4172013 AdriaVidovic Thesis - Duke University

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On the Feasibility of a Novel In-‐‑Vivo Dosimeter for Brachytherapy

by

Adria Katarina Vidovic

Graduate Program in Medical Physics Duke University

Date:_______________________ Approved:

___________________________ Mark Oldham, Supervisor

___________________________

Oana Craciunescu

___________________________ Justus Adamson

___________________________

Robert Reiman

Thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in the

Graduate Program in Medical Physics in the Graduate School of

Duke University

2013

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ABSTRACT

On the Feasibility of a Novel In-‐‑Vivo Dosimeter for Brachytherapy

by

Adria Katarina Vidovic

Graduate Program in Medical Physics Duke University

Date:_______________________ Approved:

___________________________ Mark Oldham, Supervisor

___________________________

Oana Craciunescu

___________________________ Justus Adamson

___________________________

Robert Reiman

An abstract of a thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in the

Graduate Program in Medical Physics in the Graduate School of

Duke University

2013

Copyright by Adria Katarina Vidovic

2013

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Abstract Purpose: Clinical brachytherapy systems are capable of delivering very high doses with

high dose gradients. It is important therefore to be able to accurately verify the doses

calculated by brachytherapy treatment planning. Current dose verification methods are

limited by poor resolution, and in the presence of large dose gradients, may give non-‐‑

representative results [1]. This thesis aims to evaluate the feasibility of a novel

radiochromic dosimetry system for in-‐‑vivo dose verification in organs at risk (bladder

and rectum) in high dose rate (HDR) intracavitary gynecological brachytherapy through

a comparison with a gold standard.

Methods: A novel dosimeter PRESAGE®-‐‑IV designed for in-‐‑vivo dosimetry is

investigated. PRESAGE®-‐‑IV dosimeters are small cylinders 4mm in diameter by 20mm

in height. When irradiated, the dosimeters change color in proportion to the local

absorbed dose. The dosimeters were irradiated to doses between 1-‐‑15 Gy. Two methods

were investigated for readout of this radiochromic response: (i) a volume averaged

readout by conventional spectrophotometer, and (ii) a line profile readout by a novel 2D

projection imaging method utilizing a high-‐‑resolution (50 micron) telecentric optical

system. Method (i) is considered the gold standard, as it is has been extensively used

with PRESAGE® in well-‐‑defined optical-‐‑cuvettes. The feasibility of PRESAGE®-‐‑IV was

evaluated by comparison to standard PRESAGE® in optical-‐‑cuvettes. The feasibility of

the high-‐‑resolution readout (method ii) was evaluated by direct comparison against

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method (i). Dosimeters were also tested in-‐‑vivo on six patients undergoing Iridium-‐‑192

HDR intracavitary brachytherapy treatments and dose measurements were compared to

EclipseTreatment Planning System (Varian Medical Systems).

Results: When compared to the gold standard (optical-‐‑cuvettes), the sensitivity and

noise of PRESAGE®-‐‑IV shows a linear relationship in sensitivity between 1-‐‑15 Gy with a

95% confidence interval in the slope (0.8703 +/-‐‑ 0.0192). The feasibility of the high-‐‑

resolution readout (method ii) evaluated by direct comparison against method (i)

resulted in a sensitivity of 0.0136 ± 0.0002 and for the spectrophotometer 0.0135 ± 0.0002,

which is a 0.74% difference in sensitivity within the 95% confidence interval.

Examination of patient data showed large differences, and on average gave 19% and

22% differences in measured doses vs. Eclipse measurements in the bladder and rectum,

respectively.

Conclusions: Results show that a novel radiochromic dosimetry system for in-‐‑vivo dose

verification in organs at risk is feasible. The conventional spectrophotometer readout

method had the limitation that it averages the change in optical density over a 10 mm

area of the dosimeter. The novel, high-‐‑resolution 2D readout technique was found to

have the advantage of producing images that could be further analyzed through line

profiles in any area of the dosimeter. Due to the large differences in measured doses for

organs at risk, further work is needed to validate dosimeter-‐‑positioning technique.

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Dedication

To my fiancé Adam, and my family for all the encouragement and support.

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Contents

Abstract .......................................................................................................................................... iv

List of Tables ................................................................................................................................. ix

List of Figures ................................................................................................................................ x

List of Abbreviations ................................................................................................................. xiii

Acknowledgements ................................................................................................................... xiv

1. Introduction ............................................................................................................................... 1

1.1 Gynecological HDR Intracavitary brachytherapy ....................................................... 1

1.2 HDR Intracavitary brachytherapy treatment applicators and packing systems .... 2

1.3 Imaging in HDR intracavitary brachytherapy ............................................................. 5

1.4 Limitations in HDR intracavitary brachytherapy ........................................................ 5

1.5 Current in-‐‑vivo dose verification techniques. .............................................................. 6

1.6 PRESAGE® as an in-‐‑vivo dosimeter ............................................................................... 8

1.7 Scope and aims ................................................................................................................. 9

2. Methods .................................................................................................................................... 11

2.1 Characterization of PRESAGE®-‐‑IV dosimeters .......................................................... 11

2.1.1 Gold standard method using optical cuvettes ...................................................... 11

2.1.2 Dose response ............................................................................................................ 12

2.1.3 Energy response ........................................................................................................ 13

2.1.4 Temporal stability ..................................................................................................... 15

2.1.5 Temperature stability ................................................................................................ 15

2.1.6 Effect of cuvette material on PRESAGE®-‐‑IV .......................................................... 16

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2.2 Investigating the feasibility of readout by comparison to gold standard .............. 18

2.2.1 Cuvette and dosimeter irradiation .......................................................................... 19

2.3 2D optical scanning and spectrophotometer reading ............................................... 20

2.3.1 Spectrophotometer technique .................................................................................. 21

2.3.2 2D optical scanning technique ................................................................................. 22

2.3.3 2D optical scanner image registration ...................................................................... 24

2.3.4 Quantitative comparison between the spectrophotometer and 2D optical scanner ................................................................................................................................... 25

2.4 Patient treatment ............................................................................................................ 26

2.4.1 Eclipse dose verification ........................................................................................... 28

3. Results and Discussion ........................................................................................................... 30

3.1 PRESAGE® Sensitivity and stabilities ......................................................................... 31

3.1.1 Dose response ............................................................................................................ 31

3.1.2 Energy Response ....................................................................................................... 32

3.1.3 Temporal stability ..................................................................................................... 35

3.1.4 Temperature stability ................................................................................................ 36

3.1.5 Effect of the cuvette material on PRESAGE®-‐‑IV ................................................... 37

3.2 Results of the feasibility of readout by comparison to gold standard .................... 38

3.3 Quantitative comparison between the 2D optical scanner and spectrophotometer ................................................................................................................................................. 39

3.4 Patient treatment ............................................................................................................ 40

4. Conclusions .............................................................................................................................. 49

References .................................................................................................................................... 51

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List of Tables Table 1: Monitor units delivered to 1.5% DEA formulation dosimeters and cuvettes ..... 20

Table 2: Overview of PRESAGE®-‐‑IV dosimeters irradiated in this work. .......................... 30

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List of Figures Figure 1: 45° T&R Applicator (Varian Medical Systems) [22] ................................................ 3

Figure 2: Stump Cylinder Applicator (Varian Medical Systems) [22] ................................... 3

Figure 3: Capri Applicator (Varian Medical Systems) [22] ..................................................... 4

Figure 4: PRESAGE®-‐‑IV dosimeters pre-‐‑irradiation (left) and post-‐‑irradiation 15 Gy (right). ............................................................................................................................................. 9

Figure 5: 1x1x4 cm3 cuvette (left) and Genesys® 20, ThermoSpectronic® spectrophotometer (right). ......................................................................................................... 12

Figure 6: PRESAGE® filled cuvettes irradiated with a 6MV photon beam to doses of 0-‐‑15 Gy. ................................................................................................................................................. 13

Figure 7: Axial Cross Section of Applicator with Dosimeters Visible with Beekley CT-‐‑ Spots® Localizers (left) and Sagittal Cross Section of Applicator with One Dosimeter Visible. .......................................................................................................................................... 14

