AN IMRT CLASS SOLUTION FOR PATIENTS WITH SKIN LESIONS …Rourke_Thesis.pdf · 3. Surgical reconstruction of disease in temple region and parotid region 20 4. Anatomical position of

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QUEENSLAND UNIVERSITY OF TECHNOLOGY

SCHOOL OF PHYSICAL AND CHEMICAL SCIENCES

AN IMRT CLASS SOLUTION FOR PATIENTS WITH SKIN LESIONS OF THE TEMPLE REGION THAT HAVE SPREAD TO THE PAROTID GLAND

February 2006

Submitted by Amy O’Rourke to the School of Physical and Chemical Sciences, Queensland University of

Technology in fulfillment of the requirements of the degree of Masters of Applied Science (Research)

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ABSTRACT

Patients with skin lesions of the temple region that have spread to the parotid gland are

commonly treated with three-dimensional conformal radiation therapy (3DCRT).

3DCRT has associated limitations when treating this disease. 3DCRT requires this

disease site to be treated with two junction regions, resulting in poor dose conformity

to the tumour target. Proximity of critical structures to the target volume can make

dosimetry difficult, “especially for concave-shaped targets in close proximity to

sensitive normal structures” (Saw.C et al., 2002, p76).

Intensity modulated radiation therapy (IMRT) is a relatively new treatment technology

that has potential to overcome limitations associated with 3DCRT (Garden.A et al.,

2004). IMRT has been reported to have significant advantages over conventional

3DCRT treatment, by improving dose to the tumour and lowering doses to critical

structures (Adams.E et al., 2001).

Research has been conducted into the optimal IMRT treatment for specific head and

neck carcinomas. They are identified as class solutions. “A class solution can be

defined as the historical experience in designing RT plans for a particular site”

(Intensity Modulated Radiation Therapy Collaborative Working, 2001, p913).

This study was performed to establish an optimal IMRT class solution for patients with

skin lesions of the temple region that have spread to the parotid gland, and to determine

if it is the superior treatment option over 3DCRT treatment. Dosimetry planning was

performed on computerised tomography data sets of nine patients with this disease site.

One optimised 3DCRT dosimetry plan and eight optimised IMRT plans with specific

beam arrangements were calculated. Clinical and statistical analysis was performed

on; critical structures, conformity indices (CI) and dose volume histogram (DVH)

range analysis of the planning target volume (PTV).

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Analysis of IMRT plans revealed that the 7-beam arrangement and 4-beam ipsilateral

arrangement produced significantly lower doses to the majority of critical structures

(P<0.05). The 7-beam IMRT arrangement produced the best and second best CI and

DVH PTV results, but these were not significantly different to the majority of other

beam arrangements. This indicates that the 7-beam arrangement with defined beam

angles of; 40°,120°,160°,200°,240°,300°,0°, is the superior IMRT treatment plan, and

thus class solution for this disease site. Clinical analysis confirmed results.

Analysis was performed on IMRT class solution results compared with 3DCRT results.

CI was significance higher and DVH PTV range was significantly lower for the IMRT

class solution (P<0.05). The class solution delivered significantly higher doses to the

majority of critical structures in comparison to the 3DCRT plan (P<0.05). This

indicates that the IMRT class solution is superior to 3DCRT in terms of PTV

conformity and homogeneity, but not in terms of doses to critical structures.

Skin lesions of the temple region with tumour extension to the parotid gland, is a

complicated disease site. Investigations into current and potential radiation therapy

treatments will guide treatment options and facilitate outcomes for patients with this

disease.

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CONTENTS Title Page 1 Abstract 2 Contents 4 List of Figures 7 List of Tables 9 Statement of Original Authorship 10 Acknowledgments 11 Introduction 12 1.1 Introduction 12 1.2 Aims 13 1.3 Hypothesis 13 Background Literature Review 14 2.1 Current Radiation Therapy Procedure 14 2.2 Incidence and Survival of Disease 14 2.2.1 Incidence of Malignant Parotid Primary 14

2.2.2 Incidence of Temple Skin Primary 17 2.2.3 Incidence and Survival of Disease at the Royal Brisbane and 19 Women’s Hospital (RBWH)

2.3 Treatment Options and Survival 19 2.4. Anatomy of the Parotid Gland and Surrounding Structures 21

2.4.1 Lymph Supply 23 2.5 Stabilisation 25 2.6 Prescription Terminology 25 2.7 Surrounding Anatomical Critical Structures 26 2.8 Radiation Tolerances of Critical Structures 31 2.9 Radiation Treatment Technique Transition 35 2.10 3DCRT Limitations 36 2.10.1 3DCRT and Critical Structure Limitations 36

2.10.2 IMRT Overcoming Critical Structure Limitations 37

2.10.3 3DCRT and Monoisocentric Junctions 40 2.10.4 3DCRT and Junction Limitations 41 2.10.5 IMRT Overcoming Junction Limitations 46

2.11 Radiation Doses 47

2.12 Beam Arrangements 48 2.12.1 Beam Arrangements Using 3DCRT 48 2.12.2 Beam Arrangements Using IMRT 49

2.13 Class Solutions and Benefits 51 2.14 Summary 51

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Method and Materials 53 3.1 Sample Group 53 3.2 Personnel 54 3.3 Equipment 55 3.4 Data Collection Procedure 57 3.4.1 Patient Positioning 57 3.4.2 Computerised Tomography (CT) Scanning Procedure 57 3.4.3 Planning Target Volume (PTV) Acquisition 58 3.4.4 Dose Prescribing 58 3.5 Plan Dosimetry 59 3.6 Critical Structures 60 3.6.1 Outlining Critical Structures 60 3.7 Beam Arrangements 61 3.7.1 3DCRT Beam Arrangements 61 3.7.2 IMRT Beam Arrangements 64 3.8 Dose Volume Histograms 65 3.9 Ethics Approval-RBWH/QUT 66 3.10 Analysis of Results 67 3.10.1 Bland and Altman 67 3.10.2 DVH Range Analysis on PTV 67 3.10.3 Mean Doses 67 3.10.4 Conformity index (CI) 68 3.10.5 Statistical Analysis 68 Results 70 4.1 Computerised Tomography (CT) data 70 4.2 Volume Structure Analysis 70 4.2.1 Structure Volumes 70 4.2.2 Bland and Altman Analysis 71 4.3 3DCRT Dosimetry 73 4.4 Conformity Index (CI) 74 4.4.1 Repeated Measures Anova on CI 74 4.5 DVH Range Analysis of the PTV 76 4.6 Mean Doses 77 4.6.1 Mean Contralateral Parotid Gland Dose 79 4.6.2 Mean Maximum Brain Dose 79

4.6.3 Mean Maximum Brainstem Dose 80 4.6.4 Mean Maximum External Auditory Meatus Dose 80 4.6.8 Mean Maximum Ipsilateral Lens Dose 81 4.6.6 Mean Maximum Contralateral Lens Dose 81 4.6.7 Mean Maximum Ipsilateral Retina/optic Nerve Dose 82 4.6.8 Mean Maximum Contralateral Retina/optic Nerve Dose 82 4.6.9 Mean Maximum Optic Chiasm Dose 83 4.6.10 Mean Maximum Oral Cavity Dose 83 4.6.11 Mean Maximum Spinal Cord Dose 84

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4.7 Grouped Results 84 4.8 Radiation Oncologist Clinical Analysis of IMRT Plans 86 4.9 IMRT Vs 3DCRT 86 4.9.1 CI 87 4.9.2 DVH Range Analysis of the PTV 89 4.9.3 Critical Structure Analysis 89 4.10 Radiation Oncologist Clinical Analysis of 3DCRT and 7-beam 91 IMRT plans Discussion 92 5.1 Structure Volume Analysis 92 5.2 3DCRT Dosimetric Considerations 93 5.3 IMRT Dosimetric Considerations 95 5.4 DVH Range Analysis of the PTV 96 5.5 IMRT CI Analysis 97 5.6 IMRT Critical Structure Analysis 98 5.7 IMRT Mean Contralateral Parotid Dose 99 5.8 Superior IMRT Plan 99 5.9 IMRT Class Solution 100 5.10 IMRT Vs 3DCRT 101 5.11 Radiation Oncologist Clinical Preference 102 5.12 Future Directions 103 Conclusion 105 References 107 Appendices 114 Appendix A Documentation from Nucletron Pty Ltd confirming free

software supply for a period of 90 days 114 Appendix B Ethics approval confirmation from Professor W Egerton of

the RBWH Human Ethics Research Committee 115 Appendix C QUT email confirming ethical issues were uncompromised 116

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LIST OF FIGURES Figure Description Page

1. Patients’ age at time of death from non-melanoma skin cancer, between 1994-1998 18 2. Pie graph demonstrating location of primary lesions causing death

after metastasising 18 3. Surgical reconstruction of disease in temple region and parotid

region 20 4. Anatomical position of the parotid gland 22 5. Facial nerve passing through the parotid gland 23 6. Lymphatics of the parotid gland and drainage towards the auricular

skin and temple scalp 24 7. Illustration detailing different volumes defined by ICRU 26 8. CT axial slice demonstrating position of the spinal cord and the

mandible 27 9. CT axial slice demonstrating position of the brainstem, parotids and

oral cavity 28 10. CT axial slice demonstrating position of the lenses, retina/optic

nerves and brain 29 11. CT axial slice demonstrating position of the optic chiasm 30 12. CT axial slice demonstrating position of the EAM 31 13. A transverse outline of a parotid patient showing the PTV

extending towards critical structures 37 14. Picture demonstrating IMRT plan Vs 3DCRT plan 38 15. Demonstration of superior and inferior asymmetric jaws 41 16. Photo of thermoplastic shell showing three separate treatment areas 42 17a.Photon isodose curve with straight edge penumbra 43 17b.Electron isodose curve with bulging penumbra 43 18a.Photo showing matching of the anterior oblique photon field to the

electron field on skin 44 18b.Photo showing matching of the posterior oblique photon field to

the electron field on skin 44 19. CT axial slice demonstrating spinal cord as the only critical

structure in the lower cervical photon field 46 20. Optimal IMRT class solution 50 21. Vacuum seal four point shell 55 22a.Lateral view of thermoplastic shell 55 22b.Anterior view of thermoplastic shell 55 23a.Siemens somatom sensation IV scanner 56 24. Standard dose prescription used at the RBWH 58 25. Wedge direction of anterior and posterior oblique fields 62 26. Photo of temple electron field matching on skin at the point where

the divergent edges of the oblique photon fields cross 63

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27. Diagrammatic representation of IMRT beam angles for left sided lesion 65

28. 3DCRT dose volume histogram and summary output 66 29. Bland and Altman plot of body structure volumes 72 30. Graph of CI for each beam arrangement 74 31. Graph of Mean CI vs beam arrangement number 75 32a. Beam arrangement-3 demonstrating PTV conformity distribution 76 32b. Beam arrangement-9 demonstrating PTV conformity distribution 76 33. Graph of mean DVH PTV range vs beam arrangement number 77 34. Graph of mean contralateral parotid vs beam arrangement number 79 35. Graph of mean maximum brain dose vs beam arrangement number 79 36. Graph of mean maximum brainstem dose vs beam arrangement number 80 37. Graph of mean maximum eam vs beam arrangement number 80 38. Graph of mean maximum ipsilateral lens dose vs beam arrangement

number 81 39. Graph of mean maximum contralateral lens dose vs beam arrangement

number 81 40. Graph of mean maximum ipsilateral retina/optic nerve dose vs beam

arrangement number 82 41. Graph of mean maximum contralateral retina/optic nerve dose vs

beam arrangement number 82 42. Graph of mean maximum optic chiasm dose vs beam arrangement number 83 43. Graph of mean maximum doses to oral cavity vs beam arrangement number 83 44. Graph of mean maximum spinal cord dose vs beam arrangement number 84 45a&b. Improved CI is visualised by the 95% isodose line in the 7-beam

IMRT arrangement when compared to the 3DCRT plan 88 46a. DVH demonstrating 3DCRT distribution 89 46b. DVH demonstrating IMRT distribution 89 47a&b. Mean and mean maximum doses to critical structures for the

7-beam IMRT arrangement and the 3DCRT beam arrangement 90 48. DVH’s of 3DCRT plans from different CT data sets demonstrating

similarities in PTV 93 49. 3DCRT axial slice of junction region demonstrating poor coverage

of the PTV 94 50. DVH demonstrating compromise made when determining optimal

IMRT distribution 95 51a. DVH demonstrating 3DCRT distribution 97 51b. DVH demonstrating IMRT distribution 97 52a. 7 beam IMRT distribution demonstrating doses to critical structures 99 52b. Beam arrangement-5 IMRT distribution, demonstrating dose to

critical structures 99

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LIST OF TABLES

Table Description Page

1 Incidence of various histopathological types of parotid 15 2 TNM classification for parotid carcinomas 6 3 Reported literature detailing radiation tolerances of head

and neck critical structures 32 4 Disease primary classification of patient data 54 5 Critical structures, tolerance and order of importance as determined

by radiation oncologist 60 6 Beam arrangement used on each CT data set 65 7 Beam arrangement number associated with beam arrangement 70 8 Comparison of structure volumes for one CT data set 71 9 Body structure volume data 71 10 Doses from 3DCRT plans with different photon-electron junction

matching techniques 73 11 Repeated measures ANOVA 78 12 Grouped results 85 13 Table demonstrating any significant difference between measures

of 3DCRT plans and the 7-beam IMRT arrangement 87

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STATEMENT OF ORIGINAL AUTHORSHIP

“The work contained in this thesis has not been previously submitted for a degree or diploma at 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.”

Signed ………………………..

Dated ………………………..

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ACKNOWLEDGEMENTS

I would like to thank the following people:

Ms Michelle Oppelaar, the supervisor of this study, for her continued encouragement

and feedback.

Mr Greg Rattray, for his continued time, knowledge and support.

Prof Brian Thomas, for his continued time and support especially with statistical

analysis in this research project.

Nucletron, for assistance and use of software that made this study possible.

Royal Brisbane and Women’s Hospital, for the use of equipment and data that made

this study possible.

My family and friends, for their encouragement.

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CHAPTER 1 INTRODUCTION

1.1 INTRODUCTION

An area treated with radiation therapy is skin carcinoma of the temple region that has

spread to the parotid gland. The conventional radiation therapy treatment procedure

involves three-dimensional conformal radiation therapy (3DCRT). At the Royal

Brisbane and Women’s Hospital in Brisbane (RBWH) of Queensland, eighty-six

patients were treated with 3DCRT between 1998 and 2003 (RBWH, 2005).

3DCRT has associated limitations, especially when treating this disease. Proximity of

critical structures to the target volume can make dosimetry difficult. If the tumour

extends or curves around critical structures it is difficult to achieve the required dose to

the tumour while still keeping critical structures under dose tolerance.

In order to treat skin carcinomas of the temple region that have extended to the parotid

gland with 3DCRT, the treatment field must be divided into three areas, which results

in two junction regions. A 3DCRT treatment with more then one junction region can

cause underdosing and overdosing of the tumour target volume.

Intensity Modulated Radiation Therapy (IMRT) is a relatively new radiation treatment

technology. IMRT is an advanced form of 3DCRT that utilises modulated radiation

beam intensities. Some researchers suggest that “only a few meaningful retrospective

studies are available that show its potential and possible drawbacks” (Gregoire.V and

Maingon.P, 2004, p110). In contrast other researchers propose that IMRT may have

the potential to overcome limitations associated with 3DCRT (Garden.A et al., 2004).

IMRT has been reported to have significant advantages over conventional 3DCRT

treatment, by improving dose to the tumour and lowering doses to critical structures

(Adams.E et al., 2001).

