A Thesis. entitled. based on CBCT Data Dose Calculation. Sukhdeep Kaur Gill. Master of Science Degree in Biomedical Science

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1 A Thesis entitled A Study of Evaluation of Optimal PTV Margins for Patients Receiving Prostate IGRT based on CBCT Data Dose Calculation by Sukhdeep Kaur Gill Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Biomedical Science David Pearson Ph.D., Committee Chair E. Ishmael Parsai Ph.D., Committee Member Krishna Reddy MD, PhD, Committee Member Patricia R. Komuniecki Ph.D., Dean College of Graduate Studies The University of Toledo August 2014 i

2 Copyright 2014, Sukhdeep Kaur Gill This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. ii

3 An Abstract of A Study of Evaluation of Optimal PTV Margins for Patients Receiving Prostate IGRT based on CBCT Data Dose Calculation by Sukhdeep Kaur Gill Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Biomedical Science The University of Toledo August 2014 Image-Guided Radiation Therapy (IGRT) is used in the treatment of prostate cancer to assist in precise dose delivery to the tumor and to maximize sparing of normal structures. The prostate, bladder, rectum and femoral heads can be imaged before every treatment and, with the use of Cone beam Computed Tomography (CBCT) imaging, the actual dose delivered to these organs can be monitored based on the patient s daily anatomy. Daily set-up variations during prostate IMRT yields differences in the actual doses vs. expected doses received by the prostate, rectum and bladder. This study evaluates the optimal PTV margins for patients receiving CBCT-guided prostate IMRT based on the daily CBCT dose calculation. To determine the optimal PTV margin for CBCT-guided prostate IMRT, the prostate and organ at risk doses were estimated from daily CBCT and compared to those expected from planning. Four plans were generated with different CTV to PTV margins and these plans were transferred onto the daily CBCT. The actual delivered doses to the prostate, contoured as the CTV, were calculated on daily CBCTs using anatomy specific CT to density curves. Evaluation of the dose- iii

4 volume histograms showed that a 3-5mm PTV margin was optimal for prostate IMRT, when daily CBCT is used for image guidance. The second part of this study includes a volumetric dose comparison of the rectum and bladder based on daily CBCT with respect to planned doses. The volume of the bladder and rectum changes during treatment and has an effect on the cumulative dose received by these organs. It was observed that the volumetric dose received by the bladder decreases as the volume of the bladder increases. There was no particular trend observed between volumetric dose and rectal volume. iv

5 Acknowledgements I wish to express my deepest gratitude to my advisor Dr. David Pearson for his input, guidance and support, as well as my committee members Dr. Parsai, Dr. Reddy and Dr. Chen for their day-to-day suggestions, encouragement and patience during the completion of this research. I would like to thank Dr Shvydka, all faculty & staff in the department of Radiation Oncology at UTMC, and my classmates for the great help in learning. Also, I would like to express appreciation to Nina Campbell for her help and give special thanks to Dianne Adams, for the moral support throughout my degree. Finally, I would like to thank my family, my best friends Ritesh Kumar and Roobie Garla for their continual support, and my little niece Annaya for filling my life with smiles. Thank you all. v

6 Table of Contents Abstract Table of Contents Acknowledgements List of Tables List of Figures List of Abbreviations List of Symbols iii vi v ix x xiv xv 1. Introduction Prostate Cancer Treatment of Prostate Cancer Brachytherapy Low-Dose Rate Brachytherapy High-Dose Rate Brachytherapy External Beam Radiotherapy Overview of Image Guidance Localization Modalities Rectal Balloons Radiographic Fiducials Ultrasound Localization...9 vi

7 2.4 Onboard Volumetric Imaging Electromagnetic Tracking Systems Errors in Radiation Therapy: Margins Systematic Errors Random Errors Delineation Errors Setup Errors Inter- and Intra- Fraction Prostate Motion ICRU 50/62 Definitions Gross Tumor Volume (GTV) Clinical Target Volume (CTV) Internal Target Volume (ITV) Planning Target Volume (PTV) Calculation of the PTV Computed Tomography Based Image Guided Radiation Therapy CBCT Imaging Materials and Methods Patient Group CBCT Acquisition and Contouring Treatment Planning Dose Calibration...29 vii

8 5.5 DVH Analysis Results Change in CTV Coverage with Different PTV Margin Bladder and Rectum Volume Variations Change in Bladder Dose with Respect to Different Margins Change in Rectum Dose with Respect to Different Margins Summary and Conclusions 60 References 63 Appendix A 67 viii

9 List of Tables 1.1 Risk Groups Prostate & OAR Volumes CT# to Density Calibration Values Dose-Volume Parameters Comparison for CTV dose between P-CT and Cumulated daily CBCT Comparison for Bladder dose between P-CT and Cumulated daily CBCT Comparison for Rectum dose between P-CT and Cumulated daily CBCT...55 ix

10 List of Figures 1-1: Goal of study : Anatomical location of Prostate : Ultrasound guided prostate seed implant : Low dose rate brachytherapy dose distribution : Radiographic fiducial based localization : BAT Ultrasound system for image guidance : KV-CBCT based image guidance system : Calypso 4D localization system : ICRU 62 Margins definition : Soft tissue alignment for daily CBCT with respect to Planning CT : Daily CBCT for contouring in MIM : Image registration for Daily CBCT and Planning CT in MIM : Beam arrangement on Planning CT : Dose distribution on Planning CT : Beam arrangement on treatment isocenter for daily-cbct : CT to Density calibration curve for Varian CBCT vs. Philips CTSIM : An example of a dose distribution calculated in Pinnacle on a daily CBCT : Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 1mm PTV margin...37 x

