involve energy transfer. The possibility thateach interaction will occur can be described by linear attenuation coefficients. Several commoninteractions are discussed below [6, 37].Photoelectric interactions are most likely to occur with photons with an energy E <20 keV (inwater). The probability of photoelectric interactions occurring decreases approximately with thecube of photon energy E3 and increases with the cube of material atomic number Z3. Shown inFigure 2.1, photon energy is absorbed by an electron on an inner-shell to be ionized, leaving avacancy on the inner-shell. To achieve the lowest energy for atomic stability, an electron from anouter-shell with a higher energy level jumps to the inner-shell, emitting characteristic x-rays withthe energy difference between the two electron energy levels. If the energy of x-rays is absorbed byanother electron and which is then emitted from the atom, it becomes an Auger electron.Figure 2.1: An illustration of photoelectric effect.Compton scattering occurs for photons with an energy level 20 keV< E <10 MeV (in water).The probability of Compton scattering for the whole atom decreases with E and increases with Z.As is shown in Figure 2.2, when the incident photon interacts with an orbital electron, the photon isscattered with an angle φ . With the total energy and momentum conserved, the energy difference ofthe incident photon and the scattered photon is transferred to the electron as kinetic energy and the9Compton recoil electron is deflected with angle θ . Secondary interactions may happen between thescattered photon and another free orbital electron.Figure 2.2: An illustration of Compton scattering.Pair production is more likely to occur for high-energy photons (E >10 MeV in water), with anenergy threshold of 1.022 MeV. The probability of pair production occurring increases with bothE and Z. The incident photon disappears, and a pair of electron and positron is produced in thenuclear Coulomb field, with the photon energy converted into rest mass energy and kinetic energyof position and electron [50].Figure 2.3: An illustration of pair production.For direct ionizing radiation or the second step of indirect ionizing radiation, charged parti-cles gradually lose kinetic energy while traveling through the matter with multiple interactions.The kinetic energy of the charged particles can be either deposited in the medium or radiated asBremsstrahlung radiation. The energy absorbed by the medium is called Dose, which is commonlyused to quantify the amount of radiation. The unit for dose is Gy, and 1 Gy is defined as 1 J ofradiation energy deposited in 1 Kg of matter.102.1.2 Radiation BiologyThe biological rationale of radiation damage has been investigated since radiation was initiallyapplied in the medical field, out of interest for better clinical outcome and radiation protection.Ionized molecules after radiation are highly reactive, and radiation can cause chemical bond breaksand cell damage. Although the damage can be caused at various sites in different forms, DNAdouble strand breaks (DSBs) are considered to be the primary damaging factor that induces cellkilling [24].Quantitatively, 1 Gy of irradiation can cause 20-40 DSBs [50]. However, not all the DSBs willlead to cell death because of the cell self-repair mechanism. DNA damage response consists ofmultiple pathways, which can be basically classified as sensors and effectors. Once the sensorsdetect the DNA damages, the effectors will either program the damaged cell to death or activateDNA repair pathways to physically repair the breaks, or stop the cell cycle at a certain checkpoint toavoid abnormal cell replication. While some early cell deaths happen right after irradiation, most ofthe radiation-induced cell deaths happen after the cells fail to repair damages like DSBs and causecatastrophe during cell mitosis.The linear-quadratic (LQ) model was built to quantify radiation-induced cell kill. The LQ modelassumes that cell kill is composed of two components, one linear component proportional to thedose and another quadratic component proportional to the square of the dose. The mathematicalform of the relationship between surviving fraction and dose can be described in Equation (2.1),where S stands for the surviving fraction, α and β are parameters determined by the radiation typeand the tissue type and D is the dose [24]. Figure 2.4 shows a typical curve of surviving fraction withradiation dose, and the skewness can be quantified by the ratio α/β . In other words, for differenttissues, the lower α/β ratio it has, the steeper it shows on surviving curves and the more sensitive itis to radiation.S = e−αD−βD2(2.1)11Figure 2.4: Survival fraction curves for tissues with different α/β ratios.In clinical radiation therapy treatment, the goal is to reach the maximum number of tumour cellkills while also protecting normal tissue as much as possible. Therefore, the type of radiation, thedose and fractionations can be adjusted accordingly to achieve the optimal clinical results. Becauseof the time scale of cell repair and repopulation, the time interval between fractions is also criticalto achieve the optimal tumour control.2.1.3 RadioactivityRadioactivity is a property to describe the ability of a material to go through radioactive decays,during which process unstable atoms decay to stable states and emit radiation. Some basic conceptsand types of radiation decays are introduced below [37].Radioactive decay can be described mathematically as :N = N0e−λ t , (2.2)where N0 is the initial number of radioactive atoms, N is the number of radioactive atoms at time t,and λ is the decay constant of the atom, which is used to quantify the rate of radioactive decays.The activity (A) of a radioactive material is defined as the number of disintegrations per unit time.Common units for activity are Becquerel (Bq) and Curie (Ci). One Bq is the activity of a quantityof radioactive material in which one nucleus decays per second, which is equivalent to s-1. And 1Ci equals to 3.7×1010 Bq, which means 3.7×1010 decays occur in the quantity of the radioactive12material. Activity can be mathematically written asA =−dN/dt, (2.3)and the activity at time t of the material can also be expressed in an exponential way asAt = A0e−λ t . (2.4)Another concept commonly used to quantify the radioactive decays is half-life T1/2, which isdefined as the time required for radionuclides to decay to half of the initial activity or amount ofradioactive atoms. Mathematically it can be calculated asT1/2 = ln2/λ . (2.5)Radioactive decays can happen in different forms, including α decay, β decay, electron capture,internal conversion, etc. A parent radionuclide that goes through radioactive decays will turn into adifferent daughter radionuclide, with energy and particles released.Alpha (α) decay is very common for radionuclides with high atomic numbers (Z > 82) as theCoulomb forces of repulsion between protons is large enough to overcome the nuclear forces. Con-sequentially, an α particle is emitted from the atom, and a disintegration energy Q is released as thekinetic energy of the α particle and the daughter nuclide. A general equation to show the processcan be written asAZX → A−4Z−2Y + 42He+Q. (2.6)Beta (β ) decay includes negatron emission (β− decay) type and positron emission (β+ decay)type. During β− decay an electron and an antineutrino are emitted with kinetic energies and aneutron is transformed to a proton, which is more likely to occur in radionuclides with high neutron/ proton ratios. On the contrary, β+ decays are more likely to occur in proton-rich radionuclideswhere a proton can be transferred to a neutron, with a positron and a neutrino emitted. This process13can be described asβ− decay : AZX → AZ+1Y + 0−1β +antineutrino+Q;β+ decay : AZX → AZ±1Y + 01β +neutrino+Q.(2.7)Electron Capture (EC) occurs in most low-energy brachytherapy sources like 125I or 103Pd, wherean orbital electron is captured by the nucleus and a proton is transformed into a neutron [57]. Ageneral equation to describe the EC process is shown in Equation (2.8). The resulting nucleus isstill in an excited state and will further emit photons to reach a stable state [24]. Electrons fromk-shell are most likely to be captured, leaving vacancies in the shell. To stabilize the atom, electronsfrom a higher energy level will fill in the vacancy, with x-rays or Auger electrons emitted.AZX +0−1e → AZ−1Y +neutrino+Q (2.8)Most of the radioactive decay processes involve γ-rays emission, while during Internal Conver-sion (IC) process the γ-rays are absorbed by the atom, ejecting conversion electrons from k-shellwith the energy transformed to the kinetic energy of the conversion electron and leaving vacancieson the orbit. Characteristic x-ray or Auger electrons are produced subsequently as a de-excitationstep.2.1.4 Types of Radiation Therapy2.1.4.1 External Beam Radiation TherapyEBRT is a non-surgical process where the radiation source is outside of the patient and an externalradiation beam is formed to target the tumour. EBRT treatment machines include: superficial andorthovoltage x-ray unit, 60Co teletherapy machine, particle accelerators like cyclotron or microtronand linear accelerator (LINAC). LINAC is most common in modern EBRT treatment and will beintroduced in a later text.The LINAC is a modern medical machine gradually developed since the mid-1950s to deliver high14energy photon or electron beams. Figure 2.5 shows a LINAC treating room. During the treatment,the patient is positioned on the couch and the gantry can rotate 360◦ around the patient to deliverhigh-energy beams at different angles.Figure 2.5: Clinical LINAC.A LINAC consists of a modulator cabinet, gantry and gantry stand, patient support couch andcontrol console. Figure 2.6 shows the major components of a LINAC. All the electronics are con-tained in the gantry and the gantry stand to produce a shaped electron or photon beam with certainenergy. The modulator cabinet provides a high voltage pulsed output to an electron gun. The elec-trons accelerate while traveling through a waveguide to obtain a high-energy electron beam or toproduce x-rays after interacting with a target. Multiple coils and magnets are used to steer and focusthe electron beam, and collimators are mounted to shape the photon or electron beams. Multiple-leaf collimators (MLCs) were adopted in modern LINAC design as part of the beam collimation.MLCs are composed of many pairs of individual motorized leaves that can form a customized beamshape. During the treatment, the patient is positioned on the couch, and the plan can be deliveredfrom the control console by the radiation therapists.15Figure 2.6: The major components of a LINAC.Modern radiation therapy planning methodology has developed tremendously during the last fewdecades, making treatment more efficient and safer. Common techniques for modern radiotherapyplanning include Intensity Modulated Radiation Therapy (IMRT) and Volumetric Modulated ArcTherapy (VMAT). IMRT was developed with the implementation of MLC, as a form of conformalradiotherapy. The IMRT technique allows multiple static beam angles for dose delivery. At eachangle, the intensity of the beam is modulated with all the MLC leaves moving and shaping thebeam. In VMAT, the dose is delivered dynamically during an arc trajectory of the gantry, instead ofthrough static beams at one or several gantry angles. VMAT has shown equivalent or superior dosedistribution as IMRT but significantly reduces the treatment delivery time [43].A common EBRT treatment lasts for 4-7 weeks, generally with a fractionation schedule of 2 Gyper day and 5 days per week. The prescribed dose and fractionation vary with tumour site, tumourtype and radio-sensitivity, patient health condition, etc.The essence of radiation therapy is to maximize dose to the cancer cells while minimizing doseto the normal tissues. Normal tissue complications are the main concern which limits the prescribeddose. For example, for early-stage breast cancer patients who go through lumpectomy and EBRT,possible complications