Treating temple skin lesions with extensions to the parotid gland with IMRT enables

the treatment field to be divided into two areas, resulting in only one junction region.

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This has the potential to reduce overdosing and underdosing. To treat this region with

IMRT, an optimum plan must be established.

Determining the optimum IMRT treatment plan demands a detailed process requiring

much research. The optimum IMRT treatment plan is identified as a class solution. A

class solution is defined as a solution that “consists of the criteria for optimisation and

the specification of the beam techniques used, typically including beam direction and

number” (Intensity Modulated Radiation Therapy Collaborative Working, 2001, p913).

1.2 AIM:

The aim of this study was to determine the optimal class solution for IMRT treatment

for patients who have skin lesions of the temple region with tumour extensions to the

parotid gland and determine if it is the superior treatment option over 3DCRT

treatment.

1.3 HYPOTHESIS:

The optimal IMRT class solution, for patients with temple skin lesions that extend to

the parotid gland, is the superior treatment modality. The IMRT class solution will

enable; avoidance of problems in the junction region and lower doses to critical

structures, allowing a potential increase in dose to the target volume and thus the

potential to increase local control.

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CHAPTER 2 BACKGROUND LITERATURE REVIEW

2.1 Current Radiation Therapy Procedure Patients treated with radiation therapy for skin carcinomas of the temple region with

extensions to the parotid gland, undergo a standard treatment procedure. Patients

participate in a simulation procedure that can be reproduced for daily treatment. Data

is acquired for the radiation oncologist to define the tumour target and dose

prescription. Radiation therapists produce a radiation therapy plan with acquired data

in accordance with the dose prescription. Patients proceed to a course of fractionated

radiation therapy treatment. A standard fractionated course is 1 treatment/day, 5

days/week, for 6 weeks.

The above procedure is a simple overview that has many complicated steps. For this

research study, only steps that relate directly to, or impact on aims of this study will be

addressed.

2.2 Incidence and Survival of Disease

This research study is primarily concerned with tumour in the skin temple region and

in the parotid gland. The origin of this disease type may vary. The primary disease

may be in the parotid gland and spread to the skin of the temple region. Alternatively

the primary disease may be in the temple region, and spread to the parotid gland. The

incidence and survival data for both alternatives will be addressed.

2.2.1 Incidence of Malignant Parotid Primary

As malignant parotid tumour type and histology varies, it is difficult to find in the

literature incidence and survival rates for patients who have had spread of disease

specifically to the temple region. Incidence and survival data of malignant parotid

tumours, is well documented and provides a good indication of potential incidence of

spread of disease to upper skin regions.

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Malignant tumours of the parotid gland are rare. “Malignant salivary gland neoplasms

constitute approximately 1% to 3% of all head and neck neoplasms”(Bhattacharyya.N

and Fried.M, 2005, p39). Parotid malignancies account for 50-70% of these salivary

gland neoplasms (Pohar.S et al., 2005). Incidence rates are nearly equal between

sexes. “Age standardised incidence rates per 100 000 for malignant salivary gland

tumours in the United States are 1.0 and 0.7 for males and females respectively”

(Zbaren.P et al., 2003, p57).

Malignant parotid carcinomas have large variations in histology, staging and clinical

behaviour. A study conducted in Sweden by Walhlberg et al, recorded the incidence of

various histopathological types of parotid carcinomas (Table 1).

Table 1-Incidence of various histopathological types of parotid cancer in Sweden 1960-1969, 1970-

1979, 1980-1989 and 1990-1995, respectively according to gender(Wahlberg.P et al., 2002, p707).

Malignant parotid carcinomas may present at different stages. Staging is used to define

the extent of disease. TNM classification is standardly used, and detailed in table 2.

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Table 2-TNM classification for parotid carcinomas (Licitra.L et al., 2003, p219).

Primary Tumour (T) TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Tumour 2 cm or less in greatest dimension without

extraparenchymal extension T2 Tumour more than 2 cm but not more than 4 cm in

greatest dimension without extraparenchymal extension T3 Tumour having extraparenchymal extension without seventh

nerve involvement and/or more than 4 cm but not more than 6 cm in greatest dimension

T4 Tumour invades base of skull, seventh nerve, and/or exceeds 6 cm in greatest dimension

Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in

greatest dimension N2 Metastasis in a single ipsilateral lymph node, more than 3 cm

but not more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension

N2b Metastases in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c Metastases in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3 Metastasis in a lymph nodes more than 6 cm in greatest dimension Distant Metastases (M) MX Distant metastases cannot be assessed M0 No distant metastases M1 Distant metastases

Patterns of spread for malignant carcinomas are difficult to predict because of diverse

biological behaviour (Harish.K, 2004). Due to low incidence rates, varying

histopathological types, staging and routes of spread, survival statistics are minimal.

This fact is supported by many researchers,

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“Overall rarity, determination of survival statistics and predictive factors

influencing survival has been largely dependent on single institutional series

spanning multiple decades. Most such series have been somewhat limited by

sample size and by their retrospective analysis. In addition, the wide variety of

histoplathologies that may be encountered in salivary gland malignancy

contributes to variability in survival” (Bhattacharyya.N and Fried.M, 2005,

p39).

2.2.2 Incidence of Temple Skin Primary

Skin lesions of the temple region may be the primary disease that spreads to the parotid

gland. The majority of primary skin lesions are non-melanoma skin cancers (NMSC)

which are comprised of 80% basal cell carcinomas (BCC) and 20% squamous cell

carcinomas (SCC) (Barzilai.G et al., 2005). Other less common non-melanoma skin

lesions are: merkel cell carcinoma, kaposi’s sarcoma and lymphoproliferative disorders

(Nolan.R et al., 2005).

For Caucasians the life time risk of a SCC is 8-11% and for BCC is 28-33% (Lai.S and

Weber.R, 2004). Australia has the highest reported incidence of SCC in the world,

estimated to be 205 per 100 000 population annually (Khurana.V et al., 1995). A study

by Nolan et al was conducted in Western Australia. This study determined that

“during the five years of 1994 and 1998, 120 patients died of NMSC” (Nolan.R et al.,

2005, p103). These deaths occurred mainly in the elderly (Figure 1).

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Figure 1- Figure demonstrating patients’ age at time of death from non-melanoma skin cancer,

between 1994-1998. Grey bars=all deaths, black bars=comorbidities leading to immune deficiency

(Nolan.R et al., 2005, p103).

At the RBWH between 1998 and 2000, 498 men and 272 women had primary skin

lesions treated by the oncology department (RBWH, 2003). These statistics are for

skin lesions in general. This research is concerned with skin lesions of the temple

region. Unfortunately, RBWH statistics do not break down to skin site. Nolan et al

presented breakdown statistics on primary lesion site (Figure 2).

Figure2- Pie graph demonstrating location of primary lesions causing death after metastasising

(Nolan.R et al., 2005, p104).

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NMSC lesions have a high probability of spread to the parotid and neck region. The

result of this spread is the particular area of interest in this research project. “The

occult metastases rate in the neck in the presence of metastases in the parotid gland

was 20%” (Barzilai.G et al., 2005, p855).

2.2.3 Incidence and Survival of Disease at the Royal Brisbane and Women’s

Hospital (RBWH)

Incidence and survival rates for patients who have been treated at the RBWH for skin

lesions of the temple region with spread of disease to the parotid gland or vice-versa is

documented. Most recent figures indicate that between 1998 and 2003, eighty-six

patients were treated with radiation therapy at the RBWH for this disease site (RBWH,

2005).

Of the eighty-six patients treated at the RBWH radiation oncology department between

1998 and 2003, seventy-one are still alive today. Thus an 83% survival rate exists.

This figure cannot be quoted as a five year survival rate because some patients

included in these figures were treated at the end of 2002.

2.3 Treatment Options and Survival

There are a number of treatment modalities available to patients with disease in the

parotid gland, skin temple region and the lower neck region. Common treatment

options include; surgery, chemotherapy, radiation therapy or a combination of

treatments.

Treatment of the parotid gland and skin temple region can involve surgery alone

(Figure 3).

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Figure 3- Figure demonstrating surgical excision of disease in temple region and parotid region

(Plopper.C et al., 2004, p409).

A study conducted by Khurana et al, claims surgery alone achieved disease free

survival of 61% at five years (Khurana.V et al., 1995, p448). In contrast other

researchers suggest local recurrence occurs in 20-70% of patients treated with surgery

alone (Rowbottom.C et al., 2001, p163). Complications are associated with surgery

and include permanent facial palsy, Frey’s syndrome, and anesthesia in the

periauricular skin (Licitra.L et al., 2003, p222).

Chemotherapy in the treatment of parotid lesions is rarely used alone. Marandas et al

believe that chemotherapy alone has not been proved an effective treatment option

(Marandas.P et al., 1990). For the site of interest in this research project, there is

limited recent data available to determine survival rates for chemotherapy used alone.

Licitra et al suggest, “for both major and minor salivary gland tumours chemotherapy

is only suitable for individual clinical use” (Licitra.L, et al, 2003, p220). Thus

chemotherapy alone is not a common treatment option for parotid tumours or ones that

have spread to or from the temple skin region.

Radiation therapy alone is not a successful treatment option for skin lesions of the

temple region that have spread to the parotid gland. A literature review by Laramore et

al determined a 26% local control rate (Laramore.G, 1987, p1421). Side-effects

associated with radiation therapy may include; xerostomia, pain in jaw, hearing deficits,

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bone necrosis and cataract formation (Nutting.C et al., 2001). The degree and severity

of side-effects depend on the dose prescribed and dose distribution.

The preferred treatment option for tumours in the skin region of the temple with

extension to the parotid gland or vice-versa, is a combination of surgery and post-

operative radiation therapy (O'Brien.C et al., 2002). A study by Delcharco et al

determined that disease control was 90% for surgery and postoperative radiotherapy

and 53% for surgery alone (Delcharco.J et al., 1998).

2.4 Anatomy of the Parotid Gland and Surrounding Structures

Anatomy of the parotid gland and surrounding structures challenge the delivery of

radiation therapy. The parotid gland and closely associated critical anatomy make it

difficult to deliver a radical tumour dose, without overdosing other important structures.

The anatomical information presented below will detail situation, function and

composition as related to this research topic.

The parotid glands are the largest of the salivary glands. They are situated on each side

of the face, below the left and right ear. The gland lies in the space between the ramus

of the mandible and the anterior border of the sternocleidomastoid muscle (Figure 4).

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Figure 4- Figure demonstrating anatomical position of the parotid gland (Snell.R, 2004, p744).

The parotid glands are enclosed in a fascial capsule and function to produce serous

saliva, containing enzymes (Thibodeau.G and Patton.K, 2003). Structures within the

gland provide blood supply, venous and lymph drainage. Blood supply is from the

external carotid artery and its branches. Venous drainage is via the retromandibular

vein. Lymph drainage is into the parotid lymph nodes and the deep cervical lymph

nodes (Snell.R, 2004).

The facial nerve and its branches pass through the parotid gland. The facial nerve

controls muscles of facial expression. Thus facial paralysis is a complication of

surgical treatment options (Marieb.E, 1998) (Figure 5).

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Figure 5- Figure demonstrating the facial nerve passing through the parotid gland (Snell.R, 2004,

p744).

Part of the parotid gland that lies superficial to the facial nerve is called the superficial

lobe. The portion of the gland that lies deep to the nerve is called the deep lobe. The

majority of parotid tumours originate in the superficial lobe. This may be a result of

the superficial lobe being larger, as there is no pathological difference between the two

lobes (DeVita.V et al., 1997).

The parotid glands function to produce saliva. “60-65% of total salivary volume is

produced in the parotid glands” (Cooper.J et al., 1995, p1153). Saliva plays a major

role in mastication, digestion, swallowing and speech. It provides lubrication for the

oral cavity, protects against bacterial infection and inhibits enamel decalcification

(Cooper.J et al., 1995).

2.4.1 Lymph Supply

Lymph node drainage may help predict metastatic spread of parotid cancers.

Lymphatics in and around the parotid consist of two groups; the periparotid and

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intraparotid lymph nodes. The parotid gland will mainly drain to intra-parotid nodes.

These nodes will drain to the upper, middle and deep jugular lymph nodes (DeVita.V

et al., 1997)

The parotid gland will rarely drain to periparotid nodes which lie superficial to the

gland capsule and drain to the external auditory canal, the facial and auricular skin and

the temple scalp. These nodes are particularly important drainage sites for squamous

carcinomas and melanomas of adjacent skin (DeVita.V et al., 1997) (Figure 6). Barzili

et al support this by suggesting intra-protid and periparotid nodes can be at risk for

metastatic disease originating in skin cancer, particularly from the temple (Barzilai.G

et al., 2005).

Figure 6- Figure demonstrating lymphatics of the parotid gland and drainage towards the

auricular skin and temple scalp (Moore.K and Agur.A, 2002, p567).

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2.5 Stabilisation

Patients treated for tumours of the temple skin region with spread to the parotid are

positioned in a stabilisation shell. A shell provides a reproducible position and

minimises head movement during treatment.

Different types of stabilisation devices can be used as controversy exists as to which is

the better device. Two popular stabilisation shells are thermoplastic or vacuum formed

shells. In 1995, a study by Welten et al, suggested that, “no substantial difference in

patient setup accuracy between both types of masks was detected” (Weltens.C et al.,

1995, p499). Many researchers suggest thermoplastic shells are a better alternative in

terms of accuracy (Lord.L et al., 2003) although others state, “there is no level 1

evidence that thermoplastic materials are more accurate” (Roques.T et al., 2005, p942).

Different forms of stabilisation devices are used but all provide similar and accurate

head stabilisation.

2.6 Prescription Terminology

The radiation oncologist marks target regions onto the CT data sets. Specific target

regions have defined prescription terminology that is referred to throughout this project.

Terminology such as; gross target volume (GTV), clinical target volume (CTV) and

planning target volume (PTV) are universally accepted concepts of radiation therapy.

The international commission on radiation units and measurements (ICRU) established

guidelines and recommendations with a publication in 1993 and a supplementary

publication in 1999. The publication is referred to as, “Report 50,” and the

supplementary publication is “Report 62.” Both reports define important areas of

volume.

Report 50 defined GTV as the innermost volume and is the gross palpable, visible or

demonstrated extent and location of malignant growth. CTV was defined as a region

containing the GTV with the addition of a volume to account for uncertainties in

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microscopic spread. The PTV, has a margin added to the CTV to account for

geometric uncertainties (ICRU, 1993).

Report 62 redefined the PTV by introducing the internal margin (IM) and setup

margin (SM). IM accounts for variation in size, shape and position of the CTV. SM

accounts for uncertainties in patient-beam positioning (ICRU, 1999). ICRU defines

the volume formed by the CTV and the IM as the internal target volume (ITV) (Purdy.J,

2004). This is illustrated in Figure 7

Figure 7- Illustration detailing different volumes defined by ICRU (Purdy.J, 2004, p28).

ICRU recommended the use of these defined volumes as standard terminology when

prescribing and recording radiation therapy treatment.

This research project recognises and refers to prescription terminology defined by

ICRU.

2.7 Surrounding Anatomical Critical Structures

Surrounding anatomical critical structures to the PTV are outlined on the CT data sets

and are detailed below.

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The parotid gland lies within close proximity to radiation sensitive critical structures.

These include; the contralateral external auditory meatus (eam), spinal cord, ipsilateral

lens and retina/optic nerve, contralateral lens and retina/optic nerve, brain, brain stem,

optic chiasm, oral cavity, mandible and contralalateral parotid gland.