11 6-2: Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 3 mm PTV margin : Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 5 mm PTV margin : Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 7 mm PTV margin : Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin for patient : Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin for Patient : Bladder (blue) and Rectal (green) volume variation during entire course of RT for Patient : Bladder (blue) and Rectal (green) volume variation of Patient2 during entire course of RT : Bladder (blue) and Rectal (green) volume variation of Patient3 during entire course of RT : Volumetric bladder dose comparison for planned (blue) vs. daily CBCT (grey) dose for two patients : Coronal view of the bladder volume on Daily CBCT (Upper) and Planning CT (Lower)...48 xi

12 6-12: Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 1mm PTV margin : Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 3mm PTV margin : Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 5mm PTV margin : Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 7 mm PTV margin : Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin for patient : Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin for patient : Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 1mm PTV margin : Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 3 mm PTV margin : Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 5 mm PTV margin : Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 7mm PTV margin...58 xii

13 6-22: Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin for patient : Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin for patient xiii

14 List of Abbreviations ART...Adaptive Radiation Therapy CBCT...Cone Beam Computed Tomography CT...Computed Tomography CTV...Clinical Target Volume DVH...Dose-Volume Histogram DRR...Digitally Reconstructed Radiograph EBRT...External Beam Radiation Therapy EPID...Electronic Portal Imaging Device GTV...Gross Tumor Volume IGRT...Image-Guided Radiation Therapy IMRT...Intensity-Modulated Radiation Therapy KV...Kilo voltage MV...Mega-voltage kvp...kilovoltage Peak mas...milliampere-second P-CT...Planning CT PSA...Prostate-specific antigen PTV...Planning Target Volume RT...Radiotherapy xiv

15 List of Symbols cgy...centi-gray Gy...Gray xv

16 Chapter 1 Introduction Prostate cancer is the most commonly diagnosed male cancer worldwide; other than skin cancer, prostate cancer is the most common cancer in American men (1). According to the American Cancer Society s estimates for prostate cancer in the United States in 2014, approximately 233,000 new cases of prostate cancer will be diagnosed and around 29,480 men will die of prostate cancer. It is estimated that 1 in 7 men will be diagnosed with prostate cancer during his lifetime. Treatment of prostate cancer includes surgery, chemotherapy, hormone therapy and radiotherapy. Radiotherapy has been shown to allow for good local control with very few side effects (2). Literature data shows improved tumor control with the use of higher radiation doses (3). This has been possible because of the implementation of intensity-modulated radiotherapy (IMRT) which allows dose escalation to the prostate whilst sparing the organs at risk (OAR). IMRT for prostate cancer enables the creation of a steep dose gradient between the target and the OAR, which allows a higher dose to reach the target, i.e. high cure rates and reduction of late toxicity to OAR (4). Variation in the daily set-up and volumes of the bladder and rectum can significantly influence the position of the prostate during IMRT, consequently modifying 1

17 the dose distribution in the target and adjacent organs (5). The goal of this study is to quantify the best PTV margin based on the dose coverage of the prostate during the entire course of radiotherapy; this study also includes the variation of volumetric dose of the bladder and rectum during the course of treatment. This study aims to find the minimum PTV margins required to cover the CTV, based on reduction of inter-fraction errors as shown in Fig 1.1. Fig 1.1- Goal of study 2

18 1.1 Prostate Cancer Prostate cancer is one of the leading causes of cancer death among men in the United States of America (6). With the widespread use of prostate-specific antigen (PSA) screening, the majority of patients present with clinically localized disease receive radiation therapy (RT) as primary treatment. Anatomically, the prostate is located posterior and inferior to the bladder and anterior to the rectum (Fig 1.2). According to the National Comprehensive Cancer Network (NCCN) (7), risk groups for patients are defined according to stage, PSA level and Gleason score. NCCN risk groups are given below. Table Risk Groups Stage Initial PSA Gleason LOW RISK T 1 T 2a <10 ng/ml 6 INTERMEDIATE RISK Bulky T 2b HIGH RISK T 2c >

19 Fig 1.2- Anatomical location of Prostate 1.2 Treatment of Prostate Cancer Various options for the management of prostate cancer have been developed in the past two decades of technological innovation, including: hormonal therapy, cryotherapy, highintensity focused ultrasound, surgical removal and radiotherapy (8). Out of these, the most common treatment is radiation therapy (8). Options in radiation therapy include either implant-based brachytherapy or external beam radiation therapy Brachytherapy: Brachytherapy is currently performed for favorable risk prostate cancers with either low-dose rate permanent implants or high dose rate temporary implants. In low dose rate brachytherapy, iodine, palladium or cesium radioactive 4

20 sources are used. High dose rate brachytherapy is treated by using a small iridium source and a remote afterloader Low-Dose Rate Brachytherapy: Brachytherapy with permanently implanted radioactive seeds matured in the early 1990s into a transperineal ultrasound-guided technique (8). Generally, palladium or iodine sources are used for permanent implants (Fig 1.3), and seeds are typically peripherally loaded. A total of Gy is usually delivered by iodine-125 implants and Gy with palladium-103 seed implants. The typical prescription dose with cesium is 115Gy (8) (Fig 1.4). For favorable risk prostate carcinoma, treatment with radioactive seeds alone has provided excellent control rates. Fig 1.3- Ultrasound guided prostate seed implant 5