include rib fracture, pericarditis, arm edema, breast skin fibrosis, secondarynon-breast malignancies, etc. And a ’two tangential beam’ configuration is commonly adopted inbreast cancer EBRT treatment to avoid overdose in chest wall, skin and contralateral breast [33].162.1.4.2 BrachytherapyBrachytherapy is a form of radiation therapy where radio-active sources are placed inside or nextto the treatment site while delivering radiation. Because the sources are usually positioned insideor around the target, the dose fall-off is sharper around the target compared to EBRT. The sourcescan be implanted permanently using surgery or temporarily using an applicator or catheter system.Brachytherapy will be introduced in section 2.2 in detail.2.1.5 General Treatment ProcessA general clinical radiation treatment (both EBRT and brachytherapy) process includes treatmentsimulation, treatment planning, treatment delivery and post-treatment follow-up. These steps aresummarized below.2.1.5.1 Computed Tomography SimulationA CT simulator is used for radiation treatment simulation. Treatment simulation usually involvespositioning the patient with immobilization devices, making markers or tattoos on the patient’s skinand taking images for planning.CT technology is based on the principle of x-ray imaging, where the density of the tissue can becalculated by x-ray attenuation. However, for conventional 2D x-ray images the information on thedimension parallel to the direction of x-ray is lost. In 1917 Radon developed the backprojectionmethods that with several projections at different angles 3D information on tissue density can beacquired. As a result, the tomographic image, which is essentially a slice of image in a 3D volume,can be obtained. Several generations of CT have been developed with different geometry to acquirethe projections for 3D image reconstruction. Helical CT scanner is one of the common-used moderndesigns. During the scan, the x-ray tube rotates helically around the patient, with the CT couchtranslating through the gantry [32].Figure 2.7 shows a clinical CT simulation room. During the simulation, the patient will be po-sitioned on the couch while the CT images are taken and reconstructed. Customized masks, bodymolds or vacuum cushions may be used for patient immobilization so that the position can be repro-duced for future treatment delivery. Laser alignment systems are mounted on the walls, the ceiling17and the gantry in both CT room and treatment vault to offer a rigid room coordinate system. CT-visible wires or pellets could be placed on either patients surface or on the immobilization maskto define the iso-center of the 3D volume, and markers or tattoos can be drawn on the patient as areference for treatment immobilization.Figure 2.7: A general CT room with CT simulator, couch and laser system.2.1.5.2 Treatment PlanningMost radiation therapy plans are based on CT images, while some may involve other imagingmodalities like MRI, positron emission tomography (PET), US.Treatment plans are made in computerized treatment planning system (TPS). The organs at risk(OARs) are contoured on the images, and the CTV is contoured as the visible malignancy plus sub-clinical microscopic diseases. The planning target volume (PTV) is then obtained by an extendedmargin that accounts for all the uncertainties during the treatment delivery and ensure the prescribeddose in CTV [50]. After the target and OARs are contoured, the oncologists will give a prescriptiondose on the PTV and give specific limitations on OARs, if necessary.For EBRT plans, the beam configuration is determined based on the tumor site, size and thesurrounding OARs. The LINAC can deliver a beam at several certain angles or throughout an arc,to achieve the desired dose distribution. For brachytherapy, the type of sources, location of sources18and the dwell time can be planned to achieve the prescribed dose coverage.2.1.5.3 Treatment DeliveryEBRT plans are delivered on the LINAC units. The patients are positioned in the same way assimulation on the couch. The treatment plan is delivered by the radiation therapists from the controlconsole. A common EBRT treatment takes around 10 minutes per fraction, including set-up.Brachytherapy plans are delivered either through surgery in the OR or through an applicator orcatheter system. For example, during permanent seed implant procedure, the patients are usuallyanesthetized for the procedure and the oncologists implant the seeds through needles, using US asimage guidance and sometimes fluorescent images for seeds implant verification.2.1.5.4 Post-Treatment Follow-upAfter the radiotherapy treatment, patients will have regular follow-ups to monitor and evaluatethe treatment outcome.2.2 BrachytherapySoon after the Curies’ discovery of natural radioactivity, evidence was found that Radium-226(226Ra) was effective in treating skin cancers [52]. In 1908 W. Rollins published some early resultson treatment of superficial cancers using 226Ra, which was promising when the radioactive sourceswere properly handled and indicated certain patients benefit from radioactive source treatment in-stead of operation or x-rays [65]. 226Ra was soon adopted in gynecologic cancer and other cancertreatment [38].In the 1930s different dosimetric systems were established for dose calculation. The systems setrules on dose distribution with different geometry, size and quantities of the radioactive sources.Meanwhile, new artificially isotopes were produced as brachytherapy sources. 137Cs, 60Co, 125I,103Pd were gradually used to bring in more possibilities in brachytherapy treatment, given theirdifferent decay characteristics [38].Compared to EBRT, brachytherapy delivers less dose to the surrounding OARs and skin since the19dose is delivered locally with rapid dose fall-off around radioactive sources. Meanwhile, becausethe sources are placed inside or around the target, the dose uncertainty caused by organ motion isless in brachytherapy than in EBRT. And the overall treatment duration of brachytherapy is usuallymuch shorter than EBRT, which can be favourable by patients.2.2.1 Task Group 43 Dose CalculationA method to quantify source strength is required for accurate clinical applications, furthermore,for source dosimetry assessment. However, the activity of a source is difficult to measure, and isnot directly involved in dose calculation. Thus, air kerma Kδ (δ is the cut-off energy of photonsto eliminate low-energy photons), which is the kinetic energy released per unit mass by photonsthrough ionizing radiation in air, was proposed to quantify the photon emission strength of radioac-tive sources. In 1995 American Association of Physicists in Medicine (AAPM) air kerma strength(SK) as the air kerma rate in vacuum at distance d, which can be expressed as [49]SK = K˙δ (d)d2, (2.9)and the common unit of SK is U, which is equivalent as µGym2/hr.AAPM published the standard protocol for brachytherapy dose calculation Task Group 43 (TG43)[49]. The TG43 protocol is based on a cylindrical source geometry shown in Figure 2.8. A radioac-tive source with active length of L is capsuled and the dose normalization point P0 is on the transverseaxis of the source with r0=1cm, θ0 = 90◦. For this single line source, the dose rate, D˙(r,θ ) at pointP(r,θ ) in water can be calculated asD˙(r,θ) = SKΛGL(r,θ)GL(r0,θ0)gL(r)F(r,θ), (2.10)where Λ is the dose rate in water per unit air kerma strength at r0=1 cm along the transverse axisof the source. The value of Λ depends on the radionuclide type and the physical design. GL(r,θ) isthe geometry factor that describes the dose inverse square fall-off along distance. Specifically, for a20line source,GL(r,θ) =βLrsinθ(θ 6= 0),GL(r,θ) =1r2 − 1/4L2 (θ = 0),(2.11)g(r) is a radial dose function describing the dose change along the source central transverse axisdue to absorption and scattering. F(r,θ) is the anisotropy function that describes the anisotropy ofthe dose distribution around a source.Figure 2.8: TG43 dose calculation geometry.In current brachytherapy treatment, either multiple sources will be placed simultaneously for thesame amount of time, or a single source moving to different locations and staying for a certain time,the dwell time, at each location. For treatment with multiple sources, the total dose rate at pointP(r,θ), time t is the superposition of the dose rate at P for all the sources,D˙(n, t) =n∑i=1SK0ie−λ tΛGL(ri,θi)GL(r0,θ0)gL(ri)F(ri,θi). (2.12)For the total dose delivered by source i from ti to ti+Ti, it could be calculated by integrating the21dose rate over time asD(ri,θi, ti,Ti) =∫ ti+TitiSK0ie−λ tΛGL(ri,θi)GL(r0,θ0)gL(ri)F(ri,θi)dt. (2.13)2.2.2 Types of BrachytherapyBrachytherapy can be classified into interstitial brachytherapy and intracavitary brachytherapy.Sources are placed directly in the tissue in interstitial brachytherapy, and in intracavitary brachyther-apy sources are placed in a body cavity near or within the target, like the vagina or uterus. Brachyther-apy can also be classified by source loading techniques, where the sources can be loaded into appli-cators beforehand in preloaded brachytherapy or loaded by the clinicians remotely after the applica-tors are placed in patients in remote after-loading brachytherapy. Clinically, brachytherapy is oftenclassified by dose rate. HDR brachytherapy is defined as a dose greater than 12 Gy/hr, and LDRbrachytherapy is defined as a dose lower than 2 Gy/hr [9, 38].2.2.2.1 High Dose Rate BrachytherapyHDR brachytherapy usually requires several fractions of treatment. During each treatment ses-sion, the source will be transferred into the patient then extracted, so HDR patients can leave thehospital after each treatment.A remote afterloader is used in HDR brachytherapy. Typically, 192Ir is used as HDR source.Because 192Ir has higher activity per unit mass but the emitted photon energy is lower compared to60Co or 137Cs, which were commonly used for radiotherapy in the past, less shielding is requiredand a higher dose rate is achieved for 192Ir. The source is usually made into a line shape, varyingbetween 0.3-0.6 mm in diameter and 3.5-10 mm in length, connected to a source wire, which can beflexibly driven by the remote control. Figure 2.9 shows the Varian GammaMedplus™ iX afterloaderunit (Varian Medical Systems, Palo Alto, CA), with 24 catheter channels. When not used, the sourceis stored in the well-shielded HDR unit. When being used, the source is transferred through one ofthe channels on the HDR unit into the applicator or the catheter that goes into the patient’s body.The source wire is usually programmed to stay at different dwell positions for a certain period andis driven by stepping motors. Before the active source wire is extended, a dummy wire is extended22to verify the path is clear, to make sure the active source won’t be stuck in the applicator and causeextra dose to normal tissues [37].Figure 2.9: The Varian GammaMedplus™ iX afterloader (Varian Medical Systems, Palo Alto,CA).HDR brachytherapy is commonly used as an option for treatment of cervical cancer, prostatecancer, thoracic cancer, and so on. The dose distribution can be optimized by adjusting the sourcepositions and dwell times. With the same HDR source, the treatment can be delivered immediatelyafter the plan is made, which is less time-consuming compared to LDR treatment where the seedsneed to be ordered. At the same time, it also offers more flexibility for adjustment on HDR plans. Onthe other hand, because of the high dose rate, shielding and safety is a concern for HDR treatment[49].2.2.2.2 Low Dose Rate BrachytherapyDuring LDR brachytherapy, continuous low-dose radiation is delivered to the target. The time ofirradiation varies from hours to days, with extreme cases where the implanted radioactive sourcesremain permanently in the patient’s body.LDR treatment can be delivered with remote after-loaders, like HDR treatment delivery, however,LDR treatment is commonly delivered by permanent implants. LDR brachytherapy has been show-23ing increasing potential for prostate cancer patients. 