The spinal cord (Figure 8) can be easily visualised on CT data sets. The spinal cord is

a round cylindrical structure situated between the spinus process and vertebral discs of

the spine. The spine extends from the upper border of the atlas to the junction between

the first and second lumbar vertebrae (Standring.S et al., 2005).

Figure 8- CT axial slice demonstrating position of the spinal cord and the mandible. (CT data

courtesy of RBWH)

The brainstem (Figure 9) is structurally and functionally a compact region that contains

vital cardiac and respiratory centres. It is situated at the posterior cranial fossa

(Standring.S et al., 2005). The brain is visualised as grey matter and is enclosed by

bony skull (Figure 10).

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Figure 9- CT axial slice demonstrating position of the brainstem, parotids and oral cavity. (CT

data courtesy of RBWH)

The lenses, retina/optic nerves and brain (Figure 10) can be seen clearly on CT scans.

The lens is a transparent, encapsulated body that is visualised towards the anterior of

the eyeball (Standring.S et al., 2005). The retina is the inner most coat of the eyeball

that extends to the optic nerve which arises from the eyeball (Thibodeau.G and

Patton.K, 2003). The brain is visualised as grey matter contained within the skull.

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Figure 10- CT axial slice demonstrating position of the lenses, retina/optic nerves and brain. (CT

data courtesy of RBWH)

The optic chiasm (Figure 11) is a small anatomical structure that is more difficult to

see on CT scans. It is the cross over point of the optic nerves (Tortora.G and

Reynolds-Grabowski.S, 2000)

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Figure 11- CT axial slice demonstrating position of the optic chiasm. (CT data courtesy of RBWH)

The oral cavity (Figure 9) and mandible (Figure 8) are easily visualised on a CT scan.

The oral cavity is the space between the roof and the floor of the mouth and is

surrounded by the mandible. The mandible is a bony structure that can be easily seen.

It is the lower jaw and is the largest and strongest bone of the face (Thibodeau.G and

Patton.K, 2003).

Parotid gland anatomy has been described previously. On a CT scan (Figure 9) it can

be visualised laterally on a number of CT slices as an encapsulated grey structure.

The eam (Figure 12) can also be seen on a number of axial slices. It is a canal shaped

structure visualised laterally near the temporal bone and the ear drum (Tortora.G and

Reynolds-Grabowski.S, 2000).

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Figure 12- CT axial slice demonstrating position of the EAM. (CT data courtesy of RBWH)

2.8 Radiation Tolerances of Critical Structures

In order to deliver radiation therapy to the PTV, normal tissue and critical structures

surrounding the PTV are irradiated. Radiation therapy treatment planning is made

difficult by internal inhomogeneity of the head and proximity of the parotid glands to a

number of critical structures (Bragg.C et al., 2002). Critical anatomical structures have

specific radiation tolerances and are outlined on CT data sets in this research project.

Literature documents radiation tolerances for a number of critical structures (Table 3).

If radiation tolerances to the volume of the critical structure are exceeded, detrimental

complications result.

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Table 3-Reported literature detailing radiation tolerances of head and neck critical structures

(Emami.B et al., 1991, p111).

(Td 5/5=Probability of 5% complication within 5 years from treatment)

(Td50/5=Probability of 50% complication within 5 years from treatment)

The most common side-effect of radiation treatment to all head and neck tumours is

xerostomia, dental caries and loss of taste. Xerostomia or dry mouth syndrome is a

primary symptom because “saliva becomes scant, sticky and viscous as a result of

changes in its composition during a course of radiotherapy” (Stone.H et al., 2003,

p533). There is an overall decrease in salivary gland output that can last a number of

years and cause; oral discomfort, difficulty chewing and swallowing, increased

incidence of dental caries and impaired taste (Henson.B et al., 1998). Xerostomia

symptoms are usually permanent and cause a significant impact on quality of life

(Chao.K et al., 2001).

Morbidity associated with irradiation of the salivary glands has a positive correlation

with radiation dose. Traditional research defines dose limits. The radiation tolerance

of the parotid gland is 46 Gy for a 50% chance of developing xerostomia (Emami.B et

al., 1991). More recent research suggests an exponential relationship between saliva

flow reduction and mean parotid dose, “stimulated saliva flow at 6 months after

treatment is reduced exponentially, for each gland independently, at a rate of

hoshiko

Rectangle

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This table is not available online. Please consult the hardcopy thesis available from the QUT Library

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approximately 4% per Gy of mean parotid dose” (Chao.K et al., 2001, p907). Thus an

optimal radiation dosimetry plan for a patient with skin lesions of the temple region

that have spread to the parotid gland should involve minimal mean dose to the

contralateral parotid gland in order to avoid temporary morbidity of xerostomia.

A late side-effect of radiation may include hearing loss. The middle ear and external

auditory meatus are usually within the PTV. The Cochlea, semi-circular canals and the

vestibulo-cochlea nerve lie close to the PTV and often receive a high dose (Nutting.C

et al., 2001). High doses to these structures can have detrimental effects. Schot et al

suggests there is a greater then 30% incidence of hearing loss of at least 10 dB in

patients treated with doses ranging from 38 Gy in 15 fractions to 50 Gy in 25 fractions

(Schot.L et al., 1992). Nutting reports ipsilateral hearing loss in 54% of parotid cancer

patients with conventional radiation therapy techniques (Rowbottom.C et al., 2001).

Thus hearing loss is a complication of concern associated with radiation therapy to the

parotid gland.

Anatomical visual pathways are important critical structures. Radiation tolerances are

demonstrated in table 3 and are supported by other researchers. Cook, et al,

determined a radiation tolerance of the optic chiasm as, “TD 5/5 of 50 Gy or slightly

higher” (Cook.B et al., 2004, p409). Yi, et al, determined that, “radiation doses up to

60 Gy given in conventional fractionation appears to be well tolerated by the optic

nerve” (Yi.W et al., 2004, p408). Doses exceeding tolerance may result in radiation

induced optic injury, resulting in blindness as an endpoint complication (Emami.B et

al., 1991).

Exceeding radiation tolerance to lenses has a complication endpoint of cataract

formation (Table 3). Lenses are positioned superior to the parotid gland tumour target,

but still receive dose. The dose that occurs on lenses depends on a variety of factors

including; dose delivered, proximity to the PTV and the number of treatment fields

used. Cataract formation is an undesirable side-effect of radiation dose to lenses, but in

some cases may be an acceptable trade-off for potential tumour cure (Pawlicki.T et al.,

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2004). Cataract formation can be reduced by surgery, thus the complication endpoint

is not as concerning as other critical structures.

The brain and brainstem have complication endpoints of infarction necrosis.

Infarction necrosis is a serious detrimental side-effect that can result in death (Debus.J

et al., 1997). Studies of radiation exposure to brain tissue reveal, “pallor of white

matter consistent with diffuse cerebral edema and demyelination” (Emami.B et al.,

1991, p110). Steen et al supports this research by determining “changes in white

matter, usually at doses greater than 50 Gy, which are consistent with radiation-

induced normal tissue damage” (Steen.R et al., 2001, p79). As a result Emami et al

suggests a brain tolerance dose of 4500 cGy and a brain stem dose of 5000 cGy

(Emami.B et al., 1991).

The spinal cord’s endpoint complication is myelitis necrosis (Table 3). Myelitis

necrosis is characterised by inflammation of the spinal cord with associated motor or

sensory function leading to death of the living tissue (Anderson.D et al., 2002). Spinal

cord damage is a grave complication of radiation therapy (Branislav.J et al., 2002).

Radiation myelopathy is another spinal cord complication. It is characterised by,

“progressive development of sensory, motor, or prioceptive deficits… that may lead to

spastic paralysis, loss of significant function, or even death” (Kuo.J et al., 2002, p138).

Radiation induced spinal cord injuries are avoided by applying dose constraints to this

critical structure. “To minimise the chance of spinal cord complication, treatment

regimes commonly limit the spinal cord dose to less than 20 Gy in 5 fractions, 30 Gy

in 10fractions, or 50 Gy in 25 fractions” (Kuo.J et al., 2002, p139).

Osteonecrosis is an end point complication from radiation exposure to the mandible.

Osteonecrosis can occur when a total dose exceeding 65 Gy is applied with standard

fractionation (Glanzmann.C and Gratz.K, 1995). In contrast, a study by Jereczek-fossa

et al, determined doses as high as 74.4 Gy in the mandible were associated with

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osteonecrosis, although this research was conducted with a small sample group

(Jereczek-Fossa.B et al., 2003).

The endpoint complication of irradiating the oral cavity is oral mucosa reaction which

leads to; pain, degrees of dysphagia, hoarseness and in severe toxicity, difficulty with

breathing (Cooper.J et al., 1995). Literature indicates that doses of 20-30 Gy to the

oral cavity at 1.8-2 Gy per fraction results in mucosa linings becoming erythematous.

At this dose, 20-30% of taste cells in the oral cavity are destroyed. After a further 10-

20 Gy, mucositis results, leading to desquamation (Cooper.J et al., 1995).

2.9 Radiation Treatment Technique Transition

In recent years radiation therapy has seen transition in techniques, from two-

dimensional radiation therapy (2DRT) to three-dimensional conformal radiation

therapy (3DCRT) and finally to IMRT.

2DRT is a traditional treatment used in a large majority of centres. 2DRT treatment

uses rectangular beams and usually allows a 6 mm margin between the edge of the

PTV and the collimator to account for the beam penumbra (Rowbottom.C et al., 2001).

2DRT planning utilises a two-dimensional planning system that does not account for

scatter from adjacent planning slices.

3DCRT is replacing 2DRT in many centres including the RBWH. 3DCRT uses a

three-dimensional planning system. Radiation plans use geometrically shaped beams

of uniform intensity defined from the beam’s eye view by a conformal block

(Rowbottom.C et al., 2001). In recent times, the introduction of multileaf collimators

(MLC’s) has replaced conformal blocks. “The introduction of MLC’s to shape

radiation beam portals has made conformal therapy a standard delivery technique”

(Budgell.G, 2002, p241). 3DCRT is also able to calculate the contribution to dose

from scatter from other slices.

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3DCRT has many advantages over conventional 2D radiation therapy. Advantages

include; a decrease in dose to normal tissue, a decrease in side-effects and the potential

for dose escalation. Many studies have shown that 3DCRT minimises dose to normal

tissue. According to Perez et al, conformal radiation therapy spares more normal tissue

than standard 2D radiation therapy (Perez.C et al., 2000).

A decrease in dose to surrounding tissue results in a decrease in side effects. This

enables the opportunity to explore dose escalation to the target volume while still

keeping surrounding tissues to acceptable tolerance levels. “3DCRT overcame several

of the shortcomings and limitations of conventional two-dimensional planning”

(Esiashvili.N et al., 2004, p47). Thus a transition of radiation techniques can be seen

from 2DRT to 3DCRT.

2.10 3DCRT Limitations

3DCRT has associated limitations especially when treating skin lesions of the temple

region that have spread to the parotid gland. Limitations are associated with proximity

of critical structures to the target volume and the junction regions that are required to

treat the spread of disease with 3DCRT. The junction regions required by 3DCRT will

be discussed in detail in section 2.10.4. IMRT may have the potential to overcome

limitations.

2.10.1 3DCRT and Critical Structure Limitations

Proximity of critical structures can make dosimetry difficult. If the target volume

extends or curves around critical structures it is difficult to achieve the required target

dose while still keeping critical structures under tolerance (Figure 13). The degree of

3D shaping available is limited regardless of the number of beams applied (Budgell.G,

2002). Often, compromises must be made between the target dose and tolerance doses

of critical structures. Thus 3DCRT does not always provide an optimal solution when

critical structures are in close proximity to the target volume.

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Figure 13- A transverse outline of a parotid patient showing the PTV extending towards critical

structures. Figure adapted from ((Nutting.C et al., 2001, p164).

2.10.2 IMRT Overcoming Critical Structure Limitatio ns

3DCRT is not adequate, “especially for concave-shaped targets in close proximity to

sensitive normal structures” (Saw.C et al., 2002, p76). Figure 14 demonstrates

dosimetry of a 3DCRT plan versus an IMRT plan. It can be seen that the IMRT

delivers a higher and more conformal dose to the target volume, while 3DCRT is not

able to conform high dose to the concave shaped target volume that is in close

proximity to the critical structure of the spinal cord.

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Figure 14- Picture demonstrating dosimetry of an IMRT plan versus a 3DCRT plan. The 90%

isodose line conforms to the PTV for IMRT dosimetry, but not for 3DCRT dosimetry. The isodose

line conforming to the PTV for 3DCRT dosimetry is the 62% isodose line (Cozzi.L et al., 2004,

p621).

IMRT is an advanced form of 3DCRT. The difference being that IMRT enables the

advantages of 3DCRT to be taken to a higher level while overcoming the limitations.

IMRT can provide a solution when “conventional 3DCRT as just defined, cannot

produce a satisfactory treatment plan because of limitations of the method along with

the geometry of the problem” (Verhey.L, 1999, p78).

IMRT is a relatively new technology that may have the potential to overcome

limitations associated with 3DCRT. In 2004, Garden et al stated, “the use of IMRT for

the treatment of head and neck cancers is less than a decade old” (Garden.A et al.,

2004, p103). In this short time IMRT has flooded literature with controversy regarding

clinical advantages.

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Some researchers suggest that not enough randomised trials have been conducted to

provide supportive evidence of IMRT benefits. “Only a few meaningful retrospective

studies are available that show its potential and its possible drawbacks” (Gregoire.V

and Maingon.P, 2004, p110). Garden et al support limited evidence based studies,

“justification for the benefits of IMRT compared with standard approaches has been

primarily theoretical” (Garden.A et al., 2004, p103).

In contrast, other researchers suggest the benefits of IMRT can undoubtedly overcome

limitations presented by conventional radiation treatment techniques.

“IMRT has two advantages for the treatment of head and neck cancers (ie, an

improvement in tumour coverage and better avoidance of normal tissues

resulting in a reduction in toxicity)” (Garden.A et al., 2004, p103).

“IMRT was found to offer significant advantages over conventional and

conformal radiation therapy, giving improved PTV homogeneity and reduced

dose to critical structures” (Adams.E et al., 2001, p587).

The suggested benefits of IMRT can be applied to difficult dosimetry treatments such

as skin carcinomas of the temple region with extensions to the parotid gland.

A skin lesion of the temple region with extensions to the parotid gland is an attractive

site for IMRT. Critical structures and radiation sensitive organs are in close proximity

to the target volume. High dose gradients offer potential therapeutic gain and

potentially improved mortality rates. “Dose escalation to the parotid using IMRT

should improve the likelihood of uncomplicated tumour control” (Bragg.C et al., 2002,

p737).

There is potential for reduced morbidity through spared structures. “IMRT in treating

cancers of the parotid, allows considerable sparing of critical structures without any

reduction in the quality of the coverage of the target” (Bragg.C et al., 2002, p737).

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IMRT can provide a solution where the target volume is in close proximity to critical

structures.

2.10.3 3DCRT and Monoisocentric Junctions

Traditionally all head and neck tumours that are treated with radiation therapy are

divided into two areas that are matched by one junction. The purpose of treating two

separate areas with one junction is to treat the primary tumour bed and draining

lymphatics while limiting the dose to normal structures (Fabrizio.P et al., 2000).

The two areas are the lower cervical field or supraclavicular field and the face fields or

upper neck fields. “In many instances, right and left lateral parallel opposed fields

matched to an anterior supraclavicular field are used to ensure coverage of the primary

and nodal sites” (Sohn.J et al., 1995, p809).