21 Fig 1.4- Low dose rate brachytherapy dose distribution High Dose Rate Brachytherapy: High dose rate brachytherapy is delivered with a dedicated remote afterloader which contains a radioactive source, generally iridium HDR brachytherapy can be used as the sole treatment for prostate cancer or it can be used in combination with external beam radiotherapy. Generally, a radiation dose of around 6-8 Gy per fraction is delivered for approximately 6 fractions in two implants, resulting in a total dose of 36 to 48 Gy (8) External Beam Radiotherapy: External beam radiation therapy (EBRT) uses high energy radiation to treat cancer from a distance. EBRT has evolved dramatically over the 6

22 past decade with increasing ability to shape and aim radiation field sizes according to the target shape and size, and surrounding critical structures (9). Cure rates of high-dose EBRT are similar to surgery or brachytherapy in terms of favorable-risk prostate carcinoma patients (10). EBRT is also commonly utilized as either adjuvant or salvage therapy in postprostatectomy setting for patients with rising PSA. EBRT is completed using different techniques, the most commonly used being: three- dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), arc therapy and proton beam radiation therapy. At the University of Toledo patients are treated with Image-guided IMRT, which shall be discussed further in the next chapter. 7

23 Chapter 2 Overview of Image Guidance Localization Modalities Techniques like IMRT continue to gain in popularity and their usage is becoming increasingly widespread. These new techniques have resulted in more conformal and targeted treatment plans with dose escalation whilst sparing normal tissues. Imaging plays a progressively larger role in prostate cancer management, from diagnosis to treatment and follow-up. Various strategies may be employed to reduce the uncertainties in radiation therapy planning and delivery. Imaging techniques like Computed Tomography (CT), Trans- Rectal Ultrasound (TRUS), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) can be used for accurate target delineation. Image guidance is an important component of any strategy attempting to optimize treatment accuracy and minimize treatment-related uncertainties. Localization methods used for prostate IGRT are as highlighted below. 2.1 Rectal balloons 8

24 Rectal balloons are small balloons filled with water or air; they are placed in the rectum and inflated to push the prostate against the pubic symphysis, the purpose being to reduce anteroposterior motion of the prostate and reduce the amount of posterior rectal wall in the radiation field (11). These can also be used to decrease inter- and intra-fraction prostate motion. Dose reduction to the rectal wall with the use of rectal balloons is more important in 3DCRT as compared to IMRT. 2.2 Radiographic Fiducials Electronic Portal Imaging Devices (EPID) show good bony anatomy but the prostate cannot be seen in these images. The implantation of radiopaque markers, such as gold seeds, into the prostate allows visualization of these markers on radiographs (Fig 2.1). They can also be used with kv images or with CBCT. The position of these markers on the images can then be compared with the position obtained at the time of planning, and a shift can be applied based on the manual or automatic comparison (12). This technique can be repeated for daily treatment and the shifts can be tabulated. 2.3 Ultrasound Localization Ultrasound localization technologies for prostate cancer radiotherapy utilizes brightness mode acquisition to visualize the changes in acoustic impedance found in tissue planes. The BAT (B-mode Acquisition and Targeting) system depicted below (NOMOS Corporation, Sewickley, PA) is commonly used for prostate localization (Fig 2.2). Contours from the planning CT are aligned on ultrasound images and can be moved 9

25 manually to create the best match. One limitation is that the bladder must be sufficiently full to act like a window to the prostate. Fig 2.1- Radiographic fiducial based localization 10

26 Fig 2.2- BAT Ultrasound system for image guidance 2.4 Onboard Volumetric Imaging Onboard volumetric imaging is one of the most common forms of in-room computed tomography. Most modern linear accelerators (Fig 2.3) are capable of this type of imaging for the purpose of IGRT. Cone beam computed tomography (CBCT) utilizes a kv source of radiation and a detector panel positioned orthogonally to the treatment MV source and detector panel. One advantage of onboard volumetric imaging is the ability to detect prostate deformation, allow real time re-planning, and to visualize organ at risk. This relies on the image quality of the CBCT system to be sufficiently high enough to delineate the prostate from the surrounding tissue. 11

27 2.5 Electromagnetic Tracking Systems X-ray, CT and cine-mri systems provide only a snapshot of the prostate. 4D localizations systems allow real-time tracking of organ motion; the Calypso 4D localization system (Fig 2.4) is used as a continuous tracking system for prostate cancer. It helps in real-time localization and to capture inter- and intra-fractional motion. The most common method for 4D prostate localization is through the use of radiofrequency transponders. (13) These transponders are surgically implanted into the specific regions of prostate of the patient, and the radiofrequency of these transponders is detected during treatment; each transponder response signal is unique and specific to each transponder. A magnetic source and array of receiver coils are used to track the position of the implanted transponders. This array of receiver coils is tracked by in-room infrared tracking, forming a secondary frame of reference to that formed by the position of the transponders in relation to the receiver coil array. The combination of these two continually updated frames of reference (at a rate of 10 Hz) results in the continuous feedback of the location of the prostate, allowing for accurate patient positioning and position of the prostate during the delivered treatment. 12

