Science, Irving K. Barber Faculty of (Okanagan)
Computer Science, Mathematics, Physics and Statistics, Department of (Okanagan)
DSpace
UBCO
Kudla-Hooper, Michael William
Doctor of Philosophy - PhD
University of British Columbia
Purpose: Delivering conformal treatment plans for high dose rate (HDR) gynaecological (GYN) brachytherapy (BT) using commercially available applicators can be challenging in many clinical cases. The intent of this work is to describe a treatment technology suite developed to enable treatment customization for patients with difficult-to-treat gynaecological malignancies. Methods: A workflow has been created for the creation of patient-specific cylindrical templates (PSCTs), which facilitate preplanned needle trajectories for interstitial (IS) Vaginal HDR-BT. This includes software for design automation, manufacturing processes, and sterilization. The workflow was evaluated for pre-clinical feasibility, including dosimetry, sterilization, and manufacturing quality. The Tandem and Cylinder (T&C) template has been developed for the treatment of cervical malignancies, and has a standard design which can be customized for difficult treatment cases. Both devices were evaluated in treatment cohorts, assessing preplan reproducibility, treatment dosimetry, outcomes, and practicality. A novel, easy-to-use, and fast software algorithm to generate candidate needle trajectory sets for GYN HDR-BT PSCTs is presented. Auto-planned trajectory set-based preplans were compared to original patient preplans for a retrospective patient cohort. Results: Needle trajectories can be exported directly from treatment planning software and converted into a 3D printable PSCT. PSCTs are shown to be manufactured to a clinical quality, and sterilizable. Prospective treatment plans are shown to be equivalent or improved as compared to highly specialized modern techniques. Both treatment cohorts for both PSCTs and T&C patients showed excellent treatment dosimetry, needle position reproducibility, and outcome. Auto-planner-based preplans were of high clinical quality, were equivalent in dosimetry to manually created preplans, and treatment plan libraries were able to be created very quickly. Conclusions: The technology suite developed during this research can be used to successfully preplan and deliver highly conformal treatment plans for IS GYN HDR-BT. The treatment devices are shown to be reliable and to deliver preplans accurately, and to be easy-to-use, compared to traditional treatment techniques. The autoplanning software significantly eases the pre-planning process of the PSCT, without loss of plan quality. This technology suite represents a significant step forward in the personalization of GYN HDR-BT and stands as a platform for future development.
A PATIENT-SPECIFIC TREATMENT TECHNOLOGY SUITE FOR INTERSTITIALGYNAECOLOGICAL BRACHYTHERAPYbyMichael William Kudla-HooperB.Sc., Physics, Walla Walla University, 2014B.Sc., Mechanical Engineering, Walla Walla University, 2014M.Sc., Medical Physics, The University of British Columbia, 2019A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinTHE COLLEGE OF GRADUATE STUDIES(Medical Physics)THE UNIVERSITY OF BRITISH COLUMBIA(Okanagan)©July 2023The following individuals certify that they have read, and recommend to the College of GraduateStudies for acceptance, a thesis/dissertation entitled:A PATIENT-SPECIFIC TREATMENT TECHNOLOGY SUITE FOR INTERSTITIALGYNAECOLOGICAL BRACHYTHERAPYsubmitted by Michael William Kudla-Hooper in partial fulfillment of the requirements of the degreeof Doctor of Philosophy.Andrew Jirasek, Ph.D., IKBSAS - PhysicsSupervisorDeidre Batchelar, Ph.D., IKBSAS - Physics & BC Cancer KelownaCo-SupervisorTony Teke, Ph.D., IKBSAS - Physics & BC Cancer KelownaSupervisory Committee MemberAlex Hill, Ph.D., IKBSAS - PhysicsSupervisory Committee MemberKlaske van Heusden, Ph.D., School of EngineeringUniversity ExaminerGeetha Menon, Ph.D., University of AlbertaExternal ExamineriiAbstractPurpose: Delivering conformal treatment plans for high dose rate (HDR) gynaecological (GYN)brachytherapy (BT) using commercially available applicators can be challenging in many clinical cases.The intent of this work is to describe a treatment technology suite developed to enable treatmentcustomization for patients with difficult-to-treat gynaecological malignancies.Methods: A workflow has been created for the creation of the patient-specific cylindrical template(PSCT), a novel treatment device, which facilitates preplanned needle trajectories for interstitial (IS)Vaginal HDR-BT. This novel workflow includes software for design automation, manufacturing pro-cesses, and sterilization. The workflow was evaluated for pre-clinical feasibility, including dosimetry,sterilization, and manufacturing quality.The novel Tandem and Cylinder (T&C) template has been developed for the treatment of cervicalmalignancies, and has a standard design which can be customized for difficult treatment cases.Both devices were evaluated in treatment cohorts, assessing preplan reproducibility, treatmentdosimetry, outcomes, and practicality.A novel, easy-to-use, and fast software algorithm to generate candidate needle trajectory sets forGYN HDR-BT PSCTs is presented. Auto-planned trajectory set-based preplans were compared tooriginal patient preplans for a retrospective patient cohort.Results: Needle trajectories can be exported directly from treatment planning software and con-verted into a 3D printable PSCT. PSCTs are shown to be manufactured to a clinical quality, andsterilizable. Prospective treatment plans are shown to be equivalent or improved as compared to highlyspecialized modern techniques. Both treatment cohorts for both PSCTs and T&C patients showedexcellent treatment dosimetry, needle position reproducibility, and outcome. Auto-planner-based pre-plans were of high clinical quality, were equivalent in dosimetry to manually created preplans, andtreatment plan libraries were able to be created very quickly.Conclusions: The technology suite developed during this research can be used to successfullypreplan and deliver highly conformal treatment plans for IS GYN HDR-BT. The treatment devices areshown to be reliable and to deliver preplans accurately, and to be easy-to-use, compared to traditionaltreatment techniques. The autoplanning software significantly eases the pre-planning process of thePSCT, without loss of plan quality. This technology suite represents a significant step forward in thepersonalization of GYN HDR-BT and stands as a platform for future development.iiiLay SummaryThis study focuses on a technique for treating certain types of gynaecological cancer using radiationsources placed in the body. Delivering this type of treatment can be difficult in some cases, so we havedeveloped tools to help customize the treatment for each patient.We created a software and workflow for making treatment templates, which make it easier to planwhere to place the needles that deliver the radiation. We also developed an algorithm that can quicklygenerate a list of possible needle paths to consider.We tested these tools on groups of patients and found that the treatment plans as good as plansmade using traditional techniques, but the treatments were easier and faster.This technology represents a step forward in personalizing the treatment of gynaecological cancersmaking it easier and faster to create treatment plans that are tailored to each patient’s individualneeds, with excellent treatment quality.ivPrefaceWhile this dissertation is Michael Kudla-Hooper’s Ph.D. work, many important contributions weremade by different collaborators. This preface outlines the work done by Michael Kudla and the workdone by collaborators.This manuscript was written by Michael Kudla-Hooper and reviewed by Dr. Deidre Batchelar andDr. Tony Teke.The last section of Chapter 2 is largely consisting of a paper submitted and published in the journalBrachytherapy. The original idea for a PSCT was a collaboration between Dr. Deidre Bachelar andDr. Francois Bachand, which was given to Michael for his MSc. project. Michael designed thevarious studies, wrote all software, generated all figures and tables, drafted all text, and drafted theREB application with Deidre Batchelar’s supervision and edits where needed. Michael developed all3D printing processes. Manufacturing of PSCTs was performed by Michael Kudla in most cases,although once the program became clinical both Dr. Deidre Batchelar and Mark Robinson did some3D printing when Michael was not available. Mark Robinson performed all machining. Michael andDeidre performed the PEEK dosimetry evaluation together after Michael designed the experiment.Michael worked with Nelson Labs and various PHSA and KGH personnel to develop a suitable MIFUfor sterilization of the templates, with Dr. Batchelar’s supervision.The original concept from Chapter 3 was for a tandem and ring-style device which Dr. DeidreBatchelar, Dr. Francois Bachand, and Dr. Jocelyn Moore conceived. Michael came up with the ideato include a tandem in a cylinder which would make the insertion process significantly easier. Designof the cylinders, proof of concepts, 3D printing, manuscript writing, data analysis, figure generation,and table generation were performed by Michael Kudla, with review and edits from Dr. Batchelar.This work is in preparation for submission.The idea for auto-planning software, Chapter 4, is a natural extension of the PSCT work, whichwas discussed by Michael and Dr. Batchelar during Michael’s MSc. work. The REV-CVT algorithmis Michael’s conception and design, though its development was significantly helped through talks withDr. Tony Teke. Michael did all algorithm design, coding, writing, figure generation, data analysis,and table generation. Dr. Teke and Dr. Batchelar contributed edits to the final manuscript.This work was completed under three UBC research ethics board approvals, one for Chapter 1, andone for Chapters 2 and 4:v- H20-01503 - PSCT Testing (Chapter 1)- H19-00723 - Evaluation of Patient-Specific Brachytherapy Templates (Chapters 2 and 4)viTable of ContentsContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiLay Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ivPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vTable of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viiList of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ixList of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xList of Algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiList of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xivAcknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 The Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Gynaecological Malignancies and Their Treatment . . . . . . . . . . . . . . . . . . . . . 11.3 Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.4 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.1 Clinical High Dose Rate Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.2 3D Printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132.3 Patient Specific Treatment Templates for GYN HDR-BT . . . . . . . . . . . . . . . . . 152.4 Needle Path Planning for Patient-Specific GYN HDR-BT . . . . . . . . . . . . . . . . . 183 Development and Clinical Readiness of PSCTs . . . . . . . . . . . . . . . . . . . . . 203.1 PSCT Modeling Software . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203.2 Manufacturing and Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213.3 Template Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233.4 3D Printed PEEK Dose Attenuation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243.5 Preplanning Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383.7 Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384 Clinical Evaluation of PSCTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394.2 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Development and Clinical Evaluation of Tandem and Cylinder Templates . . . . . 525.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525.2 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666 An Autoplanning Tool for 3D Printable Patient Specific Cylindrical Templates . 676.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676.2 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836.6 Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84vii7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857.1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857.2 Impact of the Thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867.3 Limitations of the Thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867.4 Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Appendix B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Appendix C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105viiiList of Tables1 PSCT Preplan - Previously Treated Patient Details . . . . . . . . . . . . . . . . . . . . . 292 Retrospective Preplan vs. Treated PSCT Dosimetry . . . . . . . . . . . . . . . . . . . . 343 PSCT Treated Patient Details . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 PSCT-Treated Dosimetric Indices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 PSCT Preplan to Final Plan Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 PSCT Needle and Dwell Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 PSCT Treatment Clinical Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488 T&C Patient Diagnosis and Treatment Details . . . . . . . . . . . . . . . . . . . . . . . 579 T&C treated indices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6110 T&C preplan to final plan dosimetry differences . . . . . . . . . . . . . . . . . . . . . . . 6211 T&C preplan to final plan needle positions comparison . . . . . . . . . . . . . . . . . . . 6312 T&C Treatment Clinical Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6413 Manual and autoplan needle counts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7914 Autoplan dosimetric indices for each patient. . . . . . . . . . . . . . . . . . . . . . . . . 7915 Preplan differences between autoplan and manual preplan. . . . . . . . . . . . . . . . . . 80ixList of Figures1 HDR-BT Source Diagram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 HDR-BT Afterloader . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Dose Representation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 IC GYN Brachytherapy Applicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 IS GYN Brachytherapy Applicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 3D Printing Example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Prospective PSCTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 3D Printed PSCT Example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Dosimetry Test Diagram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2510 Dosimetry Test Setup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2611 PEEK Dosimetry Plot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2712 Challenges of Treating Vaginal Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2813 PSCT Plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3214 PSCT DVHs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3315 PSCT Preplan and 3D Print . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4316 PSCT Preplan and Final Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4517 HR-CTV and Organ at Risk DVHs shown for each patient. . . . . . . . . . . . . . . . . 4618 Cervical BT Dose Distributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5419 T&C Configurations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5620 T&C Preplan and Print . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5821 T&C Treated DVHs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6122 T&C preplan and final plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6223 T&C preplan and final plan DVHs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6324 Surface-Based CVT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7025 REV-CVT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7226 Angle and length corrections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7327 Path to Cylinder Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7528 Straight needle addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7529 Manually created plan and autoplan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7830 Autoplan and preplan DVHs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81xList of Algorithms1 Regression-based Expanding Volume Centroidal Voronoi Tesselation. . . . . . . . . . . . 74xiList of Abbreviations3D Three-Dimensional Ultrasound3DUS Three-Dimensional UltrasoundAAPM American Association of Physicists in MedicineABS Acrylonitrile Butadiene StyreneAP Anterior-PosteriorAPI Application Programming InterfaceBC British ColumbiaBT BrachytherapyCAD Computer-Aided DesignCOMP Canadian Organization of Medical PhysicistsCT Computed TomographyCTCAE Common Terminology Criteria for Adverse EventsCTV Clinical Target VolumeCVT Centroidal Voronoi TesselationD2cm3 Minimum dose to maximally irradiated 2cm3D90 Minimum dose received by 90% of the target volumeDICOM Digital Imaging and Communications in MedicineDVH Dose-Volume HistogramEBRT External Beam Radiation TherapyEEA Endometrial Endometrioid AdenocarcinomaEMBRACE European Study on MRI-guided Brachytherapy in Locally Advanced Cervical CancerEQD2 Equivalent Dose in 2-Gy FractionsFDM Fused Deposition ModellingGPU Graphics Processing UnitGTV Gross Tumor VolumeGUI Graphical User InterfaceGy Gray (1 Joule Per Kilogram)GYN GynaecologicalHDR High Dose RatexiiHR-CTV High-Risk Clinical Target VolumeHIPO Hybrid Inverse Planning OptimizationHPV Human PapillomavirusIC IntracavitaryIGABT Image Guided Adaptive RadiotherapyIQR Interquartile RangeIr-192 Iridium-192IS InterstitialKGH Kelowna General HospitalLDR Low Dose RateLMIC Low and Middle-Income CountriesMIFU Manufacturers Instructions for UseMR Magnetic ResonanceMRI Magnetic Resonance ImagingMV MegavoltageOP Optimization ProblemOR Operating RoomPEEK PolyetheretherketonePEI PolyetherimidePHSA Provincial Health Services AuthorityPLA Polylactic AcidPS Patient-SpecificPSCT Patient-Specific Cylindrical TemplatePST&C Patient-Specific Tandem and CylinderRAM Random Access MemoryREB Research Ethics BoardREC Recurrent Endometrial CancerREV Regression-based Expanding VolumeRO Radiation OncologistRRT Rapidly Expanding Random TreesRSCC Recurrent Squamous Cell CarcinomaxiiiRT Radiation TherapySA Simulated AnnealingSABR Stereotactic Ablative Body RadiotherapySB Surface-BasedSCC Squamous Cell CarcinomaSCO Sequential Convex OptimizationSTL Standard Tessellation LanguageT&C Tandem and CylinderT&R Tandem and RingTG Task GroupTPS Treatment Planning SystemUBC University of British ColumbiaUS UltrasoundV100 Volume of tissue receiving 100% of prescribed doseV125 Volume of tissue receiving 125% of prescribed doseV150 Volume of tissue receiving 150% of prescribed doseV200 Volume of tissue receiving 200% of prescribed doseVA Vaginal AdenocarcinomaxivAcknowledgementsTo my wife Corrina. I don’t think I’ll ever meet someone more dedicated and hard-working as youare. You are a model for routine, excellence, and perseverance. You inspire me every day in how youtake care of Tobi, in your organization, your positive attitude, and your ability to make me feel lovedand wanted. Sharing my successes and frustrations with you through this project has made it all themore worthwhile. I feel so grateful we get to share a lifetime of successes and adventures together.Deidre, over the course of many long conversations I’ve come to appreciate and attempt to replicateyour practical, thoughtful, step-by-step approach to research. You’ve kept me appropriately groundedwhile encouraging me to pursue whichever directions and challenges I was interested in. Your honesty,humility, self-knowing, and self-care inspire me to be more reflective and caring to myself and others.Your ability to laugh and cultivate humorous memes at the mishaps that come along the journey havemade the hard moments pass quickly. Thank you for everything.Tony, your caring attention to my needs and interests, flexibility, and constant positivity andmentorship have made for a delightful collaboration. There are few people in one’s life with whom onecan have a highly technical conversation, fill it with jokes and laughs, and still not lose interest or theplot of the conversation. The depth of conversation we can have in the space of a 5-minute hallwayconversation is something I hope we can continue in the years ahead. And of course beers. Many morebeers.Andrew, I’m constantly impressed by your steady unassuming leadership, excellent responsiveness,and simultaneous professionalism with a laid-back vibe. You told me once that it was all injuryprevention after age 30. Unfortunately, you’re absolutely right. I hope we can get out on the ski andbike trails together many more times before the injuries take over.Dr. Alex Hill, thank you for taking an interest in my project and for taking the time to understandthe relevant background information in order to give high-quality feedback in a field in which you hadlimited expertise when you joined my committee. I will always appreciate it.To my mom, Sandra Kudla. You’ve helped me through so much through my studies over the yearsit’s really impossible to overstate how much you’ve helped me. Our relationship has developed intoone of my most meaningful and sharing time together, though far apart, is one of the happiest andmost grounding things I do. Thank you for your constant support and thank you for everything you’vegiven me.xvClaire Zhang, sharing our MSc. and Ph.D. time together has been amazing. Thank you for yoursupport, listening, and collaboration. You’ve grown into a close friend like a sister and you’ll alwayshave a special place in my heart. Thank you so much for saving me in 2022 by giving my presentationat COMP when I was so sick I couldn’t leave my bed! I know you’ll have a great time in Michigan,they’re very lucky to have you!Mark Robinson, you are one of the most valuable individuals at our cancer center. Your jovialattitude and your quick wits have made for some of the most enjoyable times I’ve spent in any workingenvironment. Working with you doesn’t feel like work, we’re always having a blast together solvingsome problem. In your retirement, I hope the wind is always at your back. I will always be at yourbeck and call to reef, hoist, and haul!xvi1 IntroductionThis chapter serves as a primer for the reader to understand the general directions of this dis-sertation including the problems that the research attempted to address, contextual information onthose problems, and an overview of the research directions. More in-depth background can be foundin Chapter 2, and the research details can be found in Chapters 3 through 6.1.1 The ProblemEffective treatment of certain gynaecological malignancies requires radiation sources to be im-planted near or within tumours, a form of radiation therapy known as brachytherapy. This is oftenchallenging due to the range of tumour locations and morphologies. Radiation source locations canbe planned on medical images, though access to the necessary imaging technologies is limited in manycenters. Implantation itself is a challenging and specialized task. While commercial