125I or 103Pd is usually used as LDR sourcesfor prostate cancer treatment. Unlike HDR, LDR dose distribution is optimized by the geometryof implants, and the seeds need to be ordered after calculating the seed strengths. During prostateLDR implant procedure, the needles loaded with seeds are inserted through a template, under tran-srectal US (TRUS) guidance. The prostate is surrounded by bladder, urethra and rectum, whichmight develop complications if over-dosed. Evidence has shown that LDR treatment offers equiv-alent effectiveness in early stage prostate cancer treatment compared to other treatment modalitiesbut shortens the treatment time to a one-day procedure [38].2.2.3 Brachytherapy for Breast CancerIntroduced in section 1.2, APBI in breast cancer treatment has been actively investigated in thelast few decades, as an alternative to conventional WBI. Multiple techniques have been developedthat have shown an equivalent effectiveness as conventional WBI in tumor control but with a shortertreatment duration.APBI in breast cancer treatment has strict patient selection criteria, which is the reason that someearly studies did not show advantages on APBI [38]. The recommended eligibility criteria weregradually refined. In 2009, a consensus statement of APBI was published by the American Societyfor Radiation Oncology to provide guidance on implementing APBI into the framework of breastcancer treatment and to point out that APBI is unlikely to replace WBI for all patients [38].The first technique developed was interstitial brachytherapy, where multiple catheters are in-serted by freehand technique or using a template. The procedure is most commonly performed afterlumpectomy, provided that the surgical cavity has a clear margin. The implantation can be per-formed with CT or US guidance, and is very skill dependent [38]. CT scans are acquired after thecatheter insertion and the dwell position and time of 192Ir can be then calculated to form the planneddose distribution. The catheters are then connected to an after-loading unit for the plan delivery.After the treatment completion, the catheters are removed. The whole treatment takes 4-5 days,with 2 fractions of HDR brachytherapy delivered each day. Some early studies showed inadequacyof interstitial 192Ir implant as a sole treatment because of poor patient selection criteria [14]. Butlater studies refined the patient criteria and long-term follow-up has shown a comparable efficacy ofAPBI using multi-catheter interstitial implantation to WBI for low-risk breast cancer patients, with24tolerable side-effects [28, 56].A more common technique is intra-cavitary balloon brachytherapy, which is less complex thaninterstitial multi-catheter method. Instead of inserting multiple catheters, a balloon applicator witha central lumen is inserted with a single entry and delivers dose with after-loaded 192Ir source. Theinsertion procedure can be performed during the breast conserving surgery or postoperatively. Avariety of balloon sizes in spherical and elliptical shape can be chosen individually and the entrypoint of the balloon is chosen to achieve the optimal dose distribution. Once the insertion is finished,saline and radiographic contrast are used to inflate the balloon and the plan can be made based on aCT scan. The catheter is connected to an after-loading unit and 192Ir source goes through the centrallumen inside the balloon for treatment delivery [38].Varieties have been developed to improve the flexibility of intra-cavitary brachytherapy withmulti-lumen balloon catheter system, multi-lumen non-balloon catheter system, etc. The outcomesof the initial clinical experience with MammoSite® single-lumen balloon catheter system was pub-lished in 2003 and showed good performance on treatment delivery, mild side effects and good toexcellent cosmetic results [25]. Later long-term follow-up confirmed the effectiveness on decreasingipsilateral breast tumour recurrence with tolerable side effects like necrosis and infections, which isequivalent to other forms of APBI techniques [53].A novel APBI technique, PBSI, was firstly performed in 2004 and started to show potentials aspost-lumpectomy treatment in the last decade. PBSI offers another option for patients who need towork or travel to have a single 1-2 hour procedure instead of weeks-long treatment. PBSI is thefocus of this thesis and details are given in section 2.2.4.2.2.4 Permanent Breast Seed Implant2.2.4.1 PBSI Literature ReviewIntroduced in section 1.2, PBSI was firstly performed by Pignol et al. at Sunnybrook and WomensHealth Science Centre in 2004, as adjuvant radiotherapy treatment for early-stage breast cancer.The first trial of PBSI showed feasibility based on the preliminary clinical data [44]. Most of thepatients reported no pain or minimal pain. All the patients reported improvement on pain symptomafter the first week of the procedure. The procedure was well tolerated, with minimal acute skin25complications during the first 2 months after the procedure and all the patients had complete healingat 2-month follow-ups. The first PBSI trial showed promising results, and since then there has beenmore trials and papers published to establish and improve the technique.Pignol et al. later published the tolerance and acceptance results of the PBSI trial in 2008 [45].From 2004 to 2007, 67 patients received the PBSI treatment. Among all the patients, 17% of themhad significant pain after the procedure and only one experienced an acute skin reaction. No recur-rence was seen after a median follow-up of 32 months. 80−90% of the patients were very satisfiedwith their treatment and the remainder were satisfied. A report on 5-year PBSI clinical outcomeswas published by the same group in 2015, suggesting PBSI is an effective and safe technique basedon 5-year outcomes from 134 patients included in 3 clinical trials [46]. PBSI significantly loweredthe contralateral recurrence and offered a 5-year overall survival of 97.4%±1.9% and a disease-freesurvival rate of 96.4%±2.1%. Overall, good cosmetic results and patient satisfaction were reported,and 5-year data suggested that PBSI is a safe APBI option after lumpectomy for early breast cancerwith a similar tolerance profile as WBI.In a paper by Keller et al. in 2011, PBSI pre- and post-implant dosimetric data was presented [27].Recommendations were made on dosimetric planning according to the outcomes from multiple clin-ical trials to improve the effectiveness and the tolerance. A dosimetry coverage of PTV is recom-mended to be: V90 (volume that receives 90% of the dose) =100%, V100 > 95%, 30% >V200 > 20%,and the maximum skin dose (the average dose over the hottest 1 cm2 on surface) should be limitedto 90% of the prescription dose. Because the seeds tend to migrate more easily in breast tissue,compared to conventional prostate implant, the treating volume limited to 60-80 cc is recommendedfor starting programs.The source options for PBSI have also been investigated. 103Pd is considered to be a low-energyradioactive source and is currently used in PBSI procedure. As shown in Figure 2.10, 103Pd decaysto the excited state of 103mRh through EC process, then 103mRh de-excites to the ground state 103Rh.With low-energy (less than 5keV) electrons and photons filtered, the mean energies of electrons andphotons emitted are 32.6 keV and 20.7 keV [57]. In a study by Keller et al., comparisons weremade between 103Pd and 125I seeds pertaining to clinical and safety concerns [26]. Because 103Pdhas lower photon energy level and shorter half-life, the radiation attenuation is more significantfor 103Pd than 125I. Same dose coverage of the PTV can be achieved using same amount of both26seeds but 103Pd seeds tend to have a more rapid dose fall-off, which results in lower dose exposureto surrounding healthy tissues and the patient’s partner or families . 131Cs was also investigatedas a PBSI source option. In another paper by Keller et al., 131Cs brachytherapy sources werecompared with 103Pd to determine whether there are dosimetric advantages to use 131Cs seeds forPBSI, considering 131Cs radionuclide has a higher energy and a shorter half-life [48]. Among the 30early breast cancer patients who underwent PBSI, 131Cs showed theoretical dosimetric advantages;however, no significant clinical benefits were expected with 131Cs thus the use of 131Cs as PBSIsource has been limited.Figure 2.10: Decay scheme of 103Pd.Methods of post-implant QA were improved as PBSI procedure was gradually refined as a novelclinical technique. In a paper by Morton et al. in 2016, the seed placement accuracy in PBSI wasstudied [39]. The overall mean difference between implanted and planned positions of the seeds was9±5 mm for the aggregate seed population, and no significant systematic directional displacementwas observed. In another paper by Hilts et al. [21], deformable image registration and adaptive con-touring were implemented to compare the contours and the dose distribution between the treatmentplan and delivered treatment. As a post-implant QA procedure, deformable image registration onpost-implant seroma was recommended as an effective tool to evaluate the uncertainty of treatmentdelivery.2.2.4.2 Patient Eligibility CriteriaFor PBSI, patients need to meet strict pathological requirements. Clinically, eligible patients forPBSI should be over 50 years old and recommended for adjuvant radiotherapy after lumpectomy.Medical history and general health conditions are considered. An appropriate patient for PBSI also27needs to have visible seroma with clear margin on CT and US, chest wall visible on US. Seromashould be roughly less than 3×3×3 cm, and the length in the direction of needle insertion shouldbe no larger than 4.5 cm as seed trains cannot be greater than 7 cm. There should be enough roomfor at least two superimposed planes of needles for treatment planning. And when the location ofseroma is too close to skin or chest wall, the patient may not be recommended for PBSI in case ofhigh toxicity to surrounding tissues and increased risk of side effects [38].2.2.4.3 Clinical Treatment ProcedureAs the second institution worldwide to offer PBSI as a treatment option, BC Cancer - Kelownahas been performing PBSI since 2012 and so far, over 70 patients have been treated through PBSI.The general clinical treatment procedure can be divided into treatment planning, PBSI procedureand post-implant QA.CT simulation is the first step for PBSI treatment plan. During CT simulation, the patient is setup as for EBRT, lying supine on the breast board, with the ipsilateral arm lifted overhead and theother arm at rest. Free-hand US images are also acquired to assess the size and location of seromaand the oncologist can decide whether the patient is potentially eligible for PBSI treatment, shownin Figure 2.11. Beads and wires are placed on patient’s surface to visualize lumpectomy scar andnipple and lateral tattoo is marked as reference, then the CT images can be acquired. The CT scancan be used for treatment planning, whether the patient is eligible for PBSI treatment or not.Figure 2.11: US evaluation on seroma for PBSI.Once the patient is eligible and chooses to have PBSI treatment, the target can be contoured, and28plan can be made based on the dose prescription in computerized TPS. Figure 2.12 shows a generalPBSI planning process. Seroma is the fluid cavity formed after lumpectomy. The clinical targetvolume is defined as the surgical cavity and the surrounding fibrosis, as shown in Figure 2.12a.Clinically, a 1-1.5 cm margin is usually added around seroma to contour the PTV, with the contourcropped 0.5 cm away from skin and at chest wall. After contouring, the fiducial needle insertionentry point and direction are determined. The fiducial needle should travel through the center ofCTV usually with an angle tangential to the chest wall, and an entry point on the posterolateral sideof the breast, as shown in Figure 2.12a. Then the location of the template for needle insertion canbe relatively determined by fiducial needle [38].103Pd seed locations are planned on the template grids, as shown in