28 Fig 2.3- KV-CBCT based image guidance system Fig 2.4- Calypso 4D localization system 13

29 Chapter 3 Errors in Radiation therapy: Margins The two types of error in RT are systematic errors and random errors. Studies have shown various errors associated in radiotherapy, leading to inadequate coverage of the disease or over-exposure of the normal structures (14). Various strategies may be employed to minimize the uncertainties of radiation therapy planning and delivery, including choosing better imaging techniques for target delineation and treatment guidance. Protocols for the bladder and bowel should be applied to reduce the inter- and intra- fraction errors. Better immobilization can reduce errors related to patient intrafraction uncertainties. Finding an adequate PTV margin requires the understanding of various types and sources of errors in treatment planning and delivery. These errors are defined below. 3.1 Systematic errors 14

30 Systematic errors are treatment preparation errors and these errors affect all of the fractions. The cause of these errors can be faulty instruments, errors in original machine set-up, or modeling or error in incorrect usage of the Instruments. Systematic errors may cause a shift in the dose distribution away from the planned CTV or cause overdose/under-dose of the target volume. 3.2 Random errors Random errors are treatment execution errors, influencing each fraction individually and being unpredictable in nature. Correcting these errors are helpful to keeping the PTV as small as possible and will minimize the toxicity related to normal structures. Margins are used in radiation therapy to account for the errors; sources of these errors in prostate RT are explained below. 3.3 Delineation errors Delineation uncertainties are related to disagreement between multiple observers contouring the prostate and differentiating between soft tissues. The magnitude of systematic delineation uncertainty for the prostate between observers, as measured on CT images, has been shown to be mm at the apex and 3.5mm at seminal vesicles (15). 15

31 Studies have compared the target delineation of CT and MRI targets, and shown that there is a tendency to contour a larger prostate on CT as compared to MRI (15). 3.4 Set up errors Immobilization helps to reduce the day-to-day set up uncertainties. Studies have shown decrease in error with improvement of immobilization. Several trials have compared the effects of immobilization compared to no immobilization for prostate radiotherapy; the repositioning rate for patients was reduced from 23.1% to 17.4% with the use of rigid hemibody immobilization (16). Rattray et al. showed that a pelvic cradle reduced the mean deviation and mean cranio-caudal deviation from mm with no immobilization, to 2-2.5mm respectively. (17). 3.5 Inter- and Intra- fraction Prostate Motion The prostate gland is a mobile organ, so while planning to cover the whole CTV during a course of radiation therapy it is important to consider the positional variability within the bony pelvis. Studies have shown that changes in the filling of the bladder and rectum influence the prostate position (18). Studies have also shown that changes in the rectal volume have a greater impact on prostate motion than the bladder volume (19). All of these changes in prostate shape and position during the whole course of radiotherapy may lead to under-dosage of the target and, simultaneously, over-dosage of the rectum and bladder. It is therefore important for these changes to be adequately accounted for in the PTV margin to minimize these risks, thus making the treatment volume larger than the 16

32 CTV. Bladder and bowel protocols and image guidance can be used to minimize the treatment volume, making it closer to the CTV volume. This results in lower CTV to PTV margins, improved normal tissue functioning, and reduced toxicity. Prostate motion occurs in all three planes but tends to be greatest in the antero-posterior (AP) and superior-inferior (SI) axes, and at its least in the lateral (RL) axis due to the confinement of pelvic walls. Rotational errors also have been reported by a few studies, meaning that systematic errors have the largest impact on the selection of PTV margins (20). Intrafractional prostate motion has been observed with cine-mri (21), cinefluoroscopy (22) and TRUS (23). 4D localization systems (Calypso) have been used to control intra fractional motion (24). Since each fraction of prostate IGRT takes approximately minutes, intrafractional errors are the result of respiratory excursions and bladder-rectal fillings. Errors caused by respiratory motion are small in comparison to the bladder-rectal filling related errors (19). Thus, the most important issue for prostate RT is to control these inter- and intra- fractional errors. 3.6 ICRU 50/62 Definitions To account for these errors, margins are prescribed on the target. The International Commission on Radiological Units and Measurements reports 50 and 62 (25) are the basis for target volume definition. Fig 3.1 shows the definition of all margins in pictorial form. These volumes are defined as follows Gross Tumor Volume (GTV) 17

33 GTV is the gross demonstrable extent and location of tumor. Delineation of the GTV is possible if the tumor is visible, palpable or through imaging. The GTV cannot be defined for surgically removed tumors Clinical Target Volume (CTV) CTV includes the GTV plus microscopic disease to be treated by the prescription dose Internal Target Volume (ITV) An internal margin (IM) is added to the CTV to compensate for internal (26) physiologic movements and variations in size, shape and position of the CTV during the course of radiation therapy. The volume that includes the CTV with the IM is called the ITV Planning Target Volume PTV includes the CTV with the IM, as well as including margins for patient movement and setup uncertainties. Setup margins account for setup uncertainties. 18

34 Fig 3.1- ICRU 62 Margins definition 19

35 3.7 Calculation of the PTV The PTV margin in prostate cases should ensure that the planned dose to the PTV represents the delivered dose to the CTV in the presence of all treatment-related uncertainties. However, an increase in the PTV margin will significantly increase the dose to the organ at risk, especially in the situation where there is a change in the shape and size of the OAR (the bladder and rectum in this case) during the entire course of radiation therapy. This means that adequate PTV margins should be defined. The PTV margin is ascertained as per institutional calculation, depending on systematic and random errors. The van Herk Formula (27) is the simplest recipe to calculate PTV margins based on systematic and random errors in a population. The principle behind the van Herk Formula is to cover the CTV for 90% of patients with 95% isodose line. An analytical solution to this formula is: PTV Margin: σ Here, represents the systematic errors that can be calculated by calculating the standard deviation of the means of the shifts in the x, y and z directions. It takes into account interpatient errors. Random errors (σ) take into account intra fraction errors and can be calculated by taking the root mean square value of all the standard deviations. 20

