The Development of Normoxic Polymer Gel Dosimetry using High Resolution MRI

Transcription

1 Queensland University of Technology School of Physical and Chemical Sciences The Development of Normoxic Polymer Gel Dosimetry using High Resolution MRI Christopher Hurley M.App.Sci.(Med Phys), M.Ed.Admin., Grad.Dip.Ed., B.Eng.(Elec) A thesis submitted at the Queensland University of Technology, in the School of Physical and Chemical Sciences, in fulfillment of the requirements of the Doctor of Philosophy. 2006

2 Keywords Polymer gel dosimetry, radiotherapy, brachytherapy, radiation dosimetry, PAG, MAGIC, MAGAT, PAGAT, normoxic polymer gel dosimeters, high-resolution MRI. ii

3 Abstract Dosimetry is a vital component of treatment planning in radiation therapy. Methods of radiation dosimetry currently include the use of: ionization chambers, thermoluminescent dosimeters (TLDs), solid-state detectors and radiographic film. However, these methods are inherently either 1D or 2D and their use involves the perturbation of the radiation beam. Although the dose distribution within tissues following radiation therapy treatments can be modeled using computerized treatment planning systems, a need exists for a dosimeter that can accurately measure dose distributions directly and produce 3D dose maps. Some radiation therapy and brachytherapy treatments require mapping the dose distributions in high-resolution (typically < 1 mm). A dosimetry technique that is capable of producing high resolution 3D dose maps of the absorbed dose distribution within tissues is required. Gel dosimetry is inherently a 3D integrating dosimeter that offers high spatial resolution, precision and accuracy. Polymer gel dosimetry is founded on the basis that monomers dissolved in the gel matrix polymerize due to the presence of free radicals produced by the radiolysis of water molecules. The amount of polymerization that occurs within a polymer gel dosimeter can be correlated to the absorbed dose. The gel matrix maintains the spatial integrity of the polymers and hence a dose distribution can be determined by imaging the irradiated polymer gel dosimeter using an imaging modality such as MRI, x-ray computed tomography (CT), ultrasound, optical CT or vibrational spectroscopy. Polymer gel dosimeters, however, suffer from oxygen contamination. Oxygen inhibits the polymerization reaction and hence polymer gel dosimeters must be manufactured, irradiated and scanned in hypoxic environments. iii

4 Normoxic polymer gel dosimeters incorporate an anti-oxidant into the formulation that binds the oxygen present in the gel and allows the dosimeter to be made under normal atmospheric conditions. The first part of this study was to provide a comprehensive investigation into various formulations of polymer and normoxic polymer gel dosimeters. Several parameters were used to characterize and assess the performance of each formulation of polymer gel dosimeter including: spatial resolution and stability, temporal stability of the R2-dose response, optimal R2- dose response for changes in concentration of constituents and the effects of oxygen infiltration. This work enabled optimal formulations to be determined that would provide greater dose sensitivity. Further work was done to investigate the chemical kinetics that take place within normoxic polymer gel dosimeters from manufacture to post-irradiation. This study explored the functions that each of the constituent chemicals plays in a polymer gel dosimeter. Although normoxic polymer gel dosimeters exhibit very similar characteristics to polyacrylamide polymer gel dosimeters, one important difference between them was found to be a decrease in R2-dose sensitivity over time in the normoxic polymer gel dosimeter compared to an increase in the polyacrylamide polymer gel dosimeters. From an investigation into the function of anti-oxidants in normoxic polymer gel dosimeters, alternatives were proposed. Several alternative anti-oxidants were explored in this study that found that whilst some were reasonably effective, tetrakis (hydroxymethyl) phosphonium chloride (THPC) had the highest reaction rate. THPC was found not only to be an aggressive scavenger of oxygen, but also to increase the dose sensitivity of the gel. Hence, a formulation of normoxic polymer gel dosimeter was proposed, called MAGAT, that comprised: methacrylic acid, gelatin, hydroquinone and THPC. This formulation was examined in a similar fashion to the studies of the other formulations of polymer and normoxic polymer gel dosiemeters. The gel was found to exhibit spatial and temporal stability and an optimal formulation was proposed based on the R2-dose response. Applications such as IVBT require high-resolution dosimetry. Combined with high-resolution MRI, polymer gel dosimetry has potential as a high-resolution 3D integrated dosimeter. Thus, the second component of this study was to iv

5 commission a micro-imaging MR spectrometer for use with normoxic polymer gel dosimeters and investigate artifacts related to imaging in high-resolutions. Using high-resolution MRI requires high gradient strengths that, combined with the Brownian motion of water molecules, was found to produce an attenuation of the MR signal and hence lead to a variation in the measured R2. The variation in measured R2 was found to be dependent on both the timing and amplitude of pulses in the pulse sequence used during scanning. Software was designed and coded that could accurately determine the amount of variation in measured R2 based on the pulse sequence applied to a phantom. Using this software, it is possible to correct for differences between scans using different imaging parameters or pulse sequences. A normoxic polymer gel dosimeter was irradiated using typical brachytherapy delivery and the resulting dose distributions compared with dose points predicted by the computerized treatment planning system.the R2-dose response was determined and used to convert the R2 maps of the phantoms to dose maps. The phantoms and calibration vials were imaged with an in-plane resolution of mm/pixel and a slice thickness of 2 mm. With such a relatively large slice thickness compared to the in-plane resolution, partial volume effects were significant, especially in the region immediately adjacent the source where high dose gradients typically exist. Estimates of the partial volume effects at various distances within the phantom were determined using a mathematical model based on dose points from the treatment planning system. The normalized and adjusted dose profiles showed very good agreement with the dose points predicted by the treatment planning system. v