Figure 2.12c. The templateallows the seeds to be placed 0.5 cm apart, on each slice of the images. The seed locations areadjusted to optimize the dose distribution, and needle will be loaded with 103Pd seeds and spacersonce the plan is made. An EBRT plan of 50 Gy in 25 fractions is biologically equivalent to a PBSIdose of 90 Gy using 103Pd seeds to the target volume, based on a time-dose fractionation schedule[27]. With a prescribed 90 Gy, the dose optimization aim is to satisfy V90 > 98%, V100 > 95%,V150 < 75%, and V200 < 25% and the 90% isodose line limited to 1 cm2 on the skin surface [22, 27].2.2.4.3.1 PBSI DeliveryOn the day of the procedure, a mark-up procedure is first performed in the CT room. Patientsposition is reproduced on the breast board. With the help of CT lasers, fiducial entry point and PTVprojection on patients surface are marked up on skin, shown in Figure 2.13. US and CT imagesand acquired to monitor the seroma changes, and once the seroma size and location is verified tobe suitable for the plan, the patient is moved to the OR and given general anaesthesia. In the OR,patient’s position is set up again and verified with portable laser. The template location is adjusted sothat the fiducial needle can be inserted at the marked entry point with the planned angle. Free-handUS is used to verify the location of fiducial needle. Once verified, the template can be set up, andthe needles can be inserted through the template following a ’zig-zag’ pattern. The needle locationsare verified by US and the depth is verified by measuring the needle protrusion distance. The seedscan be released once the needle is at planned position.29(a) (b)(c)Figure 2.12: An illustration of PBSI planning: (a) The fiducial needle insertion direction andthe seroma; (b) Several rows of seeds planned around the seroma; (c) The seed locationson the template grid, PTV contour and 100% isodose line.(a) (b)Figure 2.13: An illustration of PBSI delivery: (a) PBSI mark-up procedure; (b) Patient’s setup in the OR with the implant template and the fiducial needle.2.2.4.3.2 Post-implant QAPost-implant CT scans are acquired, both on the day of implant and 1 month following implant.30As shown in Figure 2.14, the implanted seeds show as bright dots on CT scans. Seeds need to beidentified and the dosimetry delivered can be assessed based on the contours and the seed locations.Because of the seed artifacts and fibrosis, the post-implant CTV can be hard to define. Deformableimage registration between the CT images before and after implant improves the accuracy of theQA, and dose volume histogram can be generated for delivered dose evaluation [21].Figure 2.14: A slice of PBSI post-implant CT images.2.3 Ultrasound Imaging2.3.1 The Physics of Ultrasound ImagingSound is a type of compression wave which means the propagation of sound waves in mediais achieved by compression events between the particles. US is defined as a sound wave with afrequency over 20 kHz. Although the frequency of US does not change when propagating from amedia into another, the speed varies from material. Some basic concepts of sound wave propagationare introduced below [32].Bulk modulus (B) reflects the resistance of volume change caused by the pressure of the com-pression wave. Bulk modulus is defined as [5]B =−V ∆p∆V, (2.14)where V is the initial volume, ∆V is change in the volume and ∆p is change in the pressure .Thespeed of sound wave (c) in the medium is determined by the ratio of bulk modulus and the density31(ρ) of the material, and can be calculated asc =√Bρ. (2.15)A generally-accepted sound speed in soft tissue is 1540 m/s. Based on the US frequency, thewavelength of US can be calculated to be smaller than 7.7 cm in soft tissue.Reflection, refraction, scattering and absorption may happen when US travels through the mediumand interacts with matter. Figure 2.15 shows some common US interactions at a boundary betweentwo media. Acoustic impedance (Z) is defined asZ = ρc (2.16)and can be used to quantify wave propagation during different interactions. Acoustic impedancereflects the stiffness or flexibility of a compressible medium, which plays an important role forenergy transfer during the propagation of the wave. For example, when US travels from mediumA to medium B, a large reflection will occur at the boundary if the stiffness of two media varyconsiderably. On the other hand, if medium A and medium B only have minor difference in stiffness,the US wave can be propagating with minor reflection.Figure 2.15: An illustration of US transmission, reflection and refraction.Reflection describes the phenomenon that part of the energy is reflected at a boundary in a formof reflected wave. For perpendicular incidence, the reflection coefficient (RI) is the fraction of32intensities of reflected wave (Ir) and incident wave (Ii). RI can be calculated asRI =IrIi= (Z2 − Z1Z2 +Z1)2. (2.17)Refraction describes a change in the wave direction at a boundary when there is a difference inthe speed of sound. According to Snell’s Law, the relationship between refraction angle (θt) andincident angle (θi) can be described assin (θt)sin (θi)=c2c1. (2.18)where c1 and c2 are the speed of sound in two media.Scattering occurs when a boundary is not smooth. When the surface is composed of small objectswith a dimension smaller or around the US wavelength, it is called a non-specular surface. At a non-specular surface, the sound wave can be reflected in all directions, with low intensities. Hyperechoicmaterial is the term to describe a material with larger number of scatters and higher scatter ampli-tude, and on the contrary, hypoechoic material is used to describe a material with very few scattersand low scatter amplitude. Both scattering and tissue absorption contribute to US attenuation whentraveling through a medium, with the absorbed energy converted to heat. Attenuation coefficient µ(dB/cm) is defined as the relative intensity loss per unit length.During US imaging, US waves are produced and reflecting echoes are detected from the bound-aries between different tissues with different acoustic impedance. The time taken to detect the echocan be used to locate the boundaries to form an image. A modern clinical US probe is composedof many transducers, which can produce and detect US. Piezoelectric material is commonly usedin a transducer, and it produces electrical signals when applied mechanical pressure. As shown inFigure 2.16, an electrical pulse is applied on the piezoelectric element and causes crystal vibration.A backing block dampens the crystal vibration to produce a pulse US and absorbs the backward US,leaving the US pulse only going outwards from the transducer. A matching layer is added on thesurface of a transducer, to minimize the difference on acoustic impedance between the transducerelements and tissue to avoid strong reflections. The US travels through the tissue until hitting aboundary and produces an echo. The reflected echo can be detected by the piezoelectric element33and converted to an electrical signal. An acoustic absorber is attached to absorb the rest of the en-ergy, which can be formed by an epoxy material with absorbers and scatters such as tungsten orsilica [17, 62]. A tuning coil is built in the transducer to adjust the US pulse frequency. The crys-tal and backing block are surrounded by metal for magnetic and electrical shielding [12]. ClinicalUS probes are comprised of multiple transducer elements or a transducer array, which allows thereflected sound waves to be picked up by different elements and form a 2D image.Figure 2.16: A single-element transducer.Several modes have been developed in US clinical use. Amplitude-mode (A-mode) shows theamplitude of the echo signal versus time. With the US travel time for a round-trip (t) and the speedof sound (c) in the tissue, the distance from the transducer to the boundary can be determined byd = c× t/2 (2.19)Brightness-mode (B-mode) converts the amplitude and distance information into brightness-modulated dots. The brightness is proportional to the echo signal amplitude and B-mode is usuallydisplayed as a 2D gray scale image. Motion-mode (M-mode) is developed to show the motion ofthe tissues based on B-mode information, which is displayed as real-time US images.2.3.2 US Image Quality and ArtifactsUS spatial resolution is usually investigated to assess US image quality, which can be measured inthree directions: axial, lateral, and elevational. As shown in Figure 2.17, axial resolution defines the34ability to distinguish two close objects in the direction of the beam. Axial resolution is determinedby US frequency and transducer damping factor. Lateral resolution defines the ability to distinguishtwo objects perpendicular to the beam direction. The elevational resolution is defined perpendicularto the image slice. Lateral and elevational resolutions are determined by the width and height of thetransducer element [32].Figure 2.17: US transducer three-dimension resolution axes.Image contrast is also part of US image quality assessment, and can be influenced by manyfactors. Image contrast mainly depends on acoustic impedance differences between tissues butis also affected by the size and density of the scatters in the tissue. The scattering results in abackground noise on the image, which decreases the contrast on the echo signal. Spatial resolutionalso has an impact on contrast resolution. When the spatial resolution is relatively low, some detailsmay get lost and hence lowers the contrast resolution [32].Some artifacts are commonly seen in US images. Refraction often occurs at the boundary of twotissues with different acoustic characteristics and results in a change in beam direction. Without ac-counting for the beam direction change, organ misplacement may occur in US image. Shadowing orenhancement is often observed in US images too. Because the signal processing assumes a uniformattenuation, enhancement can be usually seen distal to a low-attenuation object, while shadowingcan be seen distal to a high-attenuation object. Reverberation is another common artifact, wheremultiple echoes are detected from two closely spaced boundaries, resulting in a series of evenlyspaced signals [32]. In Figure 2.18 reverberations can be seen beneath the LDR needle on US.35Figure 2.18: An LDR needle on US image.2.3.3 3-Dimentional Ultrasound TechnologyVarious 3D US techniques have been developed to meet clinical needs. 3D US probes first be-came available with a 2D linear phased-array probe head and a geared internal stepper motor. Theseprobes need to be held steady during the scan to allow a motor to sweep and acquire a 3D volume[59]. Meanwhile, some 3D US system were developed with a regular 2D probe and position localiz-ers [23]. The basic principle to reconstruct a 3DUS volume is to acquire a series of 2D tomographicimages with spatial information.A common method is to build a mechanical scanner, where 2D images are acquired sequentiallyby a mechanically motorized US probe scanning through a region. As shown in Figure 2.19, 2Dimages can be sampled through linear translation, tilt or rotation of the transducer array. The imagesacquired are stored in order and the spatial location of each 2D image is encoded mechanicallyfor volume reconstruction. The mechanical method is able to achieve high accuracy on spatialinformation; however, the apparatus is usually bulky [13].