treatment de-vices are available to assist the implantation process, they are expensive and do not always facilitatepatient-specific interstitial (IS) (within the tissue) source placements well. This research is focusedon the development of a low-resource patient-specific gynaecological brachytherapy technology suite.This technology suite can make high-quality treatment planning, treatment delivery, treatment opti-mization, and 3D imaging accessible to all cancer centers, including the lowest resource, and highestworkload centers in the world.1.2 Gynaecological Malignancies and Their TreatmentGynaecological cancers include cancers of the vulva, vagina, cervix, uterus, ovaries, and fallopiantubes [1]. Risk factors for these cancers include obesity, hypertension, use of estrogen without proges-terone, and Human Papillomavirus (HPV) infection [1]. This section briefly describes the cancer typesfor which the innovations developed for this thesis are intended.1.2.1 Vaginal CancerCancers of the vagina include primary vaginal cancer, vaginal metastases, and recurrences of othergynaecological malignancies in the vagina. Metastases constitute most vaginal malignancies and mostcommonly arise from cancers of the endometrium, cervix, and ovary, though they can come fromcancers of the breast, rectum, and pancreas as well. The most common non-metastatic vaginal cancers1include recurrent endometrial cancer and primary vaginal cancer [2]. Primary or metastatic vaginalcancer can occur anywhere in the vagina [3]. Endometrial cancers are typically treated by hysterectomy,with adjuvant radiotherapy and/or chemotherapy [4]. While hysterectomy is intended to be curative,endometrial cancer will recur in up to 30% of patients [5], commonly in the vagina.Specific treatment options for vaginal cancer depend on the disease staging, but radiation therapy isa commonly used component of the treatment plan. For the lowest stages this may be brachytherapyalone, with external beam radiotherapy and chemotherapy added to treat more extensive disease.Local expertise often drives treatment options, as proficiency in the advanced brachytherapy techniquesneeded to create large tumours requires substantial expertise. Thus, institutional practices in treatmentcan vary substantially. Although many women are well served by standard techniques, there is a subsetwho are very difficult to treat due to tumour location or morphology.1.2.2 Cervical CancerCervical cancer is the fourth most common cause of cancer in women globally, and has the fourthhighest mortality rate for cancers in women [6]. Approximately 570,000 cases and 311,000 deathsfrom cervical cancer occurred in 2018 [7], and approximately 604,000 cases and 342,000 deaths wereexpected in 2020 [6]. Cervical cancer is treated using surgery, external beam radiation therapy (EBRT),brachytherapy (BT), and chemotherapy [6]. Hysterectomy is preferred for the lowest stage of cervicalcancer when the disease is confined within the cervix. All other stages receive EBRT concurrent withcisplatinum-based chemotherapy, with BT after or during the final week(s) of EBRT [8]. High DoseRate Brachytherapy (HDR-BT) is standard-of-care in the treatment of cervical cancer [9], [10].1.3 BrachytherapyBrachytherapy involves the use of radioactive isotopes emitting ionizing radiation which can belethal to human cells. Brachytherapy radiation sources typically come as small seed-like sources.Broadly, these sources can be divided into two categories: low dose rate (LDR) sources, which aretypically low activity and low energy sources, and HDR sources, which are high energy and highactivity sources. For this work, HDR-BT is the focus. The most common HDR-BT sources are madeof Iridium-192. The source is welded to a wire which is a component of a robotic device called anafterloader. The afterloader stores the source in a tungsten safe and can be programmed to drive thesource wire to predetermined positions (dwell positions), each for a predetermined time (dwell time),2inside brachytherapy applicators. These applicators are either devices with small channel/channelsthrough them or catheters/needles which can be placed inside or around a tumour. The generalprocess of a BT treatment is as follows: One or multiple treatment applicators are inserted to thevagina, cervix, or into tissue directly. The applicator is secured in place, and then imaging techniquessuch as Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) are used to confirm thatit is properly positioned. The treatment target volume is identified on postoperative images, and dwelltime planning is performed. Once the dwell time planning is completed, the BT plan is deliveredby transiting the radioactive source to each dwell position, for each planned dwell time. After thetreatment of radiation has been delivered, the source is moved back into the afterloader safe and theapplicator is taken out. Brachytherapy can be used successfully for treatment of many cervical andvaginal tumours.For cases with more extensive disease, BT becomes more difficult to perform, and IS needles areoften required to treat the tumour adequately. This is because high dwell times are required to treatentire large tumours from within IS applicators, which results in too-high organ doses. Needles arerequired, to assist in placing the sources directly within the tumour, so that the BT dose can coverthe tumour while sparing organ tissue. While there are a variety of “one-size-fits-all” IC/IS applicatoroptions available, most centers have limited different applicators at their disposal, reducing the clinicalpracticality of patient-specific source placement. These commercial applicators are expensive (on theorder of 5k-50k USD) and have a limited clinical lifetime due to having a limit on the number of ster-ilization cycles they can undergo (typically 100-300 cycles). Deciding where to put the sources (eitherin an IS needle or inside a specialized treatment applicator) can be difficult due to the multivariatenature of the problem. In most cases, no dose-based preplanning is done before the applicator inser-tion. The radiation oncologist will review pre-operative imaging and develop a best guess as to wherethe applicators should be placed and will manually verify the position of the tumour during insertion.Accurate placement of IS needles exactly is also challenging, requiring significant expertise on the partof the implanting radiation oncologist. Additionally, commonly only ultrasound (US) is available forintraoperative image guidance. US provides a limited field of view and is typically performed freehandwithout an ultrasonographer, making real-time guidance of multiple needles a demanding task.31.4 Overview1.4.1 Patient Specific Brachytherapy Templates for Cervical and Vaginal CancersPrototype vaginal patient-specific cylindrical templates (PSCTs) which are able to facilitate accu-rate placement of IS brachytherapy applicators for vaginal lesions were developed previously [11], buthad not been clinically tested.The objective of this project was to continue the development of PSCTs through clinical imple-mentation and to develop and clinically implement a template for the treatment of cervical cancers,the tandem and cylinder (T&C) template. These are both patient-specific, 3D printable, intracavitary(IC) / IS brachytherapy templates which guide IS needles to preplanned locations within the vaginaand/or cervix.For the PSCT, 3D modelling automation software interfaces with commercial BT treatment plan-ning software, allowing for treatment pre-plans to be exported directly from the planning software.PSCTs were tested by running simulation treatments assessing physical functionality and preplanningcapabilities.The T&C devices are designed as “standard” devices, which then can be customized as neededusing the aforementioned 3D modelling automation software.Both devices have been used clinically and retrospective clinical follow-up data have been collectedfor both the vaginal and cervical treatment cohorts. In both cases, it has been demonstrated that thedevices result in IS implants that closely match the intended preplan and deliver high-quality, effectiveIC/IS GYN HDR-BT treatments.1.4.2 IC/IS Needle Trajectory and Dwell Time OptimizationThe objective of this work was to develop an optimization algorithm which will propose needletrajectory sets for PSCTs. A novel, easy-to-use, and fast method to generate candidate needle tra-jectory sets for GYN HDR-BT PSCTs is presented, and auto-planned trajectory set-based preplansare evaluated for a retrospective patient cohort. A library of treatment pre-plan needle trajectory setswas generated for each patient. Treatment preplans are created for each patient and compared to eachpatient’s original preplan.The resultant solutions of this algorithm present the planner with a library of planned needle4trajectories from which to select, which allows the clinician to evaluate multiple results at once, andselect the best option for their patient, weighing coverage, toxicity, and IS length trade-offs. Themethod was shown to generate needle trajectory sets for PSCT preplans which are dosimetricallyequivalent to manually created preplans by clinical experts, in significantly less time. This allows forthe creation of high-quality, robust, patient-specific templates in a short clinical time frame.52 BackgroundThe background for this dissertation overviews the clinical tools and processes typically used forGYN HDR-BT, 3D printing as it relates to this project, the background on patient-specific treatmenttemplates for GYN HDR-BT, and the state-of-the-art in attempts to automate the design of needletrajectories for GYN and prostate HDR-BT.2.1 Clinical High Dose Rate BrachytherapyThis subsection describes the clinical devices and workflow used to perform HDR-BT in the clinicalsetting.2.1.1 Source and AfterloaderRadiation sources for HDR-BT are commonly comprised of Iridium-192 (Ir-192). Ir-192 has a half-life of 73.83 days, and decays by electron capture decay modes (∼5% of all Ir-192 decays), and betaminus decay modes (∼95%). Electrons are emitted from the HDR-BT source with kinetic energies upto 0.668 MeV [12]. After either of these decay modes occurs, a series of nuclear particle rearrangementsoccur, emitting a series of photons. Many photons are emitted after both decay modes, with an energyrange of 0.136 to 1.379 MeV with an effective energy of 0.38 MeV [13].Ir-192 sources are approximately cylindrical in shape, on the order of 4mm in length and 1mmin diameter, and are welded to a guide wire (Figure 1). For treatment, one or more applicators (seeSection 2.1.3) are inserted into the tumour tissue or a nearby body cavity. The source is transited toplanned positions within treatment applicators via the guide wire. The source and guide wire positionsare controlled by a robotic device called an afterloader (Figure 2). Guide tubing exits the afterloaderat each channel and is connected to applicators and used to guide the source to the applicators. TheHDR source is transited by the afterloader device into each applicator/channel to preplanned positionsfor preplanned dwell times in order to deliver the intended cumulative dose to the region [12].2.1.2 Dose Representation in Gynaecological BrachytherapyColloquially referred to as dose, absorbed dose is defined as the amount of energy deposited byradiation to a unit of mass [13]. Dose is measured in units of Gray (Gy), defined as one joule per6Figure 1: Example Ir-192 Brachytherapy source (Varian) used with a HDR afterloader. Dimensionsare approximate.Figure 2: Example Ir-192 Brachytherapy after-loader (Varian Gammamed Plus iX) . Multipleguide tubes are shown exiting the afterloader.7kilogram. Dose is the prescribed quantity to a tumour in radiation therapy and is also used to setOrgans-at-Risk (OARs) limits. The amount of dose which is prescribed to any patient is referencedwhile creating treatment plans for that patient, and while coverage of the target by the prescribeddose is sought for treatment, treatment planners must also consider OAR-specific dose limits [12].Dose calculated from a single source transited to a set of dwell positions can be displayed as 2D dosecontours, a 3D plot, and as dose volume histograms (DVHs) (Figure 3A, B, and C respectively). A DVHshows dose on the independent axis, and volume or fractional volume on the dependent axis. The doseprescription for a tumour and dose limits to OARs can be specified by DVH metrics. For example,for vaginal brachytherapy, the oncologist may prescribe a prescription dose of 25Gy in 5 fractions.Compliance with this prescription in a particular treatment plan can be measured by calculating theminimum dose to at least 90% of the tumour volume (D90), or the percentage of volume receiving atleast 100% of the prescription dose (V100). Similarly, an OAR may have an upper limit on the dosedelivered to the maximally irradiated 2cm3 (D2cm3) of that organ. Often, a cancer clinic will set itsown institutional targets, informed by international best practices, with the intention to maximize thedose to the tumour, while minimizing the dose to OARs.2.1.3 Treatment ApplicatorsVaginal Brachytherapy ApplicatorsStandard intracavitary applicators for vaginal BT are cylindrical in shape and have a single centralchannel. They come in diameters of 2-3.5 cm and variable lengths depending on the vaginal lengthand applicator fixation device. Multi-channel applicators are also commercially available [14]. Thesehave a central channel and 6-8 equally spaced channels arranged circumferentially near the surface ofthe cylinder (Figure 4A).Standard Cervical Brachytherapy ApplicatorsThe standard applicators for cervical brachytherapy include the tandem and ring (Figure 4B) andthe tandem and ovoid applicators(Figure 4C) [14]. The tandem is a narrow tube which is insertedthrough the cervix and into the uterus. Rings are placed at and around the cervix. Ovoids are placedin the lateral vaginal fornices. Different lengths and angles of tandems and different diameters of thering or ovoids are available to match individual patient anatomy.Needles8Figure 3: Example Dose Representation Plots. A: 2D View of Dose Contours. Target volume in blue,100% Prescription Dose in red. 200% Prescription Dose in Yellow. IS Needles and source positions ingreen. B: 3D View of Dose Contours. Target volume in blue. 75% Prescription Dose in Purple. 125%Prescription Dose in Red. IS Needles in green. C: DVH plot. Target volume dose in blue, Rectum inbrown, Bladder in green, Sigmoid bowel in yellow, Small bowel in purple.9Figure 4: Example commercial IC Gynaecologi-cal brachytherapy applicators (Elekta). A: Multi-channel IC vaginal brachytherapy applicator. B:Tandem and Ring applicator. C: Tandem andOvoids applicator. Images used with permission.10Figure 5: Example commercial IS Gynaecologicalbrachytherapy applicators. A: Venezia applicator(Elekta) with interstitial needles and grid template.B: Kelowna grid template (Varian) compatible witha cylinder template. Images used with permission.Flexible plastic BT needles can be freehand implanted into or near tumour tissue and can be guidedby an applicator (Figure 5A). A metallic rod, called an obturator, can also be placed down the center ofthese flexible plastic needles to increase the rigidity for the insertion process. Rigid metallic (stainlesssteel or titanium) BT needles can be used to guide the source after being placed in or near a tumour.Interstitial TemplatesTemplates guide the placement of interstitial (IS) needles. These templates have straight or fixed-angle holes which guide interstitial needles into positions with fixed geometry relative to one another.The Venezia Applicator (Elekta) [15] is a commercial IC/IS applicator for cervical treatment (Figure5A). Grid templates (Figure 5B), such as the Kelowna GYN Template (Varian) [14], can be used aloneor in combination with standard cylinder applicators to guide needles into the perineal tissue to extendalong and beside the vaginal wall, and into the cervix. Needle insertion depths can be the full lengthof the vaginal vault.112.1.4 ImagingMagnetic Resonance Imaging (MRI) and Computed Tomography (CT) imaging are common forpre- and post-procedural treatment evaluation to plan source positions within applicators, and initialapplicator plans. Ultrasound (US) is used intraoperatively to guide applicator placement. MRI isthe imaging modality of choice for gynaecological cancers due to its ability to distinguish normal softtissues and tumours, while CT is preferred for applicator identification. Some modern brachytherapysuites have dedicated MRI machines, though they are currently uncommon, and unaffordable for mosttreatment centres.State-of-the-art treatments for IS vaginal and cervical BT require both pre and post-operativeimaging, most often CT or MRI, in order to ensure that IS needles are inserted to appropriate positionsand to form a treatment plan (determine the dwell times and positions of the radioactive sources) [16],[17]. The high capital and operational costs of CT and MRI machines means that many high-caseload,low-resource centres in low and middle-income countries cannot afford to treat their patients usingmultiple imaging sessions. Since US imaging is significantly less expensive than CT and MRI, it isbeing explored as an alternative treatment planning imaging modality for IS-HDR-BT [18]–[22]2.1.5 Treatment WorkflowFractionationThere is significant variation in fractionation schedules between clinical practices, though thereare consensus guidelines for vaginal [17] and cervical [10] HDR-BT. For vaginal HDR-BT, a commonfractionation schedule is 25Gy delivered in 5 fractions, typically once or twice a day, over the courseof 3 days. In this case, a patient would typically undergo only one insertion if IS needles are used. Acommon fractionation schedule for cervical BT would be 28 Gy delivered in 4 fractions, with treatmentsonce per week. For cervical cases, insertions are performed at the beginning of each treatment day.Physical Exam and Applicator InsertionOn an insertion day, the patient is anesthetized, positioned in dorsal lithotomy, and a physical examis performed by the oncologist. This exam is used to confirm the position of the tumour manually, afterwhich the applicators selected for treatment will be inserted. Additional guidance during insertion canbe provided by trans-abdominal, trans-vaginal, or trans-rectal US imaging.Post-Operative Imaging12Once the insertion procedure is complete, it is necessary to verify the positioning of the applicatorsand/or templates to create a treatment plan based on their positioning. The patient will undergo a CTscan, and these images may be aligned, or registered, to MR images. The MR images can be acquiredwith the implant in place, if MRI-compatible applicators are used.Treatment PlanningTreatment planning is the process through which the parameters required to deliver radiationare determined to preferentially treat the tumour while protecting surrounding normal tissue. Imagestaken as described above are used to delineate targets and critical structures by the treatment planner.In HDR-BT for gynaecological cancers, the target volume is defined as the High-Risk Clinical TargetVolume (HR-CTV), which is the volume considered of having a high risk of local recurrance because ofresidual macroscopic disease. The intent of treatment is to eradicate all residual macroscopic disease.The HR-CTV for cervical cancer includes the entire cervix, as well as presumed extracervical tumourextension [23].The applicators are then identified on the CT images and dwell positions, points within the appli-cator where the source will be programmed to stop, are placed within the applicators. Dwell positionsare typically distributed equidistantly along the source path with 3-5mm spacing (Figure 3A). Thetreatment plan is then devised by varying how long the sources will dwell at each position (the dwelltime).The dose to each point in the volume is calculated to compose a comprehensive simulation of thedose to target volumes and critical structures. For each patient, the treatment plan can be customizeddependent on the treatment volume and OAR geometries. Treatment planning times can take on theorder of an hour or more while the patient waits with the inserted applicators/needles in place.2.2 3D Printing2.2.1 Fused Deposition ModelingFused Deposition Modeling (FDM) (Figure 6) is a type of 3D printing which uses a continuouslyextruded bead of liquid thermoplastic to create a thin slice of material (for example, in an X-Y plane),representing a thin cross-section element of the designed part. In a slice-by-slice (layer-by-layer)manner, the final part is created by printing layers typically uniformly spaced in the third dimension(for example, the Z-direction). The final part exhibits the layered nature of this manufacturing process,13Figure 6: A: 3D printing of a cylinder model. B: Magnified section showing individual layers. Eachlayer is 0.3mm in heightas each print layer is visible on the exterior [24]. A number of factors affect the accuracy, smoothness,and strength of the final printed part [25]. The temperature of the print nozzle is related to thetemperature at which the 3D print material will be heated to as it is deposited. When print nozzlesare too cool, gaps form, while when the print nozzle is too hot, the material can spread too muchon the build plate/bed or even burn. Some commercial systems include nozzle-integrated fluid-basedheat exchanger systems intended to improve temperature homogeneity throughout the nozzle. Thetemperature of the build plate and the material extrusion temperature affects how well the first layerof material adheres to the build plate. Poor adhesion can result in warpage of the final 3D printedmodel since as individual layers cool, they shrink and induce stress on nearby layers. The layer heightof each individual layer directly relates to the smoothness of the final part, since the outer edge of eachbead is curved. The infill percentage relates to the percentage of volume filled with material withinthe final part. A part printed with an infill percentage less than one hundred percent will containinternal, patterned voids, which allow for material and weight savings. Infill percentage can be variedin order to take advantage of weight and strength trade-offs, and to save prototyping costs.142.2.2 High-Temperature Fused Deposition ModelingMany high-temperature (> 250◦C), high-strength, 3D printable thermoplastics (often called “engi-neering thermoplastics”) are commercially available, though they are significantly more expensive 3Dprinting materials than traditional lower temperature, lower strength 3D printing materials such asAcrylonitrile Butadiene Styrene (ABS) or Polylactic Acid (PLA). These materials include PolyetherEther Ketone (PEEK), polyetherimide (PEI), and others. One advantage of using these materials ina brachytherapy context is the fact that they are already used for brachytherapy applicators and theyare known to be steam sterilizable manufacturing material for surgical tools [26].2.2.3 3D Printing for Medical ApplicationsThree-dimensional printing of custom surgical and other clinical tools for medical applications hasexisted since the mid-1990s [24]. Since that time, many hospitals, clinics, and cancer centres havedeveloped their own in-house 3D printing services [24]. In response, the 3D printing industry andacademia have developed a number of clinically important offerings, including sterile 3D printing [26],[27] and custom software for medical applications of 3D printing [28], [29]. Although this industry isgrowing quickly, there remain some important concerns in the field that can act as barriers to entryfor many clinics, such as how and where to set up in-house 3D printing operations, and how muchsterilization validation testing is required, for different applications.2.3 Patient Specific Treatment Templates for GYN HDR-BT2.3.1 RationaleWhile it is possible to preplan (to determine applicator positions, dwell positions, and dwell timesprior to implant) external template-based interstitial needle placements, as well as IC/IS techniques,efforts to do so have been met with limited success [30]–[33]. These preplans are time-consuming tocreate, often require applicator models not widely available in the treatment planning system (TPS)software, and it can be challenging for physicians to replicate the preplanned position of many needlesexactly. Thus, clinical interstitial implants forgo preplanning and due to the difficulties in replicatingpreplanned treatment plans, needle-based treatments are planned on post-procedure imaging. Appli-cators and templates/needles are inserted during the procedure, followed immediately by CT or MRI.The images are registered and contoured, then the source positions and dwell times are finalized within15the applicators in their final position.When the HR-CTV for vaginal brachytherapy is at or extending above the vaginal vault, standardIC/IS applicators can lead to inadequate coverage of the target volume. This is often the case forpatients with recurrent endometrial cancer following hysterectomy. The insertion depth from theperineum to the top of the vagina is >10cm and it is difficult to use image guidance to place needlesabove the vaginal vault. Many commercial cylinders are closed at the top so the source positionsremain within the cylinder. The intra-applicator dwell times required to cover targets with thicknessesof greater than 5mm can result in unacceptably-high OAR doses [34], [35].2.3.2 Patient Specific TemplatesIn efforts to provide patient-specific treatment care, some have demonstrated promise towards beingable to preplan interstitial vaginal and cervical brachytherapy treatments via 3D printed IC and IStemplates [36]–[40]. Lindegaard et al. [36] and Logar et al. [39] each presented a 3D-printed tandemand ring-style device which could guide needles to preplanned positions in the cervix. Wiebe et al.