6 Table of Contents ABSTRACT... III TABLE OF CONTENTS... VI LIST OF PUBLICATIONS:... IX LIST OF ABBREVIATIONS:... X STATEMENT OF ORIGINAL AUTHORSHIP:... XI ACKNOWLEDGEMENTS... XII CHAPTER 1 INTRODUCTION Description of Research Problem Investigated Overall Objective of the Study The Specific Aims of the Study Account of Scientific Progress Linking the Scientific Papers...4 References...6 CHAPTER 2 LITERATURE REVIEW Radiotherapy and Brachytherapy Radiation Dosimetry Clinical Dosimetry Requirements Dosimetry Detectors Ionization Chambers Solid-State Detectors Thermoluminescent Dosimeters Radiographic Film Chemical Dosimeters Gel Dosimeters Ferrous Sulfate (Fricke) Gels Polymer Gel Dosimeters Normoxic Polymer Gel Dosimeters Characteristics of Polymer Gel Dosimeters Effects of Oxygen Effect of Light Temperature Concentration of monomers Ageing of the gel Evaluation of Polymer Gel Dosimeters Magnetic Resonance Imaging X-Ray Computed Tomography Optical Computed Tomography Ultrasound Vibrational Spectroscopy High-Resolution MRI in Polymer Gel Dosimetry Brachytherapy Applications of Gel Dosimetry Sources of Uncertainty in Polymer Gel Dosimeters Conclusion...42 References...44 CHAPTER 3 DOSE-RESPONSE STABILITY AND INTEGRITY OF THE DOSE DISTRIBUTION OF VARIOUS POLYMER GEL DOSIMETERS...63 Abstract Introduction Materials and methods...65 vi

7 3.2.1 Gel fabrication Irradiation Scanning Results R2-Dose stability Integrity of dose distribution Discussion R2-Dose stability Integrity of the dose distribution Conclusions References CHAPTER 4 A BASIC STUDY OF SOME NORMOXIC POLYMER GEL DOSIMETERS...77 Abstract Introduction Materials and Methods MAGIC gel components Dose distribution of half-blocked field Anti-oxidants Potentiometric oxygen measurements Results MAGIC gel components Dose distribution of half-blocked field Anti-oxidants Potentiometric oxygen measurements Discussion Acrylic polymer gels Normoxic polymer gels Conclusions References CHAPTER 5 THE EFFECTS OF MOLECULE SELF-DIFFUSION OF WATER ON QUANTITATIVE MRI MEASUREMENTS IN HIGH-RESOLUTION POLYMER GEL DOSIMETRY Abstract Introduction Theory Methods Sample preparation R2 measurements Self-diffusion coefficient measurements Computer simulations of the diffusion effect on R Computer simulations of the diffusion effect on phase encoding Results R2 measurements Computer simulations of the diffusion effect on R Computer simulations of the diffusion effect on phase encoding Discussion Conclusions References CHAPTER 6 A STUDY OF A NORMOXIC POLYMER GEL DOSIMETER COMPRISING METHACRYLIC ACID, GELATIN, AND TETRAKIS (HYDROXYMETHYL) PHOSPHONIUM CHLORIDE (MAGAT) Abstract Introduction Materials and Methods Formulation Investigation of Concentration of THPC and HQ Investigation of Concentration of Gelatin and MAA R2-Dose Response Spatial Stability vii

8 6.2.4 Scanning and Processing Results and Discussion Formulation Concentrations of THPC and HQ Concentrations of Gelatin and MAA R2-Dose Response Spatial Stability Conclusions References CHAPTER 7 HIGH-RESOLUTION GEL DOSIMETRY OF A HDR BRACHYTHERAPY SOURCE USING NORMOXIC POLYMER GELS Abstract Introduction Materials and Methods Results and Discussion Calibration Dose maps Dose profiles Agreement between dose maps and treatment plans Conclusion References CHAPTER 8 GENERAL DISCUSSION The Principal Significance of the Findings Analyzing and Optimizing Polymer Gel Dosimeter Formulations Chemical Properties of Normoxic Polymer Gel Dosimeters A Normoxic Polymer Gel Dosimeter Using THPC Evaluating Polymer Gel Dosimeters using High-Resolution MRI Application of Normoxic Polymer Gel Dosimeters using High-Resolution MRI to Brachytherapy Treatment Plans Conclusions and Future Work References APPENDIX A LISTING OF THE CODE FOR DETERMINING VARIATIONS IN R2 DUE TO THE APPLICATION OF PULSE SEQUENCES DURING HIGH-RESOLUTION MRI viii

9 List of Publications: 1. De Deene, Y., Venning, A., Hurley, C., Healy, B. J., Baldock, C., Doseresponse stability and integrity of the dose distribution of various polymer gel dosimeters, Phys Med Biol, (14) De Deene, Y., Hurley, C., Venning, A., Vergote, K., Mather, M., Healy, B.J., Baldock, C., A basic study of some normoxic polymer gel dosimeters. Phys Med Biol, , Hurley, C., De Deene, Y., Meder, R., Pope, J.M., Baldock, C., The effects of molecular self-diffusion of water on quantitative MRI measurements in high-resolution polymer gel dosimetry, Phys Med Biol, : Hurley, C., Venning, A. and Baldock, C., A Study of a Normoxic Polymer Gel Dosimeter comprising Methacrylic Acid, Gelatin and Tetrakis (Hydroxymethyl) Phosphonium Chloride (MAGAT), App Radiat and Iso, : Hurley, C., McLucas, C., Pedrazzini, G., and Baldock, C., High- Resolution Gel Dosimetry of a HDR Brachytherapy Source Using Normoxic Polymer Gels: Preliminary Study, Nucl Instr Meth Phys Res A, : (In Press). ix