36 Chapter 4 Computed Tomography Based Image Guided Radiation Therapy In the past decade, prostate RT has evolved from simple 3D treatments to image-guided, intensity modulated radiation therapy. The primary advantage of cone beam CT (CBCT) guided radiation therapy is to assist in precise dose delivery to the target. Secondly, the target and OAR can be imaged before each treatment and the actual dose delivered to these organs can be tracked using the anatomy of the day. A cone beam CT is taken before each treatment, and these CBCT images are capable of delineating the gland and demonstrating the filling of the rectum and bladder. Uncertainties in prostate RT are complex because structures can move and change shape on a daily basis. Imaging techniques also allow for the localization of fiducials implanted in the prostate or visualization of bony anatomy, but these techniques cannot help to take into account change in shape and size of organs. 21

37 4.1 CBCT imaging Cone beam computed tomography is one of the most common forms of in-room computed tomography. Most modern linear accelerators are capable of this type of imaging for the purpose of IGRT. Both kilovoltage and megavoltage flat panel imagers are integrated with the linear accelerator and are used for image guidance. In CBCT imaging, a kv X-ray tube and a kv detector are utilized. The patient is centered to the treatment beam isocenter and a CBCT is acquired before each treatment. In CBCT acquisition, different kv and mas can be used for each patient depending on site-specific imaging protocol for the treatment site (pelvis, head, etc.). The kv detector panel, normal to path of the beam, captures the images and achieves CBCT reconstruction by utilizing reconstruction algorithms. The detector panel and kv source are capable of being retracted during the treatment as they are mounted on retractable arms. The CBCT images acquired before treatment are compared with the treatment planning CT and necessary shifts are made to cover the target. Alignment corrections for shifts are derived from either soft tissue based registration or bony anatomy based registration. Software allows for automatic as well as manual registration. Once the final verification has been completed, the patient can be treated. 22

38 Chapter 5 Material and Methods 5.1 Patient group Three patients (84 CBCT datasets) undergoing CBCT guided intensity-modulated radiation therapy to the prostate were included in the study. Patients for this study are low and intermediate risk prostate carcinoma patients with no lymph nodes involvement. High risk patients were not included since nodal involvement for high risk prostate carcinoma cannot be visualized by CBCT and, also, the field of view for CBCT is small to take nodes into account. An EBRT dose of 7000 cgy over the course of 28 fractions was delivered to the PTV. The PTV included the clinical target volume (CTV) that was only prostate, as drawn by the physician on a treatment-planning computed tomography (CT) image. All the patients were treated using a Varian TrueBeam linear accelerator. For all the patients investigated in this study, registration was completed with respect to soft tissue alignment as shown in Fig 5.1Before daily treatment, a CBCT was taken and the prostate was aligned in the daily CBCT and planning CT with respect to the translational shifts. All shifts were applied before each treatment and the CBCT isocenter represented the daily treatment isocenter. For the daily CBCT pelvis, CBCT protocol was 23

39 used for imaging the patients that included 120KV, 80 ma and full scan with a half bowtie filter. Fig 5.1- Soft tissue alignment for daily CBCT with respect to Planning CT 5.2 CBCT acquisition and Contouring Daily CBCTs for all patients undergoing CBCT guided prostate IMRT were exported from the 'offline review' module in Varian ARIA (record and verify system) to MIM contouring software (MIM Software, Cleveland, OH). For this study, the quality of the patients' CBCTs (Fig 5.2) was already checked and patients with artifacts and clipped 24

40 CBCTs were not used. This was due to artifacts affecting the CBCT reconstruction, which in turn affects the CBCT dose calculation (28). Fig 5.2- Daily CBCT for contouring in MIM All the contours and treatment isocenters were transferred from the planning CT to the daily CBCT using registration files (Fig 5.4). The CTV (contoured as the prostate) was edited based on the daily anatomy and minor changes were made, while the rectum, bladder and femoral heads were contoured according to the patient's anatomy of the day. The volumes of the prostate, rectum and bladder on daily CBCT as compared to planning CT are shown in Table

41 Table 5.1: Prostate & OAR Volumes p-ct Volume Mean Minimum Maximum P-CT Daily CBCT Prostate Volume (cc) Patient Patient Patient Bladder Volume (cc) Patient Patient Patient Rectum Volume (cc) Patient Patient Patient Contouring was outlined according to the Radiation Therapy Oncology Group guidelines for a male pelvis. The volume of the rectum, bladder and prostate was tabulated on a daily basis to track the day by day variations. To reduce the inter-user variability for contouring, the same investigator completed all contouring. 26

42 Fig 5.3- Image registration for Daily CBCT and Planning CT in MIM 5.3 Treatment Planning On the planning CT, four clinically acceptable plans were generated using the Pinnacle treatment planning system (Philips, Koninklijke, N.V.). PTVs with 1, 3, 5 and 7mm uniform margins from the CTV were created. All patients were planned using 9 fields with gantry angles of 0, 40, 80, 120, 160, 200, 240, 280 and 320, using a 10MV photon beam IMRT technique. The prescription dose was 70Gy in 28 fractions, with 2.5Gy per 27