Figure 8: Water Bath containing Source Guide Tube and Applicator with Dosimeters (left) and the Treatment Set Up (right). ................................................................................... 15

Figure 9: Example of the PRESAGE® molds in the shape of cuvettes. ................................ 17

Figure 10: PRESAGE®-‐‑Filled Cuvette (left) and PRESAGE® Mold (right). ......................... 18

Figure 11: PRESAGE®-‐‑Filled Cuvette (left) and Cuvette with PRESAGE®-‐‑IV (right) ....... 19

Figure 12: Side View of the Standard Treatment Set-‐‑Up ...................................................... 20

Figure 13: From left to right: Cuvette filled with mineral oil, Styrofoam holder and dosimeter, holder in cuvette, cuvette holder, spectrophotometer. ...................................... 22

Figure 14: Diagram of the DMicrOS System [15]. .................................................................. 23

Figure 15: Diagram of the jig (designed during this thesis work) that holds in-‐‑vivo dosimeters in tank. ...................................................................................................................... 23

Figure 16: An Example of a Line Profile of Two Dosimeters Irradiated to 10 Gy Using the Standard Treatment Setup Described in Section 2.2.1. The Line Profile Was Taken Along

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the Center of Each Dosimeter to Measure the Change in Optical Density at Approximately the Same Length (10 mm) and Location (3 mm from the Bottom of the Dosimeter) as the Spectrophotometer. ..................................................................................... 25

Figure 17: PRESAGE®-‐‑IV dosimeter with and without Tegaderm™ and Beekley CT-‐‑ Spots® localizers. ......................................................................................................................... 26

Figure 18: Example of Dosimeter Placed on Alatus Balloon Packing System (top) and Dosimeters In-‐‑Vivo Near OARs in T&R Treatment (left and right) .................................... 27

Figure 19: Example of Dosimeters Placed on Cylinder Applicator Axial (left) and Sagittal (right) Views. ............................................................................................................................... 28

Figure 20: Example of Dosimeter Placed inside Capri Applicator Channel Axial (left) and Coronal View of Dosimeter with Point Doses (right). ........................................................... 28

Figure 21: Dose Response (Sensitivity) of All Five Formulations. ....................................... 32

Figure 22: The Sensitivity for the 1.5% O-‐‑MeO-‐‑DEA (2/14/13) Dosimeter Formulation. . 34

Figure 23: Dosimeter Dose Measurement of a KV Brachytherapy Source Using a MV Calibration Curve. ....................................................................................................................... 35

Figure 24: Dose Response (Sensitivity) Temporal Stability of the 1.7% O-‐‑MeO-‐‑DEA (11/27/12) Formulation. .............................................................................................................. 36

Figure 25: Change in OD with Temperature for the D21 Formulation. .............................. 37

Figure 26: The Change in Optical Density of the Molds vs. Cuvettes for the 1.5% O-‐‑MeO-‐‑DEA Formulation (1/31/13). ....................................................................................................... 38

Figure 27: The Change in Optical Density of the Dosimeters vs. Cuvettes for the 1.5% O-‐‑MeO-‐‑DEA Formulation (2/14/13). ............................................................................................ 39

Figure 28: The Comparison in Sensitivity of the DmicrOS system and the Spectrophotometer for the 1.5% O-‐‑MeO-‐‑DEA Formulation (2/14/13). ............................... 40

Figure 29: Dose Response (Sensitivity) of the D21 Formulation at Body Temperature. .. 41

Figure 30: T&R Patient 6 Treatment Dose Measurement Using the D21 Formulation. .... 42

Figure 31: Capri Patient 1 fx 1 Dose Measurement Using the D21 Formulation. .............. 43

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Figure 32: Capri Patient 1 fx 1 Dose Measurement Using the D21 Formulation. .............. 43

Figure 33: Capri Patient 1 fx 3 Dose Measurement Using the D21 Formulation. ............. 44

Figure 34: Dose Response (Sensitivity) of the 2% O-‐‑MeO-‐‑DMA Formulation at Body Temperature. ................................................................................................................................ 45

Figure 35: T&R Patient 2 fx 1 Dose Measurement (2% O-‐‑MeO-‐‑DMA) ............................... 46

Figure 36: T&R Patient 2 fx 2 Dose Measurement (2% O-‐‑MeO-‐‑DMA) ............................... 46

Figure 37: Stump Patient 3 Dose Measurement (2% O-‐‑MeO-‐‑DMA) ................................... 47

Figure 38: Stump Patient 4 Dose Measurement (2% O-‐‑MeO-‐‑DMA) ................................... 48

Figure 39: Cylinder Patient 5 Dose Measurement (2% O-‐‑MeO-‐‑DMA) ............................... 48

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List of Abbreviations HDR-‐‑ High Dose Rate

CT-‐‑ Computed Tomography

MRI-‐‑ Magnetic Resonance Imaging

T&R-‐‑ Tandem and Ring

T&O-‐‑ Tandem and Ovoid

OAR-‐‑ Organ at Risk

DVH-‐‑ Dose Volume Histogram

TPS-‐‑ Treatment Planning System

TLD-‐‑ Thermoluminescent Dosimeter

MOSFET-‐‑ Metal oxide semiconductor field effect transistor detectors

O-‐‑MeO-‐‑DEA-‐‑ 2-‐‑methoxy-‐‑N, N-‐‑diethylamine

O-‐‑MeO-‐‑DMA-‐‑ 2-‐‑methoxy-‐‑N, N-‐‑dimethylamine

LED-‐‑Light Emitting Diode

CCD-‐‑ Charged-‐‑Coupled Device

DMicrOS-‐‑ Duke Micro Optical Scanner

DLOS-‐‑ Duke Large Field of View Optical-‐‑CT Scanner

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Acknowledgements I would like to acknowledge the support of my advisor Dr. Mark Oldham for his

endless advice and support. I would also like to give a special thanks to Titania Juang

for her help throughout my work and specifically in collecting patient data, performing

the temperature dependence experiment, and creating a jig for the dosimeters. I would

like to thank my committee members Dr. Oana Craciunescu, Dr. Justus Adamson, and

Dr. Robert Reiman, for their time and effort. I would also like to thank Dr. Junzo Chino,

Beverly Steffey, and Dr. Sheridan Meltsner who were involved in helping me collect

clinical data. Last, but not least I would like to thank Dr. John Adamovics and Heuris

Pharma LLC for providing our lab with PRESAGE®-‐‑IV dosimeters.

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1. Introduction

1.1 Gynecological HDR Intracavitary brachytherapy

Gynecological intracavitary brachytherapy is the clinical use of small,

encapsulated radioactive sources placed in the uterus, uterine cervix, or vagina directly

on a target volume for irradiation of malignant tumors or nonmalignant lesions [2]. The

principle advantage of brachytherapy is the superior localization of dose to the tumor

volume and the rapid dose fall-‐‑off in accordance to the inverse square law.

High Dose Rate (HDR) brachytherapy is a special method of delivering

brachytherapy at doses greater than 12 Gy/hour that employs computer controlled

remotely driven sources known as a remote afterloader. This eliminates the potential for

exposure to clinical staff, and has the ability to tailor radiation delivery to maximize

dose within a target volume and minimize dose in adjacent normal structures [3]. The

HDR brachytherapy program at Duke Medical Center uses a Varian® GammaMed™plus

iX remote afterloader for intracavitary brachytherapy treatments. This remote

afterloader delivers an Iridium-‐‑192 source and treatment plans are based on a 10 Curie

activity and an Air Kerma Rate of 0.063 Gy/hour (±5%) for 555 GBq at 1 meter.

The HDR delivery procedure involves adequate sedation of the patient that can

include general, spinal, or IV conscious sedation. The patient is kept under anesthesia

during the duration of applicator insertion and treatment delivery, which takes

approximately two to four hours [8]. The remote afterloader delivers sources through

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source guide tubes that are connected to treatment applicators that are inserted into the

body cavity. At Duke, these applicators (Section 1.2) are imaged by computed

tomography (CT) and magnetic resonance (MR) to ensure correct positioning. The

images of the patient with the applicators in situ are imported into treatment planning

software and the patient is brought into a dedicated shielded room for treatment. The

treatment plan is then optimized and delivered using the remote afterloader. On

completion of treatment, the applicators are carefully removed from the body.