10 List of Abbreviations: AAPM ABAGIC CT HDR HEA ICRU IMRT IVBT LDR MAGAS MAGAT MAGIC American Association of Physicists in Medicine Acrylamide, methylene-bis-acrylamide, Ascorbic acid, Gelatin, Hydroquinone, and copper(ii) sulphate gel Computed Tomography High Dose Rate 2-Hydroxyethyl Acrylate gel International Commission on Radiation Units Intensity Modulated Radiotherapy Intravascular Brachytherapy Low Dose Rate Methacrylic Acid, Gelatin, AScorbic acid Methacrylic Acid, Gelatin, Ascorbic Acid and THPC Methacrylic Acid, Gelatin, Initiated by Copper Sulphate (the first normoxic polymer gel proposed by Fong et al (2001). Magnetic Resonance Imaging PolyAcrylamide Gelatin gel PolyAcrylamide, Gelatin, AScorbic acid Pulsed Dose Rate MRI PAG PAGAS PDR R1 MRI Longitudinal Relaxation Rate (measured in s -1 ) R2 MRI Transverse Relaxation Rate (measured in s -1 ) T1 MRI Longitudinal Relaxation Time (measured in s) T2 MRI Transverse Relaxation Time (measured in s) TE ΔTE THPC TLD TR MRI Echo Time MRI Inter-Echo Time Tetrakis (Hydroxymethyl) Phosphonium Chloride Thermoluminescent Dosimeter MRI Relaxation Time x

11 Statement of Original Authorship: The work contained in this thesis has not been previously submitted to meet requirements for an award at this or any other higher education institution. To the best of my knowledge and belief, the thesis contains no material previously published or written by another person except where due reference is made. Christopher A. Hurley 17 th August, 2006 xi

12 Acknowledgements I would like to sincerely thank the following persons for their invaluable contributions to the project: Clive Baldock, my supervisor, for inspiring me to excellence, providing invaluable advice and for the countless hours of support in helping me to see the bigger picture in research. I am deeply and sincerely grateful for your endless enthusiasm and perseverance as you challenged me to achieve ever greater heights in this project! Yves De Deene for the incredible knowledge and experiences that you shared with me, helping me to understand and appreciate the complex world of MRI. Your ability to open my mind to understanding the world of MRI and Physics is extraordinary. Jim Pope for your exceptional ability to understand exactly what was going on when I was exploring the field of high-resolution MRI. Your advice was always exactly what I needed. Thanks to Cameron McLucas and Greg Pedrazzini for your patient work in the irradiation of the phantoms and your expert technical advice in brachytherapy and dosimetry. Thanks to Southern X-Ray Clinic of the Wesley Hospital for the use of MRI scanner, brachytherapy afterloader and linear accelerators and the Wesley Research Institute. Your commitment to research in medicine is highly commendable. Brian Thomas and Elizabeth Stein for your assistance and guidance throughout the course. Your willingness to sit and talk at any time, encouraged me to see the course through to the end. xii

13 Chapter 1 Introduction 1.1 Description of Research Problem Investigated The use of radiation to supply a lethal dose to tissue affected by disease has been a practice used for many years. A common part of most major hospitals in the world, the radiation therapy (or radiation oncology) department has formed an integral component of medicine s fight against cancer. The aim of radiation therapy has been to deliver a dose of ionizing radiation to a tumour or lesion, whilst minimizing the dose that may be delivered to the surrounding healthy tissue. Radiation therapy has advanced significantly over the past decades and now offers a wide range of techniques that can conform a radiation beam to maximize dose to a targeted tissue whilst minimizing dose to surrounding tissues. Conformal radiotherapy and intensity-modulated radiotherapy (IMRT) have made considerable advances in shaping the doses in three dimensions (3D) delivered to tissues. In a similar fashion, brachytherapy, which involves a radioactive source being placed directly inside target tissues within a patient s body, has enabled the localization of ionizing radiation to a small volume of tissue, again effectively minimizing the dose being delivered to healthy tissues that may surround the tumour or lesion. With these advances in dose delivery, the target volumes can now incorporate complex geometries with high dose gradients. Although the amount of radiation delivered to the patient s body can been easily determined through well-known and derived equations, it is more difficult to accurate determine the distribution of absorbed dose within the patient s body. Absorbed dose distributions are typically determined using computerized 1