43 fraction. For all plans it was ensured that more than 95% of PTV was receiving the full prescription dose. The whole CTV was covered by 100% of the prescription dose. For OAR, constraints were decided lesser than RTOG 0815 (29). The passing criteria for the rectum is V70<10%, V60<25% and V70<10cc. For the bladder, V70<10%, V65<20% were used for evaluation. Similarly, for the femoral heads, V50<5% and V35<15% were accepted for plan approval. Figs 5.4 and 5.5 shows a sample beam arrangement and dose distribution on the planning-ct. Fig.5.4- Beam arrangement on Planning CT Fig 28

44 Fig 5.5- Dose distribution on Planning CT 5.4 Dose Calculation All the CBCTs were transferred from MIM Maestro to the Pinnacle planning system, and all of the plans with different PTV margins were transferred from the planning CT to the daily CBCT treatment isocenter. For this, plans were first transferred to RadCalc (LifeLine Software, Austin, TX, USA), which is an MU second-check software, and then using a script file it was transferred onto the daily CBCT. The total MU and weightage 29

45 for each beam was kept the same as for the planning CT; the beam arrangement on the CBCT treatment isocenter is shown in Fig 5.6. Fig 5.6- Beam arrangement on treatment isocenter for daily-cbct As compared to fan beam kv-ct, cone beam CT suffers more from scatter, which results in reduced contrast-to-noise ratio and may lead to errors in image reconstruction. For CT number to electron density, conversions for Varian OBI have been reported in literature. Studies show that when using a site-specific CT number to density calibration of CBCT images, a 2% dose agreement is observed between treatment the planning CT and CBCT 30

46 images in phantom studies ( 30,31). For dose calculations in this study, an anatomical sitespecific CT number to density calibration curve for CBCT calculation was used (Fig 5.7). The anatomical site-specific calibration performed in this research was for the Pelvis CBCT protocol of the Varian OBI using the Catphan 404 (The Phantom Laboratory, Salem, NY, USA). The results of the CT number to density calibration in comparison to the CT number to density calibration curve used in the treatment planning of all patients at our institution are given in Table Table 5.2: CT# to Density Calibration Values Density (g/cm 3 ) Varian OBI CT# Philips TPS CT# Absolute % Difference % % % % % % % % % 31

47 Fig 5.7- CT to Density calibration curve for Varian CBCT vs. Philips CTSIM The results of the CT number to density curve of Philips Gemini CT (Philps Healthcare, Bothell, WA) and Varian OBI are in good agreement. An example dose distribution on a CBCT is shown in Fig

48 Fig 5.8: An example of a dose distribution calculated in Pinnacle on a daily CBCT 5.5 DVH Analysis Raw data was exported from Pinnacle to a spreadsheet using script files (32). V107%, V100%, V98%, V95% and V90% were recorded for cumulative daily CBCT for the CTV of different margins. For the rectum and bladder, V70%, V65%, V60%, V50% and V40% were evaluated as shown in Table 5.3. Volumes of the bladder and rectum were evaluated for each patient during the whole course of treatment. Table 5.3: Dose-Volume Parameters Structure Dose-Volume Parameter Prostate V 107% 33

49 V 100% V 98% V 95% V 90% V 70Gy V 65 Gy Bladder V 60 Gy V 50 Gy V 40 Gy V 30 Gy V 70 Gy V 65 Gy Rectum V 60 Gy V 50 Gy V 40 Gy V 30 Gy 34

50 Chapter 6 Results 6.1 Change in CTV coverage with different PTV margin PTV margins influence daily dose coverage significantly. Dose on the CBCT varies from the planning CT on a day to day basis due to set-up uncertainties and organ motion. This study shows the difference in CTV coverage with respect to different PTV margins. Table 6.1 shows the comparison of the CTV dose on the planning CT with respect to cumulative daily CBCTs for 84 CBCT data sets. Here, the CTV dose for the planning CT with 1, 3, 5 & 7mm margins is 100% for V100. On the cumulative CBCT there is a large increase of CTV coverage as the margin is increased from 1mm to 3 mm, but as shown in Table 6.1, there is no significant increase in CTV coverage from 3 mm to 7mm. Also, the standard deviation decreased by the increase in margin. The criteria to choose the best PTV margin was based on CTV coverage and OAR doses; for CTV coverage, the best PTV margins were chosen that had a cumulative CBCT dose for the CTV to be approximately 100% more than 95% of the time. 35

51 For smaller margins, superior-inferior and anterior-posterior directions of the prostate were not covered by prescription dose. However, for 3-7 mm margins the CTV coverage increased. For the cumulative CBCT, V95% was more than 99% of the CTV volume for all the margins. For the daily CBCT, the minimum of V100% for all the CBCTs for 1mm margin was 78.87%, for 3mm margins it was 90.43%, for 5mm margins 97.50% and 99.39% for 7mm PTV margins. V100 % was 95.86% for 1mm, 99.21% for 3mm, 99.90% for 5mm and for 7mm, V100% is 99.98%. For the cumulative CBCT, V95% for 1mm PTV margins was 99.13%, 99.84% for 3mm, 99.98% for 5mm and 100% for 7mm PTV margin. Table 6.1: Comparison for CTV dose between P-CT and Cumulated daily CBCT 1mm PTV margin (in%) 3mm PTV margin(in%) Planned Cum. CBCT± SD Planned Cum. CBCT± SD V107% ± ±7.01 V100% ± ±1.69 V98% ± ±1.12 V95% ± ±0.52 V90% ± ±0.16 5mm PTV margin in(%) 7mm PTV margin (in%) Planned Cum. CBCT± SD Planned Cum. CBCT± SD V107% ± ±7.21 V100% ± ±0.07 V98% ± ±0.02 V95% ± ±0.00 V90% ± ±0 36