The technique used to match these fields with one junction, is called the

monoisocentric technique. Currently most centers use the monoisocentric technique

(Dabaja.B et al., 2005). This technique avoids the problem of beam divergence

because each beam is half-beam blocked to the central axis. At the junction there is a

non-divergent beam edge so that the match between the two fields is exact, with no

theoretical overlap (Dabaja.B et al., 2005). The half-beam block is created with

asymmetric jaws (Figure 15). The superior jaws will remain at zero or at the junction

while the inferior jaws treat the lower cervical fields. The inferior jaws will remain at

zero or at the junction region while the superior jaws treat the upper face fields. This

technique also reduces the possibility of geometric error when moving to a second

isocentre.

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Figure 15- The top two figures demonstrate the superior jaws treating the upper face fields while

the inferior jaws remain at the junction. The bottom two figures demonstrate the inferior jaws

treating the lower cervical nodes while the superior jaws remain at the junction (Manske.M et al.,

2004, p87).

2.10.4 3DCRT and Junction Limitations

3DCRT has limitations when more than one junction is required. Many treatment sites

need more than one junction. For example the treatment of lesions of the skin temple

region that have spread to the parotid gland or vice-versa.

Historically, this disease site would be treated with an anterior lower cervical photon

field or an anterior and posterior lower cervical photon field. The upper face fields are

treated with anterior and posterior oblique parotid photon fields. Both oblique fields

traditionally utilise tissue compensators called wedges, to improve dose homogeneity.

As a result, treating the upper face parotid area with obliques is often called the

ipsilateral wedged pair technique (Yaparpalvi.R et al., 1998). The area of skin on the

temple field is treated with one electron field.

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Traditionally the region requiring treatment is divided into three separate areas (Figure

16). The three areas are; 1= lower cervical field, 2= parotid photon field, 3= temple

field. Junction number one (Figure 16) is positioned between fields one and two.

Junction number two (Figure 16) is positioned between fields two and three.

Figure 16- Photo of thermoplastic shell showing three separate treatment areas. 1=lower cervical

field, 2=parotid photon field, 3=temple field (Photo courtesy of RBWH).

Junction 1 separates the lower cervical fields and the upper parotid photon fields to

ensure coverage of the primary disease and nodal sites. Junction 2 is situated between

an electron field and the parotid photon fields. The electron field is needed to treat the

temple region where the PTV is at a shallow depth. Electrons are able to deposit dose

at a more shallow depth then photons, while still maintaining full dose on skin surfaces

with the use of wax bolus.

Junction two, separating the parotid photon fields and the electron field introduces

problems. This junction is often located close to the lenses. The contralateral lens

often receives high dose from the diverging posterior oblique parotid photon field. The

43

ipsilateral lens often receives high dose from the temple electron field, depending on

the size and position of this field.

Homogenous dose at this photon-electron junction region is desirable but does not

occur. Inhomogenous dose between an abutting photon and electron field is a

characteristic when the two beam penumbras are added together, and is a major

limitation for treating this disease site with 3DCRT. Photon fields have a straight edge

penumbra while electron fields bow out in the penumbra region (Figure 17a&b).

“Because the electron and photon beams have different penumbras, matching of these

beams results in an inhomogeneous dose distribution in the junction region”

(Kemikler.G, 2006, p183).

Figure 17a- Photon isodose curve Figure 17b- Electron isodose curve

with straight edge penumbra bulging at penumbra.

(Washington.C and Leaver.D, 2004, p508). (Washington.C and Leaver.D, 2004, p532).

To treat this junction daily, on alternate days the electron field edge is matched to the

divergent edges of the oblique fields on skin (Figure 18a&b). Although electron and

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photon fields are matched on skin, they overlap at depths and spread out laterally with

increasing depth (Sun.C et al., 1998). Thus an area of underdosage and overdosage is

unavoidable because of beam divergence (Kemikler.G, 2006).

Figure 18a-Matching anterior oblique photon field to the electron field on skin (photo courtesy of

RBWH).

Figure 18b-Matching posterior oblique photon field to the electron field on skin (photo courtesy of

RBWH)

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The region of high dose will occur on the photon side of the junction because electrons

will bulge out into this region. Low dose will occur on the electron side of the junction

because photons do not bulge out into the electron field and only electron penumbra

dose will occur on this side of the junction. “A hot spot on the photon side and a cold

spot on the electron side were observed in film measurements” (Kemikler.G, 2006,

p186).

Inhomogeneity at the photon-electron junction (junction 2, Figure 16) is further

impacted by patient set-up errors and congruity of the light and radiation field. “A few

mm of mismatch could seriously cause over and under-dose at the junction region”

(Kemikler.G, 2006, p187). Thus set-up errors further enhance inhomogeneity at the

junction region.

There are two types of set-up errors, random and systematic. A systematic error is

where the same error occurs systematically, causing the junction to be misplaced each

fraction. A random error occurs randomly and may cause a blurring of the dose

distribution and could actually reduce the effect of the inhomogeneity in the junction

region. This research project did not attempt to assess treatment set-up errors. All

dosimetry was performed by the author thus any dosimetric systematic errors were

performed across the sample group. As a result, comparisons between the sample

plans account for any errors occurring. Random dosimetric errors could not be

accounted for in this research project

Inhomogeneity at the photon and electron junction region results in areas of high and

low dose coverage of the PTV. A low dose to the PTV is undesirable because it

increases the risk of tumour recurrence and a high dose increases the risk of normal

tissue morbidity (Zhu.L et al., 1998).

Carcinoma of the skin temple region that has spread to parotid gland or vice-versa is a

difficult area to treat with two separate junction regions using 3DCRT. Matching one

junction region can be achieved with monoisocentric jaws, but the second junction

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between the photon and electron field results in dose inhomogeneities across this

region that are further enhanced with set-up positional errors . 3DCRT has associated

limitations when treating this disease site.

2.10.5 IMRT Overcoming Junction Limitations

IMRT overcomes limitations of 3DCRT when considering two separate junction

regions. IMRT eliminates the need for a second junction between the parotid photon

field and the temple electron field. The temple electron and photon face fields are

treated as one IMRT photon field. Thus dose inhomogeneity across the photon-

electron junction, produced with 3DCRT is removed. As a result set-up uncertainties

will not enhance inhomogeneities in this region.

“One of the ways for overcoming this problem is to use the modulated beams, which

can yield improved dose homogeneity and are less sensitive to set-up errors”

(Kemikler.G, 2006, p187).

Only the temple and upper face regions can be treated with IMRT because IMRT is

only advantageous when the PTV is in close proximity to critical structures. The major

critical structure in the lower cervical photon field is the spinal cord, which is not in

close proximity to the PTV (Figure 19).

Figure 19- CT axial slice demonstrating the spinal cord as the only critical structure in the lower

cervical photon field. (CT axial slice courtesy of RBWH).

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Thus IMRT is does not offer advantages in the lower cervical fields. Li et al suggest

treating the whole field with IMRT “usually renders treatment plans suboptimal” (Li.J

et al., 2005, p135). An alternative solution is treating the parotid and temple regions

with IMRT and treating the lower cervical region with 3DCRT.

If only one junction exists between the parotid face field and the adjoining lower

cervical photon field, it can be easily treated using monoisocentric jaws, as discussed

in section 2.10.3 (Figure 15). This is still possible when each area is treated with a

different type of radiation therapy.

“IMRT head and neck patients can be effectively treated with the field-

matching technique where superior aspect of the target volume is treated with

IMRT, and the inferior portion of the target volume is treated with a static

anterior-posterior lower anterior neck field, with a common isocenter” (Li.J et

al., 2005, p138).

IMRT treatment can easily junction a cervical field if required. Thus IMRT is capable

of treating a region involving two separate junctions.

This research project is concerned with finding a class solution for skin lesions of the

temple region with spread to the parotid gland. It is acknowledged that treating the

lower cervical photon field is necessary, although no advantage is gained by treating

this region with IMRT, instead a standard 3DCRT field is used. Thus this project will

concentrate on determining a class solution for the parotid photon region and the

temple region.

2.11 Radiation Doses

3DCRT dose prescription for parotid gland tumours and skin lesions of the temple

region that have spread to the parotid gland, is typically a reference dose (RD) of 60

Gy in 30 fractions over 6 weeks (Nutting.C et al., 2001). The aim of treatment is to

treat the PTV to between 95% and 107% of the RD, as recommended in the

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International Commission on Radiation Units and Measurements Report (Bragg.C et

al., 2002).

An IMRT dose prescription of 60 Gy in 30 fractions over 6 weeks still applies for the

same disease site although aims of treatment differ from 3DCRT. “IMRT dose

distributions are often more heterogeneous within the target” (Galvin.J et al., 2004,

p1617). As a result IMRT research has used guidelines in Radiation therapy Oncology

Group (RTOG) protocol RTOG H-0022, to evaluate dose prescriptions and plans.

“The prescribed dose must cover 95% of the volume of the PTV of the gross

tumour. Not more than 1% of the PTV of the gross tumour can receive a dose

that is less than 93% of the prescribed dose, and not more than 20% of this PTV

can receive a dose that is greater than 110% of the prescribed dose”(Galvin.J et

al., 2004, p1627).

Historically, the radiation energy used to treat head and neck tumours for 3DCRT and

IMRT is 6 Mv photons. Traditional teaching in radiation therapy is, “the deeper the

target, the higher the energy that should be used” (Pirzkall.A et al., 2002, p434).

Pirzkall et al continue to suggest that, “the basic teaching regarding energy holds true

even for IMRT” (Pirzkall.A et al., 2002, p438). Head and neck tumours such as skin

lesions of the temple with extension to the parotid gland, are not deep seated targets, as

a result 6 Mv photon energy is sufficient.

2.12 Beam Arrangements

Beam arrangements for 3DCRT are different to beam arrangements used in IMRT.

2.12.1 Beam Arrangements Using 3DCRT

The optimal unilateral treatment technique for parotid tumours alone using 3DCRT are

the ipsilateral wedged-pair technique and the 3-field and the mixed electron-photon

beam technique (Yaparpalvi.R et al., 1998). As discussed in section 2.10.4, disease in

the skin temple region that has spread to the parotid gland is historically treated with an

49

anterior or anterior and posterior lower cervical photon fields junctioned to ipsilateral

wedged pair parotid photon fields that are junctioned with an electron temple field.

2.12.2 Beam Arrangements Using IMRT

IMRT is still in its infancy (Gregoire.V and Maingon.P, 2004), as a result there is

limited literature on beam arrangements for specific disease sites. “There has been

little investigation into the optimisation of beam–orientations for IMRT compared with

unmodulated beams” (Pugachev.A et al., 2000, p169).

A fundamental step for arranging beams in IMRT is determining the beam number and

angle. “Angle selection is usually based on the experience of the treatment planners or

their intuition or by a trial-and-error approach” (Wang.X et al., 2004, p1326). The

ultimate goal in radiotherapy is to choose the optimal plan that is provided by the

minimum number of beams (Pugachev.A et al., 2000). This enables quality treatment

to be delivered quickly and efficiently.

A small number of researchers have determined IMRT field arrangements for specific

head and neck tumours, although no IMRT literature is specific to the disease site

studied in this research. Researchers such as Bragg and Nutting et al are referenced

throughout this research project, although their work discusses disease of the parotid

alone, without temple involvement.

Three IMRT fields are the minimum justifiable beam number for an IMRT plan.

Bragg et al determined that three beams had the ability to deliver the required dose to

the target, but that it was considerably better in some patients than in others (Bragg.C

et al., 2002).

Researchers also suggest that the target homogeneity may be improved by directing

beams from the same side as the tumour. “Directing a higher proportion of the beams

used from the side ipsilateral to the tumour can reduce the target underdosing and

overdosing” (Bragg.C et al., 2002, p735).

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A study by Nutting et al determined four field ipsilateral IMRT beam angles,

positioned at 15°, 40°, 140° and 170° from vertical were the optimal IMRT beam

arrangement for parotid cancer patients (Nutting.C et al., 2001) (Figure 20). For the

same tumour type, Bragg et al determined four beams positioned on the ipsilateral

tumour side at 15°, 55°, 125°, 165° from vertical and a direct lateral from the opposing

side produced the optimal IMRT beam arrangement (Bragg.C et al., 2002).

Figure 20- optimal IMRT class solution for parotid carcinoma (Nutting.C et al., 2001, p170).

Researchers suggests that, “nine, equispaced IMRT fields are sufficient to produce an

‘optimal’ treatment plan” (Rowbottom.C et al., 2001, p169). Bragg et al also

suggested that a nine field IMRT plan showed the, “largest improvement over the

3DCRT plan in terms of target dose homogeneity, target underdosing and dose

conformity” (Bragg.C et al., 2002, p734).

A beam arrangement that promotes PTV homogeneity and dose improvements is based

on a nine field equispaced beam arrangement with the removal of beams at 80° and

280° that enter and exit the parotid. This field arrangement was suggested by literature

researchers who determined that it maintained improvements seen in the nine field plan,

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51

namely the improved PTV homogeneity and reduced cochlea and parotid gland dose

(Rowbottom.C et al., 2001).

2.13 Class Solutions and Benefits

Much research has been conducted into the optimal IMRT treatment for specific head

and neck carcinomas. They are identified as class solutions and are specific to

individual departments. Some centers have followed class solution protocols for a

number of years and show promising results. For example The Ghent University

Hospital has developed a class solution for ethmoid sinus cancer. The class solution

utilises a high tumour dose that may increase survival rates (Claus.F et al., 2001).

Class solutions for individual tumour sites are developed to produce the optimal

treatment plan with ease.

“A class solution can be defined as the historical experience in designing RT

plans for a particular site …An IMRT class solution for a given treatment site

and stage of disease consists of the criteria for optimisation and the

specification of the beam techniques used, typically including beam direction

and number. Once developed, a class solution may be applied repeatedly to

generate IMRT plans for patients with the same stage of disease at the same site

and for other clinical considerations” (Intensity Modulated Radiation Therapy

Collaborative Working, 2001, p913).

Skin lesions of the temple region with extensions to the parotid gland, is a site that may

benefit from IMRT treatment. To date, no class solution exists for this disease site.

This research project aims to develop the optimal class solution specifically relating to

beam number and angles for this disease.

2.14 Summary

3DCRT is a treatment option for skin lesions of the temple region with spread to the

parotid gland. This treatment has associated limitations that may be overcome with

52

new treatment technologies. IMRT is a relatively new treatment technique that may

overcome limitations introduced with current treatment techniques.

This research proposal is an original and innovative study that will endeavour to

determine the optimal IMRT class solution for patients with skin lesions of the temple

region with spread to the parotid gland. It will be determined if the IMRT class

solution avoids problems of the junction region and lowers dose to critical structures.

Traditional 3DCRT will be assessed and compared to the IMRT class solution to

determine the superior treatment option for patients presenting with this disease site.

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CHAPTER 3

METHOD AND MATERIALS

3.1 Sample Group

In this retrospective research study, nine patient computerised tomography (CT) data

sets were used. The pre-requisite for inclusion of a CT data set was based on three

areas requiring treatment with three dimensional conformal radiation therapy (3DCRT),

resulting in two junction regions (Figure 16). The three areas requiring treatment are

the:

1. Lower cervical photon fields

2. Parotid photon fields

3. Electron field to the temple region

The junction regions can be easily visualised between fields one and two and between

fields two and three, as detailed in Figure 16.

The CT data sets that fulfilled pre-requisites were randomly chosen from the CT data

base at the Royal Brisbane and Women’s Hospital (RBWH). Six of the CT data sets

had left sided lesions and three CT data sets had right sided lesions. Not all of the CT

data sets had the same primary disease but all had the three areas requiring treatment.

Details of primary lesions are shown in Table 4.