14 treatment planning software that is based on radiation models and simulations of the absorbed dose. Direct measurements of the absorbed dose have traditionally been determined using ionization chambers, thermoluminescent dosimeters (TLDs), solid-state detectors and radiographic film. However, ionization chambers, TLDs and solid-state detectors usually exhibit poor spatial resolution (due to the size of the measuring device), radiographic film is inherently 2D and all these detectors perturb the radiation beam. Gel dosimetry provides a method by which the spatial, 3D distribution of the absorbed dose can be determined [1,2]. Currently there are several different formulations for gel dosimeters under investigation. Each comprises an aqueous gel matrix to provide spatial stability, cross-linker monomers that polymerize when irradiated and other constituents that function to maintain the chemical stability or improve the performance of the gel as a dosimeter [3-6]. Polyacrylamide polymer gel dosimeters suffer from the effects of oxygen infiltration which prevents the polymerization process that can be correlated to absorbed dose. Normoxic polymer gel dosimeters, that use an anti-oxidant to bind free oxygen, have recently been proposed but require further investigation and development before use in clinical practice. Following irradiation, phantoms of polymer gel dosimeter are evaluated using imaging modalities such as MRI [2], x-ray computed tomography (CT) [7], optical CT [8] and ultrasound [9]. To date, MRI has been the most frequently used scanning technique for gel dosimetry. Using high-resolution MRI to evaluate polymer gel dosimeters has the potential to provide dose distributions with high spatial resolutions in the order of sub-millimeters (~ 100 microns). However, the evaluation of polymer gel dosimeters using high-resolution MRI is only in its infancy and there is still much work to be done. To date, highresolution MRI has not been used to evaluate normoxic polymer gel dosimeters. 2

15 1.2 Overall Objective of the Study The objective of this study was to further develop normoxic polymer gel dosimetry using high-resolution magnetic resonance imaging and assess its feasibility in the verification of high-resolution treatment plans, such as those used in intravascular brachytherapy. 1.3 The Specific Aims of the Study The specific aims of this study included: Exploration of different formulations of polymer gel dosimeters and normoxic polymer gel dosimeters in order to obtain normoxic polymer gel dosimeters with optimal characteristics for use in gel dosimetry. Measurement of the effects of physical and chemical properties of various formulations of normoxic polymer gel dosimeters on dose maps obtained using gel dosimetry with high-resolution MRI to assess their performance for use in radiotherapy dosimetry. Investigation of high-resolution magnetic resonance imaging, to achieve in-plane spatial resolutions ~ 100 microns, for its potential use in evaluating polymer gel dosimeters accurately and efficiently. Examination of the effects of molecular diffusion on images produced using high-resolution MRI in order to eliminate the effects causing errors in the calculated dose maps of polymer gel dosimeters. Application and assessment of normoxic polymer gel dosimeters irradiated using typical brachytherapy deliveries and evaluated using highresolution MRI. 3

16 1.4 Account of Scientific Progress Linking the Scientific Papers Normoxic polymer gel dosimeters present a significant advance in gel dosimetry and show good potential to the verification of radiation therapy and brachytherapy dose distributions in 3D. However, their development is still in its infancy and normoxic polymer gel dosimeters have yet to be incorporated into clinical practice. Using high-resolution MRI provides the potential for extending the applications of gel dosimetry to include radiation therapy and brachytherapy treatments that require verification with resolutions at the sub-millimeter level (typically ~ 100 microns). This study has been broken into two aspects: the analysis and development of normoxic polymer gel dosimeters and secondly, the investigation of the use of high-resolution MRI to evaluate normoxic polymer gel dosimeters. Significant changes of the polymer structure are known to occur in polymer gel dosimeters following irradiation [10]. These changes ultimately affect the chemical and physical properties of a gel and hence its suitability for use in gel dosimetry. Chapter 3 investigates some different formulations of polymer gel dosimeter, including polyacrylamide gel (PAG), polymer gel dosimeters made with 2-hydroxyethyl acrylate (HEA), and normoxic polymer gel dosimeters including the MAGIC gel (methacrylic and ascorbic acid in gelatin initiated by copper) [11]. The effects of varying the concentrations of the constituent components of the gel on the R2-dose response was explored to produce an optimal formulation. The temporal stability of the R2-dose response was also examined by relating changes in the R2-intercept and the R2-dose sensitivity (slope) to reactions within the gel. The spatial stability was investigated using dose profiles through a phantom exposed to a half-blocked field. Chapter 4 further investigates normoxic polymer gel dosimeters through a chemical analysis of the MAGIC gel. The role of the different chemicals and reactions kinetics are explored as they affect the R2-dose response and spatial and 4

17 temporal stability of the MAGIC gel. A comprehensive investigation of the chemical reactions that take place within a normoxic polymer gel dosimeter is presented in order to explain the role that each constituent component plays in the overall gel. An understanding of these reactions assists in the development of more optimal formulations. In addition, alternative anti-oxidants to ascorbic acid are proposed and investigated as to their effectiveness for oxygen scavenging in normoxic polymer gel dosimeters. High-resolution MRI requires high gradient strengths that can significantly vary the R2 values obtained due to molecular diffusion of water molecules within the gel itself. The degree of variation is affected by the imaging parameters chosen by an operator. Chapter 5 investigates the extent to which the imaging parameters alter the R2 values and techniques that can be incorporated to provide an accurate dose map using high-resolution MRI in polymer gel dosimetry. Software is developed that can predict the variation in R2 due to the application of MRI pulse sequences that are used. Chapter 6 investigates a normoxic polymer gel dosimeter comprising tetrakis (hydroxymethyl) phosphonium chloride (THPC) as an alternative anti-oxidant to the ascorbic acid that is used in MAGIC polymer gel dosimeters. This gel, composed of methacrylic acid, gelatin, and THPC, was called MAGAT. This chapter evaluates the R2-dose response, the temporal stability of the R2-dose response, the spatial stability and provides an optimal formulation for the MAGAT polymer gel dosimeter using high-resolution MRI. Finally, chapter 7 examines the application of a normoxic polymer gel dosimeter using high-resolution MRI to typical brachytherapy deliveries. Using a line and a point irradiation pattern as a plan, dose distribution maps were produced and compared with dose points predicted by the treatment planning system. Adjusting for partial volume effects, the dose profiles show good agreement to dose points predicted by the computerized treatment planning system. 5