1.2 HDR Intracavitary brachytherapy treatment applicators and packing systems

Applicator selection is important in brachytherapy in order to customize

treatment delivery for each individual. Treatment applicators can serve many functions:

positioning the source with respect to the anatomy, shaping the anatomy, determining

the penetration of the dose, adding space between normal tissue and the sources, and

shielding normal structures [4]. The applicators used in this thesis are all CT/MRI

compatible Varian® Tandem and Ring (T&R), Stump Cylinder, Cylinder and the

multichannel Capri™.

The T&R applicator is intended for treatment of the cervix, cervix canal and

uterus (Figure 1). It consists of an intrauterine titanium tube known as a ‘tandem’ that

guides the remote afterloading sources, and a ring around the tandem shields in the

apparatus to reduce the radiation exposure to the bladder and rectum. The tandem can

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come in three different curvatures (15°, 30° or 45°) to allow for non-‐‑cylindrical dose

shaping relative to the vaginal axis.

Figure 1: 45° T&R Applicator (Varian Medical Systems) [22]

A Stump Cylinder applicator is used for post-‐‑operative treatment of the vaginal

cuff (Figure 2). A vaginal cylinder applicator is used to treat cancer of the vagina. It is a

smooth, plastic cylinder, measuring about one inch in diameter, with a single channel

where the radioactive source can travel and the distance between its tip and the source

remains constant ensuring a targeted, homogenous treatment dose.

Figure 2: Stump Cylinder Applicator (Varian Medical Systems) [22]

A Capri™ applicator is used to treat cancer of the vagina (Figure 3). It has a soft

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foam core with 13 channels, and offers flexible dosimetry designed to help provide

patient comfort. With its inflatable design, it offers flexible sizing to accommodate a

large range of patient sizes. Multichannel applicators like Capri™ facilitate better dose

optimization and reduction of the dose to the OARs [3].

Figure 3: Capri Applicator (Varian Medical Systems) [22]

Use of intracavitary applicators requires appropriate vaginal packing to secure

applicators and displace the rectum and bladder away from the radiation source to

minimize side effects and complications. Typically, this is done via gauze packing, rectal

retractor, and/or Foley balloon or packing balloon systems such as the Radiadyne®

Alatus™ Vaginal Balloon Packing System [17]. The Radiadyne® Alatus™ Vaginal Balloon

Packing System offers several benefits over traditional gauze packing, including

decreased risk of vaginal laceration during packing, greater reproducibility among

fractions, and the ability to easily reposition the applicators after the packing is in place

[18]. After treatment applicators have been inserted and secured, the patient-‐‑applicator

geometry is imaged using CT and MR.

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1.3 Imaging in HDR intracavitary brachytherapy

In the mid-‐‑1990’s, 3D brachytherapy planning systems started to emerge with the

use of CT and MR imaging. CT/MR-‐‑based planning provides the potential for rapid 3D

rendering and Dose Volume Histogram (DVH) generation, providing more realistic

calculation of dose within the tumor and adjacent OARs versus conventional orthogonal

film-‐‑based treatment planning [3]. CT is widely available, provides good spatial

resolution, the ability to discern objects on the basis of electron density, and has good

organ delineation [3]. MR has the ability to better depict target volumes than CT and

allows adequate depiction of size, location and paracervical involvement of the tumor

and its relations to an applicator [20].

The positive attributes of both imaging modalities can be displayed through the

use of image registration. CT is used for visualization of the treatment applicator, and

MR is optimal for the delineation process [3]. Imaging in brachytherapy is often

performed prior to each fraction, and all the information in the image studies acquired at

different points in time should ideally be combined to assess the total treatment

delivered to the patient. However, the use of MR prior to each fraction is costly, so a

compromise is usually made to image prior to the first fraction only, given that the

applicator type is consistent and that overall treatment duration is short [3].

1.4 Limitations in HDR intracavitary brachytherapy

The recent advances in brachytherapy planning software, MRI-‐‑compatible

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applicators, and image-‐‑guided brachytherapy have lead to more complex treatments

and a subsequent need for improved quality-‐‑assurance procedures [7]. One of the main

challenges in brachytherapy imaging is image registration of image sets taken at

different points in time [3].

Not only does organ motion increase or decrease the tumor volume, but

transportation of the patient from one location to another my influence the relative

positioning of applicators and organs. The localization, dose calculation, and the

treatment delivery for HDR intracavitary brachytherapy can take two to four hours, and

uncertainties in treatment can easily occur without detection [5]. Clinically related

uncertainties include target volume definition and contouring, applicator positioning,

organ motion, and inter-‐‑ and intra-‐‑fraction applicator movement [6]. These clinical

uncertainties can be verified, and minimized with the use of in-‐‑vivo dosimetry.

1.5 Current in-vivo dose verification techniques.

In-‐‑vivo dosimetry can help identify errors from applicators or afterloader

malfunctions during the first fraction of treatment to resolve discrepancies and can

provide dose verification to OARs, such as the bladder and the rectum. A number of

systems have been used and are being developed, such as lithium fluoride

thermoluminescent dosimeters (TLDs), diamond detectors, Metal oxide semiconductor

field effect transistor detectors (MOSFETS), and a novel scintillation detector

BrachyFOD™.

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TLDs have been frequently applied as an in-‐‑vivo dosimeter for HDR

brachytherapy because they are tissue equivalent, have a small sensitive volume, and

can be reused [8]. Diamond detectors have a small sensitive volume of a sensitive

volume of 6 mm3 and are sensitive enough for HDR brachytherapy dosimetry, but have

a much larger physical size than TLDs, MOSFETs, and scintillation dosimeters [21].

MOSFETS are attractive due to their small sensitive volume and direct readout [9]. The

RADPOS system (Best Medical, Canada) consists of a MOSFET dosimeter physically

coupled to a position-‐‑sensing probe, which deduces its 3D position in static magnetic

fields generated by a transmitter, shown to be accurate within 0.5 to 1.0mm [10]. A novel

scintillation detector, BrachyFOD™ has a sensitive measuring volume of 1 mm by 5 mm

(Bicron BC400 scintillator) coupled to a 0.98 mm core polymethyl methacrylate optical

fiber. It was found to be accurate to within 3% for distances of 10 to 100 mm from an

HDR Iridium-‐‑192 brachytherapy source in water, and it has an angular dependence of

less than 2% [21]. Only the BrachyFOD™ and the MOSFET are capable of real-‐‑time

measurements and are small enough for insertion into the urethra [21].

Although TLDs are most commonly used, they have the inability of real-‐‑time

readings, depth dependent sensitivity [6], and measure the dose only at a single point

[1]. Diamond detectors were found to have dose rate dependence whose relative

response decreases with increasing dose rate as well as its large rigid structure that

prevents it from being inserted in-‐‑vivo [21]. MOSFETS, including the RADPOS system

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that reduces positional uncertainty, still contain uncertainties in angular dependence

and are prone to calibration drift [9]. The ideal in-‐‑vivo dose verification method would

have the ability to be inserted into cavities without disruption to treatment, ability to

provide high resolution dose profiles along steep dose gradients and provide fast

acquisition read out time for a high patient load [12].

1.6 PRESAGE® as an in-vivo dosimeter

PRESAGE® is a three-‐‑dimensional dosimetry material that has the potential to be

an ideal dosimeter for in-‐‑vivo dose verification. PRESAGE® consists of an optically clear

polyurethane matrix containing a leuco dye that exhibits a linear radiochromic response

when exposed to ionizing radiation. A number of potential advantages accrue over other

gel dosimeters, including insensitivity to oxygen, radiation induced light absorption

contrast rather than scattering contrast, water equivalency (~1.05 g/cm3) and a solid

texture amenable to machining to a variety of shapes and sizes without the requirement

of an external container [11]. As the sensitivity, or optical density change per Gray, is

dependent on the concentration of leuco dye added to the polymer, each formulation of

PRESAGE® has a slightly different sensitivity [13], [14]. In addition, PRESAGE® has

been previously tested as a 3D verification dosimeter near a brachytherapy source (Ir-‐‑

192) and has shown to have no evidence of energy response [23].

