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Computational Assessment of Absorbed Dose to Tissues of the Eye for Ocular Radiotherapy

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Title:
Computational Assessment of Absorbed Dose to Tissues of the Eye for Ocular Radiotherapy
Physical Description:
1 online resource (128 p.)
Language:
english
Creator:
Cantley, Justin L
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Biomedical Engineering
Committee Chair:
Bolch, Wesley Emmett
Committee Members:
Hintenlang, David Eric
Gilland, David R
Smith, Wesley Clay
Chell, Erik

Subjects

Subjects / Keywords:
amd -- brachytherapy -- glaucoma -- melanoma -- radiotherapies
Biomedical Engineering -- Dissertations, Academic -- UF
Genre:
Biomedical Engineering thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Early attempts at ocular radiotherapy often led to more problems than were solved, and has led to a reluctance to use such treatments that still exists today.  This work explores several types of ocular radiotherapies, focusing upon two recent and innovative methods:  The IRay™ is a stereotactic radiosurgery device designed to treat age-related macular degeneration, which uses small beam sizes and precision targeting to greatly improve upon accurate delivery of dose; In-Gel™ allows a brachytherapy source to be injected directly into an ocular melanoma and achieves a unifrom source distribution as it displaces through the site.  A series of five stylized eye models was created for this work, with axial lengths ranging from 20 to 28 mm.  The models were used with the MCNPX radiation transport code to simulate treatment and assess the dose received by non-targeted tissues of the eye.  Three types of ocular radiotherapy were explored for the potential treatment of age-related macular degeneration:  brachytherapy, IRay™, and proton.  In each of the cases, it was shown that the doses to non-targeted tissues of the eye were below thresholds, suggesting that it is unlikely that patients would suffer any radiation induced complications.  In addition, the possiblilty of using the IRay™ for treatment of glaucoma was explored.  Though there is not yet definitiveevidence that radiation will be an effective treatment for glaucoma in human patients, the results show that with some modification in the targeting software the IRay™ could irradiate the proposed target while keeping dose to non-targeted tissues below threshold levels.  The series of eye models were modified to include ocular melanomas of varying size and location.  The models were then once again used with the MCNPX radiation transport to simulate the injection of In-Gel™ into the ocular melanomas. The results showed that the use of the beta emitter Y-90 results in acceptable dose levels in non-targeted tissues in small melanomas with a target dose of 85 Gy.  However, larger melanomas sometimes resulted in doses to non-targeted tissues above threshold limits, suggesting that the range of beta particles from Y-90 may be too large in some treatment scenarios.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Justin L Cantley.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: Bolch, Wesley Emmett.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045874:00001

MISSING IMAGE

Material Information

Title:
Computational Assessment of Absorbed Dose to Tissues of the Eye for Ocular Radiotherapy
Physical Description:
1 online resource (128 p.)
Language:
english
Creator:
Cantley, Justin L
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Biomedical Engineering
Committee Chair:
Bolch, Wesley Emmett
Committee Members:
Hintenlang, David Eric
Gilland, David R
Smith, Wesley Clay
Chell, Erik

Subjects

Subjects / Keywords:
amd -- brachytherapy -- glaucoma -- melanoma -- radiotherapies
Biomedical Engineering -- Dissertations, Academic -- UF
Genre:
Biomedical Engineering thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Early attempts at ocular radiotherapy often led to more problems than were solved, and has led to a reluctance to use such treatments that still exists today.  This work explores several types of ocular radiotherapies, focusing upon two recent and innovative methods:  The IRay™ is a stereotactic radiosurgery device designed to treat age-related macular degeneration, which uses small beam sizes and precision targeting to greatly improve upon accurate delivery of dose; In-Gel™ allows a brachytherapy source to be injected directly into an ocular melanoma and achieves a unifrom source distribution as it displaces through the site.  A series of five stylized eye models was created for this work, with axial lengths ranging from 20 to 28 mm.  The models were used with the MCNPX radiation transport code to simulate treatment and assess the dose received by non-targeted tissues of the eye.  Three types of ocular radiotherapy were explored for the potential treatment of age-related macular degeneration:  brachytherapy, IRay™, and proton.  In each of the cases, it was shown that the doses to non-targeted tissues of the eye were below thresholds, suggesting that it is unlikely that patients would suffer any radiation induced complications.  In addition, the possiblilty of using the IRay™ for treatment of glaucoma was explored.  Though there is not yet definitiveevidence that radiation will be an effective treatment for glaucoma in human patients, the results show that with some modification in the targeting software the IRay™ could irradiate the proposed target while keeping dose to non-targeted tissues below threshold levels.  The series of eye models were modified to include ocular melanomas of varying size and location.  The models were then once again used with the MCNPX radiation transport to simulate the injection of In-Gel™ into the ocular melanomas. The results showed that the use of the beta emitter Y-90 results in acceptable dose levels in non-targeted tissues in small melanomas with a target dose of 85 Gy.  However, larger melanomas sometimes resulted in doses to non-targeted tissues above threshold limits, suggesting that the range of beta particles from Y-90 may be too large in some treatment scenarios.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Justin L Cantley.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: Bolch, Wesley Emmett.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045874:00001


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1 COMPUTATIONAL ASSESSMENT OF ABSORBED DOSE TO TISSUES OF THE EYE FOR OCULAR RADIOTHERAPY By JUSTIN L CANTLEY A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIRE MENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2013

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2 2013 Justin L. Cantley

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3 To Mom and Dad

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4 ACKNOWLEDGEMENTS I woul d like to thank my advisor, Wesley Bolc h, for all the help and guidance he has provided over the last three years as this project has taken shape. I would also like to extend my gratitude to the other members of my committee: David Hintenlang, David Gilland, W. Clay Smith, and Erik Chell. Th eir guidance has been a great help to me in being able to better communicate the results of my research. I would also like to thank Choonsik Lee and Justin Hanlon, for all of the work they did before me and for all of the help they were willing to contrib ute during the time I was working on this research. To all of my friends, family, and the BME office staff, you have my gratitude in seeing me through this accomplishment.

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5 TABLE OF CONTENTS page ACKNOWLEDGEMENTS ................................ ................................ ............................... 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 ABSTRACT ................................ ................................ ................................ ................... 10 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 12 1.1 Age related Macular Degeneration ................................ ................................ ... 12 1.2 Glaucoma ................................ ................................ ................................ ......... 16 1.3 Ocular Melanoma ................................ ................................ .............................. 18 1.4 Purpose of This Work ................................ ................................ ....................... 19 2 BACKGROUND OF OCULAR RADIOTHERAPY ................................ ................... 22 2.1 Overview of Ocular Radiotherapy ................................ ................................ ..... 22 ................................ ................................ ................................ ............... 23 2.3 In ................................ ................................ ................................ ............ 25 3 EFFECTS OF EYE SIZE AND BEAM POLAR ANGLE TREATMENT ................................ ................................ ................................ .......... 33 3.1 Materials and Methods ................................ ................................ ...................... 35 3.2 Results ................................ ................................ ................................ .............. 38 3.3 Discussion ................................ ................................ ................................ ........ 40 3.4 Summary ................................ ................................ ................................ .......... 43 4 COMPARISON OF AMD RA DIOTHERAPIES ................................ ........................ 48 4.1 Materials and Methods ................................ ................................ ...................... 48 4.2 Results ................................ ................................ ................................ .............. 51 4.3 Discussion ................................ ................................ ................................ ........ 52 4.4 Summary ................................ ................................ ................................ .......... 54 5 GLAUCOMA TREATMENT S TUDY ................................ ................................ ....... 60 5.1 Materials and Methods ................................ ................................ ...................... 61 5.2 Results ................................ ................................ ................................ .............. 63 5.3 Discussion ................................ ................................ ................................ ........ 65 5.4 Summary ................................ ................................ ................................ .......... 66 6 OCULAR MELANOMA IN ................................ ........................ 71 6.1 Materials and Methods ................................ ................................ ..................... 72 6.2 Results ................................ ................................ ................................ ............. 75 6.3 Discussion ................................ ................................ ................................ ........ 76 6.4 Summary ................................ ................................ ................................ .......... 77

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6 7 CONCLUSIONS ................................ ................................ ................................ ..... 82 7.1 General Conclusions ................................ ................................ ......................... 82 7.1.1 Eye Size and Beam Polar Angle Variations ................................ ............. 82 7.1.2 AMD Radiotherapies ................................ ................................ ............... 82 7.1.3 Glaucoma Radiotherapy ................................ ................................ .......... 83 7.1.4 In Gel Radiotherapy ................................ ................................ .............. 83 7.2 Limitations of This Work ................................ ................................ .................... 83 7.3 Future Work ................................ ................................ ................................ ...... 84 APPENDIX A SAMPLE MCNPX INPUT F ILE FOR PROTON RADIA TION TRANSPORT ........... 86 B SAMPLE MATLAB CODE F SING .............................. 91 LIST OF REFERENCES ................................ ................................ ............................. 119 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 128

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7 LIST OF TABLES Table page 3 1 Volume of eye tissues as a function of axial length (cm3) ................................ .. 44 6 1 Volume of ocular melanomas (cm 3 ) ................................ ................................ .... 78 6 2 Dose coefficients for Y 90 uniformly distributed within ocular melanomas of differing location and size (Gy/Bq) ................................ ................................ ...... 79 6 3 Mean absorbed dose (in Gy) to non targeted tissues corresponding to an ocular melanoma mean absorbed dose of 85 Gy ................................ ............... 80

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8 LIST OF FIGURES Table page 2 1 Axial cross section of the eye (Adapted from Clinical Anatomy o f the Eye by Richard S. Snell and Michael A. Lemp) ................................ .............................. 27 2 2 Retinal geometry showing the shift of the fovea from the posterior pole ............ 28 2 3 Diagram A shows a saggital view of a single beam from the anode to the target. Diagram B shows the front view with the three beams incident upon the eye ................................ ................................ ................................ ................ 29 2 4 Arrangement of a patient ................................ ............. 30 2 5 The I ................................ ................................ ................................ ..... 30 2 6 Colloidal Y 90 microspheres ................................ ................................ ............... 31 2 7 Injection of In ................................ ................. 32 3 1 22 mm axial length stylized eye model ................................ ............................... 45 3 2 Absorbed dose to non targeted tissues of the eye as a function of axial length with a fixed beam polar angle of 26 degrees ................................ ........... 46 3 3 Absorbed dose to non targeted tissues of the eye as a function of beam polar angle with a fixed axial length of 22 mm ................................ ............................. 47 4 1 Absorbed dose to non targeted tissues of the eye for brachytherapy treatment ................................ ................................ ................................ ............ 56 4 2 Absorbed dose to non targeted tissues of the eye as a function of axial .......... 57 4 3 Absorbed dose to non targeted tissues of the eye as a function of axial length for a fixed 30 degree beam polar angle proton treatment ........................ 58 4 4 Comparison of the absorbed dose to non targeted tissues of the eye for a fixed axial length of 22 mm between the three modalities ................................ .. 59 5 1 Absorbed dose to non targeted tissues of the eye as a function of beam polar angle in the 22 mm eye for a single beam treatment using the nasal bea m ....... 67 5 2 Absorbed dose to non targeted tissues of the eye as a function of beam polar angle in the 22 mm eye for a single beam treatment using the central beam ..... 68 5 3 Absorbed dose to non targeted tissues of the eye as a function of beam polar angle in the 22 mm eye for a single beam treatment using the temporal beam 69

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9 5 4 Absorbed dose to non targeted tissues of the eye as a function of beam polar angle in the 22 mm eye for a multi beam treatment ................................ ........... 70 6 1 Schematic of the 22 mm eye with the addition of an ocula r melanoma. A: L1 position, axial slice. B: L2 position, axial slice. C: L3 position, sagittal slice. D: L4 position, sagittal slice. E: L5 position, axial slice ................................ .... 81

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10 Abstract of Dissertation Presented to the Grad uate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy COMPUTATIONAL ASSESSMENT OF ABSORBED DOSE TO TISSUES OF THE EYE FOR OCULAR RADIOTHERAPY By Justin L. Cantley August 2013 Chair: Wesley Bolch Major: Biomedic al Engineering Early attempts at ocular radiotherapy often led to m ore problems than were solved, and has led to a reluctance to use such treatments that still exists today This work explores several types of ocular radioth erapies, focusing upon two recent and in is a stereotactic radiosurgery device designed to treat age re lated macular degeneration, which uses small beam sizes and precision targeting to great ly impr ove upon accurate delivery of dose; In allows a brachytherapy source to be injected d irectly into an ocular melanoma and achieve s a uniform source distribution as it displaces through the site A series of five stylized eye models was created for this work, with axial lengths ran ging fro m 20 to 28 mm The models were used with the MCNPX radiation transport code to simulate treatment and assess the dose received by non targeted tissues of the eye. Three types of ocular radiotherapy were explored for the potential treatment of age cases, it was shown that the doses to non targeted tissues of the eye were below thresholds, suggesting that it is unlikely that patients would suffer any radiation induced c omplications. In addition, the possibility

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11 was explored. Though there is not yet definitive evidence that radiation will be an effective treatment for glaucoma in human patients, the results show that with som e modification in the targeting software proposed target while keep ing dose to non targeted tissues below threshold levels. The series of eye models were modified to include ocular melanomas of varying size and location. The models were then once again used with the MCNPX radiation transport to simulate the injection of In showed that the use of the beta emitter Y 90 results in acceptable dose levels in non targeted tissues in smal l melanomas with a target dose of 85 Gy. However, larger melanomas sometimes resulted in doses to non targeted tissues above threshold limits, suggesting that the range of beta particles from Y 90 may be too large in some treatment scenarios.