18 References [1] Maryanski, M.J., Gore, J.C., Kennan, R.P. and Schulz, R.J., NMR relaxation enhancement in gels polymerized and cross-linked by ionizing radiation: a new approach to 3D dosimetry by MRI. Magn Reson Imaging, (2) [2] Maryanski, M.J., Gore, J.C. and Schulz, R.J., US Patent: Three-dimensional detection, dosimetry and imaging of an energy field by formation of a polymer in a gel. 1994, Patent Number 5,321,357. United States. [3] Baldock, C., Burford, R.P., Billingham, N., Cohen, D. and Keevil, S.F., Polymer gel composition in MRI dosimetry. Med Phys, [4] De Deene, Y., Hanselaer, P., De Wagter, C., Achten, E. and De Neve, W., An investigation of the chemical stability of a monomer/polymer gel dosimeter. Phys Med Biol, (4) [5] Lepage, M., Whittaker, A.K., Rintoul, L., Back, S.A. and Baldock, C., Modelling of post-irradiation events in polymer gel dosimeters. Phys Med Biol, (11) [6] Lepage, M., Whittaker, A.K., Rintoul, L., Back, S.A. and Baldock, C., The relationship between radiation-induced chemical processes and transverse relaxation times in polymer gel dosimeters. Phys Med Biol, (4) [7] Trapp, J.V., Back, S.A., Lepage, M., Michael, G. and Baldock, C., An experimental study of the dose response of polymer gel dosimeters imaged with x-ray computed tomography. Phys Med Biol, (11) [8] Gore, J.C., Ranade, M., Maryanski, M.J. and Schulz, R.J., Radiation dose distributions in three dimensions from tomographic optical density scanning of polymer gels: I. Development of an optical scanner. Phys Med Biol, (12) [9] Mather, M.L., Whittaker, A.K. and Baldock, C., Ultrasound evaluation of polymer gel dosimeters. Phys Med Biol, (9)

19 [10] Lepage, M., Whittaker, A.K., Rintoul, L. and Baldock, C., 13C-NMR, 1H- NMR, and FT-Raman study of radiation-induced modifications in radiation dosimetry polymer gels. J App Poly Sci, [11] Fong, P.M., Keil, D.C., Does, M.D., and Gore, J.C., Polymer gels for magnetic resonance imaging of radiation dose distributions at normal room atmosphere. Phys Med Biol, (12)

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21 Chapter 2 Literature Review 2.1 Radiotherapy and Brachytherapy Since the development of radiation therapy and related fields, patients have been exposed to radiation for the treatment of malignant disease. The approach taken to achieve this has involved the exposure of the affected tissue area to a radiation beam of sufficient energy to cause significant damage to the cells in the affected area without affecting the surrounding normal tissue to any great extent [1]. Exposing tissues affected by cancer to sufficient levels of radiation causes irreversible cell damage therefore preventing the cancerous cells from further growth and metastasis [2]. There are currently several methods by which radiation can be delivered to a targeted area. The most widely used method is external beam irradiation. In this approach, a linear accelerator (linac) generates megavoltage energy photon or electron beams that are focused and aimed onto a patient s body. Using collimation and rotation, linacs are able to confine the radiation exposure to a particular region of the patient s body. Using x-ray computed tomography (CT) it is possible to obtain scans of a patient enabling greater anatomical delineation. This information can then be used to ensure that high doses of radiation are delivered to target volume whilst sparing the surrounding healthy tissues [3]. Magnetic resonance imaging (MRI) and positron emission tomography (PET) can enhance the process of tumour identification giving a more precise geometric definition of the tumour. A more precise tumour definition may lead to improved irradiation of the true extent of the tumour. This process is known as conformal radiation therapy (CRT). Multi-leaf collimators (MLCs) can now be used to 9

22 control the shape of the radiation beam used to treat a patient [4]. Current MLCs typically have between 40 to 120 leaves of varying widths (0.5 to 1 cm) across the leaf range. These leaves, made of tungsten, can be moved in front of the beam at specific lengths to define the radiation beam. In this way, treatment exposures can be made to conform more precisely to target volumes using sophisticated computer software that manipulates radiotherapy equipment in real time. One key objective of the clinical implementation of conformal radiotherapy is assuring that the complex manipulations of the radiotherapy equipment required for the therapy are actually performed, and that the dose distributions calculated by treatment planning systems and delivered by treatments are correct [5]. Correctly measuring the delivered dose is central to the process of assuring the accuracy of treatment plans and treatment deliveries. Intensity modulated radiation therapy (IMRT) provides the ability to vary the radiation fluence within each radiation beam during treatment. IMRT can further enhance the ability of linac to control the radiation distribution within a targeted volume. The dose distribution in this case is non-uniform across several radiation beams, which summate to produce an optimal dose distribution [6]. Combined with conformal radiation therapy using multi-leaf collimators, treatment plans can now incorporate complex geometries with non-uniform dose distributions to be delivered to a patient. With the increase in treatment complexity, the need for verification of computer generated treatment plans is most significant. The dose distribution required by a treatment plan is calculated by complex computer algorithms that model the radiation system. Monte Carlo models have the potential to predict the dose in complicated geometries using a variety of different types of radiation (electrons, photons, scatter from collimators, scatter within the patient body, etc.) as applied to the internal geometry of the region of the patient body [7]. Despite the advances in Monte Carlo modeling of radiotherapy deliveries, there is still a need to verify the absorbed dose at points within the distribution using direct measurements. 10