[37] presented an IC vaginal template which could be moulded to the vaginal vault shape. Laan etal. [40] showed a similar IC/IS template. Laan et al. [40], Zhao et al. [38], and Logar et al. [39]each developed IC/IS devices for vaginal brachytherapy. The desire for automation of the modellingof patient-specific IC/IS applicators [36], [39] has been indicated.A custom interstitial vaginal treatment template and an accompanying 3D modelling automationworkflow was developed during the author’s MSc. work [11]. The template was evaluated againstexisting techniques by comparing treatment plans for five patients previously treated using interstitialbrachytherapy, either via freehand or external template techniques.DesignA preliminary design for the Patient Specific Cylindrical Template (PSCT) was created (Figure 7).The PSCT includes tapped boreholes at the base for needle fixation via locking collets. Needles can becurved or straight, and can exit the base of the cylinder in any position. The PSCT can be designedat any diameter, but is typically 2.5 or 3.0 cm in diameter.This design differed from each of the vaginal IC/IS designs of Laan et al. [40], Zhao et al. [38], andLogar et al. [39]. The design of Zhao et al. considered only straight needles (though they could beoblique), and no method of needle fixation was indicated. The design of Logar et al. was very similarin concept, with curved needles, though featured a single locking mechanism, requiring all needles to be16Figure 7: General PSCT workflow. A: PSCT preplan. B: Wireframe CAD modelof the corresponding PSCT. C: 3D-printed PSCT. D: 3D-printed PSCT with nee-dles and colletes inserted.locked together at once. This constrains the needle trajectory options, and adds unnecessary curvatureto the needles. The design of Laan et al. conformed to the vaginal geometry, and was not evaluatedclinically. While the idea of having the vaginal template be conformal to the vaginal geometry wasconsidered, often, the vagina is wider at the top than the bottom, and thus a conformal shape can bedifficult to insert and remove through the vaginal introitus.CodeTwo scripts were written to facilitate the export of PSCT planning geometries from the Brachyvi-sion TPS (Varian Medical Systems) into an independent object representation and to create a 3Dmodel of a PSCT capable of routing the desired needle trajectories. The first script exports andperforms intersection checking, coordinate transformation, and documentation, and the second is astandalone executable which launches an instance of the Solidworks (Dassault Syste`mes) applicationin the background, creates a 3D model of the template, and saves the model to the STL format to be3D printed.Treatment Plan ComparisonsAs a prospective evaluation of this technique, treatment plans for five vaginal cancer patientspreviously treated at BC Cancer–Kelowna with IS-HDR-BT were replanned as if they were to betreated using the PSCT. The plans were compared to the treated plans to explore the potential utility17of the PSCT for these patients. Plans were found to be comparable or improved compared to thetreated plans. An insertion study on gel phantoms to understand the effect of needle placementimperfections on the final treatment plan was also conducted. Though there were needle positionvariations, acceptable simulation treatment plans were able to be created to a plan similar to thepre-insertion plan, by updating the dwell times.2.4 Needle Path Planning for Patient-Specific GYN HDR-BT2.4.1 Intracavitary Needle PlanningFew attempts have been made to automate IC needle trajectory planning for vaginal and/or cervicalbrachytherapy applications [41]–[44]. These optimization techniques are organized around identifyinga needle start and end position or region and determining a trajectory path through an allowabletrajectory space. The optimization problem (OP) is constructed as a linear or quadratic objectivefunction, with linear weighted costs (rather than hard constraints). The objective is typically to findthe shortest and straightest path while being constrained to curvature and intersection limits (such aswith other needles). The OP is then solved using a technique called Sequential Convex Optimization(SCO). This is a linear local optimization technique which can be run many times with randomizedinitial conditions in order to generate a set of possible solutions from which a final solution can beselected.Approaches which use SCO for automated needle trajectory planning in GYN BT applicationsoften do not consider interstitial needle trajectories [41]–[44]. By neglecting the interstitial needles inthe optimization process, the resulting needle trajectories can make achieving the desired treatmentoutcome more difficult, particularly in difficult treatment cases, as the interstitial needles play a criticalrole in delivering the radiation dose to the target region while minimizing damage to the surroundingtissues. Therefore, it is important to consider the interstitial needle trajectories in the optimizationprocess to ensure the best possible treatment plan for the patient.2.4.2 Interstitial Needle PlanningInterstitial brachytherapy needle trajectory planning has been primarily focused on prostate cancerbrachytherapy. Unlike IC planning, ISBT planning for the prostate is typically based on straight needletrajectories, which is a much less complicated planning process. For example, Centroidal VoronoiTessellation (CVT) technique [45] can be used to evenly space needles throughout a grid of potential18needle positions. Alternatively, the Hybrid Inverse Planning Optimization (HIPO) technique employssimulated annealing (SA), a statistical search technique, to minimize a cost function while selectingneedle trajectories, while optimizing dwell times using a gradient-descent-like solver. Other trajectoryplanning algorithms for brachytherapy [46]–[48] and neurosurgery [49] have employed Rapidly-exploringRandom Trees (RRT) to define non-intersecting paths towards predefined endpoints or regions. Whilethese techniques can be fast and produce relatively simple, smooth paths, they have not been appliedto 3D printable, IC/IS GYN patient-specific templates.The interstitial needle planning process for gynaecological brachytherapy is much more complicatedthan for prostate cancer due to two important differences: first, unlike gynaecological cancers, allprostate glands share a common morphology, and second, due to the need to fit many needles intoa small cylindrical space, while avoiding critical structures such as the rectum and bladder. Thisrequires a more advanced planning algorithm that can take into account complex geometries andspatial constraints while focusing on the distribution of needles in the tumour.193 Development and Clinical Readiness of PSCTsThis chapter describes the efforts undertaken to develop PSCTs prior to clinical implementation.The progress leading up to this is first outlined for context, and that is followed by a description ofthe manufacturing processes developed for PSCTs, then the clinical sterilization validation, dosimetricimpacts of using a 3D printed material, and finally a prospective pre-planning evaluation study whichexplores the potential benefits of using such a device. Subsections 3.1, 3.2, 3.3, and 3.5 are accepted forpublication as “Patient-specific cylinder templates for hybrid interstitial vaginal brachytherapy: Feasi-bility of automated 3-D design, 3D printing, and dosimetric outlook” [50] in the journal Brachytherapy.The chapter is sectioned by the separate clinical implementation and validation tasks, rather than thetraditional scientific order of Methods, Results, Discussion, to improve the readability of the individualvalidation tasks.3.1 PSCT Modeling Software3.1.1 Previous WorkAs discussed in Chapter 2, software was created previously [11] to automate the PSCT designfor 3D printing based on manually developed preplans. A script written using the Eclipse ScriptingApplication Programming Interface (Varian) exports needle geometries, verifies no needles intersect,and models the cylindrical template. Users can input needle-channel diameter, cylinder diameter andoverall length. A standalone application was created to take this exported information and generatean STL file for 3D printing by interfacing with Solidworks (Dassault Syste`mes). This application alsocreates a reference sheet (see Appendix A) which displays the template orientation and all needle-channel locations with their channel numbers to guide needle numbering at planning and radiationsource guide tube connection at treatment. It also gives the intended depth of insertion for eachneedle and has space to record the final needle protrusion from the template following the implant.This software is able to complete this export process in no more than one minute.3.1.2 Modelling DevelopmentFor this work, this software was modified to meet 3D printing requirements for high-temperatureplastic 3D printing to include a curved base for the cylinder to print more stably, and to providelogging information for clinical checks.203.2 Manufacturing and Quality Assurance3.2.1 PEEK 3D PrintingPolyether Ether Ketone (PEEK) is a notoriously difficult material to 3D print with, especiallywith 100% infill. PEEK has a high melting temperature of 343◦C and is commonly 3D printed in the400-450◦C range. For this application with 100% infill and with a tall slender cylinder, the 3D printingbecomes difficult as layer separation issues begin to happen as the PEEK solidifies and goes through aglass transition phase at around 143◦C. Due to these separation issues, the temperature at which thedevices were 3D printed was raised eventually to 450◦C with lower temperatures at the first few printlayers in order to ensure build plate adhesion.To ensure an expedient clinical printing turnaround, the PSCTs are printed two at a time with alayer height of 0.25 mm, using a 0.4 mm nozzle. A typical print of 2 PSCTs takes approximately 24hours. Each PSCT is printed with a slightly larger outer diameter than the input diameter by the userso that post-processing can achieve a smooth final finish at the specified diameter.Once the PSCTs are 3D printed (Figure 8A) they are allowed to cool for a minimum of 3 hours inorder to reach room temperature internally. The PSCTs are then removed from the 3D printer buildplate to be inspected and post-processed.3.2.2 Post-ProcessingBefore post-processing begins, an inspection is performed to ensure that plastic needles can passthrough each channel smoothly and that there are no major defects with the printed cylinder.Post-processing consists of two major components: surface machining and hole threading (Figure8B and C). All machining was performed by BC Cancer - Kelowna’s in-house machinist. For themachining process, the cylinder is mounted on a lathe and approximately half a millimetre of surfacematerial is removed from the cylinder in order to bring the outer diameter to the planner’s designeddiameter. The tip of the cylinder and the base are also machined to a smooth final finish. The holethreading step involves setting an M4 tap into the bottom of each needle hole such that a compatiblecollet may be threaded into the hole to lock the corresponding needle in place.21Figure 8: A: Sample PEEK 3D printed PSCT before post-processing. B: 3D printed model of anexample PSCT with manually tapped channel entry holes and machined surface. C: Base of samplePSCTs with needle and locking collet inserted and fixed in place.223.2.3 Quality AssuranceThe following checks are performed to ensure that the PSCTs are manufactured to specification:1. Needle transit check: A flexible needle is passed through each needle hole in order to ensurethat the needle transits through the hole smoothly and completely.2. Collet and needle tightening check: For each needle hole, a needle and collet are inserted andthe collet is tightened. The needle is manually tugged in order to verify that the collet has locked theneedle in place sufficiently.3. Interstitial needle angle check: Each interstitial needle is inspected to ensure that its trajectoryangle is sufficiently close to the pre-planned trajectory angle. This can be performed visually byholding the needle up to a screen with the pre-planned 3D print file loaded on the screen, or it can bemeasured using a digital angle gauge. Final interstitial angles are expected to be within 5◦, and aretypically within 3◦.4. Visual print quality inspection: The cylinder is inspected visually to look for any 3D printmaterial colour variations which would indicate a poor glass transition or poor adhesion in the finalprint, which could make the cylinder too fragile for clinical use.5. Tactile print quality inspection: The cylinder is handled manually to feel for any bumps or layeradhesion problems on the final part.3.3 Template SterilizationPEEK was selected because it is a common material used for other brachytherapy devices, it isbio-compatible, and it can withstand the high temperature and pressure of steam sterilization. Ingeneral, it is important to validate the assumption that a given 3D printing material, technique, orgeometry is adequately sterilized by the proposed sterilization methodology if it is to be used as amedical device. The long, blind, holes of PSCTs present a sterilization challenge not seen in otherdevices used in brachytherapy (the inner channels of needles and other commercial applicators are notcleaned or sterilized to prevent damage to the afterloader) nor in common 3D-printed medical devices.The government of British Columbia outlines sterilization requirements for in-house manufacturedmedical devices in [51]. In our case, this required a third-party independent sterilization validation ofour device. Four copies of a representative PSCT (Figure 8) were printed (30mm diameter, 160mm23length, 2.5mm channel diameter), inspected as described above and sent to Nelson Labs (Salt LakeCity, Utah), who performed an independent test to confirm that these 3D printed PEEK templates canbe sterilized for a single-use clinical application. The samples were inoculated internally and externallywith Geobacillus stearothermophilus ATCC 7953. Time was allowed for the microorganisms to growand the samples were sterilized as per our proposed protocol. The cylinders were then sampled atthe inoculation points and the samples were cultured. Sterility was assured if a fraction of ≤10−6 ofthe inoculated organisms remained following sterilization. Using this method, PSCTs were validatedfor sterilization as single-use to be sterilized in steripeel packages, using a 132◦C pre-vacuum for 4minutes.The methods used in the independent sterilization validation process formed the basis for a Manu-facturer’s Instruction for Use (MIFU) document, which is followed by the Kelowna General Hospital’ssterilization facility to sterilize these devices. The final MIFU document which is currently in use atBC Cancer Kelowna and Kelowna General Hospital is shown in Appendix B.3.4 3D Printed PEEK Dose Attenuation3.4.1 IntroductionThe international standard for dose calculation is based on the AAPM Radiation Therapy Com-mittee Task Group No. 43 (TG-43) formalism [52]. The TG-43 dose calculation standard assumesthat the dose to all media surrounding the radiation source will be equivalent to the dose to water.In many cases, this is a sufficient assumption for brachytherapy dose calculation, because of the 1/r2effect of radioactive fluence rate falloff [53].The material selected for the manufacture of PSCTs, PEEK, is the same material that manystandard commercial applicators are made of. These commercial devices are manufactured with thedose calculation to water (TG-43) assumptions in mind and thus have similar radiation attenuationcharacteristics to water.While it is not likely that there is a clinically significant difference either between the dose atten-uation through 3D printed PEEK and standard machined PEEK, or the difference between the doseattenuation through 3D printed PEEK and the dose calculated assuming everything is water, this isan assumption that must be validated before clinical acceptance of 3D printed templates. To do so, atest was run to compare the dose at depth of water to that of 3D printed PEEK.243.4.2 Materials and MethodsA 12mm X 120mm X 50mm block of solid (100% infill) PEEK was 3D printed with a layer heightof 0.35mm using a 0.6mm nozzle. A blind, 2.02mm borehole was drilled into the block and a 2mmneedle was inserted. Threads were tapped into the base of the hole to allow a custom collet to lockthe needle in place.The block was CT scanned and a treatment plan was created for the block and film. A dose of324cGy was prescribed to the film, a depth of 6.7 mm from the source center. The backscatter frombelow the film was from 100 mm of Solid-Water phantom [54] placed below the PEEK block. The dosewas measured using EBT3 Gafchromic film (Ashland, Inc.). A setup diagram and image can be seenin Figures 9 and 10.The film was calibrated according to the manufacturer’s instructions [55] with a 6MV 10X10 photonfield. The calibration values for the film were measured at 0-1000 cGy in 200 cGy intervals. Each hadan equivalent standard distribution of 0.2% (Red Channel). A shift was imposed to the data on thefit curve (Linear Reciprocal) by this value and the dose was recalculated at each of these shift bandedges in order to generate error bars for the measurement.Figure 9: Cross-section diagram of PEEK dosimetry testing setup.25Figure 10: PEEK dosimetry test setup with 3D printed PEEK block,locked needle and collet, film, and solid water.3.4.3 Results and DiscussionThe resultant treatment plan and film dose comparison can be seen in Figure 11. Note that thedose to film is higher than the planned dose at low depth, but lower at increasing depth. The lowdepth effect may be an air gap effect, thus reducing the attenuation, but may also be influenced bysetup measurement uncertainty, which is not included in the error bars shown. The increased doseattenuation at high depth can be explained by the effect of the PEEK material attenuating the photonfield more than water. While there are some dosimetric differences between the plan and measurement,these can be expected due to setup inaccuracies and material effects. The differences are not clinicallysignificant, especially given the fact that a substantial fraction of the dose is delivered by interstitialdwell positions. Also, most PEEK templates are on the order of 1.5cm in radius, and there is verylittle dose difference at this distance, and most predicted values are within the error. In addition,the error bars shown are very conservative and would be larger given a thorough error estimation, asdescribed below.The standard deviation of the calibration measurements encapsulates the random errors of dosedelivery to film during calibration, and film readout random errors, but not setup uncertainty ordose-response variation during the measurement. A comprehensive error analysis would involve takingmultiple measurements of dose to film using the brachytherapy source. For a given depth in PEEK,a standard deviation of colour response could be taken and applied to the fit formula to give a dose26standard deviation or confidence interval, which could be added to the standard deviations alreadycalculated. Since this is a clinical acceptance test and not a robust assessment of the dosimetric effectsof PEEK, measurement repetitions were not considered necessary.Figure 11: Depth-Dose plot of planned dose assuming water (TG-43) and measured dose to film withattenuation through a PEEK block. Planned dose values are shown as blue dots, and measured valuesare shown as red dots. Black measurement error bars are shown as described in the text.3.5 Preplanning Evaluation3.5.1 IntroductionRadiation therapy combining EBRT and high dose rate brachytherapy HDR-BT is the primarytreatment modality for gynaecological cancers recurring in the vagina, as well as primary cancersof the vagina [4]. For BT, lesions less than 5mm in thickness can be treated using an IC single ormultichannel vaginal cylinder [17], while IS or combined IC/IS techniques are required to treat thickerlesions to maintain acceptable doses to the organs at risk (OAR) [17], [56], [57]. This is typicallyaccomplished using either a perineal template or needles placed freehand in addition to the vaginalcylinder.27Although the IC/IS approach can often be successful [17], [56]–[58], treatment of lesions at andextending beyond the top of the vaginal vault remains challenging. Cylinder geometries obstructinterstitial needles from intersecting with the HR-CTV at the top of the vault, as illustrated in Figure12. In cases such as these, the