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Table 4- Table illustrating disease primary and classification of patient data used in this project.

(Information courtesy of RBWH)

Patient Number

Disease Primary

TNM Classification

1

SCC parotid gland

T1N1M0

2 SCC temple region

T3N1M0

3 SCC temple region

T2N1M0

4 SCC temple region

T2N1M1

5

SCC temple region

T1N1M0

6 BCC temple region

T1N0M0

7 SCC temple region

T3N0M0

8 SCC temple region

T1N0M0

9 SCC temple region

T3N0M0

All Case studies in this research project, followed protocol of RBWH. All patients

presenting at the RBWH with skin lesions of the temple region with spread to the

parotid gland, are discussed amongst radiation oncologists. Doctors converse to

determine the optimal treatment regime for each individual patient. All patients

studied in this sample group underwent surgery combined with post-operative radiation

therapy.

3.2 Personnel

The author performed all dosimetric planning for this project. Radiation oncologists,

Dr Lyndall Kelly and Dr Liz Kenny from the RBWH were consulted in their areas of

clinical expertise.

Areas of clinical expertise for the Radiation Oncologists related to;

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• Determining the superior dosimetric plan

• Determining the dose prescription used in this research project

• Determining critical structures and the required tolerances of structures

• Listing of critical structures in order of importance

3.3 Equipment

Shell stabilisation devices were used to position the patient. The patients used in this

study were stabilised with either a vacuum formed four point shell (Figure 21) or a

thermoplastic four point shell (Figure 22a, 22b). The fact that different stabilisation

devices were used is acknowledged, although has minimal effect on achieving aims of

the study or the final outcome.

Figure 21- vacuum seal four point shell (photo courtesy of RBWH)

Figure 22a-lateral view of thermoplastic Figure 22b- Anterior view of thermoplastic Shell (photo courtesy of RBWH) shell (photo courtesy of RBWH)

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All patients were CT scanned on a “Siemens Somatom Sensation IV Scanner” (Figure

23). This is a four slice spiral CT scanner with a seventy centimetre aperture (Siemens,

2002).

Figure 23- Siemens Somatom Sensation IV Scanner (Photo courtesy of RBWH)

The “General Electric Medical Systems Advantage Sim 4.1” (Adv Sim) was used to

define the planning target volume (PTV) on each data set. Adv Sim is a computer

system that allows visualisation of CT axial slices and enables volumes or structures to

be drawn onto them.

“Nucletron PLATO Radiation Therapy Planning Software RTS V2.3.1” (PLATO) was

used to perform all three dimensional conformal dosimetric planning. PLATO is a

radiation therapy computer planning system.

Intensity Modulated Radiation Therapy (IMRT) computer planning software was

required for this research project. Nucletron Pty Limited agreed to supply software

free of charge for a period of 90 days (Appendix A). “Nucletron PLATO Lightning

Inverse Treatment Planning V” (ITP) was the software provided and used to perform

all IMRT plans.

57

The “Digital Imaging Communication in Medicine” (DICOM 3) was used to transport

anatomical images between different computer workstations.

All equipment used in this study was provided courtesy of the RBWH.

3.4 Data Collection Procedure

All patients in this research study presented for radiation therapy after undergoing

surgery. A time-period between surgery and radiation treatment exists and is

determined by the radiation oncologist. Data collection procedure followed the

standard RBWH protocol which involves a number of steps including;

• Patient positioning

• CT scanning

• Planning target volume (PTV) acquisition

• Dose prescribing

• Plan dosimetry

3.4.1 Patient Positioning

For radiation therapy, patients were positioned supine, and straight and level. They

were immobilised and stabilised with a shell discussed in section 3.3. The radiation

oncologist determined junction 1 (Figure 16) between the lower cervical photon

region and the upper parotid face region. This line was marked onto the shell with

wire.

3.4.2 Computerised Tomography (CT) Scanning Procedure

Patients were CT scanned in their shell using a Siemens Somatom Sensation IV

scanner.

Standard CT protocol scan parameters were used, which are 120 kV and 350 mAs.

mAs varies for each patient according to size of the area scanned. A CT data set is

reconstructed at 3 mm increments with a slice width of 3 mm. The data set is then

exported via DICOM 3 to Adv Sim.

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3.4.3 Planning Target Volume (PTV) Acquisition

The PTV is drawn onto axial slices by the radiation oncologist. The CT data set

complete with PTVs, is exported via DICOM 3 to PLATO computer planning software.

3.4.4 Dose Prescribing

A radiation oncologist* determined a dose prescription of 63 Gy reference dose (RD)

in 30 fractions over 6 weeks, using 6 Megavoltage (Mv) photons and 60 Gy at 100% in

30 fractions for the electron temple region. The depth of 100% was specified by the

electron energy chosen by the radiation oncologist for each CT data set. Figure 24

demonstrates a standard dose prescription used in this study.

Figure 24- Figure demonstrating standard dose prescription used at the RBWH- image courtesy of

RBWH.

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3.5 Plan Dosimetry

For all 3DCRT plans, ICRU Report 50 guidelines were followed to determine an

optimal distribution. 95% of the reference dose was delivered to the PTV while aiming

to keep maximum doses within 107% (ICRU, 1993). Thus 60 Gy was to cover the

PTV without doses exceeding 67.4 Gy.

For all IMRT plans, the Radiation Therapy Oncology Group (RTOG) protocol RTOG

H-0022 was used, to evaluate dose prescriptions and plans. RTOG requirements are;

1) The prescribed dose must cover 95% of the volume of the PTV

2) Not more than 1% of the PTV of the gross tumour can receive a dose that is

less than 93% of the prescribed dose

3) Not more than 20% of this PTV can receive a dose that is greater than 110% of

the prescribed dose (Galvin.J et al., 2004)

The only deviation made from RTOG requirements, was that 95% of the prescribed

dose was to cover 95% of the volume of the PTV. Thus, in every plan, 60 Gy was to

cover 95% of the PTV volume. It was difficult to achieve all three objectives with

each beam arrangement. In order to achieve 1), a compromise was often made

between RTOG requirements: 2) and 3).

In this study, the prescribed dose for 3DCRT and IMRT were the same. Dosimetry

objectives varied slightly for IMRT plans but this does not affect comparisons between

the two techniques.

Nine dosimetric plans were produced on each CT data set, resulting in a total of eighty-

one isodosed distributions. The time taken to perform one IMRT plan varied between

twenty minutes to two hours depending on the geometry of the PTV and associated

structures. The time taken to perform one 3DCRT plan was approximately thirty

minutes.

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Superior and inferior field lengths of the oblique parotid photon fields for 3DCRT

planning were determined by the radiation oncologist. The anterior and posterior field

sizes of the oblique fields were 0.7 cm outside the PTV. Manipulation of beam angles,

weightings, wedges, multileaf collimators were performed to achieve an optimal

3DCRT plan. Planning experience aided manipulation choices and thus optimisation.

Field sizes for IMRT plans were determined by the computer planning system.

Manipulation of weightings, maximum and minimum doses for the PTV and body

were done to achieve the optimal IMRT plan for each beam arrangement. A trial and

error approach was the strategy used to optimise the IMRT plans.

3.6 Critical Structures

A radiation oncologist* determined critical structures or organs at risk (OAR),

tolerance doses and order of structure importance (Table 5). These were directly used

in the IMRT planning process.

Table 5: Critical structures, tolerance and order of importance as determined by radiation

oncologist.

ORGANS AT RISK MAXIMUM

TOLERANCE (Gy) ORDER OF IMPORTANCE Brain 53 3 Brainstem 45 1 Contra lateral parotid gland 10 7 External auditory meatis (eam) 55 6 contralateral lens 8 9 ipsilateral lens 8 9 contralateral optic nerve/retina 45 4 ipsilateral optic nerve/retina 45 4 Mandible 50 10 Optic chiasm 50 5 Oral cavity 20 8 Spinal cord 45 2

3.6.1 Outlining Critical Structures

Patient anatomy within CT data sets, were outlined using the contouring component of

the PLATO 3DCRT computer planning system. Outlining was performed by the same

61

person for 3DCRT and IMRT to eliminate inter-observer variability. All critical

structures detailed in table 5 were outlined. Anatomical visualisation of critical

structures on CT scans, are detailed in section 2.7.2.

For 3DCRT plans, patient’s bodies were outlined without the inclusion of bolus. To

obtain coverage of the PTV by 95% of the reference dose, different thickness bolus

was required on the skin surface for the parotid photon fields and the temple electron

field. Limitations of the PLATO planning system required different thicknesses of

bolus to be added in PLATO 3D Planning.

For IMRT plans, a constant thickness of bolus was required over the parotid fields to

cover the PTV by 95% of the reference dose. As a result bolus was added at the

outlining stage and not in PLATO planning.

To accommodate different bolus requirements for 3DCRT and IMRT plans, CT data

sets of each patient were outlined twice. To ensure critical structures were not outlined

differently for each set, statistical analysis was performed on structure volumes. Visual

analysis was also undertaken to ensure the correct spatial position.

3.7 Beam Arrangements

Beam arrangements were different for 3DCRT and IMRT. 3DCRT beam

arrangements were consistently similar for all CT data sets.

3.7.1 3DCRT Beam Arrangements

One 3DCRT plan was produced for each CT data set. The lower cervical region was

treated with an anterior or an anterior and posterior photon field. The parotid face

region was treated with the wedged pair technique. Lateral electron fields were added

to the temple region, where the PTV is shallow and close to the skin surface.

For the wedged pair technique, beam angles were dependent on PTV position and the

relation of critical structures. Wedges were used to provide a more homogenous

62

distribution; on the anterior oblique field-wedge was thick to post, on the posterior

field-wedge was thick to anterior (Figure 25).

Figure 25- Figure showing wedge direction of the anterior and posterior oblique fields. (Nutting.C

et al., 2001, p164).

As indicated in section 2.10.4, when treating this disease with 3DCRT, the temple

electron field is matched on the skin to the divergent edges of the anterior oblique and

posterior oblique photon fields on alternate days. At the RBWH, 3DCRT dosimetry is

performed by matching the temple electron field on skin at the point where the

divergent edges of the anterior and posterior oblique photon fields cross one another

(Figure 26). This technique does not replicate how this disease site is treated.

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63

Figure 26- Figure demonstrating the temple electron field matching on skin at the point where the

divergent edges of the oblique photon fields cross one another (photo courtesy of the RBWH).

3DCRT dosimetry is performed this way for two reasons. Firstly, it reduces the chance

of error when matching the divergent edge of the photon fields to the electron field in

the 3DCRT computer plan. A small misalignment error may result in an overestimate

of under and overdosage. “A few mm of mismatch could seriously cause over and

under dose to the junction region” (Kemikler.G, 2006, p187). The second reason is for

improved time efficiency in completing the 3DCRT plan.

The divergence of the anterior and posterior oblique photon fields is considered to be

minimal. As a result there is potentially no clinical difference in using this method

versus exactly replicating the matching technique used during treatment. For this

research study, 3DCRT planning was performed following RBWH clinical dosimetry

technique after clinical testing.

64

In order to test dosimetry of the two matching techniques, a 3DCRT plan was

performed using each technique. The minimum, maximum and mean dose to the PTV,

and the dose covering 95% of the PTV in each plan was obtained from DVH output

data. Doses were compared to determine if differences in doses were clinically

significant.

3.7.2 IMRT Beam Arrangements

IMRT beam arrangements varied, and were determined from literature research

detailed in section 2.12.2. In this research project, three IMRT plans used ipsilateral

beams, directed from the same side as the tumour.

Two of the five field beam arrangements were not all directed from the ipsilateral side

of the tumour. One had four beams positioned on the ipsilateral tumour side at 15°,

55°, 125°, 165° and a direct lateral from the opposing side (Figure 27). This beam

arrangement was chosen because Bragg et al determined it to be the IMRT class

solution that produces the optimal beam arrangement for parotid tumours (Bragg.C et

al., 2002).

The other five field beam arrangement uses 2 contralateral beams and 3 ipsilateral

beams (Figure 27). This beam arrangement was used to determine whether there is any

advantage of a five field beam arrangement not being equally spaced.

One seven field and nine field equispaced beam arrangement was chosen based on

research by Rowbottom et al (section 2.12.2). A seven field equispaced beam

arrangement was chosen to see if the advantages of a nine field equispaced beam

arrangement could be maintained with seven fields.

On each patient data set, eight IMRT plans were performed (Table 6) (Figure 27).

IMRT plans for each beam arrangement were considered to be optimised when RTOG

guidelines were adhered to as close as possible.

65

Table 6: Beam arrangement used on each CT data set

BEAM ARRANGEMENT BEAM ANGLE(°)-RT SIDED LESION

BEAM ANGLE(°)-LT SIDED LESION

9 beam equispaced 40,80,120,160,200,240,280,320,360 40,80,120,160,200,240,280,320,360 7 beam equispaced 51,102,153,204,255,300,0 51,102,153,204,255,300,0 7 beam 40,120,160,200,240,300,0 40,120,160,200,240,300,0 5 beam ipsilateral 330,300,240,210,270 30,60,90,120,150 5 beam (3ipsilateral+2 beams) 315,270,225,135,45 45,90,135,320,220 5 beam (4equispaced +1 beam) 345,305,90,235,195 15,55,125,165,270 4 beam ipsilateral 345,320,220,190 15,40,140,170 3 beam ipsilateral 315,270,225 45,90,135 3DCRT plan As required As required

Figure 27-Diagrammatic representation of IMRT beam angles for left sided lesion (not drawn to scale):

ant rt lt post

3.8 Dose Volume Histograms

Cumulative dose volume histograms (DVH) of 100 000 points were used to determine

end points and display a summary output of final plans (Figure 28). DVH analysis was

used in statistical analysis.

9 beam equispaced

7 beam equispaced

7 beam 5 beam (3ipsilateral+2)

4 beam ipsilateral 3 beam ipsilateral 5 beam ipsilateral 5 beam (4equispaced+1)

66

Figure 28-Figure displaying a 3DCRT dose volume histogram and summary output

3.9 Ethics Approval-RBWH/QUT

Ethics approval was sought from the RBWH and Health Service Districts- Human

Resource Ethics Committee, to perform dose distribution investigations on RBWH CT

data sets. The protocol followed to seek ethics approval was subsequently granted by

Professor W Egerton (Appendix B). Following ethics approval from the RBWH, the

Human Ethics Research Committee of the Queensland University of Technology

(QUT) stated that ethical issues were uncompromised, as a result this research project

did not require formal ethics approval from this institution (Appendix C).

67

3.10 Analysis of Results

3.10.1 Bland and Altman

A Bland and Altman plot was performed on all structure volumes. A Bland and

Altman test determined any significant difference between outlining CT data sets twice

for each patient in order to account for bolus. The bias or mean difference was

established and graphed. Limits of agreement (LOA) are equivalent to ± two standard

deviations about the mean. LOA were calculated for each volume and visualised on a

Bland and Altman plot.

3.10.2 DVH Range Analysis on PTV

Analysis was performed on the DVH range for the PTV. Research by Nutting et al in

2001, defined the;

• Minimum PTV= dose received by ≥99% of the PTV

• Maximum PTV= dose received by ≤1% of the PTV

(Nutting.C et al., 2001).

This research project defines the range as the minimum PTV subtracted from the

maximum PTV. The range indicates how well the dosimetric plan fulfilled the PTV

dose prescription within RTOG and ICRU guidelines. The smaller this range, the

better the plan was at covering the PTV and the better the plan was at avoiding

underdosing and overdosing of the PTV.

Repeated measures analysis of variance (ANOVA) was performed on the mean range

of data for all IMRT plans, to determine if significance existed between at least two of

the means when p<0.05.