23 Brachytherapy involves the use of radioactive sources that are either placed directly on the patient s skin or, more commonly, inserted into the patient and positioned close to the affected tissues [1]. In this way, high radiation doses can be delivered directly to the tumour site thereby concentrating dose in regions requiring treatment and effectively minimizing the irradiation of surrounding healthy tissues. Brachytherapy treatments can be classified as either high dose rate (HDR) or low dose rate (LDR) depending on the radioactive source used. HDR sources must be inserted into the target tissue for a short period of time, whereas LDR sources must be inserted for substantially longer periods of time to deliver sufficient dose to the targeted tissues. New brachytherapy source designs are often commissioned using a Monte Carlo-based analysis of the dose distribution surrounding the source [8-15]. More recently, a combination of the HDR and LDR brachytherapy has been used called pulsed dose rate brachytherapy (PDR) [14,16,17]. PDR involves the use of stronger radiation sources than those used in LDR brachytherapy given in a series of short exposures of 10 to 30 minutes every hour to approximate the same overall dose as with LDR brachytherapy. Typically sources include gamma and beta emitters such as 192 Ir, 32 P, 90 Sr/Y and 125 I. Each source has its own advantages and is generally chosen to match a specific treatment. These sources may be used either as wire stents, seeds inserted through catheters or liquids that can be injected into balloons during angioplasties. Intravascular Brachytherapy (IVBT) emerged from the need to resolve the problem of restenosis, a re-closing of arteries following angioplasty [18-20]. In 1995, the American Association of Physicists in Medicine (AAPM) established a task group committee to investigate and report on the dosimetry of interstitial brachytherapy sources. Their findings were presented in a report, called TG-43, that examined the role of photon-emitting sources used for interstitial brachytherapy [21]. This work was followed-up by a second report in 1999 by TG-60 that investigated the physics in intravascular brachytherapy [22]. This report examined the relative advantages of different sources available for use in brachytherapy. It found that beta emitters, such as 32 P and 90 Sr/Y have advantages in terms of high activity and dose rate, good radiation safety and a long half-life. 11

24 Gamma emitters, such as 192 Ir, have advantages in terms of radial dose uniformity, high dose rate, and reasonably long half-life. One of the key concerns to be raised in this report was dose inhomogeneity due to non-centering of the source. This concern is reflected in the need to assure the positional accuracy of the radiation delivery system that is particularly significant in brachytherapy [23]. Although Monte Carlo calculations have been effective in the determination of dose distributions surrounding brachytherapy sources, these must be verified for further optimization of procedures to be possible. 2.2 Radiation Dosimetry Dosimetry has been at the core of the development of radiation therapy and there currently exists many different methods of measuring the absorbed dose delivered to tissue (and other mediums) [24,25]. Today, complex computer algorithms are used to determine the dose distributions required in a particular treatment plan. These algorithms aim to assure that the calculated dose distributions accurately reflect the dosimetry requirements of a treatment plan. In addition, with computer controlled radiation delivery, software must assure that the complex manipulations of radiotherapy equipment are actually performed correctly [5,26]. The determination of absorbed dose in 3D is fundamental to clinical environments, but few methods exist by which 3D measurements can be made easily and accurately. Computer algorithms model the effective dose absorbed into specific volumes of tissue and other structures in the patient s body [1,22]. However useful the computer calculations might be in the prediction of absorbed dose, the problem of easily and accurately measuring the actual absorbed dose distribution in 3D still remains, even if only to provide a verification of the computed calculations [27] Clinical Dosimetry Requirements Advances in conformal radiation therapy treatments have enabled target volume to be defined with complex geometries. Similarly, radiation delivery can consist 12

25 of varied and non-uniform irradiation fields. These complexities make radiation dosimetry a difficult process that must meet stringent criteria in order to be effective in producing accurate and detailed maps of the dose distribution. The following parameters are typically significant in the design of dosimetry systems: measurement sensitivity, accuracy, precision, spatial resolution, energy and doserate insensitivity, tissue equivalence, non-directionality, ease of use and able to produce three-dimensional, integrated dose maps [7]. The International Commission on Radiation Units (ICRU) recommends that the overall accuracy in delivered dose be within 5 % of the true dose [28,29]. To be effective in a variety of radiation therapy applications, dosimeters need to measure dose accurately and to have high spatial resolution. This is particularly true for brachytherapy, where high resolution is essential since steep dose gradients exist close to the source. These high dose gradients can occur within very small regions of interest, typically < 2 mm [30]. Detectors should also exhibit tissue equivalence in order to not perturb the radiation field and hence have a significant effect on the measured dose. Non-tissue equivalent dosimeters require the application of correction factors in order to determine absorbed dose. These may introduce uncertainties. Dosimeters should also be able to integrate dose for a number of sequential fields to accommodate the time varying doses delivered to a patient Dosimetry Detectors There are currently many different dosimetry detectors that are used to determine radiation dose distribution delivered in radiotherapy treatments each with its own advantages and disadvantages based on criteria listed above Ionization Chambers Currently the most commonly used dosimeter for external beam measurements is the ionization chamber [31,32]. Ionization chambers provide one dimensional point dose measurements in radiation therapy applications. Ionization chambers 13