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12 CHAPTER 1 INTRODUCTION 1.1 Age related Macular Degeneration Age related macular degeneration (AMD) is a leading cause of vision loss in the elderly population of industrialized nations (Congdon et al. 2004). However, there is no definitive definition for the point at which a patient is diagnosed with AMD. Sometimes diagnosis is given for any change of the retinal pigment epithelium (RPE), while others reserve the diagnosis for when a patient exhibits severe vision loss (Bressler et al. 1988). Using the former defi nition of the disease, most patients do not experience any significant vision loss until progression into the advanced stage of the disease. Patients in the early stage of the disease usually develop drusen, small yellowish white deposits on the retina, w ithout significant vision loss, and drusen is present in more than half of the population over seventy years of age (Leibowitz et al. 1980). As the disease progresses into the advanced stage, it is usually classified as either wet or dry form AMD (Haddad et al. 2006). In both cases, the patient suffers central vision loss while retaining peripheral vision. For the dry form, general geographic atrophy of the RPE below the retina causes the central vision loss, and there is no treatment for the dry form. In the wet form, vasculature growth and subsequent hemorrhaging leads to the detachment of the retina (Bressler et al. 1988). While the dry form accounts for approximately 85% of the population with the disease (Haddad et al. 2006), 80 90% of the advance d cases that result in severe vision loss are due to the wet form of the disease (Gass 1985). The wet form of AMD begins when vascular tissue from the choroid breaks et al. 1988). The

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13 choroidal neovascularization (CNV) grows beneath the RPE and will leak fluids from the vasculature. This CNV leakage causes an increase in tension at the macular lesion. As the tension increases, scarring, vitreous hemorrhage, or even detachment of the RPE will o ccur (Bressler et al. 1988). This causes severe and rapid vision loss in a patient, culminating in blindness if left untreated. While vitamin supplements and antioxidants have been shown to slow the progression of the dry form of the disease (Haddad et al 2006), physicians typically will simply monitor the dry form of AMD until it progresses into the more severe wet form. Once the disease has reached this stage, there are several treatment options to slow the progression of the disease. Most physicians consider the vascular endothelium growth factor inhibitor (VEGF inhibitor) drug ranibizumab to be the current standard of care (Rosenfeld et al. 2006 While the drug is typically used for cancer treatments, the treatment is applicable for the wet form of AMD due to the CNV growth that leads to vision loss. CNV spreads by the production of VEGF, a signal protein which helps to create new blood vessels. The VEGF inhibitor hinders the process of the VEGF, and can control or slow the vascular growth, but can not reverse it. However, VEGF is still being produced by the body, whereas the VEGF inhibitor is only introduced through injection. Thus, treatment with VEGF inhibitor requires routine administration by injection into the eye, a very invasive procedure. Exploration of methods that are less invasive, less frequent, or both have led to the development of several other treatments. Photocoagulation uses a laser to thermally ablate the target area. This often leads to collateral damage to adjacent retinal ce lls. Such damage tends to cause permanent scotomas (areas of partial alteration of the field of vision) at the treatment

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14 site. This process has been known to limit the size of the central field defect (Schmidt Erfurth et al. 2007). In addition to collat eral retina damage, there tends to be a high rate of recurrence. However, severe loss of vision is less likely in photocoagulated CNVs than in cases in which the condition remains untreated, suggesting that such a treatment may be viable if other treatmen ts have failed previously. Photodynamic therapy (PDT) uses an intravenous administration of a pharmacological photosensitizer. The substance is then activated using red light. This treatment induces a photochemical oxidation of vascular endothelium. Usi ng this method, no thermal tissue damage occurs, which spares retinal tissue. PDT is considered to be a safe and durable treatment option for wet AMD. The benefits or stabilization achieved by the treatment over the first two years is usually maintained throughout an additional two years. Usually, three to four treatment sessions is required during the first year, with few treatments necessary after year two. However, the PDT treatment has limitations that occur with lesion size. As lesion size increas es, the projected outcome of patient treatment becomes much less favorable, suggesting that patients with large CNVs may need to explore other treatment options. Brachytherapy treatment of wet AMD is currently being developed to deliver a large dose to the targeted area and spare the rest of the tissue by using a beta emitting radioactive material. In the study reviewed by vila et al. (2009a), a strontium 90 source was surgically implanted and used in conjunction with anti VEGF drugs to treat patients suf fering from wet AMD. Each patient received two injections of the anti VEGF drug bevacizumab and a single treatment 24 Gy brachytherapy dose. Patients were divided into two groups. The first group of patients received an injection of

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15 bevacizumab ten days before surgery, and the second group received an injection at the time of the surgery. Both groups received a second injection one month after surgery. In order to place the device, a partial vitrectomy is performed (Avila et al. 2009b). This is done t o create an access cha nnel over the CNV. This allows ease of placement and minimizes traction on the peripheral retina. The surgeon place s the device over the fovea and match es with the appropriate ocular landmarks. The device is is done for approximately three to five minutes for each patient. A total of thirty four patients were enrolled in a study of this treatment which took place at a total of three sites in Mexico and Brazil. Approximately two t hirds of the patients were female, and the mean age of patients was 71.8 years. Of the thirty four patients in the study, twenty three had either stable or improved vision at their twelve month follow up. Even more impressive, thirteen of the patients in the study showed clinically significant improvement in their vision at twelve months after the study. However, eight patients showed evidence of lesion reactivation after treatment. In addition, a mean reduction in thicknes central retinal thickness/lesion thickness at the twelve month follow up examination. This was based upon the thirty two patients for whom a baseline was recorded. Several complications did arise during the study. One patien t experienced subretinal hemorrhaging and another experienced a retinal tear. Both of these complications were determined to occur due to the device that housed the radioactive source. Also, approximately one quarter of patients who did not previously ha ve cataracts developed them after treatment. However, all occurrences of cataracts were determined to stem from the vitrectomy procedure. No conclusions could be drawn about the timing of the

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16 initial injection of the drug bevacizumab. This was due to co mpliance problems with injection timing at the different sites used for the study. The use of a new stereotactic radiosurgery for treatment of wet AMD is being developed by Oraya Therapeutics, Inc. The details of this device and the methods of treatment w ill be discussed extensively throughout the dissertation. 1.2 Glaucoma Glaucoma is a neurodegenerative disease which is a leading cause of blindness worldwide, affecting approximately 70 million people worldwide (Quigley and Broman 2006). Vision loss occ urs from the loss of retinal ganglion cells (RGCs) and their axons, as well as a progressive degeneration of the optic nerve. Evidence suggests that RGC axon damage initially occurs at the optic nerve head (ONH), the location at which optic axons exit the eye (Burgoyne 2011). Analysis of animal models of glaucoma suggest that many non neuronal types of cells, such as astrocytes and microglia, may be involved in RGC degeneration. However, the exact contributions of these cells are not well understood (John son and Morrison 2009). Microglia, which are immune cells of the central nervous system, have been linked to multiple neurodegenerative diseases, including glaucoma (Johnson and Morrison 2009, Hanisch and Kettenmann 2007). Microglia cells will respond to neuronal injury or stress via changes in distribution and cell activation (Hanisch and Kettenman 2007, Block et al. 2007), and are found close to all RGC compartments impacted in glaucoma (Bosco et al. 2011). In human glaucoma, the ONH is the initial si te of axonal injury and microglia have been seen gathered in the area. In the DBA/2J (D2) mouse model of glaucoma, data shows that the microglia cells become activated before evidence of RGC degeneration

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17 (Bosco et al. 2011). The D2 mouse model is an esta blished inherited pigmentary glaucoma often used for research (Libby et al. 2005). The activated microglia first gather at the ONH, which is thought to be the initial site of optic neuropathy in the D2 mouse model (Howell et al. 2007, Soto et al. 2008). The microglia activation eventually spreads to the peripheral inner retina, which results in a doubling of microglia cells between four to ten months of age in the mice (Inman and Horner 2007). Analysis of the D2 mouse shows that the ONH and the retina ex hibit changes in gene expression that are consistent with an innate immune response (Steele et al. 2006, Fan et al. 2010, Howell et al. 2011). Changes similar to this have been seen in other species following acute intraocular pressure (IOP) elevation (Ah mend et al. 2004, Johnson et al. 2007, Lam et al. 2003, Miyahara et al. 2003). It has also been seen that deactivation of microglia improved RGC function and integrity (Bosco et al. 2008). This evidence suggests that the activation of microglia cells is an important initial component of glaucoma pathology. High dose irradiation of the entire animal was found to have a beneficial effect for D2 mice (Anderson et al. 2005), showing a large improvement in axon preservation. In a study by Bosco et al. (2011), the mice were irradiated between five and eight weeks of age, just before the age at which microglia is significantly activated. A follow up study delivered a high dose radiation treatment to only the head of D2 mice (Bosco et al. 2012). Results showed a reduction in proliferating microglia at the ONH. The treatment also resulted in reduced microglia activation within the retina and improved axon survival. The results of this study suggest that radiation treatment can be used to

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18 reduce the numbers of m icroglia activation in the D2 mouse model of glaucoma, and spare damage that would result if the mice were left untreated. 1.3 Ocular Melanoma Ocular melanoma of the choroid is an uncommon condition that occurs in only six out of one million annually, res ulting in approximately 1,400 new cases in the United States every year (Egan et al. 1988). However, the chance that the disease could metastasize is always a large concern. The incidence of choroidal melanoma is much less than that of skin melanoma, and the incidence of choroidal melanoma has remained stable (Inskip et al. 2003, Jemal et al. 2002). While there is some connection seen in family clusters, the incidence of choroidal melanoma is sporadic, with the role of environmental factors in disease pa thology still unclear (Margo 2004). Enucleation of the eye has long been the standard of care for choroidal melanomas. Even so, the effectiveness of enucleation in improving survival has not been well demonstrated (Zimmerman et al. 1978). Many early stu dies of enucleation did not contain enough quality data to significantly assess the effectiveness of enucleation (Markowitz et al. 1992). However, analysis of several studies did show a strong correlation between survival rates and tumor size (Diener West et al. 1992), which has provided one of the best estimates for all cause mortality rates after enucleation procedures. From the analysis, five year mortality rates were seen to be 16% for small tumors, 32% for medium tumors, and 53% for large tumors. A long term study from the Helsinki University Central Hospital followed patients of ocular melanomas who had undergone enucleation between 1962 and 1981 (Kujala et al. 2003). Of the 239 total patient deaths, 145 of those (61%) were attributed to

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19 melanoma s. The mortality data also showed that significant number of patient deaths after five or more years post enucleation were a result of metastatic disease. A desire to improve survival while also maintaining vision for the patient has led to the use of oc ular radiotherapies in the treatment of ocular melanomas. Several types of external beam radiotherapies and stereotactic radiosurg er ies are used, but the predominate radiation treatments for ocular melanomas are the use of surgically placed brachytherapy plaques and proton beam therapy. Brachytherapy plaques typically use radioactive I 125, though other sources are used. Treatment is usually done with a low dose rate of 0.4 1.0 Gy/hr, using the low dose rate to simulate multiple fractions (Stannard et al 2013). Proton therapy uses a spread out Bragg peak to tightly conform to the tumor with minimal dose to surround tissues. As such, proton therapy results in the lowest dose to normal tissue of the radiotherapy treatments (Stannard et al. 2013). Proton therapy is typically used in cases of large melanomas or pediatric patients. 1.4 Purpose of This Work Dosimetry characterization of ocular radiotherapies for treating these diseases is an important component of the development of the treatments and of th e approval process of the Food and Drug Administration (FDA). Previous Monte Carlo simulations have been used to determine optimal beam characterizations for therapy applications and dosimetry characterization for tissues inside and outside of the eye. I n the present work, new models of the eye have been created in order to determine dosimetry for tissues of the eye that were too small to be properly modeled using the previous series of voxelized eye models. In addition, dosimetry characterization is don e for new methods of ocular radiotherapy not considered in the previous work.

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20 Chapter 2 gives an overview of ocular radiotherapy, detailing the early problems within the field and the progression to the techniques explored in this dissertation. In additi on to a general overview, special attention is paid to the radiation delivery methods that will be the focus of later chapters of the dissertation. Chapter 3 describes the five stylized models of various axial lengths that were developed for ocular radiot herapy simulations. Each of these models was used in developed by Oraya Therapeutics, Inc. Dose was assessed to six non targeted tissues of the eye for each eye model to dete rmine how changes in axial length influence dose received by these tissues. In addition to axial length, the beam polar angles were varied to determine what effect the beam polar angle may have on the dose to non targeted tissues of the eye. Simulation r esults for the different treatment scenarios are presented in a series of dose volume histograms (DVHs). Chapter 4 analyzes two other possible ocular radiotherapies for the treatment of AMD, brachytherapy using a 90 Sr/90 Y radioactive source and proton t herapy. Each potential therapy is simulated for all five eye models, with the results again being displayed using DVHs for the non targeted tissues. Additionally, the three AMD ocular radiotherapies are compared based upon the doses received by the non t argeted tissues. irradiate the optic disc instead of the macula. This adjustment led to beam clearance issues, and resulted in a comparison between multi beam and single beam treatment

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21 scenarios. For scenarios that achieved proper beam clearance, simulations were used to determine the dose to non targeted tissues of the eye to determine how many of the treatment scenarios would produce doses below threshold for all of the non targeted tissues. Chapter 6 uses Monte Carlo simulations to determine dose coefficients for Y 90 microspheres injected into the ocular melanoma site. For many applicat ions, the limited range of the pure beta emitter Y 90 leaves little concern for surrounding tissue, but the size of the eye is small enough that even the range of the beta radiation from Y 90 could be a concern. Ocular melanomas of varying size and locati on were introduced into the eye models previously developed. Monte Carlo simulations were run assuming a heterogeneous distribution of Y 90 throughout the melanoma, and the average dose to each tissue was found to determine dose coefficients. Overall, th is research will provide a better understanding of the treatment physics and the risk to non targeted tissues for multiple ocular radiotherapies.