3.10.3 Mean doses

Mean maximum doses to critical structures and mean dose to the parotid gland were

calculated from summary outputs of all dosimetric plans.

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3.10.4 Conformity Index (CI)

Conformity index analysis was performed on all plans to determine how tightly the

95% isodose line conformed to the PTV. The CI was calculated using the equation:

CI=VPTV95% × VPTV95%

VPTV Vt

(Bragg.C et al., 2002a)

VPTV95%=Volume of Planning Target Volume receiving 95% of reference dose

Vptv=Volume of Planning Target Volume

Vt=Volume of tissue receiving 95% of reference dose

A CI of 1.0, represents the ideal, “in which the PTV coincides exactly with the treated

volume. A CI of 0 represents a plan in which there is no overlap between the two

volumes” (Bragg.C et al., 2002, p732). In clinical cases, it is rare for the ideal to occur.

For example a plan with a CI of 0.7 is considered to be a plan where the 95% isodose

line conforms well to the PTV (Bragg.C et al., 2002).

3.10.5 Statistical Analysis

Statistical analysis was performed on CI data, mean maximum doses to critical

structures and mean dose to the parotid gland using SPSS for windows version 12.0.1.

Repeated measures ANOVA was used to determine whether there was a statistical

difference between at least two of the;

• mean CI data for all beam arrangements.

• mean maximum doses to all critical structures

• mean parotid doses

If repeated measures ANOVA determined a statistically significant difference between

at least two of the IMRT beam arrangements, further analysis was performed. A

69

“Tukey honestly significant difference” (HSD) test was used to determine which IMRT

beam arrangements were significantly different.

In order to perform the HSD test all results were grouped from lowest value to highest

value. The highest value was statistically compared with the lowest value and then the

2nd lowest value and continued through all results. Next the 2nd highest value was

statistically compared with the lowest value and the 2nd lowest value and continued

through the list. This method of comparisons resulted in the least number of

calculations needed to derive a number of results.

For all results a table was produced listing beam arrangements from worst through to

best to aid in identifying beam arrangements producing the; highest CI, the lowest

mean maximum critical structure dose and the lowest mean contra-lateral parotid dose.

This data was used to determine the preferred IMRT beam arrangement for treating

skin tumours of the temple region that had spread to the parotid gland.

The two best IMRT beam arrangements determined by statistical analysis were shown

by DVH representation to a radiation oncologist at the RBWH. Dr Liz Kenny

determined the best clinical IMRT beam arrangement based on her expert opinion.

This IMRT plan was then compared with the optimised 3DCRT plan.

Comparison of the optimised 3DCRT with the best IMRT beam arrangement plan was

compared for each patient, using the “Students Paired T-test”. The statistical software

package that was used in the analysis was Microsoft excel.

*=Dr Lyndall Kelly

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CHAPTER 4

RESULTS

4.1 Computerised Tomography (CT) Data

On each CT data set eight IMRT plans and one 3DCRT plan were performed. Detailed

in Table 7 is the beam arrangement number assigned to each beam arrangement. See

section 3.7.2 for details of beam arrangements.

Table 7- Table showing beam arrangement number associated with beam arrangement

BEAM ARRANGEMENT BEAM ARRANGEMENT

NUMBER 9 beam equispaced 1

7 beam equispaced 2 7 beam 3 5 beam ipsilateral 4

5 beam (3ipsilateral +2) 5

5 beam (4equispaced +1) 6 4 beam ipsilateral 7 3 beam ipsilateral 8

3D plan 9

4.2 Volume Structure Analysis 4.2.1 Structure Volumes

Structure volumes were outlined twice for each patient, once for the IMRT plan and

once for the 3DCRT plan as explained in section 3.6.1. Volume data for critical

structures were obtained from DVH associated output. An example is provided in

Table 8. Visual analysis of structure outlining was also performed to ensure that the

critical structure was outlined in the same spatial position on the CT axial slices. All

critical structures were outlined in the same position on both CT data sets.

71

Table 8-Table comparing structure volumes for one CT data set STRUCTURE IMRT VOLUME (cc) 3DCRT VOLUME (cc) Body 5889.7 5362.1 Brain 1249.9 1231.1 Brainstem 8.9 10.6 Eam 0.4 0.2 Ipsilateral lens 0.4 0.4 Ipsilateral retina/optic nerve 4.9 2.8 Mandible 44.2 41.3 Optic chiasm 0.8 1.3 Oral cavity 28 31 Parotid 16.4 17.2 Ptv 182.5 165.5 Contralateral lens 0.5 0.4 Contralateral retina/optic nerve 4 2.5 Spinal cord 11.2 9

4.2.2 Bland and Altman Analysis

Bland and Altman analysis was performed on IMRT and 3DCRT volumes for all

structure volumes in each data set. Table 9 is an example of the data for the body

structure.

Table 9- Body structure volume data

PATIENT CT DATA SET IMRT VOL(cc) 3D VOL(cc)

MEAN VOL(cc)

DIFF(cc) (IMRT-3D)

A 5889.7 5362.1 5625.9 527.6 B 7118.2 6872.3 6995.25 245.9 C 10879.5 10644.6 10762.05 234.9 D 9141.8 8365.8 8753.8 776 E 11819.1 11210 11514.55 609.1 F 7005 6612.2 6808.6 392.8 G 7794.8 7644.3 7719.55 150.5 H 12706.5 12658 12682.25 48.5 I 6978.9 6726.1 6852.5 252.8

Data for structure volumes were graphed on a Bland and Altman plot. A Bland and

Altman plot makes it easy to visualise limits of agreement (LOA) of the IMRT and

3DCRT structure volumes.

72

In the Bland and Altman analysis, the calculated mean difference is the bias. LOA are

defined as ± two standard deviations of the differences about the bias. Thus for the

body volume, LOA were ± 471.9 about 359.8.

Graphed below (Figure 29) is an example of a Bland and Altman plot for body

volumes. On the graphs below, yellow and orange lines represent the LOA. A pink

line represents the bias. This plot visually demonstrates LOA about the mean in order

to determine if LOA are clinically acceptable. Bland and Altman plots were performed

on all volume structures and LOA were determined to be clinical acceptable for

structures.

A clinically acceptable variation in structure volumes was determined when the

magnitude of the LOA was small. A small variation in structure volume would not

alter the planning process or outcome. LOA were considered clinically acceptable for

all structures except the body volume. For example the LOA for body structure were

±471.9 about the mean, compared with LOA of the spinal cord which was ±9.6 about

the mean. It is acknowledged that the body volume was the largest structure volume

outlined and produced the greatest variation. The magnitude of the body LOA

indicates that a variation in outlining body structures occurred between the two CT

data sets.

Figure 29- Bland and Altman plot of body structure volumes.

Bland and Altman Plot of Body Volume

-500

-100

300

700

5000 8000 11000

Mean Body Volume (cc)

Bod

y V

olum

e D

iffer

ence

(cc)

Data

LowerLOA

Mean

UpperLOA

73

Visual analysis of structure outlining was also performed to ensure that the critical

structure was outlined in the same spatial position on the CT axial slices. All critical

structures were outlined in the same position on both CT data sets.

4.3 3DCRT Dosimetry

As discussed in section 3.7.1, 3DCRT dosimetry of the two matching techniques was

performed, producing plans A&B.

• Plan A=electron field matching divergent edges of oblique photon fields where

they cross on skin.

• Plan B=electron field matching the divergent edges of the oblique photon fields

on skin, on alternate days.

The minimum, maximum and mean dose to the PTV, and the dose covering 95% of the

PTV in each plan were obtained from DVH output data (Table 10).

Table 10- Doses from 3DCRT plans with different photon-electron junction matching techniques.

Plan A=electron field matching divergent edges of oblique photon fields where they cross on skin.

Plan B=electron field matching the divergent edges of the oblique photon fields on skin, on

alternate days.

Plan A is the junction matching technique that was used in this research study. There

was no difference between the two plan techniques for minimum dose and 95%

coverage dose. The small difference in maximum dose is minimal and considered

clinically insignificant. The difference of greater than 1 Gy in the mean dose, is of

clinical relevance but does not indicate that over and underdosing of the PTV in the

photon-electron junction region is minimised by performing dosimetry as in Plan B.

Plan A Plan B

Minimum dose (Gy) 21.50 21.50

Maximum dose (Gy) 69.64 69.94

Mean dose (Gy) 60.34 61.48

95% Dose coverage (Gy) 45.00 45.00

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As a result, for this research study it is assumed that performing dosimetry as per

standard RBWH clinical practice is justified.

4.4 Conformity Index (CI)

CI was calculated for every plan using the equation demonstrated in section 3.10.4.

Values substituted into the equation were obtained from DVH’s associated with the

dose distributions. The mean CI for each beam arrangement is demonstrated in Figure

30. The closer the CI is to 1.0, the more conformal 95% of the reference dose is to the

PTV.

Figure 30-Graph of CI for each beam arrangement

0

0.2

0.4

0.6

Mean CI

1 2 3 4 5 6 7 8 9

Beam arrangement number (refer Table 7)

Graph of Mean CI vs Beam Arrangement Number

Mean CI

4.4.1 Repeated Measure ANOVA on CI

Repeated measures ANOVA was performed on CI results for the IMRT beam

arrangements. A level of significance of 0.05 was used in determining that a

significant difference existed between at least two of the means. A post hoc “Tukey

Honestly Significant Difference” (HSD) test determined which of the beam

arrangements were significantly different.

Figure 31 demonstrates results in order from the lowest CI to the highest CI. Results

show that the CI for beam arrangements-5 and 8 are significantly lower than all other

beam arrangements except for beam arrangement-4 and each other (p<0.05). Beam

75

arrangement-4 was significantly different to the beam arrangements with the four

highest CI values. Beam arrangement-7 was significantly different to beam

arrangement-6 (p<0.05).

Figure 31-Graph of Mean CI vs beam arrangement number. Indicates beam arrangements-

8&5 were significantly different to all beam arrangements except beam arrangement-4 and each

other. Beam arrangement-4 was significantly different to the beam arrangements with the 4

highest CI values. Beam arrangement-7 was significantly different to beam arrangement-6.

0

0.2

0.4

0.6

Mean CI

8 5 4 7 1 6 3 2


Graph of Mean CI Vs Beam arrangement

8

5

4

7

1

6

3

2

Figures 32a and 32b, demonstrate CI as a distribution. The isodose distributions are in

cGy per fraction. For example, the reference dose is 63 Gy in 30 fractions, which is

equivalent to 210 cGy per fraction. Thus the daily 95% isodose line that must conform

to the PTV is 200 cGy. The figures demonstrate how beam arrangement-3 is more

conformal than beam arrangement-8.

76

Figure 32a- Beam arrangement-3 demonstrating PTV conformity

Figure 32b- Beam arrangement 8 demonstrating PTV conformity distribution

4.5 DVH Range Analysis of the PTV

Similar to statistical analysis of the CI, repeated measures ANOVA was performed on

mean DVH PTV range data, for IMRT beam arrangements. A level of significance of

77

0.05 was used to determine that a significant difference existed between at least two of

the DVH PTV ranges. A post hoc Tukey HSD test was used to determine which beam

arrangements were significantly different (Figure 33).

Figure 33- Graph of mean DVH PTV range vs beam arrangement number. Indicates that beam

arrangement-4 and 8 were significantly different to the four beam arrangements with the lowest

PTV DVH ranges. No significant difference existed between other beam arrangements.

0

10

20

30

Mea

n P

TV

DV

H

(Gy)

3 2 1 6 5 7 4 8


Graph of Mean PTV DVH Range Vs Beam Arrangement Num ber

3 2 1 6 5 7 4 8

4.6 Mean Doses

Mean dose to the contralateral parotid gland and mean maximum doses to all other

critical structures were obtained from DVH associated data. Repeated measures

ANOVA were performed on all doses for all IMRT beam arrangements. Table 11

demonstrates a summary of all results.

78

Table 11- Table showing the results of repeated measures ANOVA.

Structure

Significant difference

P-value

Parotid Yes <0.001 Body No 0.251

Mandible No 0.356 Brain Yes <0.001

Brainstem Yes <0.001 Ipsilateral Lens Yes <0.02

Contralateral Lens Yes 0.001 Ipsilateral

Retina/optic Nerve Yes <0.001 Contralateral

Retina/optic nerve Yes <0.001 Optic Chiasm Yes <0.001 Oral Cavity Yes <0.001 Spinal Cord Yes <0.001

For each structure showing significant difference between at least two of the means,

bar graphs were constructed to visually assess and assist in identifying which beam

arrangements were significantly different to one another (Figures 34-44). On the x-

axis of all graphs, beam arrangement number is visualised from those producing the

highest dose to the lowest dose.

For all structures that showed significant difference, a Tukey HSD test was performed

to determine which particular beam arrangements produced a significantly different

mean dose for the contralateral parotid gland or mean maximum dose for all other

structures. Detailed with figures 34-44 below, are results of the Tukey HSD test for all

critical structures.

79

4.6.1 Mean Contralateral Parotid Gland Dose

Figure 34-Graph showing mean contralateral parotid dose delivered by each IMRT beam

arrangement. Significant difference exists between beam arrangement-7 & 3 and all other

beam arrangements.

0

400

800

1200

Mea

n co

ntal

ater

al

paro

tid d

ose

(cG

y)

8 5 4 6 2 1 3 7


Graph of Mean Contralateral Parotid Dose Vs Beam Arrangement Number

8 5 4 6 2 1 3 7

4.6.2 Mean Maximum Brain Dose

Figure 35- Graph of mean maximum brain dose from IMRT beam arrangements. Beam

arrangements-5 and 7 respectively are significantly different to all others except their closest

counterparts . Beam arrangement-8 is significantly higher than all except beam arrangements-

4&1. Beam arrangement-6 is significantly lower then 4, 5 &8.

0

2000

4000

6000

Mea

n m

ax b

rain

dos

e (c

Gy)

5 8 4 1 2 3 6 7


Graph of Mean Maximum Brain Dose vs Beam Arrangement Number

5 8 4 1 2 3 6 7

80

4.6.3 Mean Maximum Brainstem Dose

Figure 36- Graph showing maximum doses to brainstem volume for all IMRT beam

arrangements. Beam arrangement-7 is significantly lower than all other beam arrangements.

Beam arrangement-5 is significantly higher than all others except 8&4. Beam arrangement-6 is

significantly lower to doses higher than beam arrangement-2. Beam arrangement-3 is

significantly different to doses higher than beam arrangement 4.

0

1000

2000

3000

4000

5000

Mea

n m

ax b

rain

stem

dose

(cG

y)

5 8 4 2 1 3 6 7


Graph of Mean Max Brainstem Dose vs Beam Arrangemen t Number

5 8 4 2 1 3 6 7

4.6.4 Mean Maximum External Auditory Meatus (eam) Dose

Figure 37- Graph showing mean maximum doses to eam volume for IMRT beam arrangements.

Beam arrangement-7 is significantly different to all other beam arrangements except beam

arrangement-3. Beam arrangement-3 is significantly different to all beam arrangements except

beam arrangement-5&7. Beam arrangement-2 is significantly different to all except beam

arrangement-6. Beam arrangement-6 is significantly different to beam arrangement-2&5.

0.00

500.00

1000.00

1500.00

2000.00

2500.00

Mea

m m

ax e

am d

ose

(cG

y)

2 6 1 8 4 5 3 7Beam arrangement number (refer Table 7)

Graph of Mean Maximum Eam Dose vs Beam Arrangement Number

2 6 1 8 4 5 3 7

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4.6.5 Mean Maximum Ipsilateral Lens Dose

Figure 38- Graph showing mean maximum doses to ipsilateral lens volume for all IMRT beam

arrangements. Beam arrangement-5 & 7 are significantly different to each other, but no other

beam arrangements are significantly different.