intra-cylinder dwell times required for adequate HR-CTV coveragelead to excessive OAR doses, in particular for patients post-hysterectomy [34], [35], necessitatingcompromised HR-CTV coverage. Additional challenges in these cases include the difficulty in placingthe IS component. Without intra-operative CT/MRI guidance, it is difficult to visualize the needlepositioning above the vault, in particular when IC devices have been implanted. As most patientswith vaginal cancer are post-hysterectomy, the inability to finely control needle positioning relativeto the bowels often means these patients are not offered brachytherapy and instead receive palliativetreatment or pelvic exenteration [57], [59].Figure 12: Illustration of the challenges of treating vaginal lesions atthe top of the vaginal vault. This patient, previously treated at ourinstitution has a GTV (blue) and HR-CTV (cyan) extending acrossthe vault. When treated with a single-channel cylinder and freehandneedles (reconstructed in green), the 100% isodose (red) only covers theGTV demonstrating the difficulty in achieving satisfactory dose coveragecentrally with current techniques.Previous studies have demonstrated promise in pre-planning vaginal and cervical brachytherapy28using 3D printed IC and IS templates [36]–[40], with some indicating desire for automated modellingof patient-specific IC/IS applicators [36], [39]. Our goal is to develop patient-specific IC/IS cylindertemplates that will facilitate safe, conformal treatment for patients with lesions at and above thevault using readily available and low-cost tools. To assess the feasibility of such templates, we haveconducted a treatment planning comparison of previously treated patient plans to the PSCT preplansfor the same targets and OARs, with the aim of demonstrating at least dosimetric equivalency.3.5.2 Materials and MethodsPatient CharacteristicsUnder institutional Research Ethics Board approval, plans were retrieved for ten patients treatedwith IC/IS HDR-BT at our center. As shown in Table 1, there is heterogeneity in both diagnosis(recurrent vs primary cancer) and radiation prescriptions. As this is a pre-clinical feasibility study,patients were selected to represent a range of vaginal tumour locations and geometries and the focusof this work is comparing dosimetry achieved for a single fraction of brachytherapy using conventionalapplicators vs PSCT for each patient.Table 1: Patient diagnosis and treatment details for ten patients previously treated with IC/IS HDR-BT. REC: recurrent endometrial cancer, VA: Vaginal adenocarcinoma. SCC: squamous cell carcinoma,RSCC: recurrent squamous cell carcinoma.Patient 1 2 3 4 5 6 7 8 9 10Diagnosis REC VA SCC SCC REC SCC REC RSCC SCC RECHRCVT Vol (cm3) 30.7 29.7 10.1 11.8 27.5 48.3 6.1 8.9 25.9 17.4EBRT Dose (Gy) 50 45 45 45 45 36 45 45 45 45EBRT Fx 25 26 27 28 29 31 33 34 35 36HDR-BT Dose (Gy) 24 24 19.5 14 34 22 11 13 13 27.5HDR-BT #Fx 4 3 3 2 4 4 2 2 2 5Cyl needles 1 0 1 0 1 1 0 0 0 1IS template 0 9 0 8 15 14 9 10 14 10IS freehand 4 0 5 0 0 0 0 0 0 0Total 5 9 6 8 16 15 9 10 14 11Treatment Plan Comparison: Current Clinical PracticeFor our vaginal interstitial BT patients, we acquire T2-MRIs one week prior to implant with adummy vaginal cylinder in place, typically in the last week of, or just following, EBRT. The cylinderis inserted at MRI by the treating radiation oncologist. This allows us to define the HR-CTV on MRIwith a reproducible implant geometry. At implant, a single-channel vaginal cylinder with the samediameter (2.0 – 3.0cm) is inserted along with either plastic needles placed free-hand or stainless-steelperineal template-guided needles. In the case of patient 2, a 5-channel flap-applicator was affixed to29the posterior of the single-channel cylinder.Post-implant, CT images are acquired and fused to the preoperative MRI. The MR-delineated HR-CTV is transferred to the CT, which is used to contour OARs and reconstruct the applicators. OARsare only contoured within 5cm of the applicators. All patients had bladder and rectum contoured,seven had sigmoid contours, and five had small bowel delineated. Although the normal vaginal wall isalso an OAR, due to a lack of consensus on dose limits, we do not explicitly contour the vaginal wall.We minimize 150% or greater doses within any part of the wall, restrict doses > 100% to within theHR-CTV, and do not irradiate circumferentially unless clinically necessary. Absolute dosimetric goalsare difficult to define for this patient population. Our practice is to aim for an HR-CTV D90>100%,with V100>90%, V150<40%, and V200<15%. OAR goals follow EMBRACE II [60] planning aims toD2cm3 (EQD23): bladder <80Gy, rectum <65Gy, and sigmoid <70Gy. EQD2 calculations accountedfor each patient’s individual radiation history. Treated HR-CTV V100, V150, V200, D90, D2cm3 foreach OAR, number of needles, and total interstitial path length were tabulated.Treatment plan comparison: PSCT PreplanningOriginal preplan images and structures were used to create PSCT preplans. PSCTs were con-strained to the same diameter as the cylinder used for treatment. Preplanning consists of two iterativesteps: positioning of virtual needles within the cylinder/HR-CTV and dwell time determination. Bothstraight and curved needles were allowed and a library of importable curved needle orientations (60°,45°, 30°, and 15° from vertical, each with a radius of curvature of 25mm) was created within BrachyVi-sion (Varian). This increased planning efficiency and ensured that radii were greater than the 13mmminimum radius of curvature for the source wire of our GammaMed Plus afterloader (Varian). In-terstitial needle angles were manually chosen based on HR-CTV morphology, initial needle spacingwas <1cm, and needle depth was set so that the first dwell position would be at the edge of theHR-CTV. If not adjacent to an OAR, needles could be placed within 5mm of the HR-CTV. Needleswere constrained to exit perpendicularly to the base of the PSCT.Dwell positions were placed at 5mm steps throughout the HR-CTV. Within the cylinder, dwellpositions extended the length of the HR-CTV + 5mm. Dwell times were manually determined. If theresulting plan was not at least dosimetrically equivalent to the treated plan, then needle geometries ornumbers were refined, and dwell times were adjusted. Care was taken to ensure dwell time smoothnessin accordance with our clinical practice. All plans were generated by the primary author and reviewedby the other authors (two Radiation Oncologists and one Medical Physicist). HR-CTV V100, V150,V200, D90, D2cm3 for each OAR, number of needles, and total interstitial path length were tabulated30following final plan approval.Test PSCTs for each patient were printed using an AON-M2 3D printer (AON3D, Montreal) with100% infill, 0.1mm layer height, using a 0.6 mm nozzle. Each PSCT was tested to ensure that needlescould smoothly pass through each channel and that curved needle angles matched planned angles towithin 5°. PSCTs were printed with a 1mm greater radius than required, allowing the template to bemilled down to the prescribed diameter with a smooth finish. Additional post-processing comprisedthreading the entrance holes, allowing locking collets to fix needles insertion depth, and adding ananterior orientation notch.3.5.3 ResultsClinically acceptable PSCT preplans were created for each patient (example shown in Figure 13).For each patient, DVH comparisons are shown in Figure 14 and a detailed plan comparison is foundin Table 2. The PSCT treatment plans (example in Figure 13) created had a median difference andinterquartile range in HR-CTV D90 and V100 of 0.4(-2.2, 2.7) % and 0.2(-0.8, 2.0) % respectively.The median differences in D2cm3 for Bladder, Rectum, Sigmoid, and Small Bowel were 0.0(-0.1, 0.2)%, -0.1(-0.2, 0.2) %, 0.0(-0.1, 0.0) %, and 0.0(-0.1, 0.0) % respectively. The median reduction in totalinterstitial path length was 57.1(-65, -39) cm. Only the interstitial length results were statisticallysignificant with p<0.05.31Figure 13: Axial and coronal views of clinical and PSCT plans for patients one and nine. HR-CTV(cyan), GTV (blue), and 100% isodose (red) are displayed along with digitized needles for each plan.1A and 1B: Patient 1’s cylinder and freehand interstitial treatment plan. The top of the vaginal vaultis not able to be covered when using a traditional cylinder. 1C and 1D: Patient 1’s PSCT preplanshowing improved HR-CTV coverage at the top of the vault and in the posterior edge of the HR-CTV.9A and 9B: Patient 9’s cylinder and grid interstitial treatment plan for a tumour located in a radialband around the vagina. 9C and 9D: Patient 9’s PSCT preplan.32Figure 14: DVH plots for HR-CTV (Blue), Bladder (Green), Rectum (Brown), Small Bowel (Cyan),and Sigmoid Bowel (Red) for each patient. Treated plans are shown in dashed lines, and PSCT plansare shown in solid. If an organ was not contoured for the treated plan, it was also omitted from thePSCT plan.33Table 2: Comparison of DVH metrics for Target and OARs for Treated (T) vs PSCT (P) plan for each patient. IS indicates cumulative interstitial lengths.A dash indicates the OAR was not recorded in the original plan, so was not compared. HR-CTV D90, V100, V125, V150, and V200 are given in %, and theorgan doses are reported as minimum dose to the maximally irradiated 2cm3 in units of Gray. Interstitial lengths are given in cm.Measure T1 P1 T2 P2 T3 P3 T4 P4 T5 P5 T6 P6 T7 P7 T8 P8 T9 P9 T10 P10MedianDifferenceIQRHR-CTV D90 95.1108.6105.8111.6 113 112.4109.4111.2106.2109.2112.4109.9119.6108.5126.0115.5113.8112.4106.7108.0 0.4 (-2.2, 2.7)HR-CTV V100 86.8 96.4 95.7 97.8 97.5 99 93.5 96.1 97.5 95.9 95.9 96.5 96.9 96.2 99.9 99.1 96.4 96.3 97 95.1 0.3 (-0.8, 2)HR-CTV V150 52.4 43.1 21.7 38.9 58.1 49.2 54.8 41.5 23.9 37.8 55.6 43.8 75.8 43.3 58.1 40.5 39 38.7 30.7 40.1 -9.1 (-12.9, 7)HR-CTV V200 17.6 17.2 0.1 4.8 31.3 18.8 27.2 16.1 7.8 14.1 18 20 49.1 17.7 18.9 14.2 11.2 12.2 3.9 15.7 0.3 (-9.5, 4)Bladder 4 3.9 6.1 6.1 2.9 2.9 2.6 3.2 4.9 4.5 1.4 1.8 0.5 0.4 0.7 1 1.5 1.6 3.8 3.4 0 (-0.1, 0.2)Rectum 3.7 3.6 5.6 5.5 4 3.8 2.1 1.9 3.8 3.8 2.4 2.9 2.3 1.9 2.4 2.8 2.8 3 3.1 2.0 -0.1 (-0.2, 0.2)Sigmoid 1.4 1.5 3.5 3.4 N/A N/A 1 0.9 1 0.8 0.3 0.3 N/A N/A 0.1 0.1 N/A N/A 0.8 0.7 0 (-0.1, 0)Small Bowel 2.1 2.6 1.8 1.7 N/A N/A 0.2 0.2 0.5 0.5 0.1 0.2 N/A N/A N/A N/A N/A N/A N/A N/A 0 (-0.1, 0)IS Length 34 26.5 81.9 0 0 5.7 81.4 24.6 93.3 33.8 97.5 30.7 61.3 16.9 57 19.8 102.2 23.4 80 22.6 -57.1 (-65, -39)34Custom softwareThe application created for this study can export, check, and prepare a 3D printable model inunder 1 minute using standard desktop computer hardware.Applicator ManufactureEach model passed inspection for needle passage, needle trajectory, and cylinder dimensions.3.5.4 DiscussionSummaryDelivering high-quality brachytherapy to vaginal lesions remains challenging. The overarching goalof our vaginal brachytherapy program is to increase access to this valuable treatment by developingtechniques and equipment that will enable safe, individualized treatments for any eligible patient whilesimplifying the delivery of these treatments. This study investigates the feasibility of using PSCTs toaccomplish these goals. We have demonstrated that PSCTs can be designed to produce equivalent orsuperior plans as compared to perineal templates in a variety of tumour locations and morphologies.This is accomplished with significant decreases in the overall interstitial length of implanted needlesand with the advantages of having a pre-plan of the implant.ImplantThis PSCT design makes implanting lesions extending above the vaginal vault possible even in theabsence of intraoperative image guidance, for multiple fractions. The pre-plan will allow the depth ofneedle insertion required to be decided based on pre-operative imaging while the locking collets willfacilitate needles to be advanced by a known amount and firmly locked in place. This is an advantageover similar template designs [38], [39]. The PSCT is tied in place by the oncologist using surgicalties threaded through the proximal protruding needles and attached to the patient’s hips. Individuallylocking the needles means one can be assured that the needle depth does not change after insertion,unlike designs which have no locking mechanism [38], or which lock all needles simultaneously [39]. Tolock all the needles, the design published by Logar et al. [39] requires all needles to exit around thecircumference of the base of the cylinder, whereas our design permits the needles to exit the cylinderbase at any position. This reduces constraints in the design process and increases the number ofpotential interstitial needles, allowing for improved dosimetric conformality and homogeneity.There remain some potential limitations of the approach, including how to deal with tumour or35template motion either during or after implant. Clinical implementation details such as how to fixatethe device during the implant are left for a later clinical follow-up paper once these devices have beenproperly tested, and a thorough procedure has been tested.ModellingAutomated modelling is a significant advantage of this approach. Other attempts at customizedgynaecological templates have relied on either in-house manual modelling of the template [36]–[38],[40] or have outsourced the design to a contractor [39]. Template design automation speeds up thetranslation of a clinical plan to a 3D printable model to less than a minute, saving hours of manualCAD design work. Performing the design in-house allows the clinical team to retain control over thedesign and prevents time delays generated by communication between the planner and the 3D modellerif the design needs to be changed. Quality assurance can also be performed synchronously; needle pathgeometries can be checked in the 3D CAD program immediately following model production and thefinal printed part can be inspected immediately following printing by passing a needle through eachhole to confirm print accuracy.3D PrintingPrinting an extra margin on the outside of the cylinder followed by lathing and sanding of thecylinder provides a clean finish (Figure 8B), provides the oncologist with a similar aesthetic to otherIC devices as compared to 3D printing alone and is a relatively simple and accessible technique. Ofcourse, this applies to the type of 3D printing known as Fused Deposition Modeling. Other 3D printingtechniques vary in their post-processing requirements.ImagingIn our current perineal template-based interstitial vaginal brachytherapy program, we obtain anMRI with a vaginal cylinder in place within 1 week before implant. This cylinder is the same diameteras the one that will be used during the implant and is placed by the treating physician, minimizinganatomy changes between imaging and treatment. These images are then fused to the planning CTto localize the HR-CTV. Our experience with this workflow gives us confidence in using such pre-operative MRIs to pre-plan and design PSCTs. This also obviates the need for MRI on the day ofimplant, making this technique more easily adaptable for centres with limited access to MRI.PreplanningPreplanning itself has advantages. Studies in the context of cervical cancer BT have demonstrated36that a pre-planning approach can result in accurate placement of pre-planned needle positions [30],[33]. Preplanning needle placement before the template insertion provides physicians with confidencein the needle positioning, especially close to or in between OARs like the bowels, rectum and sigmoid.It allows the implant and planning team to consider potential dosimetric trade-offs before the implant.This may be particularly advantageous for high throughput, resource-limited centers [61]. Constructinga library of importable template needles reduces the treatment planning time required, avoiding themanual design of orientation and curvature for each plan. Preplans may be used as base plans on theday of treatment, reducing the final planning time required, and creating efficiencies on the day of theimplant. It also reduces the risk of errors that could lead to unusable templates because of unworkableangles and orientations. The full utility of the pre-planning approach will be studied as we move thistechnology into routine clinical practice and the results of this will be reported in the future.Plan ComparisonsThis study demonstrates the PSCT technique to be equivalent or superior to our current conven-tional perineal implant procedure for many cases, since interstitial needle lengths may be reduced bysuch a large margin while maintaining planning dosimetry. The treatment plan comparisons show theadvantages of 3D printed IC/IS vaginal treatment templates, as well as indicate where a conventionalperineal template approach may remain the treatment of choice. PSCT treatment plans are preferablewhen the HR-CTV extends from the upper half and vault of the vagina, as seen in Figure 13, Patient1. In these cases, the HR-CTV coverage was improved while limiting V200 and V150, and the dose toOARs was reduced (example in Figure 14 and Table 2, Patient 1). Using a PSCT may not improveupon the HR-CTV coverage and dose homogeneity achievable via accurately placed interstitial needlesinserted using a perineal template for cases where the tumour extends along a long, thin portion ofthe vaginal wall (Figure 13, Figure 14 and Table 2, Patient 9). This is because each interstitial needleinserted parallel to the vaginal wall can cover a larger fraction of this geometry of tumour volumecompared to oblique needles from the PSCT. Needles which are either within a PSCT or intersect apartial ring-shaped target at a non-orthogonal angle will be less efficient in coverage due to their anglewith respect to the tumour. There are, however, still advantages to the PSCT technique in such cases.For example, for patient nine, the total interstitial path length was reduced from 102.2cm to 24.3cm,a potentially dramatic decrease in trauma for the implant. Additionally, the use of a PSCT templateremoves the need for needles to enter through the perineal skin, making the implant and removal morecomfortable for the patient. These factors alone may make the PSCT a preferable option in selectedcases.Reducing the Difficulty of IS-BT37Perineal template-based implants for vaginal cancer are not a widely available treatment option dueto the technical challenges of both achieving a good implant and maintaining the required expertise.The PSCT workflow, with the incorporation of pre-planning, simplifies patient-specific IC/IS treat-ment. Preplanning needle placement before the template insertion provides the Radiation Oncologistswith confidence in the needle positioning, especially close or in between OARs like the bowels, rectumand sigmoid. It makes it safe to implant complex tumour geometry deep in the pelvis without intra-operative imaging. It allows the implant and planning team to consider potential dosimetric trade-offsbefore the implant. This permits for pre-operative, quantitative comparison between competing IC/ISapproaches and plan geometries. This also increases planning confidence in final plan optimality, savingtime in final planning while the patient is waiting for treatment after insertion.3.6 ConclusionPerineal template-based implants for vaginal cancer are not a widely available treatment option dueto the technical challenges of both achieving a good implant and maintaining the required expertise.The PSCT workflow, with the incorporation of pre-planning, has the potential to simplify patient-specific IC/IS treatment. Plans for vaginal interstitial brachytherapy using the PSCT are preferabledosimetrically to freehand and external template IC/IS treatment plans for many cases, especially fortop-of-vault lesions. These templates have the potential to improve target coverage, reduce OAR dose,reduce interstitial needle length in normal tissue and improve confidence in needle insertion withoutintraoperative MRI or CT. Software automation can be used to very quickly generate a model basedon a preplan, which can then be 3D printed. 3D Printed PEEK can be used as a construction materialfor these applicators, and it has been validated as steam sterilizable.3.7 DisclosureFunding for this project was provided by the British Columbia Cancer Foundation.384 Clinical Evaluation of PSCTsThis chapter describes the clinical implementation of PSCTs in the treatment of vaginal cancers atBC Cancer-Kelowna and has been submitted for publication. The introduction section covers similarcontent to the background chapter of this thesis but has been kept in for the sake of continuity.4.1 IntroductionImage-guided high-dose-rate brachytherapy (HDR-BT) is the standard of care for both primary andrecurrent vaginal tumours and is often delivered as a boost following pelvic external beam radiationtherapy (EBRT) [4], [17]. Vaginal HDR-BT is usually delivered using single or multi-channel cylinders.In cases where the lesion size or location warrants, these can be combined with interstitial needles viaperineal template or freehand insertion [17]. This can improve treatment target coverage and organsparing compared to cylinder alone treatment [17], [56], [57].When lesions extend above the vaginal vault, as is common for recurrent endometrial cancer,standard intracavitary cylinders can obstruct interstitial needles from extending into or through thelesion [50], and the intra-applicator dwell times required to cover the target can result in too-high organ-at-risk (OAR) doses, in particular for patients with recurrent endometrial cancer having undergonehysterectomy [34], [35]. For some patients, an external beam boost may be possible, but this isa challenging setting to deliver curative doses solely via EBRT. If adequate brachytherapy is notavailable, the patient may require exenteration (removal of the vagina, cervix, and uterus) [57], [59].Although some commercial applicators can facilitate treatment above the vault, such as Varian’sUniversal Interstitial Cylinder set and Elekta’s Venezia applicator, these were primarily designed totreat advanced cervical cancer. Treating vaginal lesions can still be challenging due to the lack ofcustomization allowed by commercial devices combined with the wide range of tumour geometries(tumour size, location and proximity to OAR) and the preponderance of post-hysterectomy patientsin this population.An additional challenge for using interstitial brachytherapy to treat the upper vagina or abovethe vaginal vault is image guidance. Ultrasound (transvaginal, transrectal, or transabdominal), orMagnetic Resonance imaging (MRI) can be used intraoperatively to ensure that needles are placedin quality treatment locations and are not puncturing critical organs. Each of these modalities haslimitations, however. For example, transvaginal US cannot be used with a cylinder in place, tran-39srectal US is limited by the depth of insertion, transabdominal US can be difficult to interpret, andintraoperative MRI is not widely available.We have addressed these challenges by developing 3D-printed patient-specific cylinder templates(PSCTs) [50] which permit the placement of interstitial needles into pre-planned positions withoutimage guidance. In addition, other designs for 3D-printed templates/applicators have been proposedfor intracavitary or interstitial gynaecological brachytherapy [36]–[40], [62]. We have developed aclinical workflow for the in-house design and 3D printing of PSCTs [50] with the aim to providecustomized interstitial treatment templates for patients with difficult lesions, in a partially automatedworkflow.This study describes the treatment of 10 patients at our center with HDR-BT facilitated by 3Dprinted PSCTs from pre-planning through manufacture, implant, final planning, and treatment be-tween October 2020 and October 2022. Insertion positions and dosimetry are compared betweenpreplan and final plans, and the practicality of preplanning for IC/IS HDR-BT of the vagina is dis-cussed. We show that these templates can be used to create high-quality insertions and treatmentplans, without intraoperative imaging, particularly for deep, localized, and top-of-vault lesions.4.2 Materials and methods4.2.1 Cohort and Treatment CharacteristicsBetween October 2020 and November 2022, seventeen consecutive patients who were candidates forinterstitial brachytherapy for any primary or recurrent vaginal cancer were considered for treatmentwith a PSCT. Each patient’s tumour geometry was considered to determine whether the patient wouldbe better treated with a PSCT or via a perineal template and cylinder implant. Ten patients wereselected for treatment using PSCT and inclusion in this study. These patients had lesions in the upperthree-quarters of the vaginal vault and their tumour was located at the vaginal wall and extended awayresulting in a deeper lesion greater than five millimeters. Tumours were generally irregular in shape.Each patient was treated with an in-house 3D-printed PSCT without a perineal template, freehandneedles, or any intraoperative image guidance. Cohort and treatment details are given in Table 3.40Table 3: Patient diagnosis, age at treatment, HR-CTV volume, and prescription information. 