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22 CHAPTER 2 BACKGROUND OF OCULAR RADIOTHERAPY 2.1 Overview of Ocular Radiotherapy Ocular radiotherapy has pr oduced many mixed results over the years, including methods explored as potential treatments for AMD (Akmansu et al. 1998, Berson et al. 1996, Chakravarthy et al. 2000, Donati et al. 1999, Eter et al. 2001, Finger et al. 1998, Finger et al. 1999, Freire et al. 1996, Gripp et al. 2002, Hart et al. 2002, Hoeler et al. 2005, Hoyng et al. 2002, Jaakkola et al. 2005, Kobayashi and Kobayashi 2000, Lambooji et al. 2001, Marcus et al. 1999, Marcus et al. 2004a, Marcus et al. 2004b, Mauget Faysse et al. 1999, Munshi et al. 2007, Postelmans et al. 1999, Prettenhofer et al. 2004, Roos et al. 1999, Sari et al. 2001, Sivagnanavel et al. 2004, Staar et al. 1999, Stalmans et al. 1997, Valmaggia et al. 1997, Valmaggia et al. 2002). In addition, many early studies led to co nflicting information about tissue dose thresholds while also resulting in problematic secondary complications (Nakissa et al. 1983). Complications arose from the inability of delivery methods to accurately target such small areas, which often led to seco ndary complications. This has been a serious issue for external beam therapies in particular, in which limitations on beam size (generally greater than 1 cm in diameter) has greatly complicated targeting and dose delivery. In addition, patient head and e ye motion have contributed to targeting issues in the past, especially in cases of multiple fraction treatments. One technique to combat this problem has been the use of facial masks that restrain the patient head and works in tandem with a light source t hat the patient is asked to focus upon during treatment, passively restraining the eye (Schulte et al. 2000). However, this still allows the eye to stray, and requires further adjustments of the treatment beam. In treatments that required multiple fracti ons, it is

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23 unlikely that there was exact overlap for all of the treatments sessions. The lack of overlap in the multiple sessions would also lead to a larger portion of the retina being needlessly irradiated which can increase the risks of radiation reti nopathy (Parsons et al. 1994, Archerz and Gardiner 1994). These problematic results have led to a stigma in the ophthalmologic community concerning external radiation therapy. Brachytherapy plaques sewn onto the scleral surface have shown improvements in targeting and total dose delivery confidence (Finger et al. 1996). However, the procedure is quite invasive, requiring surgical placement of the plaque. In addition, the placement of the plaque is temporary (usually a few days), and requires a second surgical procedure to remove the plaque. Another issue is the lateral spread from the radiation source. This can become a serious issue if the source is placed close to the optic nerve. The use of brachytherapy plaques also requires patient specific tre atment plans for the loading of the plaque. invasive radiotherapy treatment for AMD. With previous studies having shown that radiation has been successful in inducing d to take advantage of these results while also addressing secondary complications that arose from limitations on previous techniques (Sivagnanavel et al. 2004, Finger et al. 2003, Chakravarthy et al. 2000, Gertner et al. 2010). The treatment uses three 1 00 kVp photon beams which overlap at the macula to deliver a dose up to 24 Gy with the goal of destroying the CNV under the RPE. The three beams each deliver up to 8 Gy to the target, and were chosen in order to decrease dose to the sclera upon entry, the lens, the ciliary body, the orbital bone, and brain tissue.

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24 The orientation of the beams can be described in a spherical three dimensional polar coordinate system with the z axis aligned with the geometric axis of the eye, but transposed to intersect with the fovea (Figures 2 1 and 2 2). An in house study at Oraya Therapeutics was done to determine the fovea offset from the posterior pole, the point at which the geometric axis intersects the retina. The results of the study showed that the fovea is locat ed 1.25 mm laterally and 0.5 mm inferiorly from the poster pole. Later studies with a larger sample size have confirmed the findings of the original in house study (H27). The standard polar angle for each beam is currently 26 degrees, but variations in p olar angle will be explored during the course of this work. Each beam is located at a different azimuthal angle, with the azimuthal angles being defined in the coronal plane such that 0 degrees is superior to the patient and 90 degrees is towards the nose of the patient for a treatment of the right eye. The three beams are located at azimuthal angles of 150 degrees 180 degrees (6 and 210 degrees respectively. A visual re presentation of the beam angles can be seen in Figure 2 3. Besides the point of origin, all three of the beams are identical. The anode has a 1 mm 2 focal spot that is located 150 mm from the macula target. There is also filtration of 0.75 mm aluminum and 0.8 mm beryllium as the beam exits the device. The beams are divergent, such that the beam diameter is approximately 3.5 mm upon scleral entry (this may vary slightly as the axial length of the eye changes) and 4 mm diameter at the macula target. D uring treatment, the patient is seated at the machine and the head is gently secured (Figure 2 4). After the head has been properly placed, the targeted eye is very

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25 gently immobilized using the I att ached to a central post and a control yoke with three optically sensed fiducial markers (Figure 2 but also allows any further motion to be tracked during real time using the fiducial m arkers and a two camera system. Any motion that would result in substantial dose outside of the target region will trigger a gating event of the system. This allows targeting error due to patient motion to remain below 0.4 mm at the retina. Additionally a lid retractor is used at the bottom of the eye in an attempt to gain as much polar angle clearance as possible. 2.3 In In radioactive source to a specific tumor site or deliver im aging agents. The polymer itself is 90 95% water and 5 10% non toxic synthetic polymer powders. The radionuclide (Y 90 currently being used) is contained within an insoluble colloidal phosphate microsphere that is 0.5 1.5 micrometers in diameter (Figure 2 6). The microspheres are added to the liquid polymer and then the mixture is placed by direct intra tumoral injection. After injection into the site, the mixture begins to perfuse and displaces extracellular fluids. As the mixture reaches body tempera ture (approximately 36 37 degrees Celsius), the polymers cross link and form a solid gel (solid phase water). The cross linked polymers entrap the microspheres, holding the radionuclide in place in the tissue. This process allows the delivery of a highl y localized dose while sparing surrounding tissues. One of the advantages of In therapeutic index to patients, where the therapeutic index (TI) is defined as

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26 Eq. 2 1 A study done with injections into the pro state of a beagle dog showed promising results for the gel. Nine days after injection into the prostate, the containment of the Y 90 microspheres was found to be good with a uniform distribution in the prostate. In addition, no significant radionuclide d istribution to non targeted organs was found. Given these advantages, one possible application of the In treatment of ocular melanomas. The properties of the polymer would allow direct injection of the melanoma through the front of the eye (Figure 2 7). However, limited study has been done in the area of this application. To that end, this work will endeavor to determine what kind of dose coefficients would result from the use of In treating ocular melanomas and if Y 90 is a su itable radionuclide for this application.

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27 Figure 2 1. Axial cross section of the eye (Adapted from Clinical Anatomy of the Eye by Richa rd S. Snell and Michael A. Lemp)

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28 Figure 2 2. Retinal geometry showing the shift of th e fovea from the posterio r pole

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29 Figure 2 3. Diagram A shows a sagittal view of a single beam from the anode to the t arget. Diagram B shows the front view with the three beams incident upon the eye

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30 Figure 2 4. treatment Photo courtes y of Oraya Thearpuetics, Inc. Figure 2 5. The I Photos courtesy of Oraya Therapeutics, Inc.

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31 Figure 2 6. Colloidal Y 90 microspheres Photo courtesy of Darrell Fisher.

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32 Figure 2 7. Injection of In

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33 CHAPT ER 3 EFFECTS OF EYE SIZE AND BEAM POLAR ANGLE VARIATION TREATMENT Age related macular degeneration (AMD) is a leading cause of vision loss for the elderly population of industrialized nations (Congdon et al. 2004). The current standard of care fo r the wet form of the disease is monthly injections of anti VEGF (Brown et al. 2004, Rosenfield et al. 2005, Rosenfield et al. 2006). Unfortunately, this does not destroy the underlying choroidal neovascular membrane, so it is necessary to continue therap y indefinitely. While radiation has been shown to be successful at inducing involution of the choroidal neovascularization, it historically has resulted in unimpressive gains in visual acuity (Chakravarth and MacKenzie 2000, Finger et al. 2003, Sivagnanav el et al. 2004). However, recent improvements in radiation targeting have led to a significant improvement in dose conformity to the treatment site (Avila et al. 2009a, Gertner et al. 2010, Hanlon et al. 2009, Kishan et al. 2012, Lee et al. 2008). Use of radiation treatments in tandem with anti VEGF therapies has been evaluated as a possible improvement upon anti VEGF therapy alone (Avila et al. 2009b). Results showed that epiretinal delivery of beta radiation is promising in terms of visual acuity, and suggests that 24 Gy to a small portion of the retina is very well tolerated (Avila et al. 2012, Avila et al. 2009a, Avila et al. 2009b). A radiation delivery device for the treatment of AMD has been developed which noninvasively delivers a one time single fraction dose to the macula (IRay, Oraya Therapeutics, Inc., Newark, CA) (Gertner et al. 2010, Moshfeghi et al. 2011). The goal of the system is to deliver a dose significant enough to arrest choroidal neovascularization without damaging other non targete d tissues of the eye and head.

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34 The IRay device delivers up to 24 Gy over approximately five minutes using three narrow field 100 kVp photon beams (Gertner et al. 2010, Hanlon et al. 2009, Taddei et al. 2010). The three beams enter through the inferior pa rs plana and overlap on the macula. In a multi center prospective, randomized, controlled clinical trial of 230 patients in Europe, the IRay therapy was shown to significantly reduce the need for anti VEGF injection. In the full cohort, anti VEGF injecti ons were reduced by 32%; in an analysis of best responders, anti VEGF injections were reduced by 54% and a mean vision gain of 6.8 ETDRS letters was achieved relative to the non radiation control group (Kaiser and Shusterman 2012). Each beam of the IRay is robotically positioned such that the macula is 150 mm from the x ray source regardless of eye size. The eye of the patient is gently immobilized by a suction enabled lens (I Guide, Oraya Therapeutics, Inc., Newark, CA) (Gertner et al. 2010). Concurrentl y, the IRay device uses an active tracking system during the procedure. If the position of the eye deviates beyond preset threshold limits, a gating event is registered which halts beam delivery to ensure patient safety. The peak energy used during IRay treatment is 100 kV, less than the peak energy used during a standard chest radiograph. Typical external beam radiation therapy (EBRT) involves peak energies of several MV, greater than the IRay by more than a factor of ten. The lower energy of the IRay results in significantly less scatter than would be the case for other EBRT treatments, thus resulting in lower doses to non targeted tissues. In a previous study by Hanlon et al. (2011), treatment simulations were performed with patient specific voxel mod els to explore dose to non targeted tissues as a result of

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35 varying gaze angle, ocular anatomy, and cranial anatomy. In the present study, dose assessment has been expanded to include tissues that could not be evaluated using the voxel models because the r esolution was too course to accurately define many of the smaller structures in ocular anatomy. To overcome this issue, a library of stylized models was created for this work which included the total lens, radiosensitive volume of the lens, optic nerve, d istal tip of the central retinal artery, non targeted portion of the retina, and the ciliary body. The dose dependence of these non targeted tissues was examined as a function of both eye size (axial length ranging from 20 mm to 28 mm in 2 mm increments) and treatment beam polar angle (ranging from 18 degrees to 34 degrees in 2 degree increments) for a total of 45 different treatment combinations, all of which included 3 beams with the nominal azimuthal entry angles. 3.1 Materials and M ethods A series of f ive stylized eye models was constructed with axial lengths ranging from 20 to 28 mm in increments of 2 mm with the axial length being defined as the distance from the front of the cornea to the front of the retina (Figure 3 1). The eye models were based u pon the eye model from Lee et al. (2008), but with a more sophisticated design for the optic nerve based upon data accumulated in Hanlon et al. (2009). The optic nerve was modeled as a right truncated cone that decreases in radius as it leaves the eye, as opposed to the fixed diameter cylinder model used previously. Each model was scaled according to the change in axial length. While some structures such as the lens were scaled in all three dimensions, other structures such as the retina were scaled two dimensionally while maintaining a constant tissue thickness. Volumes of the tissues as a function of eye size are given in Table 3 1. Unlike the other tissues considered, the size of the CRA is the same for each eye model. Further, in each

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36 model, the ma cula target was offset from the geometric axis of the eye by 1.26 mm laterally and 0.56 mm inferiorly. In the ophthalmology community, the fovea is known to be offset from the posterior pole of the eye, and this offset was quantified with an in house stud y of 55 healthy volunteers ( Arnoldson et al. IOVS 2009;50:ARVO Abstract 3789). Finally, a ciliary body structure was added to each model. The ciliary body was modeled as a band of muscle surrounding the edge of the lens which connects to the sclera of th e eye. The Monte Carlo N Particle eXtended (MCNPX) is a general purpose radiation transport code used to model the interactions of radiation over a broad range of energies, developed at the Los Alamos National Laboratory (Los Alamos, NM) (Pelowitz 2008). The features of MCNPX presented an efficient method to construct a set of eye models and simulate ocular radiotherapy for AMD. All simulations of ocular radiotherapy were conducted with MCNPX version 2.6.0. with 5x10 7 sampling histories. Mesh tally calcu lations were used to create DVHs for six non targeted structures within the eye: lens, sensitive volume (SV) of the lens, optic nerve, distal tip of the central retinal artery (CRA), non targeted portion of the retina (retina), and the ciliary body (Figur e 3 1). The non targeted portion of the retina was defined as the entire retina minus the macula target. MCNPX has three different mesh tally functions (cuboidal, cylindrical, and spherical), all of which were used in to overlay the critical structures o f interest. Post processing of the data was necessary to select the appropriate voxels for each mesh tally and to scale the dose according to the macula target. The SV of the lens, based on a model developed by Behrens et al. (2009), was not defined expl icitly in

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37 the MCNPX geometry, but was included through the post processing code. In addition, dose to the macula was scored for scaling purposes. Simulations were run for cases in which mesh tallies only scored photon energy deposition and in which mesh tallies scored energy deposition from both photons and secondary electrons. For the transport of photons, MCNPX default settings were used as the accuracy of these settings has been shown in previous studies (Hanlon et al. 2011, Hanlon et al. 2009, Lee et al. 2008). However, electron transport was done using both the default MCNPX settings and ITS indexing. In addition, the number of electron energy substeps (estep) was varied across an order of magnitude with little difference seen in the outputs. It w as found that the inclusion of secondary electron transport and scoring did not significantly change the values of the doses to the non targeted tissues of the eye, in agreement with the results from Lee et al (2008). As a result, secondary electron trans port was not performed for the majority of the treatment scenarios for computation efficiency, and the results presented in this paper are from simulations in which secondary electrons were not transported. An in house MATLAB code was written for the purpo se of constructing DVHs from the mesh tally data (a sample of which can be seen in Appendix B) Since the dose to the macula is known (8 Gy for each beam), dose scored to the macula tally was used to find an appropriate scaling factor which was then appli ed to all other tissues. The code used the geometry of the problem to appropriately select voxels from each mesh tally. Only voxels that were completely within the true geometry of the desired structure were selected. For spherical and cylindrical talli es, it was also necessary to create a weighting system for the voxels because not every voxel has the same volume.