0

500

1000

1500

2000

Mea

n m

axim

um

lens

dos

e (c

Gy)

5 4 3 2 8 1 6 7


Graph of Mean Maximum Ipsilateral Lens Dose Vs Beam Arrangement Number

5 4 3 2 8 1 6 7

4.6.6 Mean Maximum Contralateral Lens Dose

Figure 39- Graph showing maximum doses to contralateral lens volume for all IMRT beam

arrangements. Beam arrangement-7 produces a significantly lower dose then all other beam

arrangements.

0

500

1000

1500

Mea

n m

ax c

onra

late

ral

lens

dos

e (c

Gy)

4 1 8 2 5 6 3 7


Graph of Mean Maximum Contralateral Lens Dose vs Beam Arrangement Number

4 1 8 2 5 6 3 7

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4.6.7 Mean Maximum Ipsilateral Retina/Optic Nerve Dose

Figure 40- Graph showing maximum doses to ipsilateral retina/optic nerve volume for all IMRT

beam arrangements. Beam arrangement-7 produces a significantly lower dose to all others

except beam arrangement-6. Beam arrangements-5 produces a significantly higher dose to all

beam arrangements with a dose less than beam arrangement-1. Beam arrangements-8

produces a significantly higher dose to all beam arrangements with a dose less than beam

arrangement-2. Beam arrangements-4 produces a significantly higher dose to all beam

arrangements with a dose less than beam arrangement-3.

0

1000

2000

3000

4000

5000

Mea

n m

ax

ipsi

late

ral

retin

a/op

tic n

erve

do

se (c

Gy)

5 8 4 1 2 3 6 7


Graph of Mean Maximum Ipsilateral Retina/optic Nerv e Dose vs Beam Arrangement Number

5 8 4 1 2 3 6 7

4.6.8 Mean Maximum Contralateral Retina/Optic Nerve Dose

Figure 41- Graph showing maximum doses to contralateral retina/optic nerve volume for all

IMRT beam arrangements. Beam arrangement-7 is significantly lower than all other beam

arrangements except beam arrangement-3. Beam arrangement-3 is significantly different to all

other beam arrangements except its closest counterparts.

0

1000

2000

3000

Mea

n m

ax

cont

rala

tera

l

retin

a/op

tic n

erve

dose

(cG

y)

6 8 1 4 2 5 3 7Beam arrangement number (refer Table 7)

Graph of Mean Maximum Contralateral Retina/optic Nerve Dose vs Beam Arrangement Number

6 8 1 4 2 5 3 7

83

4.6.9 Mean Maximum Optic Chiasm Dose

Figure 42- Graph showing mean maximum doses to optic chiasm volume for all IMRT beam

arrangements. Beam arrangement-7 is significantly lower than all other beam arrangements.

Beam arrangement-3 is significantly lower than 4 &8. Beam arrangement-5 is significantly lower

than 4.

0.00

1000.00

2000.00

3000.00

4000.00

Mea

n m

ax o

ptic

chi

asm

do

se (

cGy)

4 8 1 2 6 5 3 7


Graph of Mean Maximum Optic Chiasm Dose vs Beam Arr angement Number

4 8 1 2 6 5 3 7

4.6.10 Mean Maximum Oral Cavity Dose

Figure 43- Graph showing mean maximum doses to oral cavity volume for all IMRT beam

arrangements. Beam arrangements- 8, 5 &4 are significantly higher then beam arrangements-

1,2 ,6 ,3&7 .

0.00

1000.00

2000.00

3000.00

4000.00

Mea

n m

ax o

ral

cavi

ty d

ose

(cG

y)

8 5 4 1 2 6 3 7


Graph of Mean Maximum Dose to Oral Cavity vs Beam Arrangement Number

8 5 4 1 2 6 3 7

84

4.6.11 Mean Maximum Spinal Cord Dose

Figure 44- Graph showing maximum doses to spinal cord volume for all IMRT beam

arrangements. Beam arrangement-7 is significantly different to all other beam arrangements.

Beam arrangement-5 produces a significantly higher spinal cord dose to all beam arrangements

except 2 & 8.

0.00

2000.00

4000.00

6000.00

Mea

n m

ax s

pina

l co

rd d

ose

(cG

y)

5 2 8 4 1 6 3 7


Graph of Mean Maximum Spinal Cord Dose vs Beam Arrangement Number

5 2 8 4 1 6 3 7

4.7 Grouped Results

For all results indicated, a table was produced (Table 12) listing beam arrangements

from worst through to best. For critical structures, all beam arrangements are listed

from those producing the highest mean maximum dose to the lowest mean maximum

dose. For conformity index, beam arrangements are listed from those producing the

lowest CI to the highest CI. For mean contralateral parotid dose, beam arrangements

are listed from those producing the highest mean parotid dose to the lowest mean

parotid dose. Thus beam arrangement numbers at the bottom of the list indicate better

results than those at the top of the list.

85

Table 12-Grouped results –beam arrangements listed in order of beam arrangements producing

the worst results (top of table) to beam arrangements producing the best results (bottom of table).

Brain Max

Brain Stem EAM

Contra-lateral retina/ optic nerve

Contra-lateral

lens Optic

Chiasm Oral

Cavity

Ipsi-lateral lens

Ipsi-lateral retina/ optic nerve

Spinal cord

Mean Parotid

5* 5* 2* 6* 4* 4* 8* 5* 5* 5* 8* 8* 8* 6* 8* 1* 8* 5* 4 8* 2* 5* 4* 4* 1* 1* 8* 1* 4* 3 4* 8* 4* 1* 2* 8* 4* 2* 2* 1 2 1* 4* 6* 2* 1* 4* 2* 5* 6* 2 8 2* 1* 2* 3* 3* 5* 5* 6* 5* 6 1 3* 6* 1* 6 6* 3 3 3* 3* 3 6 6 3* 3* 7 7 7 7 7 7 7 7 7 7 7 *=Significantly different to the best result (p<0.05).

CI

PTV DVH Range

8* 8*

5* 4*

4* 7

7 5

1 6

6 1

3 2

2 3

*=Significantly different to the best result (p<0.05).

Table 12 demonstrates that beam arrangement-7 (Table 7) is the best IMRT plan for

delivering the lowest doses to critical structures, followed by beam arrangement-3.

Beam arrangement-2 and beam arrangement-3 are the best IMRT plans for CI and PTV

DVH range.

Critical structure dose, DVH range and CI values are all equally important in

determining which IMRT beam arrangement is considered to provide the best

dosimetric plan for this disease site. Thus a beam arrangement would need to produce

86

good results in all three areas in order to be the best beam arrangement. Good results

are indicated by beam arrangements presenting at the bottom end of table 12. Beam

arrangement-7 produced good results in critical structure dose but not in CI or DVH

range. Beam arrangement-2 produced good results in CI and DVH range, but not in

critical structure dose. Beam arrangement-3 consistently produced good results in

critical structure dose, DVH range and CI values. Thus beam arrangement-3 is

considered to be the best IMRT plan.

4.8 Radiation Oncologist Clinical Analysis of IMRT Plans

Dr Liz Kenny at the RBWH determined the best clinical IMRT beam arrangement

from the dosimetric results and DVH analysis. Particular attention was given to beam

arrangement-3 and beam arrangement-7. Dr Kenny determined that beam

arrangement-3 (7 beam IMRT arrangement) was the best of the IMRT beam

arrangements. This decision was based on the fact that critical structures were

considerably lower but PTV conformity and dose ranges were improved over beam

arrangement-7 (4 beam ipsilateral arrangement).

Conclusion from the clinical preference of the radiation oncologist and statistical

results, is that beam arrangement-3 is the best IMRT beam arrangement to treat skin

lesions of the temple region with spread to the parotid gland.

4.9 IMRT Vs 3DCRT

Statistical analysis was performed on the best IMRT beam arrangement and compared

with results for standard 3DCRT treatment. The student’s paired t-test was performed

using Microsoft excel, to determine if significant difference existed between the mean

CI, mean maximum critical structure doses and PTV dose ranges of the two treatment

options (Table 13). Significant difference was determined with a p-value <0.05.

Where significant difference exists, sections 4.9.1-4.9.3 will explain whether results

indicate that the 7-beam IMRT treatment was better or worse than the 3DCRT

treatment.

87

Table 13- Table demonstrating any significant difference between measures of 3DCRT plans and

the 7-beam IMRT arrangement

Measure

Significant Difference

P-Value if Significantly

different

CI yes <0.05

PTV Range yes <0.05

Brain yes <0.05

Brainstem yes 0.02

Eam yes <0.05

Contralateral ret/optic

nerve

yes <0.05

Contralateral lens yes 0.03

Optic chiasm yes <0.05

Oral cavity no -

Ipsilateral lens no -

Ipsilateral ret/optic nerve no -

Spinal cord yes <0.05

Mandible no -

Body no -

Mean contralateral parotid yes <0.05

4.9.1 CI

The conformity index of the 7-beam IMRT plan was significantly higher than the

3DCRT plan. As a result the 7-beam IMRT plan was greatly improved over the

3DCRT plan. This is demonstrated in figure 45a&b where the 95% isodose line (200

cGy/fraction), is conforming more tightly around the PTV.

88

Figure 45a&b- Improved CI is visualised by the 95% isodose line in the 7-beam IMRT plan when

compared to the 3DCRT plan.

Figure 45a-7-beam IMRT plan

Figure 45b-3DCRT plan

89

4.9.2 DVH Range Analysis of the PTV

The mean PTV dose range was significantly lower for the 7-beam IMRT arrangements

when compared to the 3DCRT beam arrangements. As a result the 7-beam IMRT

distribution was a better distribution around the PTV than the 3DCRT plan. This is

visualised in the slope of the PTV DVH, in figures 46a and 46b. The 3DCRT PTV

DVH is not a steep fall off from the 95% volume mark, when compared to the 7-beam

IMRT PTV DVH.

Figure 46a -DVH demonstrating Figure 46b-DVH demonstrating

3DCRT distribution. IMRT distribution.

4.9.3 Critical Structure Analysis

The mean and mean maximum dose to the majority of critical structures (table 12) was

significantly higher in the 7-beam IMRT plan when compared to the 3DCRT plan.

Figure 47 is a visual demonstration of doses to some critical structures for the two

plans. In this figure, the IMRT plan is delivering approximately; 43 cGy to the oral

cavity, 104 cGy to the spinal cord and 21 cGy to the contralateral parotid gland. The

3DCRT beam arrangement is delivering approximately; 42 cGy to the oral cavity, 42

cGy to the spinal cord and no dose to the contralateral parotid gland.

90

Figure 47a&b- Figures demonstrating mean and mean maximum doses in cGy to critical

structures for the 7-beam IMRT arrangement and the 3DCRT beam arrangement.

Figure 47a-7-beam IMRT beam arrangement

Figure 47b-3DCRT beam arrangement

91

4.10 Radiation Oncologist Clinical Analysis of 3DCRT and 7-Beam IMRT

Plans

Results and DVH outputs were presented to a radiation oncologist at the RBWH to

determine the clinically preferred radiation treatment. Dr Kenny determined

advantages in the 7-beam IMRT arrangement for CI and PTV range, outweighed

increases in radiation doses to critical tissues, if critical structures did not exceed

maximum tolerance doses. The contralateral lens was the only critical structure that

exceeded tolerance dose.

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CHAPTER 5

DISCUSSION

This research project compared dose distributions of eight different IMRT beam

arrangements and determined the optimal IMRT beam arrangement and thus, class

solution, to treat skin lesions of the temple region with extension into the parotid gland.

This IMRT distribution was compared with the 3DCRT plan to determine the better

treatment option. Comparison was performed by dose based analysis on structure

volume, CI, PTV dose range and critical structures.

5.1 Structure Volume Analysis

This research project required CT data sets of each patient to be outlined twice as

detailed in section 3.6.1. The LOA magnitudes were assessed to determine if outlining

of critical structures were clinically acceptable. Results indicate that for each patient

there was minimal variation between the two outlined CT data sets for all volumes

except the body structure.

The variation in body structure outlining between the two CT data sets can be

explained by the introduction of bolus. Limitations of the PLATO planning system

required 3DCRT CT data sets to be outlined without the inclusion of bolus. Bolus was

added to the 3DCRT data set at a later stage of the planning process, but in a section of

the PLATO planning system that does not incorporate the bolus addition to the

magnitude of body volume structure. IMRT CT data sets required outlining with the

inclusion of bolus. The PLATO planning system includes the bolus addition when

assessing body structure volume. As a result the magnitude of body volume structure

was considerably different between the two data sets.

The differences in body volume structure between the two CT data sets can be

accounted for by the addition of bolus accommodating PLATO planning system

limitations. Thus results concerning doses to structure volumes between IMRT and

3DCRT plans could be compared.

93

5.2 3DCRT Dosimetric Considerations

For all 3DCRT plans, ICRU 50 guidelines were adhered to as closely as possible. The

aim of treatment was for 95% of the reference dose (RD) to cover the PTV while the

maximum dose was not to exceed 107% of the reference dose. DVH range analysis on

the PTV was assessed to determine if guidelines were followed.

The shape of the PTV DVH was similar in all 3DCRT plans. Figure 48 provides two

examples of 3DCRT DVH’s. Both PTV’s as shown on the DVH, fall well short of

achieving 95% of the RD, which is 60 Gy. In both cases it can be seen that

approximately 50 Gy is covering 95% of the PTV.

Figure 48- DVH’s of 3DCRT plans from different CT data sets demonstrating similarities in PTV

The slope of the curve as visualised in figure 48 is steep from the 80% volume position,

but is shallow from the 95% volume position. An ideal plan is one which produces a

PTV DVH that is steep from the 95% volume position. 3DCRT plans in this study did

not achieve the aim of treatment, which is for 95% of the RD to cover the PTV. This is

the reason why the PTV range in 3DCRT plans is so large.

94

PTV DVH’s do not indicate which part of the PTV is not achieving 95% of the RD.

Assessing the axial slices of all 3DCRT plans, visually indicated that the photon-

electron junction was the region not achieving ICRU 50 guidelines.

As described in section 2.10.4, when electrons and photons are junctioned on skin, a

hot spot will occur on the photon side, inferior to the junction and a cold spot will

occur on the electron side, superior to the junction. This cold spot can result in less

than 95% of the RD covering the PTV in this region. For example, Figure 49

demonstrates inadequate coverage of the PTV on the electron side of the photon-

electron junction region. The maximum dose in figure 49 is 167 cGy per fraction

which is 80% of the daily dose required, thus it is impossible for 95% of the daily RD

to cover the PTV. This figure shows that only 126 cGy or 63% is covering the PTV.

Figure 49- 3DCRT axial slice of junction region demonstrating poor coverage of the PTV.

As discussed in section 2.10.4, low dose to the PTV is undesirable because it increases

the risk of tumour recurrence. Conformity of the 95% of the daily dose to the PTV in

95

this junction region is not a concern for IMRT distributions, because as discussed in

the introduction, there is no junction region in the upper face fields.

5.3 IMRT Dosimetric Considerations

For all IMRT plans, RTOG guidelines were adhered to as closely as possible to avoid

underdosing and overdosing of the PTV. In every IMRT plan, 95% of the RD (60 Gy)

covered the PTV, but in order to achieve this, compromises were made between the

maximum and minimum doses to the PTV. In many cases 95% of the PTV could not

be achieved without exceeding the maximum dose (Figure 50). Figure 50 shows 95%

of the PTV receiving 60 Gy, but in order to achieve this goal, approximately 20% of

the volume is receiving greater than 114% of the RD and 4% of the PTV volume is

receiving 93% of the RD.