80% (8)were local recurrences and 20% (2) primary tumours. Patients were diagnosed as 60% (6) EndometrialEndometrioid adenocarcinoma (EEA), 30% (3) Invasive squamous cell carcinoma (SCC), 10%(1) poorlydifferentiated high-grade vaginal adenocarcinoma (VA). The tumour location was 80% (8) within thevaginal vault and 20% (2) at the vaginal wall.Patient Age Diagnosis HistologyHR-CTVVol (cm3)EBRTEQD2(Gy)Dose perBTFraction(Gy)Fractions1 56 Recurrence SCC 15.9 44.3 5 52 65 Recurrence EEA 25.7 44.3 5 53 64 Recurrence SCC 13.6 44.3 5.5 54 66 Primary VA 18.6 58.9 5.5 55 62 Recurrence EEA 6.6 44.3 5 56 76 Recurrence EEA 17.0 44.3 5 57 64 Recurrence EEA 18.7 44.3 5 58 76 Recurrence EEA 19.3 44.3 5 59 65 Recurrence EEA 22.6 44.3 5.5 510 64 Primary SCC 4.8 44.3 5 54.2.2 Pre-planningAll patients underwent pelvic T2-MRI imaging at least 7 days before brachytherapy, with a vaginalcylinder in place. The diameter of the cylinder was chosen and placed by the implanting radiationoncologist (RO) to match the patient’s anatomy, ensuring it filled and was in contact with the vaginalvault. The cylinder’s longitudinal axis was aligned with the cranial-caudal axis as far as possible.HR-CTV, bladder, rectum, sigmoid, and small bowel were contoured on the resultant axial MRIimages. The pre-planning process for PSCTs is an iterative process of placing virtual needles at desiredpositions and orientations and determining dwell times to satisfy planning goals [50]. Preplans for allpatients were created by an experienced medical physicist using the Eclipse 15.6 Brachyvision software(Varian) and reviewed by the implanting RO.A library of importable curved needles was used to increase planning efficiency. Needles wereinitially planned with a curvature that best matched the tumour geometry, at even spacing (∼7mm),after which the number, position, and interstitial length of needles were determined manually. Curvedneedle radii were 20mm by default, which is a larger radius than the minimum that the source forour HDR afterloader (GammaMedplus iX, Varian) can safely pass. The tip of each needle could beextended into tissue as required or could be an intracavitary-only needle. Each needle was oriented tohave a perpendicular entry point at the base of the PSCT, which permits threading of the entry hole,allowing each needle to be individually fixed in place with locking collets. Dwell positions were set at415mm spacing and extended a minimum of 5mm beyond and before the HR-CTV. Vaginal wall outsidethe HR-CTV was spared as much as possible (Figure 15).Preplanning times ranged from 3-8 hours, depending on the planner’s expertise and tumour ge-ometry. Plans were exported and the corresponding PSCT was 3D modelled using in-house writtensoftware [50]. The application also generates an operating room (OR) reference sheet (Appendix A)that shows the orientation of the template and the location of each needle channel, the correspondingchannel numbers, the desired depth of insertion, and space to record the final protrusion of each needlefrom the template after the implant is complete.4.2.3 Template manufacturingThe PSCTs were all 3D printed of polyetheretherketone (PEEK) with 100% infill using a 0.4mmnozzle on an AON-M2 3D (AON3D, Montreal, Canada) printer, and machined on a lathe in post-processing in order to have a very smooth final finish. The holes at the base of each cylinder weretapped to allow a locking collet to fix each needle in place, and an orientation notch was inscribedon the base of each cylinder, typically in the patient’s anterior direction (Figure 15). Further detailsabout the manufacturing process, design, and QA for the PSCTs are given in Chapter 3 and in [50].Channels were validated post-printing by passing a flexible needle through each channel, testing colletlocking functionality, and measuring the interstitial needle angle. After validation, each PSCT wassteam sterilized using an independently validated procedure [50].4.2.4 ImplantPSCTs were prepared in the OR by inserting each needle into the PSCT as far as possible withoutthe tips extending outside the cylinder so as to not damage any tissue as the cylinder was inserted. Eachcollet was locked to finger tightness so the needles did not move during cylinder insertion. Referencemarks were made on each needle using a sterile marker to indicate the insertion depth of the needleaccording to the reference sheet. All implants were performed under spinal anesthetic. Patients wereexamined under anesthesia before cylinder insertion to evaluate tumour geometry and fiducial markerswere placed to mark the clinical extent of the disease. Next, the PSCT was inserted to match thepreplan MRI positioning, and cylinder rotation orientation was verified using the orientation notch.One by one, each needle was then loosened, advanced to its final depth as noted on the OR referencesheet, and tightly locked. Once all needles were fully inserted, the PSCT was secured using a beltand surgical ties. The ties were placed between the needles at the base of the template and applied42Figure 15: Left Column: MRI-based PSCT preplan images showing IC/IS planned needle paths(green/pink), HR-CTV (dark blue), Bladder (green), Sigmoid (cyan), Rectum (brown), Small Bowel(pink), 100% idosose (red), 150% (yellow), 200% (white). The inserted dummy cylinder appears asa dark cavity in the image. A: AP view, C: Axial view. B: Example PSCT after 3D printing andpost-processing, with some needles inserted. D: PSCT Base with needles and locking collets installed.The orientation notch is shown at the 12 o’clock position, with a black marking.43pressure to the template towards the vagina, to prevent rotation or translation of the PSCT. Finally,each needle was labelled with a channel number sticker corresponding to the OR reference sheet.4.2.5 Post-insertionEach patient underwent CT scanning for final treatment planning after their PSCT insertion andrecovery from anesthesia. CT images were registered to the patient’s preplan MRI scans based onboth the cylinder position and anatomy. HR-CTV was contoured on the MRI scan while OARs werecontoured on the CT.Preplan needle geometries and dwell times were imported into the final plan as a template andthe needle set was aligned to the final CT as a group. Individual needle positions and trajectorieswere corrected as needed. Dwell times at the final dwell positions were then modified to ensure theplanning goals (Table 4) were met. While planning was not formally timed during this study, modifyinga preplan is significantly faster than de novo planning and took at most 30 minutes post-contouringto complete, often much quicker.Each patient underwent a single insertion, was admitted to hospital and received 5 fractions, onceon the first day, and twice on the second and third days, with each fraction at least 6 hours apart.After the second fraction, a check CT was performed to verify implant stability and at each treatment,the cylinder position was confirmed relative to marks on the patient’s legs.Only the brachytherapy doses are reported in this study since the aim is to evaluate the utility ofthe brachytherapy templates. For each patient, HR-CTV Volume, D90, V100, V125, V150, V200, andD2cm3 for OARs were calculated and compared for each pre-insertion and post-insertion plan. Themedian and interquartile range (IQR) were calculated for each. Dose Volume Histograms (DVHs) arecompared for each patient’s HR-CTV preplan and the final plan. The total number of needles wasrecorded as was the number of intracavitary needles, interstitial needles, straight needles, and curvedneedles. Dwell positions and times were also recorded, including the number of intracavitary dwellpositions, the number of interstitial dwell positions, the cumulative overall dwell time, cumulativeintracavitary dwell time, cumulative interstitial dwell time, and cumulative interstitial needle length.We determined the differences between preplan and final inserted plan by calculating the dwell positiondifferences, resulting in preplan to final plan position differences for straight needles, curved needles,and, cumulatively, for all needles. Patient follow-up was conducted 3 months after treatment. Thehighest toxicity score recorded for each patient, according to the CTCAE Version 5 criteria [63], duringthe follow-up period was used for the study.444.3 Results4.3.1 DosimetryAll treatment plans created for each patient at both the preplan and treatment stages were clinicallyacceptable. An example pre-plan and the corresponding final treated plan are shown in Figure 16. Thetreated median HR-CTV D90, V100, V150, V200, Bladder, Rectum, Sigmoid, and Small Bowel D2cm3,are reported in Table 4. The differences between the final treated plan and the preplan dosimetricindices are given in Table 5. DVH comparison plots for preplan and final plan for each patient areshown in Figure 17.Figure 16: Pre-plan and final inserted and re-optimized plan for patient 6. Patient 6, unlike the rest ofthe cohort, had a CT scan at the same time as the pre-plan MRI scan. The HR-CTV was contoured onthe MRI originally. The CT image is included for easier comparison between pre- and post-insertion.Table 4: Vaginal HDR-BT institutional treatment aims and treated dosimetric indices for all patients.HR-CTV volume is given in units of cm3, D90, V100, V125, V150, and V200 are given in %, and theorgan doses are reported as minimum dose to the maximally irradiated 2cm3 in units of Gray.Metric Aim 1 2 3 4 5 6 7 8 9 10 Median (IQR)HR-CTV Vol - 15.9 25.7 13.6 18.6 6.6 17.0 18.7 19.3 22.6 4.8 17.8 (14.2, 19.2)D90 ≥100 110.8 102.5 116.2 101.6 114.8 112.7 105.8 111.5 110.4 113.4 111.2 (107, 113.2)V100 ≥90 96.7 91.5 99.2 91.5 96.9 98.7 93.7 99.0 98.2 98.8 97.6 (94.4, 98.8)V125 - 76.4 72.6 83.4 59.7 84.4 75.3 69.2 69.1 71.0 71.8 72.2 (69.7, 76.1)V150 ≤40 52.8 55.1 64.9 34.6 69.2 48.1 43.5 37.8 45.5 36.3 46.8 (39.2, 54.5)V200 ≤15 28.0 30.4 29.9 16.4 32.7 10.7 19.6 13.5 20.8 10.3 20.2 (14.2, 29.4)Bladder ≤27.5 16.7 18.0 22.8 19.3 6.0 18.7 17.2 18.9 19.6 7.8 18.3 (16.8, 19.2)Rectum ≤17 14.3 17.0 18.6 15.9 3.8 15.4 13.8 19.0 13.6 19.1 15.7 (13.9, 18.2)Sigmoid ≤17 9.2 7.1 14.5 12.1 8.7 11.0 13.9 19.1 11.9 8.0 11.4 (8.8, 13.4)Small Bowel ≤11.25 15.1 1.8 16.4 1.0 2.3 13.4 12.9 8.2 6.7 4.6 7.4 (2.9, 13.3)45Table 5: Differences of final treated plan to pre-plan dosimetric indices for each patient shown in Table4. HR-CTV volume is given in units of cm3, D90, V100, V125, V150, and V200 are given in %, andthe organ doses are reported as minimum dose to the maximally irradiated 2cm3 in units of Gray.Patient 1 2 3 4 5 6 7 8 9 10 Median (IQR)HR-CTV Vol 6.9 3.1 2.6 8.2 1.2 -0.5 0.6 7.9 -2.1 -6.5 2.9 (1, 7.2)D90 5.7 -13.7 10.1 -15.1 0.3 4.2 1.1 -0.1 -0.6 2.3 0.7 (-3.5, 4.6)V100 2.9 -6.8 3.1 -7.5 -0.5 1.5 -2 -0.7 0.1 0.6 -0.6 (-3.2, 1.9)V125 13.3 -10.9 19.4 -20.5 3.6 5.4 8.7 0.6 -1.2 -2.5 4.5 (-2.3, 9.9)V150 17.0 -9.1 35.2 -13.7 20.8 13.1 5.3 -1.6 -0.2 -10.8 9.2 (-3.5, 18)V200 13.3 -3.7 18.8 -2.3 16.8 4.2 3.1 -1.6 2.4 -8.6 3.6 (-1.8, 14.2)Bladder 1.0 -0.3 7.0 2.5 -4.4 2.0 -0.8 1.5 0.5 -3.5 1.3 (-0.4, 2.1)Rectum 3.9 -1.5 0.7 -0.8 -1.1 2.4 -3.9 1.6 1.1 -0.2 0.0 (-1.2, 1.8)Sigmoid 6.8 0.5 9.6 4.0 -0.5 -6.5 -2.8 1.6 -5.7 5.4 1.0 (-1.1, 4.7)Small Bowel -1.1 -5.9 -0.8 0.0 1.6 -0.3 -7.3 -7.5 0.5 -2.1 -1.0 (-6.3, -0.2)Figure 17: HR-CTV and Organ at Risk DVHs shown for each patient.4.3.2 Needle, Dwell Position, and Dwell Time StatisticsNeedle, dwell position, and dwell time statistics are given in Table 6. Interstitial needle anglesvaried from 0o to 53o. The median overall insertion difference for all needles was 2.3mm (IQR: 1.5,3.3) and the median inserted angle difference was 4.3o (IQR: 2.4o, 7.7o).46Table 6: Final treated plan needle and dwell time results table. The number of IC and IC/IS needles,straight and curved needles, active IC, IS and total dwell positions, IC, IS, cumulative dwell times,and IS needle length. Euclidean distance insertion differences are given for each patient for straightneedles, curved needles, and all needles, as well as the inserted angle difference.Patient 1 2 3 4 5 6 7 8 9 10 Median (IQR)IC Needles 0 0 0 0 0 0 5 0 0 0 0 (0, 0)IC/IS Needles 8 9 8 9 6 6 3 9 8 6 8 (6, 8.8)Total Needles 8 9 8 9 6 6 8 9 8 6 8 (6.5, 8.8)Number of Straight Needles 1 6 2 7 1 2 5 5 5 1 3.5 (1.3, 5)Number of Curved Needles 7 3 6 2 5 4 3 4 3 5 4 (3, 5)Active IC Dwells 17 28 26 14 5 18 15 47 20 25 19 (15.5, 25.8)Active IS Dwells 15 27 29 14 22 22 40 24 27 19 23 (19.8, 27)Dwells 32 55 55 28 27 40 55 71 47 44 45.5 (34, 55)IC Cumulative Dwell Time (s) 144 120 156 170 14 117 5 174 173 56 132 (71.3, 166.5)IS Cumulative Dwell Time (s) 38 75 79 125 53 53 35 38 57 38 53 (38, 70.5)Cumulative Dwell Time (s) 182 195 236 295 67 170 40 212 230 94 188.5 (113, 225.5)IS Needle Length (mm) 135 185 163 95 110 125 200 132.4 160 105 133.7 (113.8, 162.3)Median Insertion Differencefor Straight Needles (mm)5.5 N/A 0.9 1.5 1.1 3 0.6 2.4 1.4 2.6 1.5 (1.1, 2.6)Median Insertion Differencefor Curved Needles (mm)8.1 7 5 1.6 2.7 4 2.8 2.2 5.2 2.8 3.4 (2.7, 5.2)Median Overall InsertionDifference (mm)5.6 7 1.3 1.5 2.3 3.5 1.1 2.3 1.5 2.7 2.3 (1.5, 3.3)Median Inserted AngleDifference (◦) 22.6 28.8 2.8 2.3 1.3 4.7 1.3 8.7 4.7 3.9 4.3 (2.4, 7.7)4.3.3 Clinical outcomeThe mean follow-up was 12mo. (max. 25mo.). Treatment was well tolerated, only grade 1 and2 acute and late toxicities (CTCAE Version 5) were reported. 100% of patients achieved completeclinical and radiological response at 3mo, none with local recurrence. 2 patients presented with distantmetastasis at 13 and 21mo respectively. These two patients were subsequently treated with StereotacticAblative Radiotherapy (SABR) and Chemotherapy (Chemo), respectively. Individual patient follow-up results are shown in Table 7.4.4 Discussion4.4.1 Patient selectionPatients were selected for treatment using a PSCT based on two primary criteria. First that theirtumour was located in the upper three-quarters of the vagina and second that their tumour was greaterthan five millimeters in thickness. Some HR-CTV geometries are more easily treated via this templatethan others. HR-CTV geometry which extends away from the cylinder in one or two general directions47Table 7: Clinical outcomes, showing any recurrences, time to recurrence, and CTCAE Version 5toxicities.PatientFollowup time(months)RecurrencesiteTime toRecur-rence(mo.)Treatmentafter Re-currenceAcute Toxicity Late Toxicity1 27 Liver 21 SABRGrade 1(Nausea)Grade 1 (Pelvic pain), Grade 1(Pelvic fracture), Grade 1 (Legedema)2 25 None NoneGrade 1 (Pelvic pain), Grade 1(Diarrhea), Grade 2 (Vaginalinflammation)3 22 None NoneGrade 1 (Rectal), Grade 1 (PelvicPain)4 19 None None Grade 2 (Vaginal hemorrhage)5 18Peritoneal,lung13 Chemo NoneGrade 2 (Vaginal inflammation),Grade 1 (Pelvic Pain)6 16 NoneGrade 2(Nausea,vomiting)Grade 2 (Vaginal stricture)7 14 None None Grade 1 (Vaginal hemorrhage)8 11 NoneGrade 2(Nausea,vomiting)Grade 1 (Rectal hemorrhage)9 3 None None None10 5 None None Noneis well-treated via the PSCT technique because needles can be oriented in the direction of the deepestregions of the lesion. Circumferential HR-CTV geometries are more difficult to treat via this technique,as compared to a technique involving a perineal template. This is because covering every direction ismore difficult given the needle number and curvature constraints required to fit all needles within thecylinder. It is however possible to combine a PSCT with an IS grid template to be able to have theadvantages of both methods.4.4.2 Insertion procedureAlthough subjective, all oncologists (a total of 5) involved in this study found the PCST insertionprocess easier than performing a similar implant using a perineal template or freehand needles inaddition to a vaginal cylinder. The short interstitial needle distances give confidence that needleswill not deviate substantially from their planned positions. In addition, there is no need to validatethe position of each needle in the OR using intraoperative imaging, since they are constrained by thetemplate; if the template is placed as intended, the needles will follow. Combining having the sameoncologist place the dummy cylinder for planning and insertion and using the orientation notch toobtain the correct rotational position was found to be a simple and reliable method to ensure that the48template was placed as intended. Pre-inserting the needles into the cylinder, which can be done whilethe patient is prepped for the procedure, saves time during the procedure, as each needle only needsto be pushed to its final interstitial insertion depth once the cylinder is inserted. In addition, sincethe collets are already threaded onto the base of the cylinder, they only need to be slightly loosenedindividually as each needle is advanced and then tightened after the needle is fully advanced.4.4.3 Insertion accuracyBecause the path length of the flexible needles inside the PSCT is much longer than their interstitialdistance, they can be placed accurately as deep as 3cm within the lesion, as shown by a low medianoverall insertion difference of 2.3mm. The insertion differences between preplan to inserted plan dwellpositions and insertion angle difference decreased after the first two patients because of the observationthat 3D printed needle channels tend to project the needle into a slightly less oblique trajectory thanwas pre-planned, as can be seen in the inserted angle difference row in Table 6. This is due primarilyto the gap tolerance between the needle channel and the needle, and the fact that as the needle extendsout of the cylinder, it tends to act like a cantilever. If there is not enough bending resistance in theneedle at the cylinder, it is too free to move wherever it is pushed in the tissue. To minimize thiseffect, care was taken in the following treatments to allow for as long a straight section as possible (wecall this the “barrel length”) just inside the template for the needle to project along before exiting thetemplate into tissue. This ensures that the needle is well along its intended trajectory before exitingthe template, and thus any deflection is mostly a result of tissue pressure on the needle. We targeta minimum 5mm barrel length. Since this adjustment was made, the median insertion difference forstraight needles, curved needles, and all needles was 1.5mm (IQR 1.1, 2.5), 2.8mm (IQR 2.6, 4.3), and1.9mm (IQR 1.5, 2.4) respectively, with a median inserted angle difference of 3.4◦ (IQR 2.1, 4.7).While it is natural to want to optimize this procedure to minimize insertion errors, this is notnecessarily required, or sometimes desirable in practice, rather, the more important metric is whethera sufficiently high-quality final plan can be created based on the final inserted geometry. In ourexperience, during preinsertion evaluations, the oncologist may decide to extend or retract a needlerelative to its preplanned position dependent on tumour size or organ location on the treatment day,thus making preplan insertion accuracy an unfair comparison. Regardless, these results demonstratethat even such intentional changes are relatively small, thus preplanning remains a robust approach.494.4.4 Plan qualityOverall, the plan quality for this patient cohort was very good. Institutional HR-CTV D90 andV100 planning goals were met or exceeded for all patients. Our HR-CTV V150 and V200 planninggoals are set for the preplanning stage and, based on clinical experience, are intentionally low, with therecognition that they may increase in the post-plan. We do not change those goals for the treatmentplan to ensure that planners have created as homogeneous a plan as possible. In this cohort, onlytwo of the ten patients satisfied the V150 and V200 goals. In all patients, care was taken to avoidcontiguous V200 and to avoid V150 crossing the vaginal wall. All patients exceeded two or moreOAR institutional planning aims, eight patients exceeded three or more, and 4 patients exceeded all.No patient’s treatment doses exceeded bladder limits, 3 exceeded rectum, 1 exceeded sigmoid, and 4exceeded small bowel. In all cases, the OAR doses were judged by the treating RO to be a reasonablecompromise to achieve target coverage.We have seen that the quality of the plans produced via this technique has been equivalent toor better than that achievable by our standard techniques. Compared to IC Cylinder and grid orIC Cylinder and freehand needles, treatment facilitated by a PSCT can be preferable, since highlyconformal preplanned treatments are reproducible with a single template while permitting very lowinterstitial needle lengths. The ability to consider dosimetric as well as needle number and positiontrade-offs before insertion allows for quantitative evaluation and comparison between different treat-ment options. The PSCT technique has the potential to reduce patient trauma due to the smallcumulative interstitial needle lengths required to create a highly conformal plan, and the fact that theneedle enters the patient tissue through the vaginal mucosa rather than through the perineum, thusreducing bleeding and discomfort.4.4.5 Clinical OutcomesOverall the clinical outcomes for these patients are promising. Local control (complete radiologicaland clinical response for each patient) was excellent, especially given the challenging nature of thesetumours. Most of these patients were referrals from other centers in British Columbia, and without anaccurate interstitial technique available, many would instead be given extensive surgery or palliativecare.Altogether, treatments delivered using PSCTs were well