52 The planning CT and daily CBCT DVH comparison for CTV for Patient1 is shown in Fig 6.1. For the 1mm margin, there is more deviation in the planned dose as compared to the daily CBCT dose. Fig 6.1: Comparison for the CTV dose for P-CT (Red) and daily CBCT (Grey) for 1mm PTV margin for Patient1 For the 3-mm margins, the DVH comparison for p-ct and daily CBCT is shown below in Fig 6.2. There is improved CTV coverage as compared to the 1mm margin. 37

53 Fig 6.2: Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 3 mm PTV margin 38

54 Fig 6.3: Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 5 mm PTV margin Similarly, a comparison is shown below in Figs 6.3 and 6.4 for 5mm and 7mm margins of the planned and daily CBCT doses for an entire course of RT. Here it is clear that with the increased margin, the CTV coverage is also increasing. For a 7mm margin, the CTV is covered by 100% of the dose on an almost daily basis. 39

55 Fig 6.4: Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 7 mm PTV margin Figures 6.1 through 6.4 show the effect of the PTV margin on CTV coverage for the first patient in this study. Similar results were obtained for the second and third patients. The DVH comparison of the p-ct and daily CBCT for the second patient is shown below for 1, 3, 5 and 7mm margins, combined in figures 6.5 and

56 Fig 6.5: Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin 41

57 Fig 6.6: Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 1,3,5 and 7 mm PTV margin It can be clearly seen that increasing the margin simultaneously increases the CTV coverage on the daily CBCT. Now the concern becomes the rectum and bladder doses. 6.2 Bladder and Rectum volume variations Studies have shown the effect that variation in the bladder and rectum volume has on prostate coverage. Changes in the bladder and rectal volumes allow for an increase in 42

58 inter-fraction motion and hence affects CTV coverage. For one patient, the volume of the bladder on p-ct is cc, but the minimum volume on the cumulative daily CBCT is cc and the maximum bladder volume on the basis of daily anatomy is 380 cc. The mean bladder volume for the same patient on the cumulative CBCT is cc. Similarly for another patient the bladder volume on the p-ct is cc, but the bladder volume on the cumulative CBCTs were at a maximum of 133 cc and a minimum of cc. Also, the rectum volume varies significantly during whole course of treatment. For patient1, the rectal volume on the p-ct is 41.5 cc, but the mean rectal volume on the daily CBCT is cc, with a maximum of 93.5 cc and minimum of 47.5 cc during a whole course of treatment. For patient2, the p-ct rectal volume was 83.4 cc, but the mean, minimum and maximum daily CBCT rectal volumes were 92.17, and cc respectively. To graphically express the variation in rectal and bladder volume during the whole course of radiation therapy, a time trend for the volume change of the bladder and rectum of three patients is shown in Fig. 6.7, Fig 6.8 and Fig

59 Fig 6.7: Bladder (blue) and rectal (green) volume variation of Patient1 during entire course of RT 44

60 Fig 6.8: Bladder (blue) and rectal (green) volume variation of Patient2 during entire course of RT 45

61 Fig 6.9: Bladder (blue) and Rectal (green) volume variation of Patient3 during entire course of RT These bladder and rectal volume deviations have significant effects on the bladder and rectal doses throughout the course of therapy. Effects of the change in bladder dose for the whole course of therapy with respect to the planning CT for 5mm PTV margins are shown in Fig

62 Fig 6.10: Volumetric bladder dose comparison for planned (blue) vs. daily CBCT (grey) dose for two patients having lowest (upper) and highest (lower) bladder volume on planning CT 47

63 Fig 6.11 shows the coronal view of bladder volume for daily CBCT and planning CT for Patient1. It shows the variation of bladder volume on a CBCT day as compared to p-ct. Fig 6.11: Coronal view of bladder volume on Daily CBCT (Upper) and Planning CT (Lower) 48

64 6.3 Change in Bladder dose with respect to different margins Variation in volume of the bladder during the course of RT directly altered the dose received by bladder. Comparison of the bladder dose on planned vs. cumulative CBCT for 1, 3, 5 and 7mm margins are shown in Table 6.2. Here, results show that the average change on the daily CBCT is not much in comparison to planned dose. Daily variations were averaged for all CBCTs. As the margin increased there was more variation for bladder dose on the daily CBCT versus planned dose. Standard deviation for cumulative CBCT increased with the increase in margin. Planned V70 Gy was 0.04%, 1.05%, 3.21% and 5.17% for 1, 3, 5 and 7mm PTV margin respectively. Cumulative V70 for daily CBCT was 1.13, and 6.68% for 1, 3, 5 and 7mm PTV margins. Table 6.2: Comparison for Bladder dose between P-CT and Cumulated daily CBCT 1mm PTV margin (in%) 49 3mm PTV margin(in%) Planned Cum. CBCT± SD Planned Cum. CBCT± SD V70 Gy ± ±3.01 V65 Gy ± ±3.79 V60 Gy ± ±4.44 V50 Gy ± ±5.82 V40 Gy ± ±8.05 V30 Gy ± ± mm PTV margin (in%) 7mm PTV margin (in%) Planned Cum. CBCT± SD Planned Cum. CBCT± SD V70 Gy ± ±5.50 V65 Gy ± ±6.69