(a) (b) (c)Figure 2.19: An illustration of different image acquisition methods for 3D US image recon-struction: 2D US images are acquired during a linear scan (a), a tilting scan (b), and arotational scan (c) of the transducer.363D US images can also be obtained through free-hand US scan. An acoustic tracking systemcan be used to emit acoustic signals and measure the travel time of the sound continuously duringthe scan. Then the location and orientation of the probe for each 2D image can be determined.Similar methods can be applied with an optical sensor or magnetic field sensor. Sensors can bemade compact, but also bring in more uncertainties locating the US probe, compared to mechanicalscanners, thus are not commonly used for small target imaging. Another method is to use speckledecorrelation algorithm to estimate the spacing between two adjacent 2D scan and to locate therelative positions of the image series. Speckle decorrelation method does not need any externaldevices, but assumes all the 2D scans are parallel and does not account for tilt or rotation anglebetween slices [8, 13].3D US imaging technologies have been extensively explored to provide better visualization andsurgical guidance. Imaging acquisition and reconstruction can be achieved through different ap-proaches to meet clinical needs. A prototype 3DUS system was developed based on a mechanicalscanner and 3D US imaging volume is reconstructed by 2D frames through a hybrid trajectory[35, 41]. The 3DUS system was developed for PBSI planning and delivery, and will be furtherintroduced in section 3.1.1.2.3.4 Clinical Use of USUS is widely-used in the medical field to provide real-time images. Clinical US frequency rangesbetween 2 and 15 MHz, and B-mode is the primary mode in clinical US applications. B-mode gives2D black and white images that show the local anatomy based on different acoustic characteristicsof tissues (see Figure 2.11). B-mode images are acquired by repeating an US pulse-echo cycle andmapping out the echo signals to the locations in the image pixel matrix. The pulse-echo cycle isrepeated for each image frame to achieve real-time imaging, and the frame rate is generally 20-40per second [4].US imaging is used to examine fetal, abdominal, pelvic, vascular, and superficial tissues. Asshown in Figure 2.20, US probes with different shapes and size are designed for different anatomicalstructures. US is also used in echocardiogram, which shows the structure of heart and blood flows.In this thesis, the use of US is focused on imaging the surgical cavity for PBSI planning procedure.37(a) (b) (c)Figure 2.20: Clinical used (a) abdominal probe, (b) breast probe, and (c) rectal probe for USexamination (BK Medical®, Herlev, Denmark).38Chapter 33DUS System Commissioning3D US images are desirable for improved visualization and surgical guidance for PBSI. A pro-totype 3DUS system has been developed by the Imaging Research Laboratory (Robarts ResearchInstitute, Western University) and the BC Cancer PBSI research group as a potential scanning toolfor PBSI visual guidance [35, 41]. The 3DUS system allows the visualization of a 3D imagingvolume and the implant template in the same coordinate system, and different imaging views areavailable for visual guidance.In this Chapter, the 3DUS system was commissioned by testing the scanning system linear accu-racy, volumetric accuracy, orthogonal template registration accuracy, and clinical template registra-tion limitation. The commissioning tests validate the imaging reconstruction and implant templateregistration of the 3DUS system for PBSI clinical use. The tests offered baselines on the systemaccuracy and a QA procedure was established to monitor the system performance.3.1 Materials and Methods3.1.1 3DUS for PBSIThe 3DUS system for PBSI is shown in Figure 3.1a. The scanner is composed of three parts:(a) the housing, (b) an US transparent polymethylpentene plastic (TPX) plate, and (c) a mechanicalarm. The housing includes a mount for a clinical breast US probe and encloses a motor whichmechanically drives the mount and US probe. During image acquisition, the motor simultaneously39translates (5 cm linearly) and tilts (60◦) the probe. The TPX plate is fixed to the housing and shapedto fit the transducer so that the transducer moves smoothly during the scan. The plate sits on thescanning target, and is coupled to the probe and to the breast with US gel. The mechanical arm hasthree segments that each rotates at a joint and at its end has a spherical tip. Each joint is tracked bya 12-bit magnetic encoder and communicates to the computer through a USB interface [35, 47].During a scan, a series of 2D US images is acquired by a video capture device and transferredto the computer. Simultaneously, the position of the transducer at each 2D plane is recorded. A3D imaging volume is then reconstructed in the software and can be resliced for viewing in axial,sagittal and coronal planes [34].A registration plate (Figure 3.1b) was made to assist registering the clinical implant template tothe image volume. During the registration, the plate is fixed onto the clinical implant template bytwo pins. The spherical tip of the arm can be then fit into four divots on the registration plate,sequentially, with the mechanical encoder values recorded in the software at each divot position.The location of this tip can be then determined from the encoders and used to register the implanttemplate to the scanner.(a) (b)Figure 3.1: (a) 3DUS scanner components: Part a being a housing that contains motor andelectronics; Part b being a TPX plate; Part c being an encoded mechanical arm; (b) Aphoto of the registration plate used for registration process.403.1.2 Matrix TransformationThe clinical implant template is registered to the 3DUS imaging volume through several 3Dmatrix transformations. Figure 3.2a shows the four major coordinate systems involved and thematrix transformation process. The template coordinate system (TCS) is defined relative to theregistration plate and template coordinates of the divots (xT , yT , zT ) are known as they show thephysical divot locations on the plate. The arm coordinate system (ACS) is defined relative to themechanical arm and the coordinates in ACS, (xA, yA, zA), are given by the encoder measurement andcalculation. The scanner coordinate system (SCS) is defined by its origin at the physical centre ofthe TPX plate, and scanner coordinates (xS, yS, zS) are obtained by applying matrix TA→S on the armcoordinates. And the imaging coordinate system (ICS) is defined relative to the image volume. Atranslation matrix TS→I is applied to obtain imaging coordinates (xI , yI , zI), as the origin is translatedfrom the TPX plate centre in the SCS to the image volume centre in the ICS. With the coordinatesof the divots both known in the TCS and the ICS, a transformation matrix TT→I is calculated andused to register the clinical implant template to the image volume and to reconstruct the template3D model for visualization. Figure 3.2b shows the visualized 3D implant template model and theimaging volume both in the ICS in the software [41].41(a)(b)Figure 3.2: (a) An illustration of four major coordinate systems and matrix transformationprocess; (b) A photo of visualized 3D implant template model in the software.3.1.3 System Commissioning TestsThe 3DUS system for PBSI was previously validated through a series of tests to evaluate systemaccuracy and performance [41]. Image reconstruction was validated linearly and volumetricallyby measuring both known physical distances in different directions and a known volume. Theinitial measurements for linear accuracy were all within 2% of the expected value in the axial andlateral directions, and 3% in the elevational direction. Volumetrically, the mean was found to be(3± 1)% smaller than expected. Template registration accuracy was quantified by comparing thetrajectory and angular separations between the actual needle positions and the projected needlepositions through matrix transformation. The results showed a mean trajectory separation of (1.3±0.9) mm and a mean angular separation of (0.9±0.5)◦. Preliminary needle insertion accuracy under42free-hand 2D US guidance and PBSI 3DUS system guidance was assessed and the 3DUS guidancebrought the needle insertion error down from (3.9± 0.5) mm to (1.7± 1.0) mm and reduced theangular uncertainty from 2.9◦ to 1.2◦.With these encouraging results for PBSI imaging guidance, a 3DUS system commissioning pro-cedure was established from a clinical perspective through a series of tests. The 3DUS system,with a new software version, was further validated by testing linear accuracy, volumetric accuracy,orthogonal template registration and clinical template registration limitation.3.1.3.1 Scanning System Linear Accuracy TestA string phantom, shown in Figure 3.3a, was made to assist the system linear accuracy test. Itis comprised of nylon strings separated by (10.00± 0.05) mm, in three dimensions. The stringphantom was submerged in a 7.25% isopropyl alcohol water solution to achieve a tissue-equivalentspeed of sound of 1540 m/s [58]. With the scanner sitting on top of the phantom, 3DUS images wereobtained. Axial, sagittal and coronal views were available for the reconstructed imaging volume andstring separations were measured in the software (see Figure 3.3b).(a) (b)Figure 3.3: (a) String phantom; (b) Needle separation measurement in reconstructed sagittalview.3.1.3.2 Scanning System Volumetric Accuracy TestThe scanning system volumetric accuracy test was performed with the Restitu Calibration Phan-tom (Resonant Medical®, Montreal, QC) (referred to as the Resonant phantom in later text). TheResonant phantom is a solid gelatin phantom with a sphere (1.2 cc) and four rods embedded inside.433DUS images were acquired of the phantom and the sphere was segmented and its volume wascalculated in the software, shown in Figure 3.4.(a) (b)Figure 3.4: (a) Object contour in 3DUS software; (b) Volume segmentation in 3DUS software.3.1.3.3 Orthogonal Template Registration TestThis test evaluated the accuracy of the registration of the implant template to the imaging volumewhen it is fixed orthogonal to the imaging volume. The test was performed using a needle insertiontemplate (Figure 3.5a), which held needles at known positions. The registration plate was fit ontothe jig, orthogonal to the imaging system. The needles in the jig were submerged in the 7.25%isopropyl alcohol water solution, and 3DUS images of the needles were acquired. Shown in Figure3.5b, the jig was used to simulate the clinical implant template and the registration plate was fit ontothe jig for position tracking. The location of two top divots and two left divots on the plate weretracked by the mechanical arm in a counter clockwise direction starting from the top-right divot.The divot locations were recorded to register the template location in the reconstructed imagingvolume. As shown in Figure 3.5c, the grid of the implant template and the image of the needlescan be visualized in the same coordinate system. Each needle position represented a grid on theclinical implant template grid and the needles inserted were distributed across the whole imagingvolume. The planned needle positions, following a straight trajectory from the template (in blue),and actual needle positions both were marked and the trajectory differences between them wereused to quantify the template registration accuracy.The planned needles and actual needles are segmented in the software and the angular separationand needle tip difference can be then calculated. A needle trajectory separation was calculated by44averaging the distance between a pair of the points on the needles at six different depths, as shownin Equation (3.1).Tra jectorySeparation =∑6i=1 | (xi yi zi)planned− (xi yi zi)actual |6(3.1)(a) (b)(c)Figure 3.5: (a) Needles inserted through a needle jig for imaging; (b) The registration templatefitting onto the needle jig for template registration; (c) The 3D imaging volume and thetemplate grid under same coordinates system, with the planned position of the needlesmarked in blue.3.1.3.4 Clinical Template Registration Limitation TestIn clinical practice, the implant template and the imaging volume may not be orthogonal. Thistest was performed to determine the range of the clinical template positions relative to the scannerallowing the completion of the registration process, and to validate the registration accuracy whenthe template was at different positions. The template registration test was performed using theclinical needle template in a range of positions and the registration error for each was quantified.45Five fiducial needles, which can be locked in place, were inserted through the clinical template, andsubmerged in the 7.25% isopropyl alcohol water solution. Starting from an orthogonal positionrelative to the scanner, the clinical template was rotated or tilted in three dimensions, as shown inFigure 3.6a. The registration process was performed and the registration error was evaluated every10 degrees in each dimension. The needle trajectory differences between the known and imagedpositions for the five fiducial needles were measured at three depths along the needle insertiondirection (-20 mm, 0 mm, 20 mm relative to the 3DUS imaging volume centre) and the mean valueswere used to quantify the template registration error.