Figure 50- DVH demonstrating compromise made when determining optimal IMRT distribution.

96

Violation of RTOG and ICRU guidelines results in PTV underdosing and overdosing.

The extent of violation was examined through results of DVH range analysis of the

PTV.

5.4 DVH Range Analysis of the PTV

A more homogenous distribution results from reduced underdosing and overdosing, of

the PTV. The PTV DVH range is a good indicator of a homogenous PTV distribution.

The smaller the PTV DVH range, the steeper the PTV DVH curve is resulting in a

more homogenous the PTV distribution. Section 3.10.2 discussed how the PTV DVH

range was determined. Of all the IMRT distributions, the 7-beam arrangement

produced the best PTV DVH. All IMRT beam arrangements above 7 beams plus the 5

beam- (4 equilateral +1), produced ranges within 1.6 Gy. These four IMRT beam

arrangements were the best at achieving guidelines. Bragg et al supports this finding

by stating, “there is a clear tendency toward better homogeneity when an increasing

number of fields were used” (Bragg.C et al., 2002, p734).

This study introduced three ipsilateral beam IMRT arrangements to determine the

effect on underdosing and overdosing of the PTV. Results demonstrate these beam

arrangements violated guidelines and produced the most underdosing and overdosing

of the PTV. Bragg et al suggested that introducing a number of beams from the same

side as the tumour would reduce target overdosing and underdosing (Bragg.C et al.,

2002). This study determined the opposite to be true.

The average DVH range analysis for the 3DCRT PTV was 47.2 Gy compared to 17.1

Gy for the 7-beam IMRT arrangement. A Statistically significant difference (p<0.05)

was determined between these two figures, indicating the 7-beam IMRT distribution

(Figure 51a) was a better distribution than the 3DCRT distribution (Figure 51b)

because it adheres to guidelines and avoids overdosing and underdosing of the PTV,

especially in the junction region while still achieving 95% dose coverage. This is

shown by the steep fall-off of the PTV from the 95% dose coverage in figure 51b. In

97

comparison, figure 51a shows a shallow PTV fall-off dose from the 99% volume down

to the 80% volume as detailed in section 5.2.

Figure 51a -DVH demonstrating Figure 51b-DVH demonstrating

3DCRT distribution. IMRT distribution.

One hypothesis of this research project was that IMRT would enable avoidance

problems in the junction region. IMRT avoids overdosing and underdosing problems

in the junction region by eliminating the need for a second junction during treatment.

The final outcome is a more homogenous PTV distribution which is indicated by PTV

DVH range statistical analysis.

5.5 IMRT CI Analysis

CI was assessed to determine how well the 95% isodose line conforms to the PTV. Of

all the IMRT plans, the 7-beam equitorial spaced beam arrangement proved to be the

most conformal. Similar to results for DVH PTV analysis, IMRT beam arrangements

above 7 beams plus the 5 beam- (4 equilateral +1), produced ranges within 0.02.

These 4 IMRT beam arrangements were the best at achieving conformity.

98

PTV analysis by CI and DVH range, show that IMRT beam arrangements above 7

beams along with a 5-beam arrangement (4-equitorial + 1ipsilateral), produce adequate

PTV coverage.

5.6 IMRT Critical Structure Analysis

Various IMRT beam arrangements produced different doses to critical structures. The

4-beam ipsilateral IMRT plan consistently produced the lowest dose to all critical

structures. The 7 field beam arrangement produced the next best results by delivering

the lowest dose to the; eam, contralateral lens and retina/optic nerve, spinal cord, oral

cavity and optic chiasm (Figure 52a).

Beam arrangement-5 (3 beam ipsilateral + 2) was the worst IMRT plan, producing the

highest doses to the brain, brainstem, ipsilateral structures and spinal cord (Figure 52b).

Thus there is no advantage to a five field beam arrangement not being equally spaced.

In figures 52a&b, beam arrangement-5 shows a higher dose to the; contralateral and

ipsilateral retina/optic nerve and brain than the 7 beam IMRT arrangement.

99

Figure 52a- 7 beam IMRT distribution Figure 52b- Beam arrangement-5 IMRT

demonstrating doses to critical structures. distribution, demonstrating dose to critical

structures.

5.7 IMRT Mean Contralateral Parotid Dose

Different IMRT beam arrangements were able to reduce the contralateral parotid gland

dose. Reducing dose to the contralateral parotid decreases the radiation side-effect of

xerostomia. Thus improving patient’s quality of life, post radiation therapy and

reducing the cost burden of ongoing medical care provided by medical institutions.

The 4-beam ipsilateral and 7-beam arrangement produced significantly lower doses to

the contralateral parotid than any other IMRT plan.

5.8 Superior IMRT Plan

Studies of IMRT treatment of the parotid gland alone suggest beam arrangement-6 (5

beam (4equispaced +1)) is the superior IMRT treatment plan (Bragg.C et al., 2002).

This study determined that beam arrangement-6 did not produce the best overall results.

Doses to critical structures, PTV conformity and DVH range are all equally important

factors in determining the superior IMRT plan. As detailed in section 4.7, beam

arrangement 3 or the 7-beam IMRT arrangement performed well in all three

100

determining factors. As a result, the 7-beam IMRT arrangement is the superior IMRT

beam arrangement due to highly conformal and homogenous PTV distributions and

reduced critical structure doses.

Dr Liz Kenny of the RBWH confirmed these results with clinical reasoning. She

determined that the 7-beam IMRT arrangement was preferred over the 4-beam

ipsilateral arrangement because of improved PTV conformity and homogeneity.

IMRT treatment can take a long time to deliver, depending on the number of beams.

In 2001, Rowbottom et al determined a 9-beam arrangement to produce the superior

dosimetric plan for parotid gland tumours, although a compromise was made with a 7-

beam IMRT arrangement because it maintained improvements seen with the superior

plan, but a reduced number of beams made it more clinically efficient (Rowbottom.C

et al., 2001).

The 7-beam IMRT arrangement is considered to be clinically efficient to deliver in a

clinical environment. This statement is supported by radiation oncologists of the

RBWH. Thus statistically and clinically the 7-beam IMRT arrangement is the superior

IMRT treatment that is clinical efficient to deliver.

5.9 IMRT Class Solution

As discussed in section 2.13, class solutions for individual tumour sites are developed

to produce the optimal treatment plan with ease. This research determined the superior

IMRT plan, 7-beam arrangement to be the IMRT class solution, with defined beam

angles of; 40°,120°,160°,200°,240°,300°,0°.

A class solution is the, “historical experience in designing RT plans for a particular

site” (Intensity Modulated Radiation Therapy Collaborative Working, 2001, p913).

The historical experience of a class solution is a detailed step by step guide for a

particular disease site. For example, a class solution may involve; patient stabilisation,

PTV and critical structure contouring, prescription protocol, critical structure tolerance

101

dose and importance weightings, beam number and angles, minimum and maximum

dose constraints, quality assurance and treatment delivery.

This research study followed a step by step guide to define an IMRT class solution,

although this study mainly investigated beam numbers and angles. As a result the 7-

beam arrangement forms the basis of this IMRT class solution. Further investigations

may be conducted in support of this study, to determine precise detailed steps in this

class solution.

5.10 IMRT Vs 3DCRT

The optimal 7 beam IMRT arrangement was compared to the standard 3DCRT plan.

Results demonstrate that the IMRT distribution provides better PTV conformity and

dose homogeneity. A study by Cozzi et al supports this conclusion by stating,

“delivered IMRT dose plans showed a systematic and highly significant improvement

in terms of target coverage compared to reference 3DCRT” (Cozzi.L et al., 2004,

p622)

In contrast, analysis determined that higher doses were delivered to the majority of

critical structures with IMRT planning. Only the ipsilateral lens and the oral cavity

received lower doses with the optimal IMRT plan.

One hypothesis of this research project was that the IMRT class solution would enable

lower doses to critical structures, thus allowing an increased tumour dose to be

delivered, resulting in increased local control. Results of this study indicate that higher

doses were delivered to critical structures with IMRT planning. As a result an

increased tumour dose could not be delivered thus increased local control cannot be

assessed. Therefore this hypothesis was disproved.

The mean contralateral parotid dose was also significantly increased with IMRT

planning, although it did not exceed the maximum tolerance dose. Previous research

has determined similar increases in parotid gland doses with IMRT planning.

102

“Unfortunately, the IMRT plan greatly increased the dose to the contralateral parotid

gland” (Rowbottom.C et al., 2001, p170).

To determine if IMRT is the superior treatment modality to 3DCRT, for treating skin

lesions of the temple region with extensions to the parotid gland, improvements in PTV

conformity and homogeneity must outweigh increased critical structure doses.

Doses delivered to critical structures via IMRT are higher than 3DCRT, but still not

exceeding dose tolerances determined in this research project. “In general, IMRT

plans increase the volume of OARs irradiated to low dose” (Rowbottom.C et al., 2001,

p170). Thus increasing doses to critical structures to a safe level is an acceptable

compromise for improved PTV conformity and homogeneity.

Radiation oncologists support this reasoning. Upon assessing PTV and critical

structure doses, the oncologists prefer treating skin lesions of the temple region with

extensions to the parotid gland with IMRT, if tolerance doses of critical structures are

not exceeded. This is because a more conformal and homogenous dose to the PTV will

decrease the risk of tumour recurrence and tissue morbidity.

5.11 Radiation Oncologist Clinical Preference

The superior IMRT beam arrangement delivered an ipsilateral lens dose just beyond its

critical tolerance. Results indicate that a balance exists between lens dose and PTV

conformity. For example, beam arrangement-7 (4-beam ipsilateral plan) produced a

significantly lower contralateral lens dose then the 7-beam IMRT arrangement. The

dose was below critical tolerance, but the trade-off was significantly lower PTV

conformity and poor PTV DVH range. There is no point to exceeding critical structure

dose tolerance if tumour dose is not improved. The 7-beam IMRT does improve

tumour dose, and only just exceeds lens tolerance dose.

If lens tolerance dose is exceeded, the complication end point is cataract formation. As

suggested in section 2.6, this complication may be an acceptable trade-off for potential

103

tumour cure because cataract formation can be reduced by surgery (Pawlicki.T et al.,

2004).

Radiation oncologist clinical preference for IMRT over 3DCRT was preferred to be

determined on a case by case basis, if tolerance doses were exceeded. For IMRT to be

the treatment choice, patients would need to present with an aggressive tumour

requiring PTV conformity and homogeneity that IMRT provides, while still being a

surgical candidate to reduce the radiation side-effect of cataract formation. If tumours

were not aggressive and surgery was not a viable option, 3DCRT would be the

preferred treatment option.

5.12 Future Directions

This research project determined results by assessing nine CT patient data sets. The

pre-requisite for inclusion of a CT data set was based on three field parameters

traditionally treated with 3DCRT. If sample pre-requisite was expanded to include

only patients with aggressive tumours that were medically fit to be potential surgical

candidates, then a more definitive result might be found.

Increasing sample group numbers and testing this class solution in a clinical

environment may influence results and outcomes. Increased sample number may

affect the compromise seen in this study, between the ipsilateral lens dose and PTV

conformity with IMRT plans.

One hypothesis of this study was to determine if the IMRT class solution would enable

avoidance problems in the junction region. IMRT does avoid problems because the

second junction is eliminated from treatment. Although further studies conducted

specifically on dose occurring in the photon-electron junction region with 3DCRT

treatment would better highlight problems.

Dose occurring in the photon-electron junction region in 3DCRT played a role in

determining the superior treatment plan in this research project. This study performed

104

dosimetry as conducted in a clinical setting. Resulting PTV DVH’s demonstrated that

95% of the RD was not covering the PTV, but DVH’s do not indicate the position on

the CT data, where the PTV is not covered by 95%. A future direction of this research

study would be to contour the PTV in the photon-electron junction region as a separate

structure for 3DCRT and IMRT planning. The DVH’s of this structure could then be

compared to accurately assess the dose occurring at this region from 3DCRT and

IMRT. Results from this study may better highlight any inhomogeneities in the

photon-electron junction region, and whether IMRT overcomes these.

This study determined the IMRT 7-beam arrangement as the class solution, with major

focus on determining beam number and arrangement. Current literature reports the

development of computerised beam angle selection and opitimisation algorithms to

determine the optimum beam angles and numbers. For example Wang et al developed

the ‘fast IMRT algorithm’ to provide, “a novel and realistic approach to study the

characteristics of IMRT dose distributions as a function of beam angles” (Wang.X et

al., 2004, p1326). Applying an optimisation algorithm to the disease site studied in

this research project would test the technical feasibility of the IMRT class solution of

the 7-beam IMRT arrangement.

Further studies may be carried out to develop a full and detailed class solution.

Incorporating steps such as; patient selection, patient positioning, critical structure

contouring, prescription protocol, quality assurance process plan and treatment

delivery may aid in developing a full and precise class solution.

The ultimate test of efficacy of a class solution must be the final outcome to the patient

in terms of tumour control and long-term side-effects. This takes time and is difficult

to measure in uncommon disease sites, although future studies may attempt to

document this.

105

CHAPTER 6

CONCLUSION

Skin lesions of the temple region with extensions to the parotid gland, is a treatment

site historically treated with three-dimensional conformal radiation therapy (3DCRT).

3DCRT requires this disease site to be treated with two junction regions, resulting in

poor dose conformity to the tumour target and high doses to critical structures.

Intensity modulated radiation therapy (IMRT) is a relatively new treatment technology

that has potential to overcome limitations associated with 3DCRT (Garden.A et al.,

2004). IMRT enables the disease site to be treated with one junction region, therefore

avoiding junction problems by providing high dose conformity to the tumour target.

This study has shown that the 7-beam IMRT arrangement with defined beam angles of;

40°,120°,160°,200°,240°,300°,0°, is the superior IMRT treatment plan, and thus class

solution for this disease site. This study has also shown that the IMRT class solution is

superior to 3DCRT in terms of planning target volume (PTV) conformity and

homogeneity, but not in terms of doses to critical structures. The resultant higher doses

to critical structures do not afford the potential to increase dose to the target volume

and thus increase local control.

The superior IMRT treatment plan delivered higher doses to the majority of critical

structures than the 3DCRT plan. Although, the only structure that just exceeded

critical tolerance was the ipsilateral lens. The complication end point for exceeding

lens tolerance dose is cataract formation. This study concluded that this complication

end point may be an acceptable trade-off for potential tumour cure because patients

may have the option for cataract formation to be reduced by surgery.

Clinical preference for accepting the IMRT class solution over 3DCRT treatment was

preferred to be determined on a case by case basis. For IMRT to be the treatment

choice, patients would need to present with an aggressive tumour requiring PTV

106

conformity and homogeneity that IMRT provides, while still being a surgical candidate

to reduce the radiation side-effect of cataract formation.

This study into skin lesions of the temple region with extensions to the parotid gland

determined the 7-beam IMRT arrangement to be the optimal IMRT class solution. A

definitive answer determining whether the IMRT class solution is superior to 3DCRT

did not result without conditions applied. This study suggests that the IMRT class

solution is the superior treatment option, only when patients are surgical candidates to

reduce the complication end point of cataract formation. This research study would

provide a good resource base to further investigations into this complicated disease site.

107

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Appendix A Documentation from Nucletron Pty Ltd confirming free software supply for a period of 90 days

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Appendix B Ethics approval confirmation from Professor W Egerton of the RBWH Human Ethics Research Committee

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Appendix C QUT email confirming ethical issues were uncompromised

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