65 V60 Gy ± ±7.72 V50 Gy ± ±9.84 V40 Gy ± ±12.44 V30 Gy ± ±15.53 DVH comparison of the p-ct and daily CBCT for the whole course of treatment is shown below. The volume of the bladder on the planning CT is greater than the volume during the entire treatment, meaning that the patient is receiving a lesser dose as compared to the daily CBCT. The DVH for the bladder with a 1mm PTV margin is shown in Fig For smaller margins, the spread in doses is less significant. Fig 6.12: Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 1mm PTV margin 50

66 Fig 6.13: Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 3mm PTV margin Fig 6.14: Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 5mm PTV margin 51

67 Fig 6.15: Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 7 mm PTV margin As shown in figures 6.12 to 6.15, there is large variation in day-to-day doses for daily CBCT which is due to the volume of the patient changing throughout the course of RT. Also, with increase in margins to 7mm there is more variation in the data; data spread increased as the margin increased. Similarly, the bladder DVH for Patient2 and 3, with the same 1, 3, 5 and 7mm margins for the p-ct as compared to the daily CBCT is shown in Fig 6.16 and

68 Fig 6.16: Comparison for CTV dose for P-CT (Red) and daily CBCT (Grey) for 1, 3, 5 and 7 mm PTV margin 53

69 Fig 6.17: Comparison for Bladder dose for P-CT (Blue) and daily CBCT (Grey) for 1, 3, 5 and 7 mm PTV margin for another patient 54

70 6.4 Change in Rectum dose with respect to different margins For the rectum, there was more variation in planned versus cumulative CBCT doses. Table 6.3 shows the variation between the planned and cumulative CBCT doses for 1, 3, 5 and 7mm PTV margins. As the margin increased there was considerable increase in V70% too. Standard deviation (SD) also increased with the increase in PTV margins from 1 to 7mm. The 7 mm PTV margins did not even reach the passing criteria for best PTV margins. The maximum dose variation of V70 for the planned versus daily CBCT was 18.15% (1mm), 25% (3mm), 31.25% (5mm) and 37.18% (7mm) for different PTV margins. The mean planned V70Gy for 1, 3, 5 and 7mm PTV margins was 0.31%, 2.56%, 5.00% and 11.03% respectively. The cumulative V70 dose on the daily CBCT was 5.97%, 10.05%, 13.64% and 19.66% for 1, 3, 5 and 7mm PTV margins respectively. The rectum is more sensitive to radiation than the bladder, and so these changes in dose to the rectum may result in serious complications. 55

71 Table 6.3: Comparison for Rectum dose between P-CT and Cumulated daily CBCT 1mm PTV margin (in%) 3mm PTV margin(in%) Planned Cum. CBCT± SD Planned Cum. CBCT± SD V70 Gy ± ±5.40 V65 Gy ± ±6.90 V60 Gy ± ±8.01 V50 Gy ± ±10.01 V40 Gy ± ±12.39 V30 Gy ± ± mm PTV margin (in%) 7mm PTV margin (in%) Planned Cum. CBCT± SD Planned Cum. CBCT± SD V70 Gy ± ±6.60 V65 Gy ± ±7.79 V60 Gy ± ±8.64 V50 Gy ± ±10.11 V40 Gy ± ±11.64 V30 Gy ± ±14.75 DVH comparison of the p-ct versus daily CBCT of a patient during an entire course of treatment is shown in figures 6.18 to As the PTV margins were increased from 1mm to 7mm, the dose to the rectum was increased considerably throughout the course of treatment. For the entire course of RT, the dose to the rectum based on the patient's anatomy of the day was more comparable to the p-ct. 56

72 Fig 6.18: Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 1mm PTV margin Fig 6.19: Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 3 mm PTV margin 57

73 Fig 6.20: Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 5 mm PTV margin Fig 6.21: Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 7mm PTV margin 58

74 Fig 6.22: Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 1, 3, 5 and 7 mm PTV margin for another patient For Patient2 and 3, the DVH comparison for all the margins is shown below in Fig 6.22 and Fig V70% is extremely high in comparison to the planned dose for all PTV margins. 59

75 Fig 6.23: Comparison for Rectum dose for P-CT (Green) and daily CBCT (Grey) for 1, 3, 5 and 7 mm PTV margin for another patient 60

76 Chapter 7 Summary and Conclusions Daily setup variations and organ motion during prostate IMRT yield differences in the actual vs. expected dose received by the prostate, rectum and bladder. The magnitude of these differences is significantly affected by the PTV margins utilized for RT. By controlling these errors, PTV margins can be greatly reduced which will lead to better control for doses received by OAR. It is also important to know that PTV margins are dependent on the type of registration, and whether it is with respect to soft tissue or bony anatomy. In literature it has already been demonstrated that margins for bony anatomy alignment are bigger in comparison to soft tissue alignment. Daily image guidance can improve the accuracy of treatment and reduce the uncertainties. This study has shown that for low and intermediate risk prostate carcinoma, margins between 1 to 3 mm are not sufficient to cover the whole prostate during a course of treatment. However, a margin between 3 and 5mm provides reasonable coverage of the CTV. For a uniform margin of 7mm the CTV is fully covered by the treatment dose, but the dose received by the rectum is significantly higher on the cumulative CBCT. 61