(a)(b)Figure 3.6: (a) The clinical template rotation and tilt direction; (b) The template registrationtest performed with a tilt angle of the template.3.2 Results3.2.1 Scanning System Linear and Volumetric Accuracy TestTen randomly picked string separations were measured, in axial, lateral and elevational direc-tions, as shown in Table 3.1. The mean values of measured string separations were (10.0± 0.1)mm, (10.1± 0.1) mm and (10.1± 0.3) mm, respectively. All the measurements in lateral and ax-ial directions were within 2% of the expected value, however, the maximum error in elevationalmeasurement was as high as 6% in the commissioning test. The spherical target in the Resonantphantom was measured to be 1.24 cc, which is 3% larger than the expected value.46Table 3.1: Measurements of 3DUS System Linear AccuracyNumber Lateral (mm) Axial (mm) Elevational (mm)1 9.9 10.1 9.92 9.9 10.1 10.43 10.2 9.8 10.24 10.1 10.2 10.35 9.8 10.1 9.46 9.9 10.2 10.67 10.1 10.1 10.18 10.1 10.2 10.59 9.8 10.2 9.910 10.2 9.9 9.8Ave 10.0 10.1 10.1SD 0.1 0.1 0.33.2.2 Orthogonal Template Registration Accuracy TestA MATLAB script was written to automatically calculate the angular separations, needle tipdifferences and trajectory differences between planned needles and actual needles. Five needleswere inserted through the needle insertion jig and the registration errors were quantified for eachUS scan depth, as shown in Table 3.2. The registration errors displayed similar results for all threecommonly used scan depths. For all scan depths, the average angular separation was (1.0± 0.3)◦.The average needle tip difference was (1.3±0.5) mm and the mean trajectory separation was (1.4±0.5) mm.47Table 3.2: Measurements of 3DUS System Template Registration AccuracyScan Depth Needle PositionAngularSeparation(◦)TrajectorySeparation (mm)Needle TipDifference (mm)Average(5.3cm)Fiducial C 0.8 1.2 0.8G5 0.9 0.6 0.7J6 0.8 1.0 0.9F8 0.9 1.8 1.4K3 0.9 0.8 1.2Ave 0.9 1.1 1.0SD 0.0 0.4 0.3Large(6.2cm)Fiducial C 0.6 1.4 1.2G5 1.6 1.3 1.4J6 1.4 1.4 1.2F8 1.6 1.3 1.4K3 0.7 1.8 1.8Ave 1.2 1.4 1.4SD 0.4 0.2 0.2Small(4.0cm)Fiducial C 1.1 1.3 1.0G5 0.8 0.8 0.8J6 1.1 1.8 1.7F8 1.2 2.1 1.7K3 1.0 2.5 2.7Ave 1.0 1.7 1.6SD 0.3 0.5 0.5All Scan DepthsAve 1.0 1.4 1.3SD 0.3 0.5 0.5483.2.3 Clinical Template Registration Limitations TestWith the rotation dimensions and directions as labelled in Figure 3.7, template registration can beperformed within−50◦ to 10◦ of lateral rotation, 0◦ to 30◦ of vertical rotation and−40◦ to 0◦ of tilt.The distance from the image scanning centre to the clinical template was adjusted from 7 cm to 13.5cm accordingly to allow the mechanical arm to reach all the divots needed for registration process,at each template position. Table 3.3 shows the template registration results with different templateorientations, and the mean registration error of all the template positions was (1.3±0.4) mm.Figure 3.7: The implant template limits to perform the template registration.49Table 3.3: Measurements of Template Registration Accuracy with Different Clinical TemplateOrientationLateralRotation (deg)VerticalRotation (deg)Tilt (deg)Distance Betweenthe Image Scanning Centre tothe Clinical Template (cm)TemplateRegistration Error (mm)0 0 0 11.0 1.3-50 0 0 7.0 1.2-40 0 0 9.5 1.2-30 0 0 11.5 1.2-20 0 0 11.5 0.9-10 0 0 10.0 1.010 0 0 11.0 2.40 10 0 11.5 2.00 20 0 10.0 0.80 30 0 8.0 0.90 0 -40 11.0 1.40 0 -30 13.5 1.70 0 -20 11.5 0.90 0 -10 11.0 1.2Ave 1.3SD 0.43.2.4 Clinical QA Procedure WorksheetA clinical QA procedure was developed to monitor the 3DUS system performance. The QAprocedure includes: the linear accuracy test, volumetric accuracy test, and orthogonal template reg-istration test with the needle insertion jig. Figure 3.8 shows a PBSI 3DUS QA recording worksheetwith baselines.50Figure 3.8: QA worksheet for PBSI 3DUS system.513.3 DiscussionsThe scanning system linear and volumetric mean accuracy was comparable to the original sys-tem validation results [35]. However, the linear string separation on elevational direction resultedin a larger maximum error (6%) compared to the maximum error from the initial validation results(3%) [41]. With the elevational resolution relatively larger than axial and lateral resolutions, theelevational imaging reconstruction error is expected to be slightly larger than that of the other twodirections. 2D US images are recorded during the scan and their location within the 3D volumeis determined by the mechanical position of the transducer. Thus, the motorized movement of theprobe plays an important role in the elevational 3D volume reconstruction accuracy. Therefore, lin-ear accuracy in the elevational direction is a valuable metric for monitoring any mechanical changesto the scanner. It is crucial that if the imaging system reconstruction accuracy test fails to meetaccepted criteria, diagnostics should be performed to verify the motorized scanning accuracy. Thecalibration of the US system itself or the transducer should be tested if the axial or lateral linearaccuracy tests fail.The limits to template allowing the template registration were tested and the template registrationshould be performed with the template position relative to the scanner in the range shown in Figure3.7 to ensure the registration completion and accuracy. The template registration accuracy testsshowed similar results as the initial validation accuracy, and remained consistent within a rangeof clinical template rotation/tilt relative to the scanning volume. Thus, as part of the regular QAprocedure, performing the template registration test with the registration plate orthogonally fixedon the needle insertion jig should be sufficient for QA purposes. In other words, performing theregistration test with the clinical template in random positions is not necessary to include in theclinical QA procedure once the 3DUS system is commissioned. A mechanical shift of the motoror US probe sometimes can cause a translation of the imaging volume relative to the defined imagevolume origin. If the template registration test fails to meet the accepted criteria, an additionalmatrix can be added to the matrix transformation to compensate for such a translation. However,if there is a rotational change of the 3D imaging volume relative to the defined image-coordinatesystem axes, initial system validation and commissioning should be performed again .The 3DUS system for PBSI was commissioned by performing image reconstruction accuracy(linearly and volumetrically), template registration accuracy and template registration limitation52tests. These tests provide baseline data for the QA procedures which should be regularly followedin future clinical use.53Chapter 4Rigid Registration of 3DUS and CTAs discussed in section 1.4, the visualization of the seroma cavity differs from US and CT images,which complicates the interpretation of PBSI plans on CT images during the procedure with USguidance. The 3DUS showed potential on visualization and surgical guidance for PBSI planningand delivery. Incorporating 3DUS images with CT images will offer improved visualization anddelineation of the seroma cavity for PBSI planning.To implement the 3DUS system into PBSI planning procedure, a method was developed toachieve rigid registration of 3DUS and CT images in this Chapter. The 3DUS-CT registration testswere performed on anthropomorphic gel phantoms to test the registration feasibility and accuracy.This study further validates the clinical use of the 3DUS system and facilitates the implementationof 3DUS images in PBSI planning procedure.4.1 Materials and Methods4.1.1 Point-based RegistrationRigid registration is an image coordinate transformation where only translations and rotationsare applied. Different from deformable registration, the image volumes are not deformed in rigidregistration. Common registration methods include landmark-based registration (alignment basedon pairs of points), segmentation-based registration (alignment based on segmented structures), andvoxel property-based registration (alignment based on image grey scale values) [20].54Based on the mechanical design of the encoded arm on the 3DUS scanner, it is most feasible tomeasure the location of several landmarks in both images, compared to using segmented structuresor voxel properties. Point-based registration is used to register 3DUS and CT images in the samecoordinate system. To achieve point-based registration, a few fiducial landmarks should be identifiedfollowing the same sequence in both image sets. Then the landmarks are used to align two imagestogether. Locating the landmarks and following the same landmark sequence are both critical forpoint-based registration.A 3D-printed model with landmarks visible in US and CT, described in section 4.1.4, was in-cluded in both the 3DUS and CT images. The landmarks were contoured in a same sequence inboth sets of images using MIM Symphony (version 6.5; MIM Software Inc., Cleveland, OH). Theregistration was performed in fusion mode, and pairs of landmarks were matched together to alignthe two image sets.In literature, both fiducial registration error (FRE) and target registration error (TRE) are com-monly used to quantify the registration accuracy [20]. FRE is defined by the root-mean-squaredistance between corresponding fiducial points in the two image sets after point-based registration.During the registration process, FRE is minimized to find the rotation matrix R and translation ma-trix T in MIM Symphony and both matrices are used to transform one image set into the volumespace of another image set. The mathematical form of FRE can be written as [16]FRE2 =1NN∑i=1|R× xi +T − yi|2 (4.1)where N is the number of fiducial landmarks, xi and yi being the position of landmark i in the twoimage sets. TRE is defined as the distance between corresponding target points in both image setsafter registration [16, 42]. The mathematical form of TRE is shown in Equation 4.2 [16], wherepi and qi are the position of the target in both images. In our experiment, the target (seroma) wascontoured on both image sets and the centroid of the two contour was extracted in MIM Symphonyto calculate TRE. The landmark locations were read in MIM Symphony after registration and FREcan be calculated as a secondary measurement.T RE2 = |R× pi +T −qi|2 (4.2)554.1.2 3DUS-CT Registration WorkflowA workflow, shown in Figure 4.1, was established to describe the imaging and registration pro-cesses. The 3DUS and CT images are acquired in the CT room, with a phantom set up on the CTcouch as imaging object. The 3DUS scan if firstly performed, and the landmarks in 3DUS imagesare mechanically tracked by the encoded arm. Then the 3DUS scanner can be removed from thephantom surface to acquire the CT scan.Figure 4.1: Workflow for 3DUS-CT registration process.The 3DUS system for PBSI reconstructs a 5 cm×5 cm×10 cm imaging volume. The 3D imageshave a resolution of 0.082 mm, 0.071 mm, and 0.336 mm in lateral, axial and elevational directions,respectively. The encoded landmark positions are located in the 3DUS volume using a MATLAB56script, which also exports the image files in DICOM format. CT images contain 512×512 pixelsfor each slice, with a resolution of 0.9766 mm in both in-plane directions. Slice interval and slicethickness are both set to be 1.25 mm.The point-based registration is performed in MIM Symphony. Both sets of images are importedand viewed in the treatment planning system. The landmarks are contoured following the samegeometric sequence