tolerated in all patients. The grade oftoxicities experienced aligns with our institutional experience and with similar published data [9], [56],50[64]. Distal recurrences were observed for some cases with highly aggressive disease and were likelyunaffected by the brachytherapy treatment.This technique can deliver high-quality treatments with acceptable toxicities, encouraging earlylocal control and organ preservation for patients who otherwise would have very invasive treatmentsor no treatment at all.4.5 Conclusion3D-printed patient-specific templates for the guidance of interstitial high-dose-rate brachytherapy ofthe vagina can be used to preplan and deliver highly conformal interstitial vaginal HDR-BT treatments.Treatment preplanning can be used to generate 3D printable templates which accurately facilitatethe placement of deep IC/IS dwell positions. These templates can be used to create high-qualitytreatment plans, particularly for deep, localized, and top-of-vault lesions, improving target coverage,reducing OAR dose, reducing interstitial needle length and trauma in non-tumour tissue and improvingconfidence in needle insertion without intraoperative MRI or US. Longer follow-up is needed to assesslocal control, although early results are promising for the efficacy and safety of the technique.515 Development and Clinical Evaluation of Tandem and Cylin-der TemplatesThis chapter describes the ongoing development and evaluation of an alternative to PSCTs forcervical cancer and is under preparation for publication. Like the previous chapter, some backgroundinformation is reiterated for continuity.5.1 IntroductionImage-guided HDR-BT is the standard of care for primary cervical tumours and is delivered inconjunction with pelvic external beam radiation therapy (EBRT) [6], [8], [9]. Cervical brachytherapyis typically given in three to five fractions, typically separated by at least 24 hours.Cervical HDRBT is usually delivered using intrauterine tandem applicators in combination withring or ovoid vaginal applicators (Figure 4B and 4C). These applicators result in a symmetrical “pear-shaped” dose distribution (Figure 18A). In most cases, IC applicators are sufficient for treatment. Ifthese applicators are insufficient, interstitial needles can be added either via free-hand insertion orthrough guide holes in the vaginal applicator, such as in the Venezia Applicator (Elekta). In addition,some IC/IS applicators, such as the Venezia applicator, contain multiple parts which must be assembledin the vagina, which can be challenging. An example is shown in Figure 5A, where the tandem andeach half of the Venezia ring must be clicked together. Different treatment considerations, such as thesize of the tumour [65], dictate the appropriate applicator.In cases where there is vaginal extension of the disease, the ring or ovoid applicator is replaced bya cylinder (Figure 4A). This allows for treatment of both the cervix and the vagina. Standard tandemand cylinder applicators have only a single, central channel through which the source can transit.This results in a symmetric dose distribution (Figure 18B) around the channel, and does not facilitatethe degree of broadening of the dose distribution at the cervix, that the ring or ovoid applicators do.For very extensive disease, it is possible to pair the tandem and cylinder applicator with a perinealtemplate.Recently, commercial applicator sets have been developed where the vaginal portion of the applica-tor set has multiple IC channels through which needles can be placed, such as the Universal InterstitialCylinder Set (Varian). These applicators can help broaden and customize the dose distribution forlarge tumours (Figure 18C). These templates are, however, very expensive, and the needle trajectories52are not customizable.Image guidance plays an integral role in IC/IS cervical BT. Ultrasound (transvaginal, transrectal,or transabdominal), computed tomography (CT) and magnetic resonance imaging (MRI), dependingon local resources, are used intraoperatively to ensure that needles are placed in quality treatmentlocations and are not puncturing critical organs [18]. Each of these modalities has limitations, however.US results can be variable, difficult to repeat, and are operator-dependent [18]. Intraoperative MRIand CT require increased anesthesia and treatment times, are not widely available, and are resource-intensive [18].We have developed a cost-effective, customizable, 3D printable IC/IS cervical tandem and multi-channel cylinder template. This template pairs the generic tandem and cylinder template dose distri-bution with the benefits of the full “pear-shaped” dose distribution at the cervix, with the ability tofurther customize the dose distribution using IC/IS needles. IC/IS needles can be planned with genericgeometries or can be customized. The addition of IC/IS needles allows us to treat larger cervical dis-ease adequately without over-dosing the OARs, and customization allows us to have patient-specificsolutions for large and/or asymmetrical disease, with the intent of reducing toxicity to OARs.This study describes the design of a new IS T&C template (which can be generic or fully customized)and the treatment of 6 patients at our centre with HDRBT facilitated by 3D-printed T&C templatesbetween September 2021 and July 2022. The treatment cases are described from pre-planning throughimplant, final planning, and treatment. For cases where patient-specific T&C templates were created,positions and dosimetry are compared between preplan and final plans. The practicality of preplanningfor IC/IS HDRBT of the cervix is discussed. These templates are shown to be able to create high-quality insertions and treatment plans, without intraoperative imaging.5.2 Materials and Methods5.2.1 Design and Clinical DevelopmentThe T&C template was designed based on the previously discussed PSCT, with the modificationof being able to accommodate a 60-degree tandem within the cylinder.Tandem-On-Top DesignThe first iteration of the design featured a large central channel for the template to pass through,with a curved slot for the tandem radius to sit in. The cervical stopper sits directly on a sloped surface53Figure 18: Example Cervical Applicator Dose Distributions. A: Example of pear-shape dose distribu-tion (red) of a tandem and ring applicator. B: Example of symmetrical dose distribution (red) arounda standard tandem and cylinder applicator with no additional needles. C: Example of asymmetricaldose distribution achievable with a tandem and cylinder with additional needles surrounding the cen-tral channel.54of the cylinder (Figure 19A). In this and the following designs there is no need for a means to laterallyor rotationally fixate the tandem, since the curved portion of the tandem sits in a correspondinglycurved slot in the cylinder, fixing its rotation, and since the cylinder is tied using surgical ties withforward pressure which keeps the tandem fixed in the longitudinal direction.Embedded Tandem Design The second iteration of the design improved upon the first iteration byallowing the cervical stopper to drop into a slot within the cylinder (Figure 19B, 19C, and 19D). Thisdesign creates less of an air gap between the cylinder surface and the vaginal wall as compared to thefirst design where the cervical stopper pushes the vaginal wall away from the cylinder.IC/IS Needle TrajectoriesNeedles are locked using collets (Figure 19E). Depending on the tumour geometry, the preferredorientation of interstitial needle trajectories changes. Sometimes straight needles are preferred toextend out of the cylinder, sometimes the needles should flare out, and sometimes they should exitthe cylinder towards (Figure 19F) or parallel to the tandem. Generic designs were made for eachconfiguration.Patient-Specific Tandem and Cylinder DesignsFor complicated cases, the needle trajectories of the generic designs may be insufficient to satisfac-torily treat the tumour. Because these devices are manufactured in-house, it is possible to manuallydesign non-uniform, custom needle trajectories which will improve the coverage of the tumour (Figure19A). This is done by manually planning the needle trajectories in the treatment planning software,and then exporting them using the previously described PSCT export software, and then editing theCAD model in SolidWorks to accommodate the tandem.55Figure 19: Example T&C templates. A: Tandem-on-top design, with custom needle trajectory holes.B: Embedded tandem design, with generic holes and tandem inserted. C: Generic embedded tandemdesign, with needles inserted. D: Embedded tandem design with needles inserted. E: Base of T&Cdesign, with tandem and needles inserted. F: Full T&C design, with needles and tandem inserted.Needles are designed to orient slightly in the anterior direction.5.2.2 Cohort and Treatment CharacteristicsBetween September 2021 and July 2022, six patients with cervical cancers with vaginal extensionwere treated with a T&C template, for three or more fractions. Each patient was treated with an in-house 3D-printed T&C template, without a perineal template, freehand needles, or any intraoperativeimage guidance. Cohort and treatment details are given in Table 8.5.2.3 Pre-planning WorkflowTo pre-plan PSCT templates, we acquire a pelvic T2-MRI scan one week before the brachyther-apy insertion, with a dummy cylinder in situ. This workflow is, however, not generally sufficient ornecessarily desirable for cervical treatments. To replicate treatment geometry a tandem would needto be inserted along with the dummy cylinder, which would require the patient to receive an extrainstance of anaesthetic for an insertion without delivering treatment. There may be cases where therisk of additional anaesthetic is outweighed by the benefit of preplanning before the first insertion,56Table 8: Patient age at treatment, diagnosis, HR-CTV volume for each fraction, and prescriptioninformation. All patients were diagnosed with primary squamous cell carcinoma (SCC). EBRT pelvicprescription and nodal boost are both shown. Each EBRT course was given in 25 fractions, with atotal of 45 Gy prescribed to the primary tumour with a boost (55 or 57 Gy) to involved lymph nodes.Patient Age HistologyHR-CTV Vol(cm3)Fr1HR-CTV Vol(cm3)Fr2HR-CTV Vol(cm3)Fr3HR-CTV Vol(cm3)Fr4EBRT(Gy)Dose per BTFraction (Gy)Fractions1 65 SCC 58.7 45.6 40.1 37.2 45/55 7 42 58 SCC 72.8 64.9 53.9 46.4 45/55 7(3), 6(1) 43 60 SCC 61.3 53.6 61.3 50.4 45/57 7 44 77 SCC 26.5 26.6 28.5 30.2 45/55 7 45 75 SCC 13.5 13.1 14.2 11.8 45/55 7 46 49 SCC 59.6 60.7 57.4 55.7 45/55 7 4but in general it is sufficient to use a generic tandem and cylinder template for the first fraction, andthen to use the post-insertion MRI scan from this insertion to preplan the subsequent fractions. Thisgives the planner the ability to adapt the treatment based on the first fraction without an additionalinsertion. The two patients who received a pre-plan were treated using a generic T&C template fortheir first fraction and then were treated using a patient-specific T&C template for their subsequentfractions.For patients 3 and 6, based on their first fraction post-insertion MRI-based contours, needle trajec-tories were designed to improve the dose distribution for subsequent fractions. A library of importablecurved needles was used to increase planning efficiency. Curved needle radii were 20mm by default.Needles were initially planned at the first fraction needle locations, after which the number, position,and interstitial length of needles were adjusted manually. The tip of each needle could be extended intotissue as required or could be an intracavitary-only needle. Like the PSCT, each needle was orientedto have a perpendicular entry point at the base of the T&C template, which permits threading of theentry hole, allowing each needle to be individually fixed in place with locking collets. Dwell positionswere set at 5mm spacing and placed throughout the HR-CTV. Preplans for both patients were createdby an experienced medical physicist using the Eclipse 15.6 Brachyvision software (Varian) and reviewedby the implanting RO. Once this pre-plan was created, a matching T&C template was exported usingthe PSCT 3D modelling software, the final result of which was modified to accept the tandem usingSolidworks. An operating room (OR) reference sheet was created for each patient-specific T&C tem-plate (Appendix C) that shows the orientation of the template and the location of the tandem, eachneedle channel, the corresponding channel numbers, the desired depth of insertion, and space to recordthe final protrusion of each needle from the template after the implant is complete.57Figure 20: Example Preplan and 3D Printed T&C. A: Axial View of Preplan. Needles are shown ingreen/pink, Bladder (green), Rectum (brown), Sigmoid (yellow) Small Bowel (purple). B: Tandemand needles exiting T&C template top. C: Saggital View of Preplan. D: T&C template with tandemand some needles inserted.585.2.4 Template ManufacturingThe T&C templates were all 3D printed of polyetheretherketone (PEEK) with 100% infill usinga 0.4mm nozzle on an AON-M2 3D (AON3D, Montreal, Canada) printer, and machined on a lathein post-processing in order to have a very smooth final finish. The needle holes at the base of eachcylinder were tapped to allow a locking collet to fix each needle in place. Channels were validatedpost-printing by passing a flexible needle through each channel, testing collet locking functionality, andmeasuring the interstitial needle angle. The tandem fit was verified manually. After validation, eachT&C template was steam sterilized using the previously described independently validated procedure( Appendix B).5.2.5 ImplantT&C templates were prepared in the OR by inserting each needle into the T&C template as faras possible without the tips extending outside the cylinder to not damage any tissue as the cylinderwas inserted. Each collet was locked to finger tightness, so the needles did not move during cylinderinsertion. Reference marks were made on each needle using a sterile marker to indicate the insertiondepth of the needle according to the reference sheet. All implants were performed under spinal anes-thetic. Patients were examined under anesthesia before T&C insertion to evaluate tumour geometryand fiducial markers were placed to mark the clinical extent of the disease. The tandem was insertedfirst, then the cylinder template was inserted and fit to the tandem positioning. One by one, eachneedle was then loosened, advanced to its final depth as noted on the OR reference sheet and tightlylocked. Once all needles were fully inserted, the T&C template was secured using a belt and surgicalties. The ties were placed between the needles at the base of the template and applied pressure to thetemplate towards the vagina, to prevent rotation or translation of the T&C template. Finally, eachneedle was labelled with a channel number sticker corresponding to the OR reference sheet.5.2.6 Post-InsertionEach patient underwent CT scanning for final treatment planning after their T&C template inser-tion and recovery from anesthesia. For the first fraction, both CT and MRI images were acquired.The MRI was used to delineate the HR-CTV and was fused to the CT images, which was used for theOAR contours and treatment planning. For subsequent fractions, only a CT was acquired which wasregistered to the patient’s first fraction MRI scan, based on both the applicator position and anatomy.59The HR-CTV was then transferred to the CT. For the 2 patients with preplans, needle geometries anddwell times were imported into the final plan as a template and the needle set was aligned to the finalCT as a group. Individual needle positions and trajectories were corrected as needed. Dwell timesat the final dwell positions were then modified as needed to satisfy planning goals. While planningwas not formally timed during this study, modifying a preplan was significantly faster than de novoplanning and took at most 30 minutes post-contouring to complete, often much quicker. For patientswith generic cylinders, the needles and the tandem were identified on the initial CT, a treatment planwas devised and then saved as a plan template. For subsequent fractions, this template was imported,aligned to the planning images of the day, and adjusted as necessary.5.2.7 AnalysisFor each patient, HR-CTV D90 and OAR D2cm3 were determined. Only the brachytherapy dosesare reported in this study since the aim is to evaluate the utility of the brachytherapy templates. Dose-volume histograms (DVHs) were calculated for each treated plan. The differences between the finalinserted plan and preplan for HR-CTV D90 and OAR D2cm3 for patients who received a preplan weredetermined. The needle dwell position and needle angle differences between the final inserted plan andpreplan for patients who received a preplan were also calculated. Patient follow-up was conducted aminimum of 3 months after treatment. Each patient’s clinical and radiological response, along withtheir highest toxicity score, was documented based on the CTCAE Version 5 criteria [63].5.3 Results5.3.1 DosimetryThe BC Cancer— Kelowna institutional treatment objectives, and treated HR-CTV D90, andBladder, Rectum, Sigmoid, and Small Bowel D2cm3, are reported in Table 9. DVH plots for eachpatient’s treated fractions are given in Figure 21.60Table 9: Cervical HDR-BT institutional targets and treated dosimetric indices for all patients. HR-CTV D90 is given in units of Gy, and the OAR doses are reported as minimum dose to the maximallyirradiated 2cm3 in units of Gy. The applicator used for each treatment is given in the rightmostcolumn. PS stands for patient-specific.Patient-FractionD90(Gy)BladderD2cm3(Gy)RectumD2cm3(Gy)SigmoidD2cm3(Gy)Small BowelD2cm3 (Gy)ApplicatorTypeTarget >7.3 <6.3 <3.9 <3.9 <2.61-1 6.8 6.5 5.2 2.5 2.9 T&R1-2 7.6 5.8 5 1.8 1.7 T&C1-3 6.6 5 4.4 2.7 1.9 T&C1-4 7.6 6.3 5.1 1.7 2.1 T&C2-1 7.2 6.2 5.8 4.3 4.6 T&R2-2 6.9 6.3 5 3.9 4.1 T&C2-3 7.4 5.6 4.9 4.3 3.7 T&C2-4 6.3 5.3 4.3 3.4 3 T&C3-1 7.1 6.4 4.7 4 2.2 T&C3-2 7.5 6.5 4.6 3.4 2.4 PST&C3-3 7.4 5.9 4.6 4.1 2.6 PST&C3-4 7.4 6 4.7 3.4 3.1 PST&C4-1 7.6 5.8 3.9 3.9 4.5 T&C4-2 7.8 4.6 2.6 3.6 4.6 T&C4-3 8.1 5.8 3.9 4.1 1.4 T&C4-4 7.8 4.8 3.1 4.4 4.4 T&C5-1 5.4 4.8 3 3.2 0.8 T&C5-2 5.8 3.9 2.8 2.8 3.1 T&C5-3 5.9 4.1 3.2 3.4 2.5 T&C5-4 5.0 3.8 2.9 2.5 1.4 T&C6-1 7.8 5.6 4.4 2.3 0.8 T&C6-2 7.6 6.3 4.2 3 1 PST&C6-3 7.6 5.2 4.3 2.1 1.1 PST&C6-4 7.5 4.8 4 2.5 1 PST&CFigure 21: HR-CTV and Organ at Risk DVHs shown for each treated plan for each patient.615.3.2 Preplan to Final Plan ComparisonAn example pre-plan and the corresponding final treated plan are shown in Figure 22. The differ-ences between the final treated plan and the preplan dosimetric indices are given in Table 10. DVHcomparison plots for preplan and final plan for each patient are shown in Figure 23.Figure 22: Example Preplan and Final Plan for T&C template. A: Sagittal view of preplan. Needlesare shown in green/pink, Bladder (green), Rectum (brown), Sigmoid (yellow) Small Bowel (purple),B: Sagittal view of final plan.Table 10: Cervical HDR-BT preplan and treated dosimetric indices differences (treated plan minuspreplan) for all insertions which were preplanned. HR-CTV D90 is given in units of Gy, and the OARdoses are reported as minimum dose to the maximally irradiated 2cm3 in units of Gy.Patient-Fraction 3-2 3-3 3-4 6-2 6-3 6-4 MedianD90 (Gy) -0.1 0 0 0.4 0.4 0.5 0.2Bladder D2cm3 (Gy) 0 0.6 0.5 -0.6 0.5 0.9 0.5Rectum D2cm3 (Gy) 0 0 -0.1 0.1 0 0.3 0Sigmoid D2cm3 (Gy) 0.9 0.2 0.9 -0.9 0 -0.4 0.1Small Bowel D2cm3 (Gy) 0.1 -0.1 -0.6 -0.2 -0.3 -0.2 -0.262Figure 23: Preplan and Preplan-based Treated Plan DVHs for T&C template.Preplan to final plan needle positions for patients 3 and 6 are shown in Table 11. The medianoverall insertion difference for all needles was 3.3mm and the median inserted angle difference was7.0◦.Table 11: Preplan to final plan dwell positions comparison for patients 3 and 6. Euclidean distanceinsertion differences are given for each patient for straight needles, curved needles, and all needles, aswell as the inserted angle difference.Patient Pt3 F2 Pt3 F3 Pt3 F4 Pt6 F2 Pt6 F3 Pt6 F4 MedianMean InsertionDifference forStraight Needles(mm)3.0 3.4 2.9 N/A N/A N/A 3.0Mean InsertionDifference for CurvedNeedles (mm)2.4 2.1 2.1 3.8 6.0 6.2 3.1Overall MeanInsertion Difference(mm)2.7 2.7 2.5 3.8 6.0 6.2 3.3Median InsertedAngle Difference forCurved Needles (◦)13.7 12.6 11.8 1.2 2.1 1.8 7.0635.3.3 Clinical OutcomeThe median follow-up time was 10.5 months. Five of the six of patients achieved complete clinicaland radiological response at 3mo, one with local recurrence. No patients presented with distantmetastasis. Treatment was well tolerated, with only grade 1 acute and late toxicities (CTCAE Version5). Individual patient follow-up results are shown in Table 12.Table 12: Clinical outcomes, showing any recurrences, time to recurrence, and CTCAE Version 5toxicities.PatientFollow uptime(months)RecurrenceTime toRecurrence(mo.)TreatmentafterRecurrenceAcute Toxicity Late Toxicity1 18 NoneGrade 1(Radiationcystitis)None2 6Cervicalmass6 NoneGrade 1(Fibrosis)Not available3 12 NoneGrade 1(Fibrosis)Grade 1 (FibrosisandTelangiectasias)4 12 None None None5 9 NoneGrade 1(Telangiectasias)None6 9 NoneGrade 1 (VaginalBleeding andStricture)None5.4 DiscussionPatients were selected for treatment using a T&C template if they had vaginal extension of theirdisease. Tumour geometries which extend in the posterior direction are well treated via the T&Ctechnique because needles can be oriented in the direction of the deepest regions of the lesion, straightor flared away from the tandem (Figure 22). Tumours which are too large to be treated by thetandem alone are also good candidates for the IS T&C technique, as the needles can be orientedcircumferentially around and parallel to the intrauterine segment of the tandem.The IS T&C device described here solves the described problems with current cervical IC and IC/IStemplates. It can be used to create symmetric and asymmetric dose distributions in both the cervix64and the vagina simultaneously, needles can be flared or kept parallel to the tandem, depending on thetumour anatomy, and, if needed, the needle orientations can be customized. The ability to changethe next fractions needle positions based on the most recent fraction brings a new adaptive elementto cervical brachytherapy template design. Manufacturing these T&C templates in-house brings bothcost-savings benefits in addition to the benefits of increased treatment options.Determining patient-specific needle orientations for the T&C is more challenging than for a PSCT,given the amount of space within the cylinder that the tandem takes up, which makes both havingmore than 6-8 needles and providing a barrel length sufficient to achieve the intended insertion angledifficult. The development of a few generic designs allows for quick decision-making and assessment ifa custom approach is necessary, rather than custom-planning each template.Although subjective, the T&C insertion process is very simple. Given that there is no assemblyof the device required, the insertion process is less cumbersome as compared to the Venezia templatefor example. The short interstitial needle distances give confidence that needles will not deviatesubstantially from their