26 consist of a cavity containing gas, usually air, in which charge is liberated by the ionization of a gas within the chamber by radiation. This charge is collected by electrodes, typically composed of aluminum or carbon based material. The charge can then be correlated to the delivered dose through calibration factors traceable to a standards laboratory. Although these detectors have high accuracy and practicality, they do introduce a perturbation of the photon beam which must be corrected for. The active volumes of ionization chambers are typically between 0.1 and 0.6 cm 3 resulting in poor spatial resolution making them unsuitable for dosimetry in the near-zone of brachytherapy sources. Measuring the dose distribution in 3D using ionization chambers is a laborious process. Dose distributions resulting highly conformal external beam delivery typically require spatial resolution beyond the capabilities of ionization detectors Solid-State Detectors Solid-state detectors, such as semiconductor diodes, can be manufactured with an active volume around 0.1 mm 3, and hence are more suited to applications such as brachytherapy. Solid-state detectors function by measuring the amount of charge liberated by the passage of ionizing radiation in solid semiconductors [33-36]. Arrays of solid-state detectors can be spatially arranged or translated around static fields to achieve 2D and 3D maps of dose distributions. These detectors have the ability to measure dose distributions with higher resolutions than ionization chambers, in real-time and are easy to use, however, they are not tissue equivalent and require independent calibration. Solid-state detectors also suffer from an energy dependence and their response drifts over time due to radiation damage Thermoluminescent Dosimeters Thermoluminescence refers to the emission of light from an irradiated crystalline material following heating. The amount of light emitted from a crystal can be correlated to absorbed dose. Thermoluminescent dosimeters (TLDs) consist of small crystals available in a range of sizes, some as small as 1 mm 2, that act as point detectors. When exposed to radiation, these crystals store a small amount of the energy in the crystal lattice. Upon heating, these crystals release this stored energy as light, which can be detected using a photomultiplier tube. They can be used to provide higher resolutions using a spatially arranged array of closely 14

27 packed TLDs. The main advantages of TLDs include: their wide useful dose range, small physical size, reuseability and economy for most radiation types [37-40] Radiographic Film Radiographic films are used to capture a 2D image of a dose distribution. Conventional films are based on silver-halide (typically silver bromide) and have a strong energy dependence at photon energies in the 10 to 200 kev range [41], an effect derived from the high atomic number of the silver in the film and absorption due to the photoelectric effect that is significant in this energy range. In addition, silver-halide films are non-tissue equivalent. They function by converting silver ions to silver upon irradiation. The bromine is removed during developing leaving opaque clusters of silver on the film in irradiated regions. Radiochromic films are relatively tissue equivalent and do not require chemical developing, however, they exhibit significant temperature dependence and their sensitivity varies photon energy. They develop a specific colouring in irradiated regions as a result of a dye-forming or polymerization process in which energy is transferred from an energetic photon or particle to the receptive part of a leukodye or colourless photomonomer molecule [41]. Gaf-chromic films, a type of radiochromic film, were developed with a more uniform response with photon energy. Gaf-chromic films are popular in clinical radiation dosimetry as they also exhibit high sensitivity and high spatial resolution [42,43]. Film dosimeters are inherently 2D and can be used to obtain dose information by relating the absorbed dose to the optical density of the film. Although sheets of film can be stacked between tissue equivalent material to provide a 3D dosimetry system, the process is cumbersome and time consuming. The use of radiographic films in dosimetry is complicated by their non-tissue equivalence, uncertainties in film processing and their inherent 2D nature [44] Chemical Dosimeters Chemical dosimeters function on the phenomenon that chemical changes occur in the dosimeters when exposed to ionizing radiation. The absorbed dose delivered 15

28 to the dosimeter can be correlated to the extent of radiation-induced chemical change within the dosimeter itself. These chemical changes can be measured as a change in the spin-lattice or spin-spin relalaxation rates, the change in concentration of ions present in solution or the optical turbidity within the sample. One of the more widely known chemical dosimeters is the Fricke dosimeter, proposed by Fricke and Morse in 1927 [45]. The Fricke dosimeter functions by the conversion of ferrous ions (Fe 2+ ) to ferric ions (Fe 3 +) in solution when irradiated. A second type of chemical dosimeter uses the radiolysis of water within a gel matrix to initiate polymerization reactions. The degree of polymerization can be correlated to the absorbed dose [46]. Chemical dosimeters are capable of high precision dose measurements and can provide spatial information when dissolved into an aqueous gel matrix. 2.3 Gel Dosimeters As outlined above, there is a need for a dosimeter that does not perturb the radiation beam, is inherently three-dimensional and has the ability to integrate radiation doses over time. The use of radiation sensitive gels to fulfill these requirements has great potential. Radiation sensitive gels were first considered for use in radiation dosimetry in the 1950s by Day et al. who were investigating radiation induced colour changes in dyes [47,48]. With the addition of gelling agents, a chemical dosimeter could be made to be spatially stable and hence to provide spatial dose information. With the development of methods to image the chemical changes within gel dosimeters, this became the basis of modern gel dosimetry. Gel dosimetry has advanced significantly over the past two decades. Now gel dosimeters have the ability to measure three-dimensional dose distributions with high resolution (less than 1 mm in-plane resolution) [49] and the dose sensitivity of the gel is independent of the energy of the irradiating beam and the dose rate 16