in both images. An imaging object is also contoured in both images as thetarget. In fusion mode, the two sets of images are aligned and viewed in the same coordinate systemafter running a point-based registration. The geometric centres of the target contours in both imagessets are then extracted. The TRE is determined by the displacement between the centres of twotarget contours and is used to evaluate the registration accuracy.4.1.3 Imaging PhantomsThe Resonant phantom, which is a commercial US QA phantom, was used for the initial registra-tion tests. Introduced in section 3.1.3, the Resonant phantom is made of gel which has an equivalentspeed of sound as in soft tissue (1540 m/s), and the sphere embedded in the phantom is used as theimaging target to evaluate the registration accuracy.To further test the 3DUS scanning ability and the geometric limits of the registration process, agel breast phantom was constructed and imaged. The gel phantom was made of water and gelatinwith sugar-free psyllium hydrophilic mucilloid fiber as the scattering agent [7]. Several differentobjects including carrots, olives (with and without pits inside), and water-filled balloons were testedas the embedded objects. Both US and CT images of the phantom were taken to test the visibilityof the object on US and CT. Water-filled balloons were used as the embedded targets in the gelto simulate a seroma, yielding the best visualization. Several phantoms were constructed, and thevolume of the balloon varied from 5 cc to 10 cc.For imaging, the gel breast is placed on the Rando® Phantom (Alderson Research LaboratoriesInc., Stamford, CT) to mimic the clinical breast CT simulation set up using a breast board. Figure4.2a shows the phantom and the 3D-printed model set up on CT couch. A clamp was made tokeep the 3D-printed model fixed to the breast board. The location of the 3D-printed model can beadjusted vertically and horizontally according to a patient’s body geometry. As well, the modelcan be rotated through 180◦. Figure 4.2b shows the movement flexibility of the 3D-printed model57relative to the gel breast.(a) (b)Figure 4.2: (a) Gel breast phantom placed on the Rando® Phantom (Alderson Research Lab-oratories Inc., Stamford, CT), and a clamp fixed on the breast board and holding the3D-printed model; (b) An illustration showing the clamp allowing translation in two di-rections and 180◦ rotation of the 3D-printed model.4.1.4 Landmarks Configuration DesignSome basic principles were followed to design the geometric configuration of the landmark mark-ers: (1) The landmarks should be arranged to be as non-coplanar as possible; (2) Spread the land-marks over a large spatial range; (3) Keep the centre mass of all the landmarks as close as possibleto the target [42].A 3D-printed model was made with divots on the surface to assist the registration process. Differ-ent landmark configurations (A, B, C) were designed (see Figure 4.3), and the 3DUS-CT registrationtest was performed with the Resonant phantom using each of them, and the results are given in sec-tion 4.2.2. In configuration A, five landmarks were used. The 3D-printed model (A) was placedclose to the scanner with an angle relative to the 3DUS coordinate system (the two coordinate sys-tems are shown in Figure 4.3a) so that the tip of the encoded arm was able to reach all the divots,covering approximately 5 cm, 5 cm and 3 cm in elevational, lateral and axial direction of the 3DUScoordinate system. In configuration B, landmarks ranged over 6 cm in all directions and only fourlandmarks were used. In configuration C the same 3D-printed model was used but a total of eightlandmarks were tracked for 3DUS-CT registration.58All three configurations were tested for the registration and the registration accuracy was eval-uated. Ten registration trials were performed using configuration A, five trials were performedusing configuration B, and fifteen trials were performed using configuration C. Configuration Cwas adopted as the ultimate design for 3DUS-CT registration with the highest registration accuracy.Shown in Figure 4.3c, the fiducial landmarks in 3DUS images are the virtual centres of the divots.In CT images, standard CT-visible pellets are placed at the centre of the divots and the landmarklocations are determined by the CT markers.(a) (b)(c)Figure 4.3: Different landmarks configurations used for 3DUS-CT registration; (a) Configu-ration A, the red arrows showing the 3DUS image coordinate system; (b) ConfigurationB; (c) Configuration C.During the 3DUS-CT registration tests, the 3D-printed model (final design: Configuration C) waskept orthogonal to the scanning volume to achieve an optimal non-coplanar spatial coverage. Thesame process for registering the template using the encoder arm was used to locate the landmarksin the 3DUS image. Following a certain sequence of the landmarks, the spherical end of 3DUStracking arm was fit into each divot, and the encoder recorded each position of the sphere centre.By applying 3D matrix transformation described in section 3, all eight landmarks were registered59into the 3DUS imaging coordinate system. To visualize the virtual centre of the divots in the 3DUSspace, different grey scale values were assigned to each landmark. When viewing the 3DUS imagesin MIM Symphony, the landmarks were distinguished from the background, and the difference ingrey scale values told the tracking sequence. Then all landmarks were contoured following thetracking sequence in 3DUS images.CT-visible pellets (CT-SPOT®119, Beekley Medical, Bristol, CT) were used to locate the centreof the divots in CT images. Eight pellets were manually placed on the centre of each divot. Byvarying the CT image window level in MIM Symphony, the 3D-printed model and all the pelletswere visible and the same sequence of landmarks as in 3DUS imaging system was followed forlandmark contouring in CT images. Figure 4.4 shows an example of the visualization of CT markersand virtual centres of the divots in 3DUS images.Figure 4.4: The landmarks contours in MIM Symphony.4.1.5 3DUS-CT Registration Test4.1.5.1 Initial 3DUS-CT Registration Test with the Resonant PhantomFifteen 3DUS-CT registration trials were done using the Resonant phantom, with the set-upshown in Figure 4.5a. The scanner was placed on the Resonant phantom diagonally to cover thewhole volume of the embedded sphere, and the 3D-printed model was placed orthogonal to thescanning volume. Because of the limited length of the encoded arm, the location of the modelsometimes needed to be adjusted in order for all the landmarks to be reached by the encoder arm.60Twenty-five registration trials were done using the gel breast phantoms. For these the scannerwas sitting on the anterior surface of the gel breast for scanning, shown in Figure 4.5b. The scannerwas rotated laterally throughout all the trials with 0◦ < θ < 40◦. The 3D-printed model orientationwas adjusted to keep orthogonal to the scanner for each trial.4.1.5.2 Registration Test with Gel Breast Phantoms(a) (b)Figure 4.5: (a) The 3DUS-CT registration test setup on the Resonant phantom; (b) The 3DUS-CT registration test setup on gel breast phantom, with the 3DUS scanner able to be rotatedlaterally within 0◦ < θ < 40◦.4.1.6 3DUS Scanner Positioning Limits TestWhen used in CT, the scanner was locked by a mechanical arm for stabilization during scanning.The scanner orientation limits were tested and a recommended range on scanner tilt/rotation wasgiven for registration tests on gel breast phantoms. Registration tests were also performed withthe 3DUS scanner imaging from different breast quadrants instead of from the breast centre, andregistration accuracy was quantified.614.1.6.1 3DUS Scanner Orientation LimitsShown in Figure 4.6, a mechanical arm mounted to the cart holds the 3DUS scanner and a toggleis used to lock the scanner in position during scanning. The scanner could be vertically tilted up to25◦ (angle α), however, it was tested that the tilt angle should be kept within 10◦ to keep the scannerfixed during the process with no obvious drifting. Laterally, the scanner could be rotated and lockedwithin a 40◦ - 50◦ (angle β ) range. Figure 4.6 shows a commonly adopted 3DUS scanner orientationwhile used in CT. The scanner was placed on the anterior surface of the breast with a vertical tiltangle (α) and could be rotated within a 40◦ range.Figure 4.6: 3DUS scanner orientation limits4.1.6.2 3DUS Scanner Position LimitsThe imaging and 3DUS-CT registration processes were performed with the 3DUS scanner sittingon different quadrants of the gel breast phantom, as shown in Figure 4.7. Three registration testswere repeated for each quadrant of the breast. In each trial the scanner was placed on different breastquadrants and the whole target included in the scanning volume. The position of the 3D-printedmodel was adjusted so that all the divots could be reached for tracking. The same workflow (shownin Figure 4.1) was followed for the registration process and the registration error was calculated.62Figure 4.7: Four quadrants of the gel breast phantom.4.1.7 DICOM Files Sagittal/Axial Writing TestMIM Symphony was used to perform point-based registration, as described in section 4.1.2. Withthe landmarks contoured in both sets of images, a primary image set was selected, and the secondaryimage volume could be translated and rotated to match the landmark locations. Figure 4.8 showeda common set up for the 3DUS scanner relative to the CT couch (with 0◦ < θ < 40◦).Figure 4.8: Top View of 3DUS and CT Imaging VolumeA MATLAB script was written to convert the 3DUS data to DICOM files and to write the vol-ume as a series of axial or sagittal images. To test the dependence of the registration accuracy onthe way that 3DUS DICOM images are written, registration tests were performed with the 3DUSscanner oriented at different θ (0◦ < θ < 40◦), and the registration errors (both FRE and TRE) werecalculated and compared with the DICOM files written in both axial or sagittal view.634.2 Results4.2.1 Gel Breast Phantom Construction TestDifferent objects were tested as embedded targets in the gel. Carrots were hard to shape intosmooth curvatures thus added uncertainty when contouring the object. Artifacts were seen on USimages of the gel breast with olives inside (see Figure 4.9a). For olives with and without pits, the airtrapped inside the olives was hard to exclude, making the bottom half of the olive invisible on USimages. The CT images of gel phantoms with olives proved the existence of the air layer (Figure4.9c). Water-filled balloons offered good visibility on both US and CT images and the shape waseasy to contour (see Figure 4.9b and Figure 4.9d, thus they were used as embedded targets for3DUS-CT registration tests.