These qualities, and the pressing need for in-‐‑vivo dose verification in

brachytherapy, prompted the development of PRESAGE®-‐‑In-‐‑Vivo, or PRESAGE®-‐‑IV.

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Supplied by Heuris Pharma LLC, PRESAGE®-‐‑IV was specifically developed for the

purpose of in-‐‑vivo dose verification for organs at risk such as the bladder and rectum.

PRESAGE®-‐‑IV dosimeters are small cylinders 4mm in diameter by 20mm in height.

When irradiated, the dosimeters change color in proportion to the local absorbed dose as

seen in Figure 4 where the dosimeter on the left has not been exposed to radiation and

the dosimeter on the right has been exposed to 15 Gy.

Figure 4: PRESAGE®-‐‑IV dosimeters pre-‐‑irradiation (left) and post-‐‑irradiation 15 Gy (right).

1.7 Scope and aims

This thesis aims to evaluate the feasibility of a novel dosimetry readout system

for PRESAGE®-‐‑IV dosimeters and to demonstrate its utility as an in-‐‑vivo dosimeter for

brachytherapy treatment. The feasibility is investigated by delivering a range of doses to

dosimeters, measuring the change in optical density using spectrophotometry and a

novel 2D optical scanning technique, and comparing the change in optical density to a

gold standard. To demonstrate its utility as a dosimeter for in-‐‑vivo dose verification,

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dose measurements from PRESAGE®-‐‑IV dosimeters will be compared to dose line

profiles created in Eclipse® treatment planning system (TPS) for OARs in patient

treatments.

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2. Methods The characterization of PRESAGE®-‐‑IV dosimeters including a description of the

gold standard, dose response, energy response, temporal and temperature stabilities and

the effect of cuvette material on PRESAGE®-‐‑IV are introduced in Section 2.1. The

feasibility of a dosimetry system for PRESAGE®-‐‑IV dosimeters tested against the gold

standard is introduced in Section 2.2. The feasibility was verified by two dose readout

techniques (i) a volume averaged readout by spectrophotometer introduced in Section

2.3.1, and (ii) a 2D projection imaging in a high-‐‑resolution (50 micron) telecentric optical

system introduced in Sections 2.3.2-‐‑2.3.3. The quantitative comparison between the 2D

optical scanning technique and the spectrophotometer is described in Section 2.3.4. The

applicability of PRESAGE®-‐‑IV dosimeters in-‐‑vivo was tested in six HDR intracavitary

gynecological brachytherapy treatments described in Section 2.4 and compared to

Eclipse TPS dose estimations in Section 2.4.1.

2.1 Characterization of PRESAGE®-IV dosimeters

The characterization of PRESAGE®-‐‑IV dosimeters including a description of the

gold standard, dose response, energy response, temporal and temperature stabilities and

the effect of cuvette material on PRESAGE®-‐‑IV are introduced in this section.

2.1.1 Gold standard method using optical cuvettes

A cuvette is a small tube of square cross section, sealed at one end and made of

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clear plastic designed to hold samples for spectroscopic experiments. A

spectrophotometer measures intensity as a function of the light source wavelength and

is commonly used for the measurement of transmittance of solutions, and transparent or

opaque solids (Figure 5). The spectrophotometer’s simple, convenient, and reliable

readout over a precise and standardized distance and the ability to choose a specific

wavelength made it a perfect choice for measuring the change in optical density of

PRESAGE® material. PRESAGE® prepared in 1x1x4 cm3 cuvettes has been investigated

and provides reliable linear optical response to radiation dose, reproducibility, and

temporal stability [11].

Figure 5: 1x1x4 cm3 cuvette (left) and Genesys® 20, ThermoSpectronic® spectrophotometer (right).

2.1.2 Dose response

To measure the dose response, a standard calibration treatment (Section 2.2.1)

was delivered to three formulations of PRESAGE®. The sensitivity of each formulation

was determined by irradiating 1 x 1 cm plastic cuvettes filled with PRESAGE® with a

6MV photon beam, to doses in the range of dose per fraction used in HDR

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brachytherapy (1-‐‑15 Gy) (Figure 6) using a standard treatment set up. In gynecology, the

typical range of dose per fraction can be between 5.5-‐‑6 Gy [3]. A Genesys® 20,

ThermoSpectronic® spectrophotometer was used to measure the optical density of each

sample, using an empty cuvette as a zero. Cuvettes were scanned prior to the treatment

and irradiated to various known doses before being re-‐‑scanned. A linear calibration

curve was calculated by relating the delivered dose to the optical density change with

the slope being the sensitivity.

Figure 6: PRESAGE® filled cuvettes irradiated with a 6MV photon beam to doses of 0-‐‑15 Gy.

2.1.3 Energy response

To measure energy response from brachytherapy sources, three PRESAGE®-‐‑IV

dosimeters were taped onto a 3.5 cm diameter stump cylinder applicator and irradiated

to 7 Gy at a lateral distance of 1.95 cm from (2 mm to the center of PRESAGE®-‐‑IV

diameter) by a 7.046 Curie Ir-‐‑192 source (Figure 7). The PRESAGE®-‐‑IV dosimeters were

wrapped in two layers of Tegaderm™ film dressings. Two Beekley CT-‐‑ Spots® skin

markers 2.3mm and 4mm in diameter were placed on either end of the dosimeter for CT

localization. The applicator was placed in a water bath at room temperature 23°C and a

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source guide tube was attached to the applicator through the lid of the water bath,

securing the applicator position. The Ir-‐‑192 source was delivered by a Varian®

GammaMed™plus iX remote afterloader (Figure 8). In order to verify the dose in the

Eclipse Brachytherapy TPS, the dosimeters were read using the spectrophotometer

technique described in Section 2.3.1 and the 2D optical scanning technique described in

Section 2.3.2.

Figure 7: Axial Cross Section of Applicator with Dosimeters Visible with Beekley CT-‐‑ Spots® Localizers (left) and Sagittal Cross Section of Applicator with

One Dosimeter Visible.

15

Figure 8: Water Bath containing Source Guide Tube and Applicator with Dosimeters (left) and the Treatment Set Up (right).

2.1.4 Temporal stability

Since previous formulations of PRESAGE® have been known to drift in optical

density over time, the optical density of each PRESAGE®-‐‑filled cuvette was tested for

temporal stability. Using a spectrophotometer, the optical density was measured

immediately after treatment delivery, a half hour, hour and every three days for 9 days

to test stability. Cuvettes were stored in a refrigerator (3 to 5°C) to improve stability by

minimizing kinetic effects that could lead to optical density drift. To avoid direct

temperature dependence effects while measuring optical density, cuvettes were taken

out of the refrigerator 1-‐‑2 hours prior to being scanned each day.

2.1.5 Temperature stability

Because the dosimeters will be placed in-‐‑vivo, it was important to test the

16

dosimeters for temperature stability. To determine the change in optical density in

relation to temperature at the time of irradiation, dosimeters were placed in a water tank

at body temperature, 37°C and ±5°C and ±10°C from body temperature (27°C, 32°C,

42°C, 47°C). Two in-‐‑vivo dosimeters were placed side-‐‑by-‐‑side in a 1 cm thick sheet of

bolus material and treated with a 10x10 field at 100 cm SSD and a depth of 1.5 cm below

the water surface. They were placed on top of a 5 cm of solid water to allow for

backscatter. The treatment was delivered using 6 MV photons and a dose rate of 500

monitor units/min. With the field size and SSD set to calibration conditions, scatter

factors were 1.00 and only the percent depth dose table was necessary to calculate the

monitor units for the desired dose at 1.5 cm depth.

2.1.6 Effect of cuvette material on PRESAGE®-IV

In order to make sure there was no interaction between the cuvette material and

PRESAGE®-‐‑IV and its effects on the sensitivity of PRESAGE®-‐‑IV, a batch of PRESAGE®-‐‑

filled cuvettes and PRESAGE® molds in the shape of cuvettes had been created (Figure

9).

17

Figure 9: Example of the PRESAGE® molds in the shape of cuvettes.