intended positions.Pre-inserting the needles into the cylinder saves the oncologist time and effort during the procedureas each needle only needs to be pushed to its final interstitial insertion depth once the cylinder isinserted. This process is completed by a nurse or radiation therapist in the operating room, duringset-up In addition, since the collets are already threaded onto the base of the cylinder, they only needto be slightly loosened individually as each needle is advanced and then tightened after the needle isfully advanced.Patient 5 had uncharacteristically low D90 values (Table 9). Upon investigation, it was noted thatthe patient had a primary cervical tumour with a vaginal sidewall extension. In the clinical notesat the time of BT, the vaginal extension had resolved, but the geometry was kept in the HR-CTVcontour, though it was not treated with the full dose. When we removed this portion of the HR-CVTand recalculated, the treatment D90 for the cervical portion of the tumour for fractions 1 through 4were 9.5, 8.6, 8.6, and 7.8 Gy respectively, which are above the minimum targets.The average curved angle for Patient 3 was 34.0◦ with two needles planned over 45◦. The averagefor Patient 6 was 15.1◦, with only one needle just above 30◦. The two needles at 46◦ had significantpreplan to final plan insertion angle differences, around 20◦. Patient 3’s design had no appreciablebarrel length. We subsequently learned that a minimum barrel length of 3-5mm is necessary to keepoblique angles accurate to within 5◦. This was incorporated as a design principle for later iterations ofthe template design. This change of design practice explains the differences in the “Median Inserted65Angle Difference for Curved Needles” between Patient 3 and Patient 6 in Table 11.During pre-insertion examinations, the oncologist may decide to extend or retract a needle relativeto its preplanned position, thus making preplan insertion accuracy a somewhat unfair comparison.These results demonstrate that even such intentional changes are relatively small, and thus preplanningremains a robust approach.There is no need to validate the position of each needle in the OR using intraoperative imagingsince they are constrained by the template; if the template is placed as intended, the needles willfollow, as is shown by the accuracy of needle placement in Table 11 and the pre-plan to final plansimilarity as shown in Table 10 and Figures 22 and 23.Overall, the plan quality for this patient cohort was very good. In any case where the OAR dosesexceeded our goals, the excess dose was judged by the treating RO to be a reasonable compromise toachieve target coverage. The T&C template treatment produces highly conformal treatments that canbe pre-plannable with a single, easy-to-use template.Overall, the clinical outcomes for these patients are promising. Local control (complete radiologicaland clinical response for five of six patients) was good and toxicities were acceptable.Thus, this technique can deliver high-quality treatments with acceptable toxicities and encouragingearly local control.5.5 ConclusionA clinical workflow has been described for the in-house design and 3D printing of IS HDRBT T&Ctemplates which can facilitate high-quality treatments for cervical patients with vaginal extension.Treatment dosimetry, pre-planning reproducibility (where used), and patient outcomes for six patientstreated at BC Cancer-Kelowna were shown to be promising. These templates have been shown topermit the placement of interstitial needles, whether preplanned or not, without image guidance. Theability to adapt a patient’s radiotherapy plan, including the treatment template, fraction-by-fraction,has been demonstrated, opening avenues in adaptive radiotherapy for cervical brachytherapy, andproviding practitioners with a new dimension of treatment options and plan adaptability. While thesize of the patient cohort is small, the T&C template stands to be an effective, simple, and customizabletreatment template.666 An Autoplanning Tool for 3D Printable Patient SpecificCylindrical Templates6.1 IntroductionThe objective of this work was to develop a geometry-based autoplanning algorithm which couldgenerate high-quality patient-specific needle trajectory sets for 3D printable interstitial (IS) vaginalhigh-dose-rate (HDR) brachytherapy (BT) templates in an acceptable clinical timeframe.6.1.1 Interstitial Vaginal BrachytherapyImage-guided vaginal HDR-BT is the standard of care for advanced primary and recurrent vagi-nal tumours and is delivered concomitantly with pelvic External Beam Radiation Therapy [4], [17].Interstitial (IS) HDR-BT of the vagina can be performed using single or multi-channel vaginal cylin-ders in combination with IS needles inserted freehand or using a perineal template, IS template, orusing solely freehand inserted needles [17]. Several commercial applicators are available to assist inthe placement of IS needles, both through the perineum (Kelowna GYN Template, Varian) and thevaginal wall (Universal Interstitial Cylinder Set, Varian, and the Venezia Template, Elekta).6.1.2 3D Printing in Gynaecological Brachytherapy3D printed templates have been proposed as a means of providing customized, patient-specificbrachytherapy for patients with challenging gynaecological lesions. These templates, which can be acombination of intracavitary (IC) and IS dwell positions or IS alone, aim to accurately place flexibleHDRBT needles in pre-planned positions [36]–[40], [66], [67]. Creating patient-specific BT templatesrequires pre-planning of both the needle trajectories and dwell times, in order to assess the design.These templates are manually designed, which can take significant planning time, and then a 3D modelmust be created prior to printing, which is also time-consuming to perform manually [50].A clinical workflow for the in-house design and 3D printing of patient-specific cylindrical templates(PSCTs) [50] has been developed and clinically implemented at our centre. The template design ispreplanned using a T2-MRI scan taken with a dummy cylinder in place a minimum of one week beforethe HDR-BT insertion. The design can incorporate both straight and curved needle trajectories whichmay be IS or entirely IC. In our workflow, the 3D template model is automatically generated based on67the preplanned needle positions exported from the treatment planning system using a custom scriptand then is 3D printed in-house [50]. This has also been described in Chapters 3 and 4. While thisexport-based software speeds up the manufacturing process, the manual pre-planning process for theseneedle trajectories remains time-consuming. In order to accelerate the clinical adoption of PSCTsand similar tools, it is imperative to have an automated needle trajectory pre-planning software whichallows the planner to explore planning options, and generate the relevant trajectories.6.1.3 Automated Needle Determination in BrachytherapyIC needle trajectory planning automation has been attempted for vaginal and/or cervical BTapplications [43], [44]. These techniques generally attempt to identify needle start and end positionswithin a patient-specific applicator and determine source trajectories through the allowable space bysolving a linear or quadratic trajectory optimization problem. Other trajectory planning algorithms forIS prostate and IC GYN BT [41], [42], [46], [48] and neurosurgery [49] have employed Rapidly exploringRandom Tree methods to define non-intersecting paths toward predefined endpoints or regions.As described in Chapter 3, IS needles are critical to the treatment of many vaginal GYN cases.Unfortunately, none of the efforts to automate needle trajectories thus far have shown IS needletrajectory determination for GYN BT.Automated needle planning has been successful in prostate brachytherapy by using the CentroidalVoronoi tessellation (CVT) [45] algorithm to plan the placement of needles. The algorithm partitionsthe prostate into cells, which approximately evenly spaces out the needles within the prostate.6.1.4 Interstitial Needle Trajectory Determination for PSCTsThe purpose of this work was to develop an autoplanning algorithm that can generate high-quality,clinically feasible needle trajectory sets for 3D printable interstitial vaginal high-dose-rate brachyther-apy templates. It addresses the difficulty and time-consuming nature of manually planning IS needletrajectories for patient-specific brachytherapy templates.In the following sections, we present a novel technique for the determination of high-quality needletrajectory sets for PSCTs. We first describe the algorithm used to generate IC/IS needle trajectoriesfor PSCTs. Then we describe the evaluation of the algorithm in a plan comparison study betweenplans created using the autoplanning software trajectory sets and manual preplans from a retrospectivepatient cohort.686.2 Materials and methods6.2.1 Description of AlgorithmThe overall autoplanning algorithm consists of a series of steps to solve for a single candidate needletrajectory set (or PSCT geometry). First, based on a user-defined number of curved IC/IS needlesto be solved for, the IS segments of the curved IC/IS needles are determined using two algorithms:a cylindrical surface-based (SB) CVT algorithm, and a Regression-based Expanding Volume CVT(REV-CVT) algorithm. Second, the auto-generated IS segments are adjusted based on user-selectedneedle obliquity and extension constraints. Thirdly, the curved paths to the base of the cylinder aredetermined for each curved needle. Finally, straight needles are added where they are able to fit. Thisalgorithm can be run many times in order to generate a library of candidate plans to select from. Thefollowing subsections describe the algorithm inputs, the SB-CVT algorithm, the REV-CVT algorithm,each of the solution steps, and how a library of candidate needle trajectory sets is generated andpresented.Algorithm InputsThe autoplanning software uses the target contours, and the contour of the dummy cylinder insertedfor the preplan T2-MRI scan [50]. These are extracted from a DICOM structure set file exported fromthe Brachyvision (Varian) treatment planning system (TPS).The user may input the following variables: a range of numbers, or a single number, of curved ISneedles desired, the number of plans to generate for each number of curved IS needles, a “skip margin”,a “barrel length”, an intersection tolerance distance, the minimum needle radius of curvature, theminimum needle exit angle, and a search step size. The “skip margin” is the distance out from thecylinder where the algorithm begins its needle search. The “barrel length” is the straight length withinthe cylinder before the needle exits the cylinder. The intersection tolerance distance is the minimumallowable distance between two needle path centerlines.Surface-Based Centroidal Voronoi Tesselation AlgorithmThe SB-CVT algorithm iteratively computes approximately uniformly-partitioned regions (Cen-troidal Voronoi Tesselation (CVT) regions [68], [69]) and their centroids on a full or partial cylindersurface. The algorithm takes as input a set, S, of points that are located on a cylinder surface, thedesired number of regions to generate and, optionally, seed points for each region to be generated (Fig-ure 24A). The seed points are used as generator points, or the points used to generate CVT regions69(Figure 24B). The seed points can alternatively be randomly chosen. The CVT regions are generatedby sorting each point in S into a region associated with its nearest generator point. At the beginning ofeach iteration, the algorithm determines the CVT regions associated with each generator point (Figure24B). The algorithm then calculates the surface centroid (Figure 24C) of each CVT region, which isthe geometric centre of the points within the region, on the cylinder surface. This algorithm thensets the next iteration of generator points at the current CVT region centroids. This iterative processcontinues until a stopping criterion is met, such as a maximum number of iterations or a thresholdfor the change in generator point positions, indicating that the algorithm has converged to a stableconfiguration (Figure 24D). The algorithm then outputs the list of points that belong to each CVTregion, as well as the surface centroid for each CVT region.Figure 24: Surface-based Centroidal Voronoi Tesselation. A: A surface point cloud representing aportion of a cylinder surface. Generator points are shown as red, green, and blue x’s B: Each pointin the surface point cloud is sorted into CVT regions based on proximity to generator points. C: Thecentroid of each region is calculated. D: The final regions and centroids after SB-CVT has converged.Regression-based Expanding Volume Centroidal Voronoi Tesselation (Step 1)REV-CVT uses SB-CVT to solve for the IS segments of IC/IS curved needles. The algorithm70attempts to evenly space needles inside the region of the target (Algorithm 1) by running SB-CVTat increasing depths in the target volume and fitting a regression line through needle-matched sets offinal SB-CVT centroids.To accomplish this, the cylinder surface and target volume (Figure 25A) are used as the startinggeometry. A virtual cylinder is intersected with the target to determine the portion of the virtualcylinder surface which is touching the target (Figure 25B). The first virtual cylinder has a radius equalto the nominal radius plus the skip margin, as seen in Figure 25B (the first virtual cylinder has alarger radius than the PSCT cylinder). CVT regions and centroids are generated on this resultantintersection surface (Figure 25C). For the first iteration, the current IS needle segments intersectthrough the first centroids (Figure 25C). Each IS needle segment is extended by the step size (Figure25D) . The endpoints of the extended needle segments are used as seed points for the next SB-CVTcall. Progressively larger cylinder shells are created (Figure 25 E). At the beginning of each subsequentiteration, lines of best fit for matching centroids from the previous shells are generated and extrapolatedto be used as seed points for the next shell (Figure 25F and G). If the extrapolated point lands outsidethe HR-CTV, that IS segment is considered completed and is not further iterated upon. This algorithmcontinues until all the line segments have endpoints outside the target (Figure 25H and I).71Figure 25: A: PSCT cylinder (dark blue) and target volume (grey). B: PSCT cylinder, target volume,virtual cylinder (light blue), and the points (black) on the surface of the first virtual cylinder wherethe target volume intersects the virtual cylinder. C: SB-CVT Regions (red, green, blue) and centroids(colored dots) and centroids (large dots) for the intersection points shown in B. Initial IS needlesegments are shown (red, green, blue lines). D: Extended current IS needle segments after the firstiteration (red, green, blue lines). E: The virtual cylinder (light blue) radius is expanded by the stepsize and the points where the target volume intersects the virtual cylinder are determined (black). G:SB-CVT is performed on the points shown in F. The endpoints from E are used as seed points for theCVT algorithm computation. F: For the second and subsequent iterations, each IS needle segment isgenerated using a regression fit of all previous centroids for that needle. A 2-D Example of centroidregression is shown. At iteration 4, there are 4 virtual cylinders (dashed). One IS Needle segment(black) is shown, calculated as a linear regression through its corresponding centroids. G: Each ISneedle segment is updated. In this case, the segments are fit lines between the matching centroids inC and G. H: Each IS needle segment is extended. I: Shows the final state of REV-CVT, with the ISneedles having fully exited the target volume.Angle and Length Correction (Step 2)In order to limit the optimizer from creating needles that are too oblique, the user is able to selecta minimum IS needle angle, which is defined as the angle between the IS needle and the cylinder axialplane. If an IS needle segment angle is less than the minimum angle, the needle segment is rotatedabout its midpoint to the minimum allowable angle (Figure 26A and B). Each needle is extended into72the cylinder by the barrel length (Figure 26C) to ensure the needle is exiting the cylinder in a straighttrajectory. Each needle is trimmed or extended so as to extend approximately 3mm past the targetvolume, to ensure at least one dwell position will sit on the distal side of the target (Figure 26C).These corrections are considered post-processing steps to REV-CVT and are not shown in Algorithm1. Once this step is complete, the IS needle segments are completed (Figure 25D)Figure 26: A: The angle of each IS needle is measured relative to the cylinder axial plane, and comparedto the minimum IS angle. B: Angle corrections to satisfy the minimum angle requirement have beenperformed as needed. C: The barrel length is added. The needles are extended or shortened as neededso as to extend 3mm past the target volume. D: Final IS needle segments.73Algorithm 1 Regression-based Expanding Volume Centroidal Voronoi Tesselation.function REV CV T (Target, Cylinder,Normals,Npaths, SkipMargin) //Fig.25Ai = 0Cylinderi = Cylinder +Normals× SkipMargin //Expanded cylinder (Fig.25B)IPs0 = GetIntersectingPoints(Target, Cylinderi) //Fig.25BCentroids0 = SurfaceCV T (IPs0, Npaths) //Fig.25CCentroidNormals0 = GetNormals(Centroids0, Normals, Cylinderi)Seeds = Centroids0 + CentroidNormals0 ∗ StepSize //Seeds for next CVT(Fig.25D)Centroids = Centroids0FinalPaths = [ ]while len(FinalPaths) < Npaths doi← i+ 1Cylinderi = Cylinder +Normals× StepSize× i //Expanded cylinder (Fig.25E)IPsi = GetIntersectingPoints(Target, Cylinderi) //Fig.25ECentroidsi = SurfaceCV T (IPsi, Seeds) //Fig.25GCentroids = Append(Centroidsi, Centroids)Paths = LinearRegression(CentroidsT ) //Fit through centroids (Fig.25F, G)NewEndpoints = Extrapolate(Paths, StepSize) //Fig.25HSeeds = [ ]for EPj ∈ NewEndpoints & Pathj ∈ Paths doif IsOutside(EPj , Target) thenFinalPaths = Append(PathTj , F inalPaths) //Fig.25ICentroids = Remove(j, CentroidsT )elseSeeds = Append(EPj , Seeds)end ifend forend whilereturn Nend functionPath to Cylinder Base Generation (Step 3)Once the IS segments of the curved needles are generated, the remainder IC section of the needle isconstructed by appending a tangent semicircular segment with the minimum allowable radius to eachsegment, which directs the needle path toward the base of the cylinder. The remaining straight lengthof the needle to the base is then appended (Figure 27A and B).An intersection check is performed to ensure there is a user-defined minimum distance between nee-dles within the cylinder and between each needle and the walls of the cylinder. A python-implementedbounded version of the limited memory Broyden–Fletcher–Goldfarb–Shanno algorithm [70] is used tovary the radius of curvature of the curve in each needle’s IC section, in order to find a set of radii thatresults in no inter-needle or wall intersections (Figure 27C).74Figure 27: A and B: The remainder IC section of the needle is appended. C: If there are intersectionsin the cylinder, radii are optimized to eliminate intersections. Note that the radii of the red and greencurves have been increased as a result of an intersection correction.Straight Needle Addition (Step 4)To increase the density of needles at the top of the vault, and to increase dwell time planningoptions, straight needles are added to the template, extending through the top of the cylinder throughany target voxels. These straight needles are added in a circular pattern and in the central axis of thecylinder as long as they do not intersect the curved needles (Figure 28B).Figure 28: A: The final curved needles. B: Straight needles are added to the cylinder, wherever theyfit, and are extended through the target.Plan Library GenerationThe user is able to search over a range of number of curved needles and may specify how manytimes to run the search for each configuration. For example, searching from 3 curved needles to 7curved needles while running the algorithm 5 times for each number of curved needles will generate 25candidate needle trajectory sets.75Once all plans have been generated, the algorithm sorts the plans based on the number of curvedIS needles. Once a library of plans is generated, the user may review the generated plans in the 3Dplots created, and select a plan to import back to the TPS. Once imported back into the TPS, thepreplan can be directly exported to a 3D printable format (.stl) using our in-house developed software[50], and/or dwell times can be determined to validate the pre-planned trajectories.6.2.2 Pre-planning Validation Study10 patients previously treated at our centre using a PSCT that was manually designed and pre-planned were included in this study. All patients had either primary or recurrent vaginal cancer. Onlythe results of the pre-planning process are relevant to this study and are included below, but patientcharacteristics and treatment details may be found in Chapter 4 for interested readers.Autoplan Generation and ComparisonAutoplanned needle trajectory set-based preplans were created for each patient to explore thequality of planned needle sets as provided by the autoplanner. The skip margin was varied patient-to-patient as determined appropriate by an expert treatment planner. The skip margin is set so asto initiate the search so that the needles will tend towards the deepest part of the lesion, so as tonot over-search the parts of the lesion closest to the cylinder. A range of 3-7 curved IS needles wassearched over, with 5 plans for each, resulting in a solution with 25 potential plans for each patient.The patient’s pre-plan MRI contoured HR-CTV was the target for each case. A 3mm stepsize was usedfor each autoplanned trajectory set. Once the algorithm had finished, the best set of needle trajectories(in the opinion of the planner) was selected and the associated plan and structure DICOM files were re-imported back to the TPS. Typically, the planner will look for an even distribution of needles throughthe target volume, with as many needles as possible in order to be able to generate a homogeneous dosedistribution. No modifications were made to needle trajectories. Once in the TPS, the dwell timeswere determined to produce a preplan respecting the institutional planning constraints. The numberof curved, straight, and total needles were recorded for each patient. The manually planned numberof needles for each case was compared to the autoplans. For each patient, the time required for theautoplanning software to generate 25 plans was recorded. Dose metrics and DVHs for each patient’streatment preplan and autoplan trajectory set-based preplan were calculated and compared.766.3 Results6.3.1 Plan GenerationExamples of a manually created preplan and an autoplan trajectory set-based preplan for the samepatient are shown in Figure 29. A 3D view (A and C) of the needle and tumour geometries are shown,as well as a 2D projection (B and D), showing needles, HR-CTV, and 100% isodose line are shown.The manually created plan in this case had 3 curved needles and 5 straight needles. The autoplan had5 curved needles and 5 straight.Table 13 shows the number of curved needles, straight needles and