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38 Appropriately scaled voxels (scaled for dose and, if necessary, volume) were then used to construct data for each of the non targeted tissue s. The same mesh tally was used to construct the DVHs of the lens and the SV of the lens, using different geometrical parameters. It should be noted that the geometry of the lens is the entire lens, including the SV of the lens. The source definition con sisted of three beams at the nasal, central, and temporal positions (azimuthal angles of 150, 180, and 210 degrees respectively) with polar angles 18, 20, 22, 24, 26, 28, 30, 32, and 34 degrees relative to the geom etric axis of the eye The spectrum used was generated with the Institute of Physics and Engineering in Medicine computer software described in Report No. 78 (Cranley et al. 1997). The x ray emission spectrum was characterized using a tungsten anode tube operated at 100 kVp, anode angle of 12 de grees, and total filtration of 0.75 mm aluminum and 0.8 mm beryllium. The beam source was an area of 1 mm by 1 mm, representing a 1 mm 2 focal spot. The divergent beam was collimated with a tungsten aperture such that the beam diameter was 4 mm at the mac ula target, with a source to target distance of 150 mm in all cases. Output from each treatment simulation was compared to see if there was any significant difference in dose to the six non targeted tissues as eye size or polar beam angle changed. 3.2 Resu lts Graphical representations of the dose to non targeted tissues as a function of eye size for the 26 degree polar entry angle are shown in Figure 3 2. Study results indicate that as the size of the patient's eye increases, there is an insignificant inc rease in dose by percent volume for both the optic nerve and CRA. This increase is due to corresponding increases in x ray scatter of the primary beam. An eye with a longer

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39 axial length also has a longer tissue path length, which results in more scatter ed radiation. In addition, the distance between the macula target and both the CRA and optic nerve does not change across the different eye models. The dose by percent volume of the lens, SV of the lens, and ciliary body generally decrease as the eye size increases. For these tissues, the increase in scatter does not have as large of an effect as the increase in tissue volume. Most of the difference in scatter due to tissue path length for different sized eyes occurs downstream of the lens and ciliary bo dy. Furthermore, for larger eyes, the three beams intersect the ciliary body further from the macula target and thus overlap less on the ciliary body. Output data of dose to the non targeted retina shows a decreasing trend as the axial length increases. Though there is enhanced scatter from longer tissue path length, there is a larger distance between the beam path and the peripheral parts of the retina and a larger retina volume. However, larger point doses are seen in the retina as the axial length inc reases, though the affected volumes are very small (less than 1%). This pattern is primarily due to areas of the retina immediately adjacent to the macula target. Dose tally errors varied between the different structures. For the optic nerve, errors were as large as 3%, but were typically less than 1%. Errors for the lens and SV of the lens were as large as 4%, but were usually less than 3%. For the retina, errors rose as large as 10%, but were typically at 4% or less. Errors for ciliary body values ro se as large as 9%, with values typically at 5% or less. Errors for the CRA were the largest ranging between 8% and 10%. While these errors are larger, the volume of the

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40 voxels was extremely small for the CRA which resulted in consistently larger statisti cal errors. Graphical representations of the doses to non targeted tissues as a function of beam polar angle for the 22 mm axial length eye are shown in Figure 3 3. Only the results for the 22 mm eye are shown, but the results of the other eye sizes are v ery similar. Doses to the lens, SV of the lens, and ciliary body decrease as the beam polar angle increases. Doses to the non targeted retina increase as the beam polar angle increases for two reasons. First, the overlapping beam spot is more ellipsoida l at the back of the eye for larger polar angles, and so some voxels of the mesh tally defining the non targeted portion of the retina that are closest to the macula receive a larger dose. Second, some voxels defining the anterior portion of the retina sc ore a larger dose because they are in the path of the entering beams. Dose variations for the CRA and the optic nerve were smaller than the associated errors, indicating that they do not significantly change for different beam entry polar angles. 3.3 Disc ussion For the different sized eye models, small fluctuations can be seen in the doses to non targeted tissues. It can also be seen that not all tissues have the same trend, as some increase in dose while other tissues decrease in dose with changes in eye size. Overall, the fluctuation in dose is not large enough to have a significant effect on treatment. The sensitivity of the optic nerve to radiation has been previously studied for cases in which the optic nerve was unavoidably or accidently exposed (Gi rkin et al. 1997). From these cases, it was suggested that optic nerve doses of 8 Gy may create problems in the optic nerve. Of the forty five eye size/polar entry angle combinations,

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41 each of which included 3 beams with the nominal azimuthal entry angle s, explored in this study, none resulted in any portion of the optic nerve receiving a dose exceeding 1 Gy. None of the treatment scenarios resulted in any portion of the CRA receiving 1 Gy or more. The ICRP has sighted animal studies in which no retina l vascular changes were seen in rats irradiated with an 8 Gy proton beam (ICRP 2012). Therefore, it seems unlikely that there would be any radiation induced complications to the CRA for patients treated with the IRay system. For some of the larger polar beam angles, portions of the non macular retina receive a dose approaching the macular target dose. However, the percent volume receiving this larger dose is very small. Less than one third of all eye size/polar entry angle combinations resulted in doses 1 Gy or greater to more than one percent of the retinal volume. Furthermore, only two of the combinations (34 degree polar angle for the 20 and 22 mm eye) showed more than 1% of the retinal volume receiving 10 Gy or more. Given that the majority of the retina receives a very small dose and the absence of complication in other EBRT and brachytherapy studies (Evans et al. 2010, Finger et al. 1996, Finger et al. 1999, Finger et al. 2003, Finger et al. 2005, Jaakkola et al. 1998, Jaakkola et al. 2001, Jaakko la et al. 2005, Zambarakji et al. 2006), it seems unlikely that any radiation induced sight limiting complications would be expected in patients treated with the IRay system. Indeed, in a three year follow up of 34 patients receiving 24 Gy from intravitre al brachytherapy, only one patient showed any microvascular changes associated with radiation; their visual acuity was unaffected (Avila 2012).

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42 For most scenarios, no portion of the ciliary body received more than 35 Gy, with the largest doses seen in the 20 mm eye due to overlap of the dose profiles of the beams. Maximum doses trended down through the 24 mm eye, but increased in the 26 and 28 mm eyes. The decrease is caused by less overlap of the beam dose profiles, with the increase coming as a result o f larger surface doses needed for a single beam entry. This dose is larger because the increased tissue path length to the macula target requires longer treatment time and the anterior portion of the larger eyes is closer to the source. For shallow polar angles, portions of the ciliary body in the 20 mm eye received doses approaching 45 Gy, though the volumes receiving these larger doses are less than 0.5% of the total volume. In all cases, less than 25% of the volume of the ciliary body received 1 Gy or greater. The ICRP recommends a dose limit of 55 Gy to muscle tissue based upon evidence from 2 Gy fraction schemes (ICRP 2012). While the IRay is a single fraction treatment, the ciliary body is a parallel tissue and large point doses should not affect the entire ciliary body systematically. This is supported by the results of the INTREPID trial, in which no adverse radiation related events were seen (Kaiser and Shusterman 2012). A potentially significant dose to the lens was measured in treatment simu lations of small polar beam angles that are outside the current range of clinical use for the IRay. While the volumes receiving large doses were generally small, there is still a possibility of causing opacities that could eventually lead to cataracts if smaller polar beam angles were allowed. There has been an increased focus upon dose received by the lens, as the ICRP has recently lowered their recommended threshold for radiation induced cataracts down to 0.5 Gy for both acute and fractionated exposures (ICRP, 2012). The

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43 results of this study show that, for beam polar angles of 26 degrees or greater, no portion of the sensitive volume of the lens would receive a dose of 0.5 Gy or greater. A proprietary beam algorithm to check beam clearance is employed by the IRay which prevents treatment at shallow polar beam angles that could potentially cause complications. 3.4 Summary Given the small effects of eye size on tissue dose, the natural variation in the typical patient population will have a minimal impa ct on non targeted tissue dose. While beam polar angle can have a significant effect on tissue dose, steps have already been taken to ensure that only beam polar angles resulting in a dose of less than 0.5 Gy to the sensitive volume of the lens are used c linically. Therefore, proper selection of beam polar angle within the typical patient population will reduce concern for dose to non targeted tissues with stereotactic radiosurgery for wet AMD.

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44 Table 3 1. Volume of eye tissues as a function of axial le ngth (cm 3 ) Axial Length Ciliary Body Lens SV of Lens Retina Optic Nerve CRA 20 mm 0.1501 0.1290 0.0151 0.1586 0.2153 3.02E 5 22 mm 0.1812 0.1736 0.0206 0.2112 0.2607 3.02E 5 24 mm 0.2276 0.2213 0.0244 0.2531 0.3103 3.02E 5 26 mm 0.2710 0.2931 0.0394 0. 3232 0.3642 3.02E 5 28 mm 0.2952 0.3562 0.0447 0.3947 0.4224 3.02E 5

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45 Figure 3 1. 22 mm axial length stylized eye model

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46 Figure 3 2. Absorbed dose to non targeted tissues of the eye as a function of axial length with a fixed beam polar angle of 26 degrees

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47 Figure 3 3. Absorbed dose to non targeted tissues of the eye as a function of beam polar angle wit h a fixed axial length of 22 mm

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48 CHAPTER 4 COMPARISON OF AMD RADIOTHERAPIES Age related macular degenerat ion (AMD) is a leading cause of vision loss for the elderly of industrialized nations (Congdon et al. 2004). Currently, the standard of care for the disease is monthly injections of a vascular endothelium growth factor inhibitor (VEGF inhibitor) (Brown et al. 2004, Rosenfield et al. 2005, Rosenfield et al. 2006). However, this treatment does little to destroy the underlying choroidal neovascularization, and must be continued indefinitely. Studies have shown that radiation can be successful at inducing in volution of the choroidal neovascularization, but it has also resulted in unimpressive gains in visual acuity in the past (Chakravarth and MacKenzie 2000, Finger et al. 2003, Sivagnanavel et al. 2004). However, improvements in radiation targeting since th ese studies have led to a significant improvement in dose conformity to the treatment site (Avila et al. 2009a, Gertner et al. 2010, Hanlon et al. 2009, Kishan et al. 2012, Lee et al. 2008). In addition, the use of radiation along with VEGF inhibitor ther apies has been evaluated as an improvement over only using VEGF inhibitors (Avila et al. 2009b). This study and other have also shown that epiretinal delivery of beta radiation is promising in terms of visual acuity, and results suggest that 24 Gy to a sm all portion of the retina is very well tolerated (Avila et al. 2012, Avila et al. 2009a, Avila et al. 2009b). 4.1 Materials and M ethods The f iv e stylized models used in Chapter 3 with axial lengths ranging fro m 20 to 28 mm were used for this study as well (Figure 3 1). The Monte Carlo N Particle eXtended (MCNPX) is a general purpose radiation transport code used to model the interactions of radiation over a broad range of energies, developed at the Los Alamos National

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49 Laboratory (Los Alamos, NM) (Pelowitz 2008). The features of MCNPX presented an efficient method to construct a set of eye models and simulate ocular radiotherapy for AMD. All simulations of ocular radiotherapy were conducted with MCNPX version 2.7.0, using 5x10 7 sampling histories. Mesh ta lly calculations were used to create DVHs for six non targeted structures within the eye: ciliary body, lens, sensitive volume (SV) of the lens, non targeted portion of the retina (retina), optic nerve, and the distal tip of the central retinal artery (CR A) (Figure 1). The SV of the lens, based on a model developed by Behrens et al. (2009), was not defined explicitly in the MCNPX geometry, but was included through the post processing code. In addition, dose to the macula was scored for scaling purposes. An in house MATLAB code was developed in order to process the MCNPX mesh tally data. Since the dose to the macula is known for each treatment (24 Gy), the macula tally was used to find an appropriate scaling factor, which was then applied to all other ti ssues for each treatment. The code used the geometry of the problem to appropriately select voxels from each mesh tally, and only voxels that were completely within the true geometry of the desired tissue were selected. For spherical and cylindrical tall ies, it was also necessary to create a weighting system for the voxels because not every voxel has the same volume. The scaled voxels were used to construct DVHs for each of the non targeted tissues. The same mesh tally data was used to construct the DVH s of the lens and the SV of the lens by the use of different geometrical parameters. It should be noted that the geometry of the lens is the entire lens, including the SV of the lens.

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50 The brachytherapy source consisted of four 0.5 mm diameter beads with a 90 Sr/ 90 Y source, with the isotopes being in secular equilibrium based upon the design presented by Hamilton et al. (2012) The beads are contained in a 1.8 mm diameter steel cannula. The spectrum was obtained using the software provided by ICRP 107 (2 008). The center of the device was placed outside of the eye, directly behind the center of the macula for each model. However, it was necessary to shift the device slightly in the larger eye models so that the geometry of the cannula did not overlap wit h the modeled geometry of the eye. nasal, central, and temporal positions (azimuthal angles of 150, 180, and 210 degrees respectively) with a polar angle of 26 degrees relative to the ge ometric axis of the eye. The 100 kVp spectrum was generated using the Institute of Physics and Engineering in Medicine computer software described in Report No. 78 (Cranley et al. 1997). The x ray emission spectrum was characterized using a tungsten anod e tube operated at 100 kVp, anode angle of 12 degrees, and total filtration of 0.75 mm aluminum and 0.8 mm beryllium. The beam source was an area of 1 mm by 1 mm, representing a 1 mm 2 focal spot. The divergent beam was collimated with a tungsten aperture such that the beam diameter was 4 mm at the macula target, with a source to target distance of 150 mm in all cases. The proton source consisted of a single beam in the central position at a polar angle of 30 degrees relative to the geometric axis of the eye. The source was monoenergetic, but with energies varying between models due to different beam path lengths to the macula. Energies used for simulations were 42.6, 44.9, 47.2, 49.3, and

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51 51.4 MeV and were chosen so that the Bragg Peak would occur at t he macular depth The beam was modeled as a Gaussian beam with a 6 mm full width half maximum, and kept at a constant diameter of 6 mm (the input used for the radiation transport of the proton beam in the 20 mm eye can be seen in Appendix A) 4.2 Results Graphical representations of the dose to non targeted tissues as a function of eye size for the three tre atments are shown in Figures 4 1 through 4 3 The results show that there is some change in the absorbed dose of the non targeted tissues as eye size changes. However, the study results also indicate that as the size of the patient's eye changes, there is no clinically significant change in the dose to the non targeted tissues for any of the three treatments. Small doses are received by the ciliary body, lens, and sensitive volume of the lens during brachytherapy treatment All three structures are much further from the source than the maximum beta range for the 90 Sr/ 90 Y emissions, and the dose contributions are a result of Bremsstrahlung photons e mitted by electrons. The dose by percent volume of the lens, SV of the lens, and ciliary body generally tissue volume outweighs the increase in scatter due to extended b eam path through the beams begin to intersect on the tissue for smaller axial lengths, causing a decrease and then increase in dose as eye size increases. No dos e is deposited in the lens or SV of the lens for proton treatment. The beam does not directly intersect the lens and there is not sufficient scattering of the proton beam for the lens to receive any dose. The ciliary body does receive some dose, which

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52 de creases as the size of the eye increases. This is expected given the Bragg peak energy deposition of protons and the use of higher energies as axial length increases. For all three treatments, dose to the retina by perc ent volume decreases slightly as eye size increases. For each case, this is most likely the result of the constant target size and the increase in retinal volume as axial length increases. as axial length in creases. Both of these trends can be attributed to increased scatter at the target for each beam. In the case of brachytherapy treatment small fluctuations are seen but the dose is fairly consistent over the range of eye sizes. Very little change is see Some fluctuation is seen for brachytherapy treatments. In the case of proton treatment, there is some noticeable change by percent volume. As the eye models were increased in size, the distance between the macula and the opti c disc (and hence the CRA) was kept fixed. Therefore, the larger point doses with increasing axial length is most likely due to an increase in scatter near the end of the beam path and the fact that the distance between the macula target and the CRA does not change. 4.3 Discussion For each of the three treatments, small dose fluctuations can be seen as the axial length of the eye changes. These changes do not show the same trend over all tissues, as some may increase slightly as axial length increases, wh ile some decrease. However, none of these fluctuations are large enough to have a clinically significant effect on the treatment and safety of patients. In addition, none of the simulated treatments resulted in point doses that were above average dose th resholds for the non targeted tissues.