(a) (b)(c) (d)Figure 4.9: (a) US image of an olive (with pit) embedded in gel; (b) US image of a water-filled balloon embedded in gel; (c) CT image of an olive with pit in gel; (d) CT image ofa water-filled balloon in gel.644.2.2 Landmarks Configuration TestTable 4.1 shows the registration error using the three different landmark configurations (see Figure4.3). The average TRE using configuration A, B and C is (3.4±1.7) mm, (4.2±1.4) mm, (1.8±0.8)mm. With the minimum registration error, configuration C was adopted for the 3DUS-CT registra-tion tests.Table 4.1: Measurements of TRE (Ave ± SD) Using Different Landmark ConfigurationsTRE (mm)Elevational Lateral Axial TotalConfiguration A −0.1±1.7 0.3±1.6 −1.8±2.5 3.4±1.7Configuration B 2.8±2.2 −0.1±1.3 0.1±2.4 4.2±1.4Configuration C 0.5±0.6 0.7±0.9 0±1.4 1.8±0.84.2.3 Initial 3DUS-CT Registration Test with the Resonant PhantomFigure 4.10 shows the Resonant phantom 3DUS-CT registered images in MIM Symphony’s fu-sion mode. Both image sets were overlapped together and viewed in the same coordinate system.The contours of the sphere were marked in different colours. Table 4.2 shows the average 3DUS-CT registration error for the Resonant phantom. The average TRE was (1.8±0.8) mm and the trialwith maximum uncertainty showed a total registration error of 3.2 mm. 73% of the trials have aregistration error within 2.0 mm. The average FRE was (1.7±0.7) mm, and showed the uncertaintyfor landmarks matching.Table 4.2: Measurements of Registration Accuracy on the Resonant PhantomTRE (mm) FRE (mm)Elevational Lateral Axial TotalAve±SD 0.5±0.6 0.7±0.9 0±1.4 1.8±0.81.7±0.7Trial with the Maximum Error 2.3 1.2 -2.0 3.2Number of trials with TRE<2 mm 11/15 (73%)65Figure 4.10: An axial view of CT(red) and 3DUS(grey) registered images of the Resonantphantom in MIM Symphony fusion mode, the pink contour being the sphere in 3DUSimages, and the blue contour being the sphere in CT images.4.2.4 3DUS-CT Registration Test with Gel Breast PhantomsFigure 4.11 shows the axial, sagittal, and coronal views of the registered 3DUS-CT images ofa gel breast phantom. Table 4.3 shows the average 3DUS-CT registration errors for gel breastphantoms. The average registration error was (1.9±0.8) mm and worst error was 4.6 mm for the gelbreast phantoms. The 3DUS-CT registration test on both phantoms showed 76% of the trials have aregistration error within 2.0 mm. The average FRE was (1.7±0.2) mm.Table 4.3: Measurements of Registration Accuracy on Gel Breast PhantomsTRE (mm) FRE (mm)Elevational Lateral Axial TotalAve±SD 0.5±1.1 -0.7±1.0 -0.6±1.1 1.9±0.81.7±0.2Trial with the Maximum Error 3.3 -0.5 -3.1 4.6Number of trials with TRE<2 mm 19/25 (76%)66(a) (b)(c)Figure 4.11: Axial view (a), sagittal view (b), and coronal view (c) of the CT (red) and 3DUS(grey) registered images of a gel breast phantom with a water-filled balloon inside,the blue contours being the balloon in CT images, and the almond contours being theballoon in 3DUS images.4.2.5 3DUS Scanner Positioning Limits TestRegistration tests with the 3DUS scanner on different breast quadrants showed similar results(Table 4.4) and an average registration error of (2.5±0.8) mm was calculated. While moving thescanner position from the breast centre to different quadrants, the uncertainties in the lateral di-rection increased from (0.7±1.0) mm to (1.6±1.2) mm, and in the axial direction increased from(0.6±1.1) mm to (-1.1±1.1) mm.67Table 4.4: Measurements of TRE (Ave ± SD) with the Scanner Placed on Different BreastQuadrantsAverage Error for All Breast QuadrantsQuadrant TRE (mm) Elevational (mm) Lateral (mm) Axial (mm) Total (mm)1 2.6±0.40.5±0.5 −1.6±1.2 −1.1±1.1 2.5±0.82 2.2±0.23 2.0±0.34 3.0±1.34.2.6 DICOM Files Sagittal/Axial Writing TestThe registration accuracy was comparable writing the DICOM files in sagittal or axial viewswith the 3DUS scanner orientation 15◦ < θ < 40◦. However, a difference on the registration errorcan be seen with θ < 40◦. To quantify the point-based registration performance, FRE and TREwere both calculated for all 9 trials where the scanner orientation θ < 15◦, shown in Table 4.5.An obvious positive correlation can be seen between FRE and TRE. When using sagittal views,the FRE was (4.2±3.1) mm, while it was (1.7±0.2) mm with axial images. This means that thecorresponding landmarks were not matched perfectly when the images imported were sagittal views.With a reduced FRE, the landmark matching was improved when importing axial views, and itbrought the TRE down to (2.3±1.0) mm, compared to (10.2±8.7) mm when importing sagittalviews. The 3DUS scanner orientation θ (see Figure 4.8) was also recorded for each trial. As θ gotsmaller, the registration error increased significantly with sagittal images, while stayed relativelystable with axial images.68Table 4.5: Measurements of Registration Accuracy Using Sagittal Views and Axial Views of3DUS ImagesTrial # Angle θ (◦)Import Sagittal Views Import Axial ViewsFRE(mm) TRE(mm) FRE(mm) TRE(mm)1 0 11.5 31.6 1.7 2.32 6 6.9 14.1 1.6 1.33 6 2.4 13.1 1.3 4.74 7 2.5 9.9 1.8 2.95 8 3.7 5.1 1.9 1.36 9 5.3 9.8 2.0 1.27 12 2 2.8 2.0 2.68 13 1.7 1.3 1.7 1.99 15 1.9 3.9 1.5 2.1Ave 4.2 10.2 1.7 2.3SD 3.1 8.7 0.2 1.04.3 DiscussionsThrough the point-based registration method developed here, PBSI 3DUS images can be regis-tered to CT images with an error of (1.9± 0.8) mm. This work facilitates integrating 3DUS intoPBSI planning procedure. Some basic guidelines should be followed during the registration processto minimize the registration error and will be discussed below.4.3.1 Landmark Configuration and 3D-printed Model PositionDifferent landmark configurations will influence the registration error. The 3D-printed model wasdesigned to provide landmarks in both 3DUS and CT Images. In 3DUS, the landmark locations aremechanically tracked by an encoder, while in CT, the landmarks are visualized by CT-visible pelletsthat are manually placed on the 3D-printed model.69Shown in Figure 4.3, landmarks in configuration A are spread in a coplanar geometry, relativeto configuration B/C. The vertical arrangement of the landmarks only covers 3 cm and it results ina larger vertical (axial direction in 3DUS imaging system) registration error compared to the othertwo configurations. Configuration B and C both improved the landmark geometry by being lesscoplanar. However, because only 4 landmarks are used in configuration B, the human uncertaintywhen placing the CT-visible pellets on the model becomes crucial to the registration error. Relativelylarger uncertainties are seen in all directions in configuration B. In configuration C, 8 non-coplanarlandmarks are used to minimize the human uncertainty when placing CT-visible pellets, bringingthe registration error down to (1.8±0.8) mm.During the registration process, the 3D-printed model location and orientation should alwaysbe adjusted to be as orthogonal to the imaging system as possible, so that the landmarks are lesscoplanar in the 3DUS coordinate system (Illustrated in Figure 4.12). Special attention should alsobe paid when positioning the 3D-printed model to avoid collision with CT gantry.(a) (b)Figure 4.12: (a) An illustration when the 3D-printed model is placed orthogonal to the 3DUScoordinate system; (b) An illustration when the 3D-printed model is not placed orthog-onal to the 3DUS image coordinate system.4.3.2 3DUS Scanner PositioningThe 3DUS scanner has some limits on the scanning position and orientation. The arm that holdsthe 3DUS scanner can lock the scanners position to stabilize it for image acquisition as long as thevertical tilt is less than 10◦ and the lateral rotation is within 40◦. When the US unit and 3DUS cartare set-up beside the CT couch, the scanner orientation shown in Figure 4.5b (0◦ < θ < 40◦) isrecommended so that the scanner can be locked in position with the mechanical arm able to track70all the landmark divots. It is also recommended to place the scanner on the anterior surface withthe target close to the imaging centre. When imaging from a quadrant not centred on the target, thetarget (seroma) is usually far from the imaging centre and extra gel needs to be applied betweenthe breast skin and the 3DUS TPX plate to obtain good image quality. More human interactionis needed during the 3DUS scanner positioning and scanning, and the registration error is slightlylarger compared to that where the scanner is placed so that the target is near the image centre.4.3.3 DICOM Files Sagittal/Axial WritingWhen performing the point-based registration in MIM Symphony, a primary image set was se-lected, and the secondary image volume could be translated and rotated to match the landmarklocations. However, reducing the extent to which the secondary image volume needed to be trans-lated and rotated, increases the registration accuracy. This is illustrated in Figure 4.8, which displaysa top view of two image sets. When axial images were used, the whole image volume needed tobe rotated by θ ◦ to match the CT image orientation. When sagittal images were used, the 3DUSimage volume needed to be rotated by (90−θ)◦. A reasonable hypothesis is that, as θ approaches90◦, because of the limited size of the landmarks on the image pixel matrix, some pixel informationmight get lost during the imaging reconstruction while performing the registration, thus ended upwith a larger registration error.While positioning the 3DUS scanner, the scanner orientation should be recorded for future ref-erence. When the lateral rotation angle θ < 15◦ (see Figure 4.5b), the 3DUS images should beimported into MIM Symphony from axial view, to achieve a more precise point-based registration.To be prudent, it is also recommended to record the landmark locations from both image sets andcalculate FRE to ensure the point-based registration is performed properly.To summarize, the 3DUS scanner should be placed as close as possible to the imaging target whenscanning, with a vertical tilt less than 10◦ and lateral rotation less than 40◦ , shown in Figure 4.5b.A special-designed 3D-printed model is used during the registration process. The model shouldbe fixed on the breast board and the orientation should be adjusted to be as orthogonal as possibleto the 3DUS imaging volume. Eight landmarks are used to perform a point-based registration inMIM Symphony and FRE is recommended to be calculated to verify the success of the point-basedregistration. The workflow in Figure 4.1 should be followed for 3DUS-CT registration and the71average registration error is (1.9±0.8) mm.72Chapter 5ConclusionPBSI is a novel brachytherapy technique for early-stage breast cancer patients. A prototype 3DUSsystem developed for PBSI was commissioned and a QA procedure was established with baselines.A method was developed to achieve rigid registration of 3DUS images and CT images. The 3DUS-CT registration was tested on anthropomorphic gel breast phantoms and the average registrationerror was (1.9±0.8) mm. The 3DUS system showed potential to provide improved visualizationand surgical guidance for PBSI planning and delivery. This thesis facilitates the implementation ofthe 3DUS system in current PBSI clinical workflow.5.1 Future WorkThe basic workflow for 3DUS-CT registration has been built and proven to be feasible on phan-toms. However, human interaction is required when importing corresponding images, contouringlandmarks and performing point-based registration in current workflow, which may impact regis-tration accuracy. Automation of the registration process should be attempted to simplify the clini-cal procedure and to minimize possible human errors. The automation process may include auto-contouring the landmarks and building automated workflows in MIM Symphony to auto-import filesand perform registration.Some preliminary results were presented on 3DUS-CT registration using commercial and home-made gel phantoms. To clinically validate the process and incorporate the 3DUS scanning into thecurrent clinical workflow, review and approval by an Research Ethics Board (REB) are required.73Clinical trials for 3DUS scanning should be initiated after the REB approval. Further adjustmentshould then be made based on the feasibility to perform the registration on patients and to utilize3DUS clinical images. Further clinical limitations of the 3DUS-CT imaging and registration shouldbe explored. QA procedures should also be established for rigid 3DUS-CT registration.The 3DUS system has shown potential on imaging and visual guidance for PBSI planning anddelivery. Possibilities should also be explored for the 3DUS use in the OR during PBSI implantprocedure.74Bibliography[1] Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-yearbreast cancer death: meta-analysis of individual patient data for 10 801 women in 17randomised trials. The Lancet, 378(9804):1707–1716, Nov. 2011.doi:10.1016/s0140-6736(11)61629-2. URL https://doi.org/10.1016/s0140-6736(11)61629-2.→ pages 2, 3[2] Canadian cancer society’s advisory committee on cancer statistics, 2017. URLhttp://www.cancer.ca/en/cancer-information/cancer-type/breast/breast-cancer/?region=bc.Retrieved on 2019-02-20. → page 1[3] Breast cancer: prevention and control, 2018. 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Thesis/Dissertation
eng
Medical Physics
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Rigid registration of 3D ultrasound images and computed tomography images for permanent breast seed implant brachytherapy treatment planning
Text