total number of needles for eachautoplan-based preplan, and for the corresponding manual preplan. The difference between the totalnumber of needles used in the manual and the autoplan for each patient are shown in the right-mostcolumn.The median time to generate 25 preplan needle trajectory sets for each patient was 10min7s (IQR:4m51s, 12m23s) on a computer with an Intel(R) Core(TM) i7-10700 CPU @ 2.90GHz with 16 GB ofRAM.77Figure 29: Manually created treatment preplan, and autoplan-based preplan. A: Manual preplan 3Dview of HR-CTV (transparent blue), cylinder outline (blue line), and preplan needles (green and pinklines). B: Manual preplan AP view of needles (green and pink lines), HR-CTV (blue outline), and100% isodose line (red). C: Autoplan-based preplan 3D view. D: Autoplan-based preplan AP view.78Table 13: Manual preplan and autoplan-based preplan needle counts for each patient. The difference(autoplan minus preplan) is shown in the rightmost column.Manual Plan AutoplanPatient# ofCurvedNeedles# ofStraightNeedlesTotalNeedles# ofCurvedNeedles# ofStraightNeedlesTotalNeedlesTotal NeedlesDifference1 1 7 8 5 5 10 22 6 3 9 4 6 10 13 2 6 8 4 5 9 14 7 2 9 5 6 11 25 1 5 6 7 3 10 46 2 4 6 3 7 10 47 5 3 8 4 5 9 18 5 4 9 4 5 9 09 3 5 8 5 5 10 210 1 5 6 5 3 8 26.3.2 Plan DosimetryFinal autoplan dosimetric indices for each patient are shown in Table 14. HR-CTV D90, V100,V125, V150, and V200 are shown, as well as the maximally irradiated D2cm3 for the Bladder, Rectum,Sigmoid, and Small Bowel. Institutional goals for HDR-BT are shown in the rightmost column. We donot define an institutional goal for V125, though it was recorded for interest. Table 14 shows that thepreplans created using the autoplanning software met or exceeded all D90 and V100 clinical planningtargets, and most V150, V200, and organ targets.Table 14: Autoplan dosimetric indices for each patient, including the institutional goals for eachplanning target index. HR-CTV volume is given in units of cm3, D90, V100, V125, V150, and V200are given in %, and the organ doses are reported as minimum dose to the maximally irradiated 2cm3in units of Gray.PatientMetric 1 2 3 4 5 6 7 8 9 10 GoalHR-CTV D90 105.5 117.1 108.9 117.9 112.2 106.3 104.0 114.0 113.2 110.6 ≥100HR-CTV V100 94.9 97.8 96.3 99.6 96.4 95.0 93.9 99.7 98.5 97.3 ≥90HR-CTV V125 66.7 83.9 67.5 80.7 80.6 66.3 66.1 71.5 75.8 73.9 -HR-CTV V150 39.7 60.8 32.0 49.7 53.2 39.1 37.4 38.1 43.9 47.5 ≤ 40HR-CTV V200 13.6 32.0 10.9 20.4 15.4 11.9 17.1 16.1 16.4 22.9 ≤ 15Bladder 3.2 3.6 3.4 3.1 2.1 3.6 4.1 3.5 4.1 2.5 ≤ 5.5Rectum 2.1 3.7 3.2 3.3 1.0 2.7 3.7 3.5 2.7 4.2 ≤ 3.4Sigmoid 0.5 1.3 0.7 1.6 1.9 3.7 3.7 3.6 3.7 0.5 ≤ 3.4Small Bowel 3.3 0.6 3.7 0.2 0.1 2.9 4.7 3.4 1.3 0.1 ≤ 2.25796.3.3 Manual Preplan vs Autoplan DosimetryThe preplan differences between autoplan and manual preplan (autoplan minus preplan) are shownin Table 15. Differences for HR-CTV D90, V100, V125, V150, and V200 are shown, as well asmaximally irradiated D2cm3 for Bladder, Rectum, Sigmoid, and Small Bowel. The median differencesfor each metric are shown in the rightmost column. The DVHs for the original preplan and autoplanpreplan are shown in Figure 30. On average, autoplans were of equal quality to the patient’s originalmanual preplan, with no statistically significant difference, using an α of 0.05 for a paired t-test. Thep-values for each difference metric are given in Table 15.Table 15: Preplan differences between autoplan and manual preplan. HR-CTV volume is given inunits of cm3, D90, V100, V125, V150, and V200 are given in %, and the organ doses are reported asminimum dose to the maximally irradiated 2cm3 in units of Gray.PatientMetric 1 2 3 4 5 6 7 8 9 10 Median p-valueHR-CTV D90 0.4 1.0 2.8 1.2 -2.3 -2.2 -0.7 2.4 2.2 -0.5 0.7 0.53HR-CTVV1001.1 -0.5 0.2 0.6 -1.0 -2.1 -1.8 0.0 0.4 -0.9 -0.2 0.12HR-CTVV1253.6 0.4 3.6 0.5 -0.2 -3.6 5.6 3.0 3.6 -0.4 1.8 0.17HR-CTVV1503.9 -3.4 2.3 1.4 4.8 4.2 -0.8 -1.3 -1.8 0.4 0.9 0.50HR-CTVV200-1.1 -2.1 -0.2 1.7 -0.5 5.4 0.6 1.0 -2.0 4.0 0.2 0.32Bladder 0.1 -0.1 0.2 -0.2 0.0 0.2 0.4 0.1 0.3 0.2 0.2 0.09Rectum 0.0 0.0 -0.4 0.0 0.0 0.1 0.2 0.0 0.2 0.4 0.0 0.47Sigmoid 0.0 0.0 -0.2 0.0 0.0 0.2 0.4 0.1 0.2 0.0 0.0 0.25Small Bowel 0.0 -1.0 0.3 0.0 0.0 0.2 0.7 0.3 0.1 -1.2 0.1 0.7480Figure 30: DVH plots for each patient, showing HR-CTV (Blue), Bladder (Green), Rectum (red),Sigmoid (Cyan), and Small Bowel (Pink). Manual preplans are shown in dashed, and autoplans areshown in solid lines.6.4 Discussion6.4.1 Plan QualityHigh-quality vaginal HDR-BT PSCT preplan trajectory sets are created efficiently using this de-scribed workflow. Autoplan-based preplans were very similar to the patients’ original manually plannedpreplans (Table 15 and Figure 30). The plans created using the autoplanning software workflow wereall clinically viable plans, as reviewed by expert planners. Not all institutional planning targets weremet for all patients (Table 14), though this is common for many clinical cases, as can be seen by thesmall, statistically insignificant differences of plans as shown in Table 15. Perhaps most importantly,in practice, a range of 3-7 needles has produced a library of feasible solutions for each patient we havetested so far, each of which has resulted in a clinically acceptable preplan.6.4.2 Planning ProcessThere are multiple capabilities of this software that improve the preplanning process for PSCTs.When manually planning a PSCT design, the planner can spend significant time (∼2-10 hoursfor the cylinders in this study) iteratively changing needle trajectories and dwell times to produceas optimal a plan as possible. This means that, in practice, the planner can only consider one set81of needle trajectories at a time. Conversely, autoplan generation takes on average 10 minutes tocreate 25 plans, significantly decreasing the time required to design a set of PSCT needle trajectorieswhich will lead to a high-quality treatment plan, while at the same time providing a wide range ofplan options. The autoplanner-based workflow allows planners to generate a dosimetrically equivalentplan in significantly less time, needing only to select their preferred autoplanner-generated needletrajectories and then determine the required dwell times. In our experience, the time required togenerate a needle trajectory set and a preplan of the treatment times significantly reduced when usingthe autoplanner-based method to less than one hour, as the needle trajectories do not need to beadjusted in order to create a high-quality plan. Thus, a benefit of this treatment planning software isthe ability to save significant planning time and effort without loss of plan quality.Searching over a range of curved needles allows the planner to gain confidence that they do notneed to attempt to add additional needles since the optimizer has searched a wide range. For example,if there is a result which has 5 curved needles with no intersections, but the algorithm was unable tofind feasible trajectory sets for 6 or 7 curved needles, the planner can be confident that their selectedplan with 5 curved needles is at or at least very near the limit of how many needles will fit within thecylinder, and that there is no need to attempt to manually add more.Table 13 shows that the autoplans generated more needles than the manual plans had, for eachplan except for one. Meanwhile, we saw no significant improvement in DVH parameters for the plansoverall, as typically, a needle trajectory set with the most feasible curved needles was selected for thisstudy, in order to ensure adequate tumour coverage. However, it has been shown in the prostate BTplanning literature, that the addition of more needles does not always result in a clinically significantimprovement in plan quality [45]. If a planner wishes to perform a dosimetric trade-off analysis fordifferent numbers of needles, the user can pick a number of the generated trajectory sets and importeach plan back into the planning system. Optimizing the dwell times for each plan using the sameplanning goals and constraints allows the user to explore dosimetric trade-offs very quickly betweenplans with different needle configurations. This gives planners increased flexibility in planning dosecoverage while minimizing patient trauma from IS needles.The built-in visualization capability of the software helps the planner know that the input param-eters are set appropriately. The IS curved needle trajectories are shown as the algorithm runs, whichallows for quick validation of the input parameters such as skip margin and step size as the algorithmis running. The user can stop the algorithm at any time if there is an issue with the algorithm asit is running. The user doesn’t have to wait for the algorithm to finish in order to adjust a setting,which saves planning time. In addition, it gives confidence to the user that their parameters are set82appropriately, and they can work on other tasks as the algorithm runs.6.4.3 Future workA natural extension of this work is to include dwell time optimization in the loop for each plan.With such integration, a solver could iteratively search for both needle trajectories and perform dwelltime optimization, and allow practitioners to minimize the number of needles, while still achieving theplanning goals. Pareto surface generation could be performed for each candidate plan and the set ofall optimal plans could be displayed to the user using a Pareto navigation tool [71], [72] from whichthe user could sort and select the preferred plan. Of course, the more of these features which are builtinto this tool, the more computational time and performance would be required in order to completethe optimization. Advancements in GPU and low computational cost solvers may provide sufficientperformance in order to solve such a complex and wide-ranging search in a clinically viable time frame.We are in the process of evaluating a dosimetric optimizer and plan generation and comparisontool for this purpose, to further ease the process of planning these templates. Such development willimprove the planning process for PSCTs, as the user will not need to plan the dwell times within theirplanning system, but rather this will be done as part of the autoplanning process.6.5 ConclusionWe have developed an efficient and robust method to generate high-quality candidate IC/IS needletrajectories for PSCTs for vaginal HDR-BT. The method was shown to generate needle trajectorysets for PSCT preplans which are dosimetrically equivalent to manually created preplans by clinicalexperts, in significantly less time. The resultant needle trajectories generated using this techniquerequire no adjustment in order to generate acceptable clinical plans. This allows for the creation ofhigh-quality, robust, patient-specific templates in a short clinical time frame. The resultant library ofplans allows the planner to evaluate multiple results at once, and select the best option for their patient,weighing target coverage, OAR toxicity, and IS needle trauma trade-offs. The method is independentof any dose calculation method, meaning it can be implemented into any existing commercial TPSworkflow. Further investigations will extend this work to include in-the-loop dwell time optimizationand Pareto-front-generation.836.6 DisclosureMichael Kudla and Deidre Batchelar have a patent pending for the described software and algo-rithm.847 Conclusion7.1 SummaryInterstitial HDR-BT for vaginal cancers is difficult to perform and is not a treatment option formany patients who it would be appropriate for, due to the technical challenges of achieving a goodimplant and maintaining the required expertise, due to the fact that there are relatively low patientnumbers. Cervical cancer patients with advanced disease require IS HDR-BT to be treated effectively,and commercial applicators are currently expensive and not customizable. The purpose of this work hasbeen to develop and implement a suite of technologies to make IC/IS HDR-BT for vaginal and extensivecervical cancers easier to perform, with the intention to treat patients who would not otherwise betreated with BT while achieving the highest possible treatment quality.In Chapter 3, PSCTs were demonstrated to be a potentially viable treatment option for vaginalcancer patients. Preplans for vaginal IS-BT using PSCTs were shown to be preferable dosimetricallyto traditional IC/IS treatment plans for many cases, especially for top-of-vault lesions. Softwareautomation was shown to be able to very quickly generate a model based on a preplan, which can thenbe 3D printed. 3D Printed PEEK was shown to be a clinically viable construction material for thesetemplates and was validated as steam sterilizable.In Chapters 4 and 5, 3D-printed templates for vaginal (PSCTs) and cervical (T&C) cancers wereused to treat clinical patients at BC Cancer - Kelowna, and were shown to facilitate high-qualityIC/IS treatment for difficult-to-treat tumours. These templates improve the ease of IS needle insertionwithout the need for intraoperative imaging, can be reliably preplanned, and can allow for the treatmentof patients who would not otherwise be treated.In Chapter 6, a novel autoplanning algorithm was presented which enables the generation of high-quality candidate IC/IS needle trajectories for PSCTs. This algorithm enables planners to generateand select high-quality needle trajectory sets very quickly, which can be used to create a high-qualitytreatment preplan. This software alleviates much of the preplanning burden posed by PSCTs, makingthe PSCT technique a more practical and accessible treatment option.857.2 Impact of the ThesisThis dissertation describes a significant step forward in the treatment of gynaecological malignanciesusing HDR-BT. What began as a conceptual design and limited software tool has now been developedinto two novel clinically implemented patient-specific template-based treatment workflows and anadvanced software suite which makes the planning and design of patient-specific templates very simple.Due to the customization capabilities of these templates, more conformal treatments are possibleas compared to what is achievable using standard templates. Many of the patients who were treatedas a part of the treatment cohorts in Chapters 4 and 5 would have been previously untreatable orvery difficult to treat with standard applicators due to geometry limitations of placing the sourceonly within the various commercially available templates. These treatment workflows can increase thepatient-specific treatment capabilities of brachytherapy centres while reducing costs and potentiallyincreasing accessibility. The ability of this design and needle insertion technique obviates the necessityfor intraoperative imaging. In some cases, because the preplans are reproducible, it may be possibleto treat without postoperative imaging.If this were achievable, more conformal treatment quality could be possible without requiring sig-nificant investment in expensive imaging modalities, which may improve treatment for some caseswhere interstitial needles are appropriate, but they are not currently possible due to resource limita-tions. Brachytherapy treatment planning has, in many cases, lagged behind external beam treatmentplanning in terms of both automation and optimization capabilities in commercial software. The nee-dle trajectory auto-planning software described in this dissertation advances the treatment planningcustomization and automation capabilities in this space.This technology suite can enable treatment centres and clinicians who are proficient with high-dose-rate brachytherapy to implement a program for the high-quality patient-specific treatment ofgynaecological malignancies with very low cost and experience barriers to entry.7.3 Limitations of the ThesisWhile the work described in this dissertation has been clinically implemented successfully, thereare drawbacks to the technique and there are challenges to overcome before widespread adoption ofthe technique can be realized.867.3.1 Technique LimitationsPEEK, the material chosen for this particular project, is a challenging material to 3D print andrequires a substantial level of expertise to print reliably. In addition, the post-processing required fortemplates 3D printed with this technique requires some machining expertise, which may not be readilyavailable to many treatment centres.The number of needles that can fit in a PSCT or in a T&C template is limited by the needletrajectories and the diameter of the cylinder. For very large lesions, it may be the case that thesetypes of templates are insufficient to adequately cover the lesion alone. In this case, a perineal templatecould be substituted or added to the treatment to fully cover the target with an adequate dose.7.3.2 Barriers to Widespread AdoptionManufacturing this medical device in-house also presents challenges of navigating regional regu-latory and internal sterilization requirements. It may be the case that a commercial solution that3D prints the custom-designed devices and delivers them in a timely manner to the cancer centre ispreferable. This may also be preferable in the context of the billing structure in for-profit healthcaremodels such as in the United States.While SolidWorks is one of the premier 3D modelling tools used around the world, it requiresexpensive licensing in order to use for commercial applications and thus a widespread use of thesoftware developed for this thesis would be prohibitive for many users. The use of an open-source 3Dmodelling or custom-developed 3D modelling software would be preferable for an open-source versionof this technology suite.The auto-planning script developed for this research is still in a research state, in the sense that itis run from within a Python terminal and is not user-friendly for non-programmers. There is no GUIand there is no user manual. In order for widespread acceptance of such software, either a standaloneapplication or a script that can be launched from within a treatment planning system should bedeveloped.In addition, the auto-planning script generates only needle trajectories and does not fully optimizethe final plan. While we have shown the generated needle trajectory sets to be of high enough qualityto generate treatment plans which are equivalent to manually designed plans, there is no guaranteethat the needle trajectories generated via this technique are optimal.877.4 Future Work7.4.1 Technical and Clinical DevelopmentThe export software designed for this project can be translated to interface with an open-sourceCAD program which would be free to use. The 3D print slicing could also be automated using aback-end API script interface now that the settings have been tested in our clinical program withsuccess. Some of the current software is vendor-specific. Since the PSCT export software interfaceswith Varian’s TPS, to encourage the use of the use of PSCTs and customizable T&C’s, we will bedeveloping software to export from within the Elekta ecosystem. The autoplanning software is vendorunspecific, only requiring DICOM structure files.Resin 3D printing is an increasingly common 3D printing modality that offers speed, accuracy,precision, and layer adhesion reliability improvements as compared to PEEK FDM 3D printing. Therenow exist resin 3D printers which are marketed specifically to healthcare, and which can produce finalparts that are sterilizable, such as the Formlabs 3B+ and 3BL printers (Formlabs, USA). The resultant3D prints would require no post-process machining and the material (BioMed Clear Resin, Formlabs)is significantly less expensive than PEEK.The auto-planning software described in this dissertation only generates needle trajectories whichthen can be selected and re-imported back to the planning system. The software does not do any dwelltime optimization, a crucial step in pre-planning patient-specific treatment templates. It is a naturalextension of this work to include a dwell time optimizer in the autoplanning software, as it is a crucialstep in pre-planning PSCTs. This would have the benefit of presenting a final optimized treatmentpreplan for the treatment planner, accelerating the planning process to a simple final plan review.In addition, further automation of the planning software is possible, such as needle position iterationbased on dosimetry, and planning pipeline automation with auto-segmentation. An autoplanning andexport software for patient-specific T&C templates will also be developed.7.4.2 Improving Accessibility of Conformal BT to Low and Middle-Income CountriesLow and middle-income countries (LMIC) bear the bulk of the global cervical cancer disease burden(nearly 85%) [6]. Patients in these countries predominantly present with locally advanced or metastaticdisease due to poor screening and public health awareness of cancer symptoms and prevention [73].Effectively addressing the resultant disproportionately poor outcomes for patients in LMIC is a global88priority [74], and improving access to treatment is an important component of the solution. Thereliable addition of any IS needles, whether the applicator geometry is patient-specific or not, is animprovement for many cases [61]. This thesis has outlined a technology suite which can be used toimplant IS needles reliably without substantial technical expertise and with a low treatment planningburden, at a low cost.However, in order to plan an IC/IS treatment, an imaging technique must be available to generate2D or 3D image sets for treatment planning, and the treatment target must be identifiable on imaging.The gold standard imaging modality for target identification is MRI [10], which is impractical for manyLMIC due to high incidence rates and resource limitations.Alternatively, US has been identified as being capable of target volume measurement [10], [20], [75],and 3-Dimensional US (3DUS) has been investigated for treatment planning, and applicator/needlepositioning verification [18], [19], [76], [77]. US may prove to be a high-quality, lower barrier-to-entry imaging technology for the treatment of advanced GYN cancers, and may someday be able toreplace CT and MR-based planning in some circumstances. However, the 3DUS technique is still indevelopment, and at this time, an end-to-end treatment planning system using only US for imageguidance of IC/IS BT has not been reported in the literature. To explore this possibility, we aimto acquire a transabdominal and transvaginal/transrectal 3DUS system and begin development andprospective evaluations on the use of 3DUS for IC/IS GYN BT target delineation, OAR delineation,and ultimately, treatment planning. The ultimate goal of this work would be to provide a proof ofconcept of a low-cost, end-to-end IC/IS BT workflow.With the addition of the PSCT and T&C templates to provide accurate needle placement, and au-toplanning software to alleviate the patient-specific treatment planning burden, a US-based treatmentworkflow may facilitate IC/IS BT for many patients worldwide who are currently unable to receivethis necessary care.89References[1] K. Albuquerque, S. Beriwal, A. N. Viswanathan, and B. 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Thesis/Dissertation
eng
Medical Physics
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Jirasek, Andrew
Batchelar, Deidre
A patient-specific treatment technology suite for interstitial gynaecological brachytherapy
Text