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53 with doses reaching approximately 35 Gy, while maximum doses were significantly less in the proton (less than 10 Gy) and brachytherapy ( le ss than 0.5 Gy) treatments. However, none of the treatments resulted in more than 25% of the ciliary body volume receiving more than 1 Gy. The ICRP recommends a dose limit of 55 Gy to muscle tissue, which is based upon evidence from 2 Gy fraction schemes (ICRP 2012). While each of these treatments considered would be done in a single fraction, the ciliary body is a parallel tissue and large point doses should not affect the entire ciliary body systematically. This assertion is supported by the results o f the INTREPID trial, in which no adverse radiation related events were seen (Kaiser and Shusterman 2012). The recent lowering of the ICRP recommended dose threshold for radiation induced cataracts to 0.5 Gy for both acute and fractionated exposures has le d to an increased focus upon dose received by the lens (ICRP 2012). The results of this study show that none of the three treatment methods result in point doses to the sensitive volume of the lens of 0.5 Gy or higher. In addition, a proprietary beam alg orithm to beam treatment angles that could potentially cause complications. In each of the treatments, portions of the retina received doses greater than 1 Gy, with the highest point doses seen in the proton treatment. However, the percent volume of the retina receiving these doses is extremely small, typically less than one percent. With the vast majority of the retina receiving very small doses and a lack of retinal complica tion in other EBRT and brachytherapy studies (Evans et al. 2010, Finger et al. 1996, Finger et al. 1999, Finger et al. 2003, Finger et al. 2005, Jaakkola et al. 1998,

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54 Jaakkola et al. 2001, Jaakkola et al. 2005, Zambarakji et al. 2006), it seems quite unlik ely that any radiation induced sight limiting complications would be expected in patients undergoing one of these treatments. Especially when considering that, in a three year follow up of 34 patient trial with patients receiving 24 Gy from intravitreal b rachytherapy, only one patient showed any microvascular changes associated with radiation and, even so, their visual acuity was unaffected (Avila 2012). Studies of the sensitivity of the optic nerve to radiation has been document ed previously by studying c ases in which the optic nerve was either accidently irradiated or unavoidably irradiated (Girkin et al. 1997). Using the information from these cases, it was suggested that radiation induced problems were unlikely until the optic nerve received a dose of 8 Gy or greater. Of the three treatments, not a single one resulted in point doses to the optic nerve greater than 1 Gy, well below the suggested average dose threshold. In none of the three types of radiotherapies did any portion of the CRA receive 2.5 Gy or more. The ICRP has sighted animal studies in which no retinal vascular changes were seen in rats irradiated with an 8 Gy proton beam (ICRP 2012). Therefore, it seems unlikely that there would be any radiation induced complications to the CRA for p atients undergoing any of these three treatments. 4.4 Summary The small variations between the doses to non targeted tissues as axial length changes suggest that there is little concern for the natural variation of eye size in the patient population for a ny of the three treatments. Of the three treatments, the proton treatment resulted in the lowest dose to the non targeted tissues in four out of the six cases (Figure 4 4) However, each of the three treatments resulted in the non targeted

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55 tissues receiv ing doses well below suggest ed thresholds, making all three potentially viable treatments for AMD.

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56 Figure 4 1. Absorbed dose to non targeted tissues of the eye for brachytherapy treatment

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57 Figure 4 2. Absorbed dose to non targeted tissues of the eye as a function of axial

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58 Figure 4 3. Absorbed dose to non targeted tissues of the eye as a function of axial length for a fixed 3 0 degree be am polar angle proton treatment

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59 Figure 4 4. Comparison of the absorbed dose to non targeted tissues of the eye for a fixed axial length of 22 m m between the three modalities

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60 CHAPTER 5 GLAUCOMA TREATMENT STUDY Glauco ma is a leading cause of vision loss that is estimated to affect over 60 million people worldwide (Quigley and Broman 2006). Age and high intraocular pressure (IOP) are two of the major risk factors for glaucoma. Most treatments attempt to lower IOP, but are often not effective (Whitmore et al. 2005). The development of therapies that target processes that mediate and propagate the initial damage to retinal ganglion cells (RGCs) and their axons in the optic nerve may be able to prevent glaucoma in many p atients (Howell et al. 2012). Several studies have shown successful treatment of glaucoma with radiation, whether used by itself or in parallel with other treatments. Radiation treatments used in conjunction with surgical procedures resulted in lower rate s of surgical failure than in those patients who had surgical procedures without radiation treatment (Kirwan et al. 2012). Electron irradiation has also been used to successfully treat a case of otherwise untreatable glaucoma (Gartner and Kutzner 1997). Recent animal studies have shown that an x ray treatment can inhibit monocyte entry into the optic nerve head and reduce levels of microglia activation in a mouse model of glaucoma (Bosco et al. 2012, Howell et al. 2012). These studies indicate promise in using radiation therapy techniques as a treatment for glaucoma. As these studies progress and show more promise for the use of radiation treatments in glaucoma, it is necessary to analyze methods in which such treatments could be delivered safely to pati ents. A non invasive radiation delivery device has been developed for treatment of patients suffering from the wet form of age related macular degeneration (AMD) (IRay, Oraya Therapeutics, Inc., Newark, CA). Currently, the system is designed to deliver a

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61 total dose of 24 Gy to the macula using a 100 kVp three beam delivery system, in which each beam delivers 8 Gy (Figure 1). Each beam of the IRay is robotically positioned and the eye of the patient is gently immobilized by a suction enabled contact lens ( I Guide, Oraya Therapeutics, Inc., Newark, CA) (Gertner et al. 2010). In addition, the IRay device uses an active tracking system during any procedure. If the position of the eye deviates beyond the preset threshold limits the x ray beam is gated off to ensure the safety of the patient. By adjusting the targeting parameters of the IRay device, as well as changing the prescribed dose, it is possible that the IRay could be used to treat patients in the early stages of glaucoma. In this study, targeting p arameters were changed such that the system targets the optic nerve head (target). The purpose of this study was to determine if this target can be irradiated with a prescribed dose of 7.5 Gy by the IRay system without delivering significant doses to othe r tissues of the eye. To this end, absorbed dose to non targeted tissues of the eye is assessed for several treatment scenarios. 5.1 Materials and M ethods A stylized eye model of axial length 22 mm was used for this study (Figure 3 1), with the axial leng th being defined as the distance from the front of the corn ea to the front of the retina. The Monte Carlo N Particle eXtended (MCNPX) is a general purpose radiation transport code used to model the interactions of radiation over a broad range of energies, developed at the Los Alamos National Laboratory (Los Alamos, NM) (Pelowitz 2011). The features of MCNPX presented an efficient method to construct the eye model and simulate the proposed ocular irradiation. All simulations of ocular radiotherapy were co nducted with MCNPX version 2.7.0., using sample histories of

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62 5x10 7 for mesh tally calculations. Mesh tally calculations were used to construct dose volume histograms (DVHs) for six non targeted tissues of the eye: the ciliary body, lens, sensitive volume (SV) of the lens, retina, optic nerve, and the distal tip of the central retinal artery (CRA). MCNPX has three different mesh tally functions (cuboidal, cylindrical, and spherical), all of which were used in assessing dose to non targeted structures. Me sh tallies were used to overlay all of the critical structures and the voxels scored energy deposited. Post processing of the data was necessary to select the appropriate voxels for each mesh tally and to scale the dose according to the optic nerve head t arget. The SV of the lens, based on the model developed by Behrens et al. (2009), was not defined explicitly in the MCNPX geometry, but was included through the post processing code. In addition, dose to the optic nerve head target was scored for scaling purposes. An in house MATLAB code was written for the purpose of constructing DVHs from the mesh tally data. Since the dose to the target is known (7.5 Gy total), this dose was used to find an appropriate scaling factor which was then applied to all oth er tissues. The code also used the geometry of the problem to appropriately select voxels from each mesh tally. Only voxels that were completely within the true geometry of the desired structure were selected. For cylindrical and spherical mesh tallies, it was also crucial to create a weighting system for the voxels, as not every voxel had the same volume. Appropriately scaled voxels (scaled for dose and, if necessary, volume) were then used to develop DVHs for each of the non targeted tissues. The sam e mesh tally was used to construct the DVHs of the lens and the SV of the lens, using different

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63 geometrical parameters. The geometry of the lens is that of the entire lens structure, including the SV of the lens. The source definition consisted of three b eams at the nasal, central, and temporal positions (azimuthal angles of 150, 180, and 210 degrees respectively) with polar angles 18, 20, 22, 24, 26, 28, and 30 degrees relative to the geometric axis of the eye The spectrum used was generated with the In stitute of Physics and Engineering in Medicine computer software described in Report No. 78 (Cranley et al. 1997). For each polar angle, doses were assessed for a combination of all three beams (2.5 Gy each), or a single beam (7.5 Gy). For cases in which beam clearance could not be achieved at the given polar angle, that beam was removed from consideration. For situations where only two beams could achieve clearance, doses were assessed for the combination of those two beams (3.75 Gy each), and the singl e beams. Comparisons were made for the dose received by each structure as a function of the polar beam angle and combination of beams. 5.2 Results Beam clearance was an issue for both the nasal and central beams. In only two cases (18 and 20 degrees) did the nasal beam achieve clearance in the eye model, while the central beam achieved clearance for all polar angles except 28 and 30 degrees. The temporal beam achieved clearance for all angles in the study. Graphical representations of the non targeted ti ssue dose volume histo grams can be seen in Figures 5 1 through 5 4 For the case of multiple beams (Figure 5 4) it should be noted that all three beams are used for polar beam angles of 18 and 20 degrees, while a two beam combination of the central and t emporal beams are used for all other polar angles.

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64 Optic nerve doses decreased marginally as the polar beam angle increases, but the maximum doses did not change in a clinically significant way, nor did the maximum doses vary between the beam combinations. Maximum doses to the optic nerve never exceeded 7.5 Gy in any of the treatment scenarios studied, and less than 10% of the volume of the optic nerve received 7 Gy or more. Doses to the CRA did not vary in any clinically significant way for any of the tr eatment scenarios, and in no case was the maximum dose to the CRA larger than 7.5 Gy. Retina doses also did not vary between cases in a clinically significant way, with maximum doses just over 7.5 Gy and less than 5% of the retina volume receiving 2 Gy or more. A trend seen in all beam combinations was that the maximum dose to the lens and SV of the lens decreased as beam polar angle in creased, as expected since larger beam polar angles increases the distance between the lens and the beam path. The larg est doses to the lens and SV of the lens were seen at shallow angles when the temporal beam was used, either separately or in combination with other beams. Maximum doses to the ciliary body also decreased slightly as polar beam angle increases. The most notable difference in the maximum doses to the ciliary body was between beam combinations. Single beam treatments lead to larger maximum doses in the ciliary body, as more dose is required per beam in the single beam treatment than in the multiple beam t reatment. Dose tally errors varied between the different structures. For the optic nerve and the CRA, errors were less than 1%. Errors for the lens and SV of the lens were as high as 6%, but were usually less than 3%. For the retina, errors reached as high as 7%, but

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65 most were 3% or less. Errors for ciliary body values rose as high as 10%, with values generally at 5% or less. 5.3 Discussion Previous studies of the sensitivity of the optic nerve to radiation suggest that average doses of et al. 1997). In none of the treatment scenarios explored did a portion of the optic nerve receive greater than 7.5 Gy. Therefore, it is unlikely that such a treatment would result in radiation induced complications for the optic nerve. The ICRP has cited animal studies in which rats were irradiated in a single fraction with an 8 Gy proton beam with no change seen in retinal vasculature (ICRP 2012). Since no portion of the CRA received more than 7.5 Gy in any of the treatment scenarios, it also seems unlikely that any radiation complications would arise in this tissue from the proposed treatment. Maximum retinal doses were just over 7.5 Gy for most treatment scenarios, but even these doses were only fo r very small portions of the retina volume, less than 0.5%. For most cases, 95% of the retinal volume receives less than 2 Gy. Taken in conjunction with the lack of radiation induced retinal complications seen in EBRT and brachytherapy studies (Evans et al. 2010, Finger et al. 1996, Finger et al. 1999, Finger et al. 2003, Finger et al. 2005, Jaakkola et al. 1998, Jaakkola et al. 2001, Jaakkola et al. 2005, Zambarakji et al. 2006) it seems unlikely that any radiation induced complications would be seen in the retina for this treatment. The largest doses to the ciliary body were seen in single beam treatments, with maximum doses to the ciliary body reaching just over 19 Gy for some of the single beam treatment scenarios. However, the volume receiving thes e large doses is very

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66 small, less than 0.1% of the entire ciliary body. Furthermore, in all single beam cases it was seen that 90% or more of the ciliary body volume received 1 Gy or less. ICRP suggests an average limit of 55 Gy to muscular tissues based upon evidence gathered from 2 Gy fraction schemes (ICRP 2012). Though treatment from the IRay would be given in a single fraction, the ciliary body is a parallel tissue and large doses to very small volumes of the tissue should not affect the entire cili ary body systematically. This is supported by the fact that no adverse radiation related events were seen in the INTREPID trial (Kaiser and Schusterman 2012). Even so, the maximum dose to the ciliary body can be reduced further by using a multi beam trea tment. For multi beam treatments, the majority of beam polar angles produced a maximum dose to the ciliary body less than 13 Gy (with the 22 degree angle reaching 15 Gy), and 80% or more of the ciliary body volume receiving 1 Gy or less. Potentially sign ificant doses to the lens and SV of the lens were found for small beam polar angles (18, 20, and 22 degrees) for both the multi beam treatment and the temporal only beam treatment. In no other cases did the dose to any portion of the SV of the lens exceed 0.5 Gy, the suggested average threshold for radiation induced cataracts for both acute and fractionated exposures (ICRP 2012). 5.4 Summary Proper selection of both beam combination and polar angle is important to keep non targeted tissue doses below acce pted thresholds. Of the nineteen possible treatment scenarios explored in this study, thirteen were shown to satisfy this criterion. It would therefore be possible to investigate potential neuroprotective effects of radiation in the treatment of glaucoma using an existing clinical device.

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67 Figure 5 1. Absorbed dose to non targeted tissues of the eye as a function of beam polar angle in the 22 mm eye for a single beam tre atment using the nasal beam

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68 Figure 5 2. Absorbed dose to non targeted tissues of the eye as a function of beam polar angle in the 22 mm eye for a single beam treatment using the central b eam

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69 Figure 5 3. Absorbed dose to non targeted tissues of the eye as a function of beam polar angle i n the 22 mm eye for a single beam treatment using the temporal beam

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70 Figure 5 4. Absorbed dose to non targeted tissues of the eye as a function of beam polar angle in the 22 mm eye for a multi beam treatment

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71 CHAPTER 6 OCULAR MELANO MA IN Melanoma of the choroid occurs in approximately six individuals out of every million, with a mean age at diagnosis in the mid 50s ( Egan et al. 1988 ). Enucleation of the eye has been a standard of care for choroidal melanomas since the 19 th century. However, the desire to not only improve survival but also preserve the vision of patients has led to other treatment options, including plaque brachytherapy and proton therapy ( Margo 2004 ). I 125 plaques are commonly used for brachytherapy treatment of ocular melanomas. Plaques are surgically inserted and deliver a low dose rate to simulate multiple small fractions ( Stannard et al. 2013 ). Total target doses to the melanoma are typically in the range of 80 to 85 Gy ( Shah et al. 2013, Krema et al. 2013 ). Proton therapy uses a spread out Bragg peak (SOBP), which results in a tight conformity to the tumor (approximately 60 Gy) and minimal dose to the surrounding tissues (Tran et al. 2012) The dose to surrounding tissues is generally much l ower for proton therapy than for brachytherapy ( Stannard et al. 2013 ). A new potential brachytherapy treatment for ocular melanomas uses In synthetic polymer developed at Pacific Northwest National Laboratory (PNNL). In is a polymer composite (90 95% water and 5 10% non toxic synthetic polymer powders) containing Y 90 microspheres in an insoluble colloidal phosphate which is injected directly into the tumor site. After injection, the polymer will then perfuse through the tumor, displacing ext racellular fluid. When In 37 o C), the polymers cross link and form a solid gel (solid phase water), effectively

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72 containing the Y 90 radionuclide ( http://energyenvironment.pnnl.gov/highlights/highlight.asp?id=435 ) 6.1 Ma terials and M ethods A stylized computational eye model of axial length 22 mm was used for this study with the axial length being defined as the distance from the front of the cornea to the front of the retina. The eye model w as based upon the eye model developed by Lee et al. (2008) A more sophisticated design for the optic nerve was used based upon data accumulated by Hanlon et al. (2009) The optic nerve was modeled as a right truncated cone that decreases in radius as it leaves the eye as opposed to the fixed diameter cylinder model used prev iously In addition a ciliary body structure was added to each model. The ciliary body was modeled as a band of muscle surrounding the edge of the lens which connects to the sclera of the eye. Oc ular melanomas of varying sizes were added to the models in five different locations. Melanoma s were placed in right lateral (L1) left lateral (L2), superior (L3) inferior (L4) and posterior (L5) positions with respect to the eye center as shown in Figure 6 1 In reference to the head, the melanoma at L1 is closest to the nose, while the melanoma at L2 is furthest from the nose in right eye of the patient At each tumor location, f ive different melanoma sizes were further considered with ap ical heights of 1 mm (S1), 2.5 mm (S2), 4 mm (S3), 7 mm (S4), and 10 mm (S5 ), as based upon the size classification developed by the Collaborative Ocular Melanoma Study group (COMS ) ( Diener West et al. 2003 ). Volumes of each melanoma are given in Table 6 1 It should be noted that volumes are generally larger at the L5 site due to the fact that the melanoma at L5 is not bounded by the cil i ary body or lens as it often was for the L1 through L4 sites

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73 The Monte Carlo N Particle eXt ended (MCNPX) is a general purpose radiation transport code used to model the interactions of radiation over a broad range of energies, developed at the Los Alamos National Laboratory (Los Alamos, NM) ( Pelowitz 2011) The features of MCNPX presented an ef ficient method to construct the eye model and determine the dosimetric outcomes if the melanoma was injected with the Y 90 In version 2.7.0., and the spectrum for Y 90 was obtained usi ng ICRP 107 ( 2008 ). For simplicity, it was assumed that the Y 90 was uniformly distributed through the melanoma in the source modeling. MCNPX outputs provided S values (absorbed dose per nuclear transformation) for various tissues using the melanoma as t he source tissue. According to MIRD Pamphlet No. 21 ( Bo lch et al. 2009) the radionuclide S value is given as: Eq. 6 1 where is the mass of the target region, E i is the mean energy of the i th nuclear transition, Y i is the number of i th nuclear transitions per nuclear transformation, and is the absorbed fraction at energy E i for a given source/target region combination. Within MCNPX, however, one may directly sample the Y 90 beta spectrum and report the *F8 tally (unit s of MeV deposited per starting beta particle). Consequentl y, the radionuclide S values were directly assessed in this study as: Eq. 6 2 where k is 1.602 x 10 10 Gy per Mev/ g.

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74 Simulations were used to determine the effect of twenty five treatment scenarios on six non targeted tissues of the eye: the ciliary body, lens, sensitive volume (SV) of the lens ( Behrens et al. 2009 ), retina, optic nerve, and the distal tip of the central retinal artery (CRA). Dose coefficients were found for the non targeted tissues using the formulation from MIRD Pamphlet No. 21 ( Bolch et al. 2009 ). The dose coefficient for a given tissue, is given by: Eq. 6 3 where the summation simplifies since there is only one source tissue, the melanoma. The time integrated activity coefficient, can be found using the equation: Eq. 6 4 Because the In 90 in place, there is no biological component to the decay constant, and the loss of Y 90 in the melanoma is dictated solely by the physical decay constant. This resul ts in: Eq. 6 5 90. This simplifies equation 2: Eq. 6 6 and equation 1 reduces to: Eq. 6 7

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75 Therefore, the dose coefficient for each tissue can be found using the physical decay constant of Y 90 and the S value for the tissue with the ocular melanoma as the source. In addition to providing dose coefficients, MCNP X values were scaled to deliver a target dose of 85 Gy to the melanoma ( Shah et al. 2013 ). Doses for the non targeted tissues were scaled accordingly to determine what range of doses might be seen in these tissues during treatment. 6.2 Results Dose coefficients in units of Gy per Bq injected are given in Table 6 2 for all combinations of target tissue, tumor size, and tumor location. For each case, the physical decay constant was converted from th e half life of Y 90 (64.1 hours ) (ICRP 2008) into uni ts of inverse seconds. Sites L1 through L4 deliver similar doses to the ciliary body, lens, sensitive volume of the lens, and retina for a given melanoma size. This is not unexpected giv en the emmetropic shape of the eye models. L5 results in the lowest doses to the ciliary body, lens, and sensitive volume of the lens as it is by far the furthest of the five sites from these tissues. Sites L1 through L4 deliver similar doses to the ciliary body, lens, sensitive volume of the lens, and retina for a given melanoma size. This is not unexpected given the emmetropic shape of the eye models. L5 results in the lowest doses to the ciliary body, lens, and sensitive volume of the lens as it is by far the furthest of the five sites from these tissues. Doses to the optic nerve and the CRA showed more variation since each melanoma site is a differe nt distance to these tissues. However, for each melanoma size, the largest doses received by these tissues came from melanomas at the L5 site, with dose from the other sites often being much smaller or even zero.

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76 In these Monte Carlo simulations, statisti cal e rrors were generally less than one percent for the given tissues. Some tissues, such as the CRA and optic nerve, were associated with errors greater than ten percent in certain cases. However, in each of these situations, the values were small enoug h that even these larger errors are of little consequence clinically. 6.3 Discussion Doses to non targeted tissues for an 85 Gy treatment dose to the ocular m elanoma can be found in Table 6 3 Potentially significant doses to the lens or SV of the lens were noted in four of the twenty five treatment scenarios. For the largest melanoma (S5) in locations L1 through L4, the average dose received by the SV of the lens exceeded 0.5 Gy, the suggested average threshold for radiation induced catara cts for both acute and fractionated exposures ( ICRP 2012 ). Similarly, the largest doses to the ciliary body were seen in the same treatment scenarios in which the lens and SV of the lens received the highest average doses. For the largest melanoma, avera ge doses to the ciliary body approached 9 Gy for locations L1 to L4 ICRP suggests an average limit of 55 Gy to muscular tissues based upon evidence gathered from 2 Gy fraction schemes ( ICRP 2012 ). While this is a single treatment, the dose delivered wou ld be spread out over time and is unlikely to result in radiation reduced complications to the ciliary body. Previous study concerning the effect of radiation on the optic nerve suggests that average doses of 8 Gy or greater may result in damage to the op tic nerve ( Girkin et al. 1997 ). In none of the treatment scenarios did the average dose to the optic nerve exceed 2.5 Gy, making it unlikely that any of the treatment scenarios presented would result in radiation induced complications to the optic nerve.

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77 The ICRP has cited animal studies in which rats were irradiated with an 8 Gy proton beam with no change seen in retinal vasculature ( ICRP 20 12 ). Of the twenty five treatment scenarios, four treatment scenarios at the L5 site resulted in average doses to the CRA of greater than 8 Gy. Of the four, three resulted in average doses greater than 30 Gy, which suggest that there is a possibility of radiation induced complications to the CRA. While one scenario resulted in an average dose of 30 Gy to the retina, the majority of treatment scenarios resulted in an average dose to the retina of less than 15 Gy. Taken in conjunction with the lack of radiation induced retinal complications seen in EBRT and brachytherapy studies ( Evans et al. 2010, Finger et al. 1996, Finger et al. 1999, Finger et al. 2003, Finger et al. 2005, Jaakkola et al. 1998, Jaakkola et al. 2001, Jaakkola et al. 2005, Zambarakji et al. 2006 ), it seems unlikely that radiation induced complications would be a concern in the retina for this treatme nt, but it is a possibility. 6.4 Summary Of the twenty five treatment scenarios explored, seventeen were show n to result in none of the non targeted tissues receiving doses at or above threshold levels. The eight scenarios resulting in doses above thresho lds were the largest melanomas (S5) and the mel a n o m a s located at the posterior of the eye (L5), excepting the S 1 melanoma For treatment of larger melanomas and melanomas located near the posterior of the eye, even the relatively small range of beta particles is a complication in a structure as sma ll as the eye. Study into the use of alpha emitting radionuclides may be prudent for the cases in which beta radiation presents complications for the non targeted tissues of the eye.

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78 Table 6 1. Volume of ocular melanomas (cm 3 ) S1 S2 S3 S4 S5 L1 L4 0. 0126 0.0794 0.1983 0.5429 0.9908 L5 0.0061 0.0947 0.2817 0.9119 1.8089

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79 Table 6 2. Dose coefficients for Y 90 uniformly distributed within ocular melanomas of differing location and size (Gy/Bq)

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80 Table 6 3 Mean absorbed dose (in Gy) to non targeted tissues corresponding to an ocular mela noma mean absorbed dose of 85 Gy

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81 Figure 6 1. Schematic of the 22 mm eye with the addition of an ocular melanoma. A : L1 position, axial slice. B : L2 position, axial slice. C : L3 position, sagittal slice. D : L4 position, sagittal slice. E : L5 position, axial slice

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82 CHAPTER 7 CONCLUSIONS 7.1 General Conclusions Improvements in targeting and delivery methods have led to a new generation of s afer and potentially more effective radiotherapy treatments. The dosimetry studies performed have shown that each radiotherapy treatment explored has the potential to treat the target site while keeping doses to other tissues below t he suggested threshold limits. This new generation of treatments is a vast improvement over the previous treatments that resulted in many secondary complications and have created a stigma about ocular radiotherapy in the ophthalmological community. 7.1.1 Eye Size and Beam Pola r Angle Variations The variations in axial length did not lead to clinically significant variations in dose for any of the non to clinically significant variations in dose, most notably f or the lens tissues. Proper selection of beam polar angle will reduce concern during patient treatments for AMD with stereotactic radiosurgery. 7.1.2 AMD Radiotherapies As was the case with stereotactic radiosurgery, variations in axial length did not sh ow any clinically significant variations in dose for the non targeted tissues for either brachytherapy treatment or proton therapy. Of the three treatments, brachytherapy treatment resulted in the lowest doses to the non targeted tissues of the eye. It s hould be noted, however, that all three ocular radiotherapies resulted in doses to the non targeted tissues that were well below threshold doses.

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83 7.1.3 Glaucoma Radiotherapy The change in targeting for possible glaucoma treatment substantially limits the number of beam orientations that achieved clearance for the eye model used. Additionally, the selection of both beam polar angle and beam combination (for the beams that achieved clearance) has a clinically significant effect in regards to the dose receiv ed by the non targeted tissues of the eye. However, several of the proposed treatment scenarios resulted in doses to these tissues below thresholds, including beam could be used for the proposed glaucoma treatment with some targeting modification. 7.1.4 In Gel Radiotherapy For the treatment of ocular melanomas using Y 90 microspheres, several of the treatment scenarios resulted in doses to the non targeted tissues that w ere within acceptable limits. However, treatment of larger melanomas often resulted in some non targeted tissues receiving doses above approved thresholds. These findings suggest that even the small range of betas may be too large for the treatment of la rger ocular melanomas. For these cases, it may be advisable to explore the use of alpha emitters for radiotherapy. 7.2 Limitations of This Work All of the eye models used in this work were derived from NCRP 130, and are thus reference models. Reference models, while useful, cannot account for the wide variation seen in patients. The creation of some patient specific stylized models could be very useful in determining what effect, if any, is seen in the dose to the non targeted tissues as the size and sh ape of these tissues deviates from the reference models. In addition, each model assumed a constant distance for the Oraya shift, though this is not

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84 the case. The distances provided for this study were gathered from many patients, and variability is seen in these distances between patients. None of the computational modeling explored in this dissertation addressed the issue of targeting uncertainties. While targeting methods have improved drastically in this generation of ocular radiotherapies, there is still some targeting error associated with these treatments. The effect of these targeting errors on the dose to non targeted tissues has yet to be evaluated. glaucoma while stayi ng below dose thresholds of non targeted tissues, there is still significant study needed to prove the benefits of radiotherapy in treating glaucoma. Currently, all research showing possible benefits of radiation treatment for glaucoma has been done with mouse models. This research would need to be extended to animals with eyes more similar to human eyes and, if those results are promising, eventually to human trials. In simulations of ocular radiotherapy for ocular melanomas, it was assumed that there w as a uniform distribution of Y 90 throughout the melanoma. However, this may always be the case and could lead to the non targeted tissues receiving significantly higher or lower doses depended upon the actually distribution of the isotope. Therefore, re search into how the given dose coefficients change with a non uniform distribution of Y 90 may be of interest. 7.3 Future Work All five of the eye models created and used in this study were emmetropic eyes based upon NCRP 130. However, a potentially sign ificant number of the patient population would be likely to have myopic eyes. This change in the eye shape could

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85 have an effect on the dose received by the non targeted tissues. Also, the elongation of the eye and distortion of the tissues could lead to beam clearance issues not seen with emmetropic eyes. The construction and subsequent testing of a series of myopic eye models could determine what, if any, modifications may be needed for treatment of patients with myopic eyes. Incorporation of targeting errors and patient change in the Oraya shift could lead to variations in the dose received by non targeted tissues of the eye. Further studies could incorporate the targeting errors associated with each treatment to evaluate how significant of an effect targeting uncertainties could have on the doses to non targeted tissues. For some of the ocular melanoma models, the simulations suggest that even the range of beta particles may be too great when dealing with irradiation of the eye. Given the flexibilit y of the In Gel polymer, the substitution of an alpha emitter for ocular radiotherapy treatments may be prudent. The viability of this could be determined using the Monte Carlo simulations outlined in Chapter 6, but with the substitution of a suitable alp ha emitting source for the Y 90 source previously used.

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86 APPENDIX A SAMPLE MCNPX INPUT FILE FOR PROTON RADIATION TRANSPORT The input file below was used to run radiation transport simulations of proton therapy for the 20 mm axial length eye. The c ell card section defines the tissues of the eye and its surroundings and assigns a material (soft tissue, bone, etc.) to each of these tissues. The geometry section establishes the geometry of the problem and is used by the cell cards to define boundaries of tissues. The data card section defines the type of particle to be transported, the mesh tallies, the material composition, and the source term. Stylized Axial Length 20mm Proton Treatment c Justin Cantley c Derived from previous model made by Choonsik and adjusted by J. Hanlon c ------------------------c Cell Cards c ------------------------1000 3 0.001205 #2000 ( 100 130 112 140):( 100 110 112) imp:h ,e=1 $Inside Universe 1001 0 100 imp:h ,e =0 $Outside Universe 1100 2 1.525 110 111 112 imp:h ,e =1 $Orbital Bone 1101 4 0.95 111 112 120 170 imp:h ,e =1 $Fat Layer 1200 1 1.03 120 121 112 173 imp:h=1 $Sclera 1201 1 1.03 121 122 112 174 180 imp:h ,e =1 $Retina 1300 1 1.03 ( 130 131 112 132):(121 131 112) imp:h ,e =1 $Iris 1301 6 1.00 130 131 132 112 imp:h ,e =1 $Hole in Iris 1400 1 1.03 140 141 13 0 imp:h ,e =1 $Cornea 1500 8 1.07 150 151 vol=0.13078 imp:h ,e =1 $Lens 1600 1 1.03 160 161 131 112 121 #1500 imp:h ,e =1 $Ciliar Body 1700 7 1.04 170 171 120 imp:h ,e=1 $Optic Nerve Sheath 1701 7 1.04 ( 171 120):( 173 172 121 120 112) :( 174 172 122 121 112) vol=0.2015 imp:h ,e =1 $Optic Nerve 1702 1 1.03 172 112 122 120 vol=3.01593e 5 imp:h ,e =1 $Central Retinal Artery 1800 1 1.03 180 121 122 vol=6.2831853e 3 imp:h ,e =1 $Macula 2000 3 0.001205 200 201 202 imp:h ,e =1 $Aperture 9999 6 1.00 ( 141 130):( 122 121 131) #1500 #1600 imp:h ,e =1 $Vitreous Fluid c -----------------------c Surface Cards c ------------------------100 so 50 $Universe 110 sy 1 4.5 $Outer Orbital Bone 111 sy 1 4.2 $Inner Orbital Bone 112 py 1.319 $Plane to Cutoff Bone and Fat

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87 120 sy 0.900 1.050 $Back of Eye/Sclera 121 sy 0.938 0.988 $Back of Retina/Front of Sclera 122 sy 0.979 0.979 $Front of Retina 13 0 sy 0.538 1.251 $Front of Iris 131 sy 0.403 1.297 $Back of Iris 132 cy 0.1354 $Hole in Iris 140 sy 1.411 0.635 $Front of Cornea 141 sy 1.406 0.587 $Back of Cornea 150 sy 0.886 0.813 $Front of Lens 151 sy 1.861 0.542 $Back of Lens 160 sy 0.083257 1.70655 $Front of Ciliary Body 161 sy 1.26339 2.7413 $Back of Ciliary Body 170 8 trc 0 0 .09 0 0 2.867 .2292 .1678 $Optic Nerve Sheath (Dura Mater) 171 8 trc 0 0 .09 0 0 2.867 .1792 .1178 $Optic Nerve 172 9 cz 0.008 $Central Retinal Artery 173 9 cz 0.135 $Lam ina Cribrosa 174 9 cz 0.0722 $Optic Disc 180 c/y 0.126 0.056 0.2 $Macula including Oraya Shift c Aperture 200 11 cy 0.3 201 11 py 5 202 11 py 10 c ------------------------c Data Cards c -----------------------mode h e dbcn 17j 1 tr6 0 1.26339 0 1 0 0 0 1 0 0 0 1 1 tr7 0 0.979 0 1 0 0 0 1 0 0 0 1 1 *tr8 0.31888 .0486 .0368 22.4 112.4 90 90.30484743 90.73963334 0.8 112.3976981 157.5864537 90.8 *tr9 0.31888 .0486 .0368 24.6155 114.6155 90 88.99 87.7964 2.424 f16:h 1800 c DVH Tallies (MeV/cm^3/sourceparticle) tmesh c Macula c Eye Lens rmesh1:h pedep cora1 0.45 19i 0.45 corb1 1.70 9i 1.32 corc1 0.45 19i 0.45 c Macula rmesh11:h pedep cora11 0.32 19i 0.08 corb11 0.05 9i 0.05

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88 corc11 0.26 19i 0.14 c CRA cmesh21:h pedep trans 9 cora21 0 i 0.008 corb21 0.15 19i 0 corc21 i 360 c Optic Nerve cmesh31:h pedep trans 8 cora31 0 i 0.1792 corb31 0.78425 19i 0.09 corc31 i 360 cmesh41:h pedep trans 8 cora41 0 i 0.16385 corb41 1.4785 19i 0.784 25 corc41 i 360 cmesh51:h pedep trans 8 cora51 0 i 0.1485 corb51 2.17275 19i 1.4785 corc51 i 360 cmesh61:h pedep trans 8 cora61 0 i 0.13315 corb61 2.867 19i 2.17275 corc61 i 360 c Retina smesh71:h pedep trans 7 cora71 0.979 10i 1.029 corb71 29i 180 cor c71 59i 360 c Ciliary Body smesh81:h pedep trans 6 cora81 2.7413 9i 2.8867 corb81 65 49i 115 corc81 240 59i 300 ******Electron Mesh tallies omitted for space***** endmd c ------------------------c Material Cards c ------------------------c S oft tissue (male) (rho=1.03) m1 1000 0.105 6000 0.256 7000 0.027 8000 0.602 11000 0.001 15000 0.002 16000 0.003

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89 17000 0.002 19000 0.002 c ICRP adult Skeleto n (density=1.525) Cranium, Mandible m2 1000 5.434 6000 23.442 7000 3.831 8000 43.526 11000 0.177 12000 0.176 15000 7.346 16000 0.271 17000 0.006 1 9000 0.006 20000 15.773 26000 0.011 c Air (rho = 0.001205) m3 6000 0.000124 7000 0.755267 8000 0.231781 18000 0.012827 c Adipose (rho=0.95) m4 1000. 0.114 6000. 0.598 7000. 0.007 8000. 0.278 11000. 0.001 16000. 0.001 17000. 0.001 c Water (rho=1) m6 1000 2 8000 1 c Brain (rho=1.04) m7 1000 0.107 6000 0.145 7000 0.022 8000 0.712 11000 0.002 15000 0.004 16000 0.002 17000 0.003 19000 0.003 c Eye lens (rho=1.07) m8 1000 0.096 6000 0.195 7000 0.057 8000 0.646

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90 11000 0.001 15000 0.001 16000 0.003 17000 0.001 c Tungsten (rho=19.3) m9 74000 1 c -------------------------------------------------------------------c beam description c ------------------------------------------------------------------sdef par=h x=d4 y= 6.6418 z=d5 erg=42.6 dir=1 vec=0 1 0 cel=2000 tr=11 sp4 41 0.6 0 sp5 41 0.6 0 *tr11 0.126 0 0.056 0 90 90 90 30 60 90 120 30 $ beam 6 o'clock nps 5e7

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91 APPENDIX B SAMPLE MATLAB CODE This code was used to process data gathered from three different radiation transport simulations. The code reads in the three output files, and separates the data for each tissue. The doses are then converted from Me V/cm 3/particle to Gy/particle. The data is then scaled according to a target dose of 8 Gy to the macula for each beam. For each tissue, the voxels within the true geometry are selected, and added across the three beams. Finally, dose volume histograms a re constructed for each of the non targeted tissues. % 20mm Eye S ize fid_import=fopen('20mm6data'); fid_exportlens=fopen('lens20mm6','w'); fid_exportmacula=fopen('mac20mm6','w'); fid_exportcra=fopen('cra20mm6','w'); fid_exporton1=fopen('on20mm61','w') ; fid_exporton2=fopen('on20mm62','w'); fid_exporton3=fopen('on20mm63','w'); fid_exporton4=fopen('on20mm64','w'); fid_exportret=fopen('ret20mm6','w'); fid_exportcb=fopen('cb20mm6','w'); for count=1:42 tline=fgetl(fid_import); end for count=1:20 0 tline=fgetl(fid_import); fprintf(fid_exportlens,'%s/n',tline); end for count=1:203 tline=fgetl(fid_import); end for count=1:200 tline=fgetl(fid_import);

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92 fprintf(fid_exportmacula,'%s/n',tline); end for count=1:203 tline =fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exportcra,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton1,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton2,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fpri ntf(fid_exporton3,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import);

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93 fprintf(fid_exporton4,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:1891 tline=fgetl(fid_import); fprintf(fid_exportret,'%s/n',tline); end for count=1:1894 tline=fgetl(fid_import); end for count=1:1891 tline=fgetl(fid_import); fprintf(fid_exportcb,'%s/n',tline); end fid_import=fopen('20mm5data'); fi d_exportlens=fopen('lens20mm5','w'); fid_exportmacula=fopen('mac20mm5','w'); fid_exportcra=fopen('cra20mm5','w'); fid_exporton1=fopen('on20mm51','w'); fid_exporton2=fopen('on20mm52','w'); fid_exporton3=fopen('on20mm53','w'); fid_exporton4=fopen('on20 mm54','w'); fid_exportret=fopen('ret20mm5','w'); fid_exportcb=fopen('cb20mm5','w'); for count=1:42 tline=fgetl(fid_import); end for count=1:200 tline=fgetl(fid_import); fprintf(fid_exportlens,'%s/n',tline); end

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94 for count=1:203 tline=fgetl(fid_import); end for count=1:200 tline=fgetl(fid_import); fprintf(fid_exportmacula,'%s/n',tline); end for count=1:203 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exportcra,'%s/ n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton1,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton2,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton3,'%s/n',tline); end

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95 for count=1:23 tline=fgetl(fid_import); end for count=1: 20 tline=fgetl(fid_import); fprintf(fid_exporton4,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:1891 tline=fgetl(fid_import); fprintf(fid_exportret,'%s/n',tline); end for count=1:1894 tline=f getl(fid_import); end for count=1:1891 tline=fgetl(fid_import); fprintf(fid_exportcb,'%s/n',tline); end fid_import=fopen('20mm7data'); fid_exportlens=fopen('lens20mm7','w'); fid_exportmacula=fopen('mac20mm7','w'); fid_exportcra=fopen(' cra20mm7','w'); fid_exporton1=fopen('on20mm71','w'); fid_exporton2=fopen('on20mm72','w'); fid_exporton3=fopen('on20mm73','w'); fid_exporton4=fopen('on20mm74','w'); fid_exportret=fopen('ret20mm7','w'); fid_exportcb=fopen('cb20mm7','w'); for count=1:4 2 tline=fgetl(fid_import);

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96 end for count=1:200 tline=fgetl(fid_import); fprintf(fid_exportlens,'%s/n',tline); end for count=1:203 tline=fgetl(fid_import); end for count=1:200 tline=fgetl(fid_import); fprintf(fid_exportma cula,'%s/n',tline); end for count=1:203 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exportcra,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fi d_import); fprintf(fid_exporton1,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton2,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import);

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97 end fo r count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton3,'%s/n',tline); end for count=1:23 tline=fgetl(fid_import); end for count=1:20 tline=fgetl(fid_import); fprintf(fid_exporton4,'%s/n',tline); end for count=1:23 t line=fgetl(fid_import); end for count=1:1891 tline=fgetl(fid_import); fprintf(fid_exportret,'%s/n',tline); end for count=1:1894 tline=fgetl(fid_import); end for count=1:1891 tline=fgetl(fid_import); fprintf(fid_exportcb,'%s/n ',tline); end xlens= 0.45:((0.45+0.45)/20):0.45; ylens= 1.70:((1.70 1.32)/10): 1.32; zlens= 0.45:((0.45+0.45)/20):0.45; xmac= 0.33:0.0205:0.08; ymac= 0.05:0.01:0.05; zmac= 0.26:0.0205:0.15; sizex=20; sizey=10;

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98 sizez=20; rret=0.979:((1.029 0.97 9)/11):1.029; thetaret=(0.0001:((180 0.0001)/30):180)*(pi/180); phiret=(0.0001:((360 0.0001)/60):360)*(pi/180); sizer=11; sizephi=61; sizetheta=31; rcb=2.7413:((3.013 2.7413)/20):3.013; thetacb=(0.0001:((180 0.0001)/30):180)*(pi/180); phicb=(0.0001 :((360 0.0001)/60):360)*(pi/180); sizercb=20; % Reshape Lens Matrix meshlens20mm5=load('lens20mm5'); meshlens20mm5=reshape(meshlens20mm5,20,10,20); meshlens20mm6=load('lens20mm6'); meshlens20mm6=reshape(meshlens20mm6,20,10,20); meshlens20mm7=load( 'lens20mm7'); meshlens20mm7=reshape(meshlens20mm7,20,10,20); %Reshape Macula Matrix meshmac20mm5=load('mac20mm5'); meshmac20mm5=reshape(meshmac20mm5,20,10,20); meshmac20mm6=load('mac20mm6'); meshmac20mm6=reshape(meshmac20mm6,20,10,20); meshmac20mm7= load('mac20mm7'); meshmac20mm7=reshape(meshmac20mm7,20,10,20); %Reshape CRA Matrix meshcra20mm5=load('cra20mm5'); meshcra20mm5=reshape(meshcra20mm5,1,1,20); meshcra20mm6=load('cra20mm6'); meshcra20mm6=reshape(meshcra20mm6,1,1,20); meshcra20mm7=load( 'cra20mm7'); meshcra20mm7=reshape(meshcra20mm7,1,1,20); %Reshape Optic Nerve Segment 1 Matrix meshon20mm51=load('on20mm51');

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99 meshon20mm51=reshape(meshon20mm51,1,1,20); meshon20mm61=load('on20mm61'); meshon20mm61=reshape(meshon20mm61,1,1,20); meshon2 0mm71=load('on20mm71'); meshon20mm71=reshape(meshon20mm71,1,1,20); %Reshape Optic Nerve Segment 2 Matrix meshon20mm52=load('on20mm52'); meshon20mm52=reshape(meshon20mm52,1,1,20); meshon20mm62=load('on20mm62'); meshon20mm62=reshape(meshon20mm62,1,1,20 ); meshon20mm72=load('on20mm72'); meshon20mm72=reshape(meshon20mm72,1,1,20); %Reshape Optic Nerve Segment 3 Matrix meshon20mm53=load('on20mm53'); meshon20mm53=reshape(meshon20mm53,1,1,20); meshon20mm63=load('on20mm63'); meshon20mm63=reshape(meshon20 mm63,1,1,20); meshon20mm73=load('on20mm73'); meshon20mm73=reshape(meshon20mm73,1,1,20); %Reshape Optic Nerve Segment 4 Matrix meshon20mm54=load('on20mm54'); meshon20mm54=reshape(meshon20mm54,1,1,20); meshon20mm64=load('on20mm64'); meshon20mm64=resha pe(meshon20mm64,1,1,20); meshon20mm74=load('on20mm74'); meshon20mm74=reshape(meshon20mm74,1,1,20); %Reshape Retina Matrix meshret20mm5=load('ret20mm5'); meshret20mm5=reshape(meshret20mm5,11,31,61); meshret20mm6=load('ret20mm6'); meshret20mm6=reshape (meshret20mm6,11,31,61); meshret20mm7=load('ret20mm7'); meshret20mm7=reshape(meshret20mm7,11,31,61); %Reshape Ciliary Body Matrix meshcb20mm5=load('cb20mm5');

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100 meshcb20mm5=reshape(meshcb20mm5,20,31,61); meshcb20mm6=load('cb20mm6'); meshcb20mm6=reshap e(meshcb20mm6,20,31,61); meshcb20mm7=load('cb20mm7'); meshcb20mm7=reshape(meshcb20mm7,20,31,61); % MeV/cm3 / density(g/cm3) 1.6e 13 1e3 = Gy/particle meshmac20mm5=meshmac20mm5*(1.6e 10)/(1.03); meshmac20mm6=meshmac20mm6*(1.6e 10)/(1.03); mesh mac20mm7=meshmac20mm7*(1.6e 10)/(1.03); meshlens20mm5=meshlens20mm5*(1.6e 10)/(1.07); meshlens20mm6=meshlens20mm6*(1.6e 10)/(1.07); meshlens20mm7=meshlens20mm7*(1.6e 10)/(1.07); meshcra20mm5=meshcra20mm5*(1.6e 10)/(1.03); meshcra20mm6=meshcra20mm6 *(1.6e 10)/(1.03); meshcra20mm7=meshcra20mm7*(1.6e 10)/(1.03); meshon20mm51=meshon20mm51*(1.6e 10)/(1.04); meshon20mm61=meshon20mm61*(1.6e 10)/(1.04); meshon20mm71=meshon20mm71*(1.6e 10)/(1.04); meshon20mm52=meshon20mm52*(1.6e 10)/(1.04); meshon2 0mm62=meshon20mm62*(1.6e 10)/(1.04); meshon20mm72=meshon20mm72*(1.6e 10)/(1.04); meshon20mm53=meshon20mm53*(1.6e 10)/(1.04); meshon20mm63=meshon20mm63*(1.6e 10)/(1.04); meshon20mm73=meshon20mm73*(1.6e 10)/(1.04); meshon20mm54=meshon20mm54*(1.6e 10 )/(1.04); meshon20mm64=meshon20mm64*(1.6e 10)/(1.04); meshon20mm74=meshon20mm74*(1.6e 10)/(1.04);

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101 meshret20mm5=meshret20mm5*(1.6e 10)/(1.03); meshret20mm6=meshret20mm6*(1.6e 10)/(1.03); meshret20mm7=meshret20mm7*(1.6e 10)/(1.03); meshcb20mm5=mesh cb20mm5*(1.6e 10)/(1.03); meshcb20mm6=meshcb20mm6*(1.6e 10)/(1.03); meshcb20mm7=meshcb20mm7*(1.6e 10)/(1.03); % DVH scaling to 8 Gy Macula Beam Delivery count=0; tally_mac_5oclock=zeros(1,49); for i=8:14 for j=8:14 count=count+1; tally_mac_5oclock(count)=meshmac20mm5(i,6,j); end end scale5=8/mean(tally_mac_5oclock); count=0; tally_mac_6oclock=zeros(1,49); for i=8:14 for j=8:14 count=count+1; tally_mac_6oclock(count)=meshmac20mm6(i,6,j); end end scale6=8/mean(tally_mac_6oclock); count=0; tally_mac_7oclock=zeros(1,49);

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102 for i=8:14 for j=8:14 count=count+1; tally_mac_7oclock(count)=meshmac20mm7(i,6,j); end end scale7=8/mean(tally_mac_7oclock); meshmac20mm5=meshmac20mm5*scale5; meshmac20mm6=meshmac20mm6*scale6; meshmac20mm7=meshmac20mm7*scale7; meshlens20mm5=meshlens20mm5*scale5; meshlens20mm6=meshlens20mm6*scale6; meshlens20mm7=meshlens20mm7*scale7; meshcra20mm5=meshcra20mm5*scale5; meshcra20mm6=meshcra20mm6*scale6; meshcra20mm7=meshcra20mm7*scale7; meshon20mm51=meshon20mm51*scale5; meshon20mm61=meshon20mm61*scale6; meshon20mm71=meshon20mm71*scale7; meshon20mm52=meshon20mm52*scale5; meshon20mm62=meshon20mm62*scale6; meshon 20mm72=meshon20mm72*scale7; meshon20mm53=meshon20mm53*scale5; meshon20mm63=meshon20mm63*scale6; meshon20mm73=meshon20mm73*scale7; meshon20mm54=meshon20mm54*scale5;

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103 meshon20mm64=meshon20mm64*scale6; meshon20mm74=meshon20mm74*scale7; meshret20mm 5=meshret20mm5*scale5; meshret20mm6=meshret20mm6*scale6; meshret20mm7=meshret20mm7*scale7; meshcb20mm5=meshcb20mm5*scale5; meshcb20mm6=meshcb20mm6*scale6; meshcb20mm7=meshcb20mm7*scale7; %DVH Calculation of the Macula count=0; mesh_hist_mac _total=zeros(1,4000); for x1=1:sizex; for y1=1:sizey; for z1=1:sizez; % if ((xmac(x1)^2+(ymac(y1)+1.0625)^2+zmac(z1)^2)>1.0875^2) & ((xmac(x1)^2+(ymac(y1)+1.0008)^2+zmac(z1)^2)<1.0875^2) & ((x(2,x1)^2+z(2,z1)^2)<0.2^2)% equation count=count+1; mesh_hist_mac_total(count)=meshmac20mm6(x1,y1,z1)+meshmac20mm5(x1,y1,z1)+meshmac20mm7(x1,y1,z1); % end end end end mesh_count_mac=count; %DVH Calculation of the Lens, will ch ange for different eye sizes count=0; mesh_hist_lens_6oclock=zeros(1,4000); mesh_hist_lens_5oclock=zeros(1,4000);

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104 mesh_hist_lens_7oclock=zeros(1,4000); mesh_hist_lens_total=zeros(1,4000); for x1=1:sizex; for y1=1:sizey; for z1=1:sizez ; if ((xlens(x1)^2+(ylens(y1)+1.861)^2+zlens(z1)^2)<0.542^2) && ((xlens(x1)^2+(ylens(y1)+0.886)^2+zlens(z1)^2)<0.813^2) % equation count=count+1; mesh_hist_lens_total(count)=meshlens20mm6(x1,y1,z1)+meshlens20m m5(x1,y1,z1)+meshlens20mm7(x1,y1,z1); end end end end mesh_count_lens=count; %DVH Calculation of the Sensitive Volume of the Lens, will change for different eye sizes count=0; mesh_hist_svlens_6oclock=zeros(1,4000); m esh_hist_svlens_5oclock=zeros(1,4000); mesh_hist_svlens_7oclock=zeros(1,4000); mesh_hist_svlens_total=zeros(1,4000); for x1=1:sizex; for y1=1:sizey; for z1=1:sizez; if ((xlens(x1)^2+(ylens(y1)+1.861)^2+zlens(z1)^2)<0.542^2) && ((xlens(x1)^2+(ylens(y1)+0.886)^2+zlens(z1)^2)<0.813^2) && (sqrt((xlens(x1))^2+(zlens(z1))^2) (3.2893*(ylens(y1)+1.699)))>=0;% equation count=count+1; mesh_hist_svlens_total(count)=meshlens20mm6(x1,y1,z1)+meshlens20mm5(x1 ,y1,z1)+meshlens20mm7(x1,y1,z1); end end end end mesh_count_svlens=count;

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105 % DVH Central Retinal Artery count=0; mesh_hist_cra_total=zeros(1,4000); x1=1; y1=1; for z1=1:sizez; count=count+1; mesh_hist_cra_total(count)=meshcra20mm6(x1,y1,z1)+meshcra20mm5(x1,y1,z1)+meshcra20mm7(x1,y1,z1); end mesh_count_cra=count; % DVH Optic Nerve Segment 1 count=0; mesh_hist_on1=zeros(1,4000); x1=1; y1=1; for z1=1 :sizez; count=count+1; mesh_hist_on1(count)=meshon20mm61(x1,y1,z1)+meshon20mm51(x1,y1,z1)+meshon20mm71(x1,y1,z1); end mesh_count_on1=count; % DVH Optic Nerve Segment 2 count=0; mesh_hist_on2=zeros(1,4000 ); x1=1; y1=1; for z1=1:sizez; count=count+1;

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106 mesh_hist_on2(count)=meshon20mm62(x1,y1,z1)+meshon20mm52(x1,y1,z1)+meshon20mm72(x1,y1,z1); end mesh_count_on2=count; % DVH Optic Nerve Segment 3 co unt=0; mesh_hist_on3=zeros(1,4000); x1=1; y1=1; for z1=1:sizez; count=count+1; mesh_hist_on3(count)=meshon20mm63(x1,y1,z1)+meshon20mm53(x1,y1,z1)+meshon20mm73(x1,y1,z1); end mesh_count_on3=count; % DVH Optic Nerve Segment 4 count=0; mesh_hist_on4=zeros(1,4000); x1=1; y1=1; for z1=1:sizez; count=count+1; mesh_hist_on4(count)=meshon20mm64(x1,y1,z1)+meshon20mm54(x1,y1,z1)+meshon20mm74(x1,y1,z1); end mesh_count_on4=count; % Total Optic Nerve Count mesh_count_on_total=(1.81147*mesh_count_on1)+(1.514295*mesh_count_on2)+(1.243857*mesh_count_on3)+mesh_count_on4;

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107 %DVH Calculation of the Retina, will change for different eye sizes ratio ret=zeros(1,11); for i=1:sizer ratioret(i)=((rret(i+1))^3 (rret(i))^3)/((rret(2))^3 (rret(1))^3); end count=0; retcount=0; rret1count=0; rret2count=0; rret3count=0; rret4count=