29 used to irradiate the gel [50]. Most importantly, the gel is the dosimeter and thus does not perturb the radiation beam like conventional dosimetry techniques [51]. In addition, gel dosimeters are also tissue equivalent. The gel dosimeter can be used to simulate the tissue of the human body undergoing radiation therapy, by pouring into anthropomorphic phantoms [52]. There are two main varieties of gel dosimeter: ferrous sulfate gel dosimeters and polymer gel dosimeters. More recently, normoxic polymer gel dosimeters have become popular due to their ability to be manufactured under normal atmospheric conditions Ferrous Sulfate (Fricke) Gels In 1984, Gore et al. proposed the use of nuclear magnetic resonance imaging of ferrous sulfate gel dosimeters, also called a Fricke gel, which exhibit a change in their paramagnetic species as a result of exposure to ionizing radiation [53]. Gore et al. also proposed the potential of this chemical response as a dosimeter capable of producing 3D dose distributions of the nature required for use in radiation therapy. The use of a Fricke gel has been developed into a method founded on the principle that ferrous ions (Fe 2+ ) are oxidized to ferric ions (Fe 3+ ) when subjected to free radicals produced by exposing water to ionizing radiation. To achieve this, a gel consisting of an aerated dilute solution of ammonium ferrous sulfate is suspended in an aqueous gel, such as agarose or gelatin. The gel matrix provides the support structure by which the dosimeter can maintain a spatial arrangement, and hence provide spatial information about the dose distribution within the irradiated gel dosimeter. This was significant for gel dosimetry as Gore et al. were able to show that the radiation-induced change could be detected using nuclear magnetic resonance (NMR) [53]. The change from ferrous to ferric ions that occurs in regions exposed to the radiation, provides changes in the gel dosimeter s nuclear magnetic resonance (NMR) spin-lattice relaxation rate, R1, and spin-spin relaxation rate, R2, as both 17

30 ferrous and ferric ions are paramagnetic species capable of reducing the proton relaxation times of water. In particular, the ferric ions exhibit a stronger paramagnetic enhancement of the water-proton NMR relaxation rates. Gore et al. were also able to show that by spatially distributing the ferrous ions, the spatial distribution of dose could be imaged using MRI [53]. This was a significant advance in dosimetry as this was the first evidence for a truly 3D dosimeter for clinical radiation therapy. Since then, many studies have investigated combining Fricke chemical dosimeters with gelling agents and imaging using MRI [54-56]. Optical tomography, an alternative to MRI, has also been investigated by many authors as an imaging modality for Fricke gel dosimetry [57-60]. A great deal of research has been performed to investigate various aspects of Fricke gel dosimetry, including the effects of: ferrous ion concentration, radiation dose rate, beam energy, oxygenation, agarous concentration and acid content [61-64]. Additionally, the use of alternative gelling agents, such as gelatin [65-67] and polyvinyl alcohol (PVA) [68], have been explored. There are two major drawbacks with the use of Fricke gels for 3D dosimetry. The first limitation of ferrous gels is the continual diffusion of the ferric ions through the gel post-irradiation (see references cited in Baldock et al [69]). This diffusion leads to a blurring of dose distributions over time, and hence a degradation of spatial integrity of the dosimetry. However, with the use of chelating agents, this diffusion can be reduced to better maintain the spatial information over extended time periods [69]. The addition of saccarides to ferrous-agarose-xylenol orange gels have also improved dose sensitivity [70]. The problems experienced with Fricke gel dosimeters, have prompted an alternative gel formulation that could provide a more stable dosimeter that would provide both a better spatial resolution as well as being relatively insusceptible to problems caused by ageing [71]. A more detailed discussion of Fricke gel dosimeters can be found in Back et al [72] and Schreiner 2004 [73]. 18

31 2.3.2 Polymer Gel Dosimeters In 1993, Maryanski et al. introduced the use of radiation initiated polymerization into gel dosimetry [74]. It was well-known that polymerization and cross-linking could be initiated by irradiation and that the degree of polymerization could be correlated to the amount of radiation delivered [75-78]. Maryanski et al. used this knowledge to construct a gel dosimeter based on the polymerization [74]. This polymer gel dosimeter used an agarose gel infused with acrylamide and N,N - methylene-bis-acrylamide (bis) co-monomers. It functioned on the premise that ionizing radiation would initiate the polymerization of the co-monomers and induce cross-linking by way of the bis forming a connection between two acrylamide chains. Nitrous oxide was used to saturate the solution in order to remove any oxygen. Likewise, the manufacture of these dosimeters had to occur in a hypoxic environment as oxygen was shown to inhibit the polymerization process [74]. The use of polymer gel dosimeters provided solutions to some of the problems that had been encountered with Fricke gels and hence provided the ability to conduct improved dosimetry in 3D. Polymer gel dosimeters do not suffer the diffusion problems observed in Fricke gels and the range of doses that the polymer gel dosimeters responded to can be engineered by varying the chemical constituents that make up the gel [5]. Another desirable property of polymer gel dosimeters is their optical characteristics, in particular the observable transparency of regions of the gel that are unexposed to ionizing radiation and the opaque regions where ionizing radiation has affected the gel provided immediate visual clues as the distribution of absorbed dose. The opacity of regions within the irradiated regions of gel are due to the formation of polymer aggregates initiated by free radicals formed by the radiolysis of water molecules. Polymer gel dosimeters were found to exhibit significant changes in both the NMR spin-lattice relaxation rate (R1) and the spin-spin relaxation rate (R2). However, unlike the Fricke gel, in polymer gel dosimeters, a change in R2 is much more pronounced than the change in R1 [74,79-81]. Therefore, the spinspin relaxation rates (R2 = 1/T2) determined from a suitable magnetic resonance 19