Since the path length through PRESAGE®-‐‑filled cuvettes is smaller (1 cm) than

PRESAGE® molds (1.2 cm) (Figure 10), a quantitative comparison needed to be made

between the optical densities of the molds and cuvettes. The sensitivity of PRESAGE®-‐‑

filled cuvettes and PRESAGE® molds was determined by irradiation to doses 1, 2.5, 5

and 8 Gy using a standard treatment set up (Section 2.2.1). The molds and cuvettes were

read using the spectrophotometer technique described in Section 2.3.1. A plot between

the change in optical density of the molds versus the cuvettes was created and the

change in optical density of the molds was multiplied by a factor of 1/1.2 cm to account

for the difference in path length between the molds and cuvettes. A linear slope would

indicate that the change in optical density with dose between the molds and cuvettes

was comparable, and that there was no effect on the sensitivity of PRESAGE® from the

cuvette material.

18

Figure 10: PRESAGE®-‐‑Filled Cuvette (left) and PRESAGE® Mold (right).

2.2 Investigating the feasibility of readout by comparison to gold standard

Since the path length through PRESAGE®-‐‑filled cuvettes is larger than

PRESAGE®-‐‑IV dosimeters read in mineral oil, a quantitative comparison needed to be

made between the optical densities of the dosimeters and cuvettes (Figure 11). The

sensitivity of PRESAGE®-‐‑filled cuvettes and PRESAGE®-‐‑IV dosimeters was determined

by irradiation to different doses using a standard treatment set up (Section 2.2.1). The

dosimeters and cuvettes were read using the spectrophotometer technique described in

Section 2.3.1. A plot between the change in optical density of the dosimeters versus the

cuvettes was created and the change in optical density of the dosimeters was multiplied

by a factor of 1/.4 cm to account for the difference in path length between the dosimeters

and cuvettes. A linear slope would indicate that the change in optical density with dose

between the dosimeters and cuvettes was comparable, and that a novel dosimetry

system for PRESAGE®-‐‑IV dosimeters is feasible.

19

Figure 11: PRESAGE®-‐‑Filled Cuvette (left) and Cuvette with PRESAGE®-‐‑IV (right)

2.2.1 Cuvette and dosimeter irradiation

Pairs of PRESAGE®-‐‑IV dosimeters and cuvettes were placed side-‐‑by-‐‑side and

treated with a 10 x 10 cm field at 100 cm SSD and a depth of 5.5 cm (Figure 12) between

doses of 1-‐‑15 Gy (Table 1). The treatment was delivered using 6 MV photons from a

Varian Clinac® 600C/D and a dose rate of 600 monitor units/min. The dosimeters and

cuvettes were placed in a 1 cm thick sheet of bolus material, with two 1 cm thick sheets

of bolus material below to reduce any air gap created by the difference in thicknesses of

the cuvettes and dosimeters. 10 cm of solid water was placed below to allow backscatter

and 5 cm of solid water above to achieve the 5.5 cm depth to the center of the 4mm

dosimeters and 1 cm cuvettes. With the field size and SSD set to calibration conditions,

scatter factors were 1.00 and only the percent depth dose table was necessary to calculate

the monitor units for the desired dose at 5.5 cm depth.

20

Figure 12: Side View of the Standard Treatment Set-‐‑Up

Table 1: Monitor units delivered to 1.5% DEA formulation dosimeters and cuvettes

Cuvette and

Dosimeter

1 2 3 4 5 6 7 8

Dose (Gy) 0 1 2.5 5 8 10 12 15 MU 0 119 297 593 949 1186 1423 1779

2.3 2D optical scanning and spectrophotometer reading

The change in optical density of each dosimeter is proportional to dose [11]. To

determine the change in optical density, each dosimeter must be scanned before and

after irradiation. PRESAGE®-‐‑IV dosimeters were scanned to measure optical density

using a 2D projection telecentric optical system developed in house: the Duke Micro

Optical scanner (DMicrOS) and a spectrophotometer (Genesys® 20, ThermoSpectronic®).

The DMicrOS uses visible light and a CCD camera to take single projection images at 50-‐‑

21

micron resolution. The spectrophotometer measures the absorbance at the peak

absorption wavelength of 633 nm.

2.3.1 Spectrophotometer technique

To avoid direct temperature dependence effects while measuring optical density,

cuvettes were taken out of the refrigerator 1-‐‑2 hours prior to being scanned each day

and the Genesys® 20, ThermoSpectronic® was turned on 1 hour before performing the

scan to let the light source warm up. The spectrophotometer was then set to the peak

absorption wavelength of 633 nm. An empty cuvette is used as a zero, and a cuvette

filled with mineral oil was read before and after each scan to ensure no fluctuation in

absorbance affected the readings. The dosimeter is placed in a holder and immersed in a

1x1x4 cm cuvette filled with mineral oil, which matches the refractive index of the

dosimeter to minimize bending of the light at the dosimeter-‐‑fluid interface. The cuvette

is placed in the spectrophotometer and the absorbance is read, which is directly

proportional to the thickness of the sample and to the concentration of the absorbing

material in the sample (Figure 13). A Kimwipe® with ethanol, following a dry Kimwipe®

is used to remove any residual oil that may appear outside of the cuvette between

readings.

22

Figure 13: From left to right: Cuvette filled with mineral oil, Styrofoam holder and dosimeter, holder in cuvette, cuvette holder, spectrophotometer.

2.3.2 2D optical scanning technique

The DMicrOS system, a modified version of the Duke Large field of view

Optical-‐‑CT Scanner (DLOS) [15] illustrated in Figure 15, uses a 2W LED light source

behind a narrow band filter, giving the source a uniform flood field with wavelength of

633 nm. A 79 mm diameter telecentric lens provided a central region of parallel light

where the dosimeter can be imaged free of object magnification effects. The imaging lens

has a magnification of 0.25X and collimates any light with more than a 0.1-‐‑degree

deviation from the optical axis, effectively minimizing scattered light contributions. A

1608 x 1208 CCD based Basler camera is used for imaging.

23

Figure 14: Diagram of the DMicrOS System [15].

A jig (Figure 15) was created during the time of this thesis work to hold two

PRESAGE®-‐‑IV dosimeters in a fluid bath with a matched refractive index to minimize

bending of the light. The jig fits onto the tank of the optical system in only one

orientation, guaranteeing registration between pre and post scans.

Figure 15: Diagram of the jig (designed during this thesis work) that holds in-‐‑vivo dosimeters in tank.

One projection was taken and to reduce noise, each projection was captured 100

times and averaged. After removing the dosimeter from the system, an image of the

flood field was captured with 100 averages. The light source was then blocked to acquire

24

a dark field with 100 averages. The optical density of the scan was calculated by

subtracting out the background (dark) and normalizing by the flood to remove

inhomogeneity, as shown in the equation below:

2.3.3 2D optical scanner image registration

A graphical user interface (GUI) was created in MATLAB in order to ensure

registration between the pre and post scan images. The DMicrOS Image Registration

GUI reads in the pre and post scan images and converts them to the change in optical

density. The GUI displays the pre and post scan images and the change in optical

density between the two images. The GUI allows the user to move the post scan image

over the pre scan image through rotation and translation in order to visually observe the

image registration.

After the images are registered, a line profile is taken along the center of each

dosimeter to measure the change in optical density at approximately the same length (10

mm) and location (3 mm from the bottom of the dosimeter) as the spectrophotometer

(Figure 16). The mean of the line profile is calculated for each dosimeter and the average

of the two dosimeters is taken to get an average optical density reading.

25

Figure 16: An Example of a Line Profile of Two Dosimeters Irradiated to 10 Gy Using the Standard Treatment Setup Described in Section 2.2.1. The Line Profile Was Taken Along the Center of Each Dosimeter to Measure the Change in Optical Density at Approximately the Same Length (10 mm) and Location (3 mm from the Bottom of

the Dosimeter) as the Spectrophotometer.

2.3.4 Quantitative comparison between the spectrophotometer and 2D optical scanner

To verify the 2D optical scanning technique (Section 2.3.2) with the

spectrophotometer technique (Section 2.3.1) a quantitative comparison needed to be

made between the optical densities of the dosimeters. The sensitivity of PRESAGE®-‐‑IV

dosimeters was determined by irradiation to doses between 1-‐‑12 Gy using a standard

treatment set up (Section 2.2.1). The dosimeters were read within minutes of each other

using the spectrophotometer and 2D optical scanning techniques. A linear calibration

26

curve was calculated by relating the delivered dose to the optical density change with

the slope being the sensitivity.

2.4 Patient treatment

PRESAGE®-‐‑IV dosimeters were tested on their ability for in-‐‑vivo dose

verification for the bladder and rectum in six patients undergoing gynecologic

intracavitary HDR brachytherapy treatment. Dosimeters were taken out of the

refrigerator one hour before being delivered to the physician for use in patient

treatment. To ensure no direct contact with patient tissue, PRESAGE®-‐‑IV dosimeters

were wrapped with two layers of Tegaderm™ film dressings. Two Beekley CT-‐‑ Spots®

skin markers 2.3mm and 4mm in diameter were placed on either end of the dosimeter

for CT localization (Figure 17).

Figure 17: PRESAGE®-‐‑IV dosimeter with and without Tegaderm™ and Beekley CT-‐‑ Spots® localizers.

Dosimeter attachment is applicator dependent. For the T&R treatment, the

physician taped the dosimeters on a Radiadyne® Alatus™ Vaginal Balloon, one facing the

27

bladder and the other facing the rectum and inserted the treatment applicator into the

patient (Figure 18). For cylinder and stump treatments the physician taped the

dosimeters directly on the applicator nearest to the OARs (Figure 19). For the

multichannel Capri™ applicator, the physician placed the dosimeters in the channels

facing the OARs (Figure 20). After treatment, the dosimeters were removed by the

physician and taken back to the lab and read on the spectrophotometer using the

method described in section 2.3.1. The time from end of treatment to the first reading

was approximately 10 minutes.

Figure 18: Example of Dosimeter Placed on Alatus Balloon Packing System (top) and Dosimeters In-‐‑Vivo Near OARs in T&R Treatment (left and right)

28

Figure 19: Example of Dosimeters Placed on Cylinder Applicator Axial (left) and Sagittal (right) Views.

Figure 20: Example of Dosimeter Placed inside Capri Applicator Channel Axial (left) and Coronal View of Dosimeter with Point Doses (right).

2.4.1 Eclipse dose verification

In order to verify the dose measured by the dosimeter, a dose line profile was

taken along the length of the dosimeter in the Eclipse Brachytherapy TPS (Figures 18-‐‑

19). Since the spectrophotometer takes an average absorbance reading 3mm from the

bottom and 10mm along the height of the dosimeter, the dose profile in Eclipse was

29

taken along the same dimensions to keep measurement consistency. The dose profile

from Eclipse was then averaged and compared to the measured dose.

30

3. Results and Discussion Results reported in this section include the sensitivities of the five formulations

of PRESAGE® used in this experiment (Section 3.1) using the techniques described in

Sections 2.2 and 2.3. The dose response, energy response, temporal and temperature

stabilities, and the effect of the cuvette material on PRESAGE® are reported in Section 3.1

as well. Proof of feasibility of novel in-‐‑vivo dosimeters compared to the gold standard

cuvettes is reported in Section 3.2. Comparison between the 2D optical scanning and

spectrophotometer technique results are reported in Section 3.3. Finally, the results of

the comparison between the measured doses from the PRESAGE®-‐‑IV dosimeters and

Eclipse TPS in patient treatments is reported in Section 3.4. Table 2 reports the

formulations of the dosimeters irradiated in this thesis.

Table 2: Overview of PRESAGE®-‐‑IV dosimeters irradiated in this work.

Date Manufactured Formulation Dose (Gy)

Sensitivity Rank

Change in OD Over Time

10/28/2011 D21 2.36, 5, 7.50 2 Increase

05/04/2012 2% O-‐‑MeO-‐‑DMA

1.003, 2.504, 5, 8.002 1 Stable

10/01/2012 1.7% O-‐‑MeO-‐‑DMA 2.504, 8.002 6 Stable

11/27/2012 1.7% O-‐‑MeO-‐‑DEA

1.003, 2.504, 5, 8.002 5 Stable

01/31/2013 1.5% O-‐‑MeO-‐‑DEA

1.003, 2.504, 5, 8.002 3 Stable

02/14/2013 1.5% O-‐‑MeO-‐‑DEA

1, 2.5, 5, 8, 10, 12, 15 4 Stable

31

3.1 PRESAGE® Sensitivity and stabilities

The D21 formulation and four formulations (2% O-‐‑MeO-‐‑DMA, 1.7% O-‐‑MeO-‐‑

DMA, 1.7% O-‐‑MeO-‐‑DEA and 1.5% O-‐‑MeO-‐‑DEA) [16] were irradiated as described in

Section 2.2.1. In Section 3.1.1, the dose response, or sensitivity, of each formulation are

reported. In Section 3.1.2, the KV energy response of the experiment described in Section

2.1.3 is reported. The temporal stability and temperature stability is reported in Sections

3.1.3 and 3.1.4, respectively. The results of the effect of the cuvette material on

PRESAGE®-‐‑IV is reported in Section 3.1.5.

3.1.1 Dose response

The sensitivity changes for all five formulations are presented in Figure 21. The

2% O-‐‑MeO-‐‑DMA formulation had the highest sensitivity with a slope of 0.0494 ± 0.0007

change in OD/Gy/cm. Next was the D21 formulation, which had a sensitivity of 0.0375 ±

0.001 change in OD/Gy/cm. The 1.5% O-‐‑MeO-‐‑DEA (1/31/13) formulation had a

sensitivity of 0.0356 ± 0.0015 change in OD/Gy/cm. The 1.5% O-MeO-DEA (2/14/13)

formulation had a sensitivity of 0.0299 ± 0.0005 change in OD/Gy/cm, and 83% of the

sensitivity of the 1.5% O-MeO-DEA (1/31/13) formulation. The 1.7% O-‐‑MeO-‐‑DEA

(11/27/12) formulation had a sensitivity of 0.0179 ± 0.0002 change in OD/Gy/cm and the

1.7% O-‐‑MeO-‐‑DMA (10/1/12) formulation had a sensitivity of 0.0073 ± 8.9E-‐‑05 change in

OD/Gy/cm and 14.8% of the sensitivity of the 2% O-‐‑MeO-‐‑DMA formulation. All were

within the 95% confidence level.

32

Figure 21: Dose Response (Sensitivity) of All Five Formulations.

3.1.2 Energy Response

The sensitivity for the 1.5% O-‐‑MeO-‐‑DEA (2/14/13) dosimeter formulation is

presented in Figure 22 with a sensitivity slope of 0.0136 ± 0.0002 change in OD/Gy/cm.

This formulation was calibrated using a 6 MV photon beam using the technique

described in Section 2.2.1, and the slope of this sensitivity curve was used to calculate

the dose measured by the dosimeters irradiated by a KV Iridium-‐‑192 brachytherapy

source (Figure 23).

A dose of 7 Gy was delivered to the center of three dosimeters, with an 8.4 Gy

isodose line at the applicator/dosimeter wall indicating a 1.4 Gy dose drop off in 2 mm.

The average measurement using the spectrophotometer was 7.05 ± 0.11 Gy (0.66%

33

difference), and the average measurement using a line profile in the 2D optical scanning

method read a dose of 7.18 ± 0.32 Gy (2.6% difference). The difference between the

Eclipse dose and the measured dose using the spectrophotometer reading technique

shows that the overestimation of dose is within the dose fall off range of 1.4 Gy with a

value of 1.35 Gy. The 2D Optical scanning technique has a larger difference of 2.6% and

the overestimation of dose is also within the dose fall off range of 1.4 Gy with a value of

1.22 Gy. The higher dose is indicative of its slightly (0.74%) greater sensitivity than the

spectrophotometer method, but the main reason could have been due to the reading

technique. The change in optical density line profile was taken in the center of the

dosimeter, but the positioning of the dosimeter in the jig could have allowed it to be

read on the side that had been exposed to the larger dose.

34

Figure 22: The Sensitivity for the 1.5% O-‐‑MeO-‐‑DEA (2/14/13) Dosimeter Formulation.

35

Figure 23: Dosimeter Dose Measurement of a KV Brachytherapy Source Using a MV Calibration Curve.

3.1.3 Temporal stability

In Figure 24, the results show that the 1.7% O-‐‑MeO-‐‑DEA formulation is stable

over time. This formulation had an initial sensitivity of 0.0179 ± 0.0002 change in

OD/Gy/cm in the 95% confidence level. The sensitivity was tracked daily over nine days

and decreased to 0.0178 change in OD/Gy/cm nine days after irradiation. The difference

between the initial sensitivity and the sensitivity nine days after irradiation was found to

be within the 95% confidence level. The differences could have been attributed to a small

error in the reading technique, which could have been caused by residual mineral oil on

the outside of the cuvette.

36

Figure 24: Dose Response (Sensitivity) Temporal Stability of the 1.7% O-‐‑MeO-‐‑DEA (11/27/12) Formulation.

3.1.4 Temperature stability

The change in optical density with temperature of the D21 formulation at the

time of irradiation is illustrated in Figure 25. There is a 35% difference between the

optical density of the dosimeter at 27°C and 47°C and a 5% increase in the change in

optical density from body temperature 37°C to 47°C. Extrapolating the line to room

temperature 22°C, there is a 30% increase in optical density from room temperature to

body temperature 37°C indicating a temperature dependence that makes the dosimeters

more sensitive at higher doses.

37

Figure 25: Change in OD with Temperature for the D21 Formulation.

3.1.5 Effect of the cuvette material on PRESAGE®-IV

The change in the optical density between the molds and the cuvettes for the

1.5% O-‐‑MeO-‐‑DEA formulation had a slope of 0.9108 ± 0.05 in the 95% confidence

interval. The results shown in Figure 26 shows that there is a maximum difference of

10% between the sensitivities of the molds and the cuvettes, with the difference getting

larger as the dose increases from 1-‐‑8 Gy. This 10% difference could be attributed to the

aberrations (tacky surface) on the surface of the molds compared to the smooth surface

of the cuvette.

38

Figure 26: The Change in Optical Density of the Molds vs. Cuvettes for the 1.5% O-‐‑MeO-‐‑DEA Formulation (1/31/13).

3.2 Results of the feasibility of readout by comparison to gold standard

The results of the change in optical density between the gold standard 1x1x4cm

optical cuvettes filled with PRESAGE® and PRESAGE®-‐‑IV dosimeters read in mineral

oil are reported in Figure 27. The 1.5% O-‐‑MeO-‐‑DEA (2/14/13) formulation was used for

the proof of feasibility for its temporal stability and good sensitivity. In Figure 27, the

slope 0.8703 ± 0.0192 indicates that there is a linear relationship between the cuvettes

and in-‐‑vivo dosimeters within the 95% confidence interval and a dosimetry system for

PRESAGE®-‐‑IV dosimeters is feasible.

39

Figure 27: The Change in Optical Density of the Dosimeters vs. Cuvettes for the 1.5% O-‐‑MeO-‐‑DEA Formulation (2/14/13).

3.3 Quantitative comparison between the 2D optical scanner and spectrophotometer

The results of the sensitivity difference between the 2D optical scanner and the

spectrophotometer for PRESAGE®-‐‑IV dosimeters read in mineral oil for dosimeters

irradiated between the doses of 1-‐‑12 Gy are reported in Figure 28. The 1.5% O-‐‑MeO-‐‑

DEA (2/14/13) formulation was used for this comparison for its temporal stability and

good sensitivity. In Figure 28, the sensitivity, or change in OD/Gy/cm slope of the

DmicrOS technique was found to be 0.0136 ± 0.0002 and for the spectrophotometer

0.0135 ± 0.0002, which is a 0.74% difference in sensitivity within the 95% confidence

interval. The results show that the 2D optical scanning method is slightly more sensitive

40

than the spectrophotometer method as predicted and that the DmicrOS system is a

feasible method of reading PRESAGE®-‐‑IV dosimeters.

Figure 28: The Comparison in Sensitivity of the DmicrOS system and the Spectrophotometer for the 1.5% O-‐‑MeO-‐‑DEA Formulation (2/14/13).

3.4 Patient treatment

Figure 29 shows the dose response curve of the D21 formulation taken at body

temperature (37°C) with a control at room temperature using the technique described in

Section 2.1.4. This dose response curve was used to estimate the dose in the following

patient treatment plots using the D21 formulation (Figures 30-‐‑33).

41

Figure 29: Dose Response (Sensitivity) of the D21 Formulation at Body Temperature.

The results of T&R patient 6 treatment are displayed in Figure 30. The T&R

patient measured dose shows a 0% and 2.8% difference between the measured doses

and the Eclipse doses for the bladder and rectum, respectfully. These results are the best

results received from using PRESAGE®-‐‑IV dosimeters for in-‐‑vivo dose verification. In

the following patient results, the differences between measured doses and Eclipse doses

for OARs are quite large. A number of reasons for these large differences could be due to

the positional stability of the dosimeters, organ motion, and patient motion for the

duration of treatment (2-‐‑4 hours on average).

42

Figure 30: T&R Patient 6 Treatment Dose Measurement Using the D21 Formulation.

The results of the Capri patient 1 fraction (fx) 1 treatment are displayed in Figure

31. The Capri patient measured dose shows a 12% and 20% difference between the

measured doses and the Eclipse doses for the bladder and rectum, respectfully. The

results of the Capri patient 1 fraction 2 treatment are displayed in Figure 32. The Capri

patient measured dose shows a 4% and 7% difference between the measured doses and

the Eclipse doses for the bladder and rectum, respectfully. The results of the Capri

patient 1 fraction 3 treatment are displayed in Figure 33. The Capri patient measured

dose shows a 9% and 19% difference between the measured doses and the Eclipse doses

for the bladder and rectum, respectfully.

43

Figure 31: Capri Patient 1 fx 1 Dose Measurement Using the D21 Formulation.


44


The variation in dose verification over the course of three fractions shows that

patient organ motion can be a big factor in in-‐‑vivo dose verification. The rectal dose

differences remained the larger of the two OARs indicating that rectal filling could be a

cause for these differences.

Figure 34 shows the dose response curve of the 2% O-‐‑MeO-‐‑DMA formulation

taken at body temperature (36.8°C) with a control at room temperature using the

technique described in Section 2.1.4. This dose response curve was used to estimate the

dose in the following patient treatment plots using the 2% O-‐‑MeO-‐‑DMA formulation

(Figures 35-‐‑39).

45

Figure 34: Dose Response (Sensitivity) of the 2% O-‐‑MeO-‐‑DMA Formulation at Body Temperature.

The results of the T&R patient 2 fraction 1 treatment are displayed in Figure 35.

The T&R patient measured dose shows a 38% and 19% difference between the measured

doses and the Eclipse doses for the bladder and rectum, respectfully. The results of the

T&R patient 2 fraction 2 treatment are displayed in Figure 36. The T&R patient

measured dose shows a 34% and 73% difference between the measured doses and the

Eclipse doses for the bladder and rectum, respectfully.

46

Figure 35: T&R Patient 2 fx 1 Dose Measurement (2% O-‐‑MeO-‐‑DMA)

Figure 36: T&R Patient 2 fx 2 Dose Measurement (2% O-‐‑MeO-‐‑DMA)

47

The results of the stump patient 3 treatment are displayed in Figure 37. The

stump patient measured dose shows a 13% and 11% difference between the measured

doses and the Eclipse doses for the bladder and rectum, respectfully. The results of the

stump patient 4 treatment are displayed in Figure 38. The stump patient measured dose

shows a 39% and 14% difference between the measured doses and the Eclipse doses for

the bladder and rectum, respectfully. The results of the cylinder patient 5 treatment are

displayed in Figure 39. The stump patient measured dose shows a 19% and 30%

difference between the measured doses and the Eclipse doses for the bladder and

rectum, respectfully.

Figure 37: Stump Patient 3 Dose Measurement (2% O-‐‑MeO-‐‑DMA)

48

Figure 38: Stump Patient 4 Dose Measurement (2% O-‐‑MeO-‐‑DMA)

Figure 39: Cylinder Patient 5 Dose Measurement (2% O-‐‑MeO-‐‑DMA)

49

4. Conclusions The aims of the project were to evaluate the feasibility of a dosimetry system for

PRESAGE®-‐‑IV dosimeters by comparing it to the gold standard using PRESAGE®-‐‑filled

optical cuvettes in spectrophotometry and validating the DMicrOS 2D optical scanning

system, and to demonstrate its utility as an in-‐‑vivo dosimeter for brachytherapy

treatment. The aim of evaluating the feasibility of a dosimetry system was met, but there

is substantial room for future investigation of PRESAGE®-‐‑IV dosimeters in patient

treatment.

The spectrophotometer reading of the change in optical densities of the 1.5% O-‐‑

MeO-‐‑DEA formulation of the gold standard 1x1x4cm optical cuvettes filled with

PRESAGE® and PRESAGE®-‐‑IV dosimeters in mineral oil had a linear slope 0.8703 ±

0.0192 when plotted against each other (Figure 27), and indicated that a dosimetry

system for in-‐‑vivo dosimeters is feasible. The results provide verification of the potential

that this dosimetry system has for easily and quickly reading PRESAGE®-‐‑IV dosimeters.

In Figure 28, the sensitivity, or change in OD/Gy/cm slope of the DMicrOS technique

was found to be 0.0136 ± 0.0002 and for the spectrophotometer 0.0135 ± 0.0002, which is

a 0.74% difference in sensitivity within the 95% confidence interval, which showed that

the two techniques are comparable.

With the positive results of the feasibility of the dosimetry system, came the

negative results of patient treatment. The estimated doses for patient 6 treatment using a

50

T&R (Figure 30) showed a 0% and 2.8% difference between the estimated doses and the

Eclipse doses for the bladder and rectum, respectfully. These results were the best

results received from using PRESAGE®-‐‑IV dosimeters for in-‐‑vivo dose verification. In

the following patient results, the differences between measured doses and Eclipse doses

for OARs were quite large. A number of reasons for these large differences could be due

to the positional stability of the dosimeters, organ motion, and patient motion for the

duration of treatment (2-‐‑4 hours on average). More patient trials need to be investigated

to show proof of concept for the dosimeter as a reliable method of dose verification for

OARs in HDR brachytherapy treatments.

There are several future directions to expand on the results of this work. Since

PRESAGE®-‐‑IV has the capability of 3D readings, the 2D optical scanning system can be

turned into an optical-‐‑CT system capable of reading the dose gradients that are surely

present in the dosimeters. Also, creating a standard procedure of application of in-‐‑vivo

dosimeters on intracavitary treatment applicators to eliminate unknowns is a high

priority. Once a standard procedure is achieved, dose estimates can become more

reliable and the differences from Eclipse measurements will decrease.

51

References 1. McJury, M., Oldham, M., Cosgrove, V., et al. 2000. Review article: Radiation

dosimetry using polymer gels: methods and applications. The British Journal of Radiology 73: 919-‐‑929.

2. Nath, Ravinder, Lowell L Anderson, Jerome A Meli, Arthur J Olch, Judith Anne

Stitt, and Jeffrey F Williamson. 1997. Code of Practice for Brachytherapy Physics  : Report of the AAPM Radiation Therapy Committee Task Group No . 56. 24 (56): 1557–1598.

3. Hendee, W. et al. 2013. Comprehensive Brachytherapy: Physical and Clinical Aspects.

CRC Press. p. 370-‐‑71 4. Thomadson, B.R., (2000). Achieving Quality in Brachytherapy. London, England:

IOP Publishing. 5. Nag, S, B Erickson, B Thomadsen, C Orton, J D Demanes, and D Petereit. 2000.

The American Brachytherapy Society Recommendations for High-‐‑dose-‐‑rate Brachytherapy for Carcinoma of the Cervix. International Journal of Radiation Oncology, Biology, Physics 48 (1) (August 1): 201–11.

6. Palmer, Antony, David Bradley, and Andrew Nisbet. 2012. Physics-‐‑aspects of Dose

Accuracy in High Dose Rate (HDR) Brachytherapy: Source Dosimetry, Treatment Planning, Equipment Performance and in Vivo Verification Techniques. Journal of Contemporary Brachytherapy 4 (2) (July): 81–91.

7. Williamson, J. 2008. Current brachytherapy quality assurance guidance: does it meet

the challenges of emerging image-‐‑guided technologies? International Journal of Radiation Oncology, Biology, and Physics 71 (1): 518-‐‑522.

8. Devlin, P.M 2007. Brachytherapy: Applications and Techniques. Lippincott Williams

& Wilkins p. 233-‐‑35. 9. Haughey A, Coalter G, Mugabe K. Evaluation of linear array MOSFET detectors for

in vivo dosimetry to measure rectal dose in HDR brachytherapy. Australas Phys Eng Sci Med 2011; 34: 361-‐‑366.

52

10. Reniers B, Landry G, Eichner R, Hallil A, Verhaegen F. (2012). In vivo dosimetry for gynaecological brachytherapy using a novel position sensitive radiation detector: feasibility study. Med Phys. 2012 Apr. 39(4):1925-‐‑35.

11. Guo, P Y, J a Adamovics, and M Oldham. 2006. Characterization of a New

Radiochromic Three-‐‑dimensional Dosimeter. Medical Physics 33 (5): 1338–1345. 12. Guo, P., J. Adamovics, and M. Oldham, A practical three-‐‑dimensional dosimetry

system for radiation therapy. Med Phys, 2006. 33(10): p. 3962-‐‑72. 13. Pierquet, M., et al., An investigation into a new re-‐‑useable 3D radiochromic dosimetry

material, Presage. J Phys Conf Ser, 2010. 250(1): p. 1-‐‑4. 14. Brown, S., et al., Radiological properties of the PRESAGE and PAGAT polymer

dosimeters. Appl Radiat Isot, 2008. 66(12): p. 1970-‐‑4. 15. Thomas, A., et al., Commissioning and benchmarking a 3D dosimetry system for

clinical use. Med Phys, 2011. 38(8): p. 4846-‐‑57. 16. Juang, T., et al., Customising PRESAGE for Diverse Applications. IC3D Dose 2012.

Shangri La Hotel, Sydney, Australia. 5 November 2012. 17. Ahmed, M.I., et al., Initial Experience with Alatus Vaginal Balloon Packing (VBP)

Compared to Standard Vaginal Gauze Packing (SGP) for Tandem and Ovoid Brachytherapy Treatment of Carcinoma of the Cervix. International Journal of Radiation Oncology, Biology, and Physics 78 (3): S409.

18. Rockey, W.M., et al., The Dosimetric Impact of Vaginal Balloon Packing on

Brachytherapy for Gynecological Cancer. International Journal of Radiation Oncology, Biology, and Physics 81 (18): S457.

19. Kirisits, C., et al., 2011 “Physics for Image-‐‑Guided Brachytherapy” Gynecologic

Radiation Therapy: Novel approaches to Image-‐‑Guidance and Management. Springer Heidelberg Dordrecht. London. New York. p.143.

20. Petric, P. et al., 2011 “Physics for Image-‐‑Guided Brachytherapy” Adaptive

Contouring of the Target Volume and Organs at Risk. Springer Heidelberg Dordrecht. London. New York. p.99.

21. Lambert, J. et al. 2007 “In vivo dosimeters for HDR brachytherapy: A comparison of a

53

diamond detector, MOSFET, TLD, and scintillation detector” Med Phys, 2007. 34(5): 1759-‐‑65.

22. Varian Medical Systems, 2011. “Varian BrachyTherapy Applicators and Accessories Catalog” Varian Medical Systems, Inc.

23. Pierquet, M., et al., On the Feasibility of Verification of 3D Dosimetry Near

Brachytherapy Sources Using PRESAGE/Optical-‐‑CT. J Phys Conf Ser, 2010. 250(1): 012091-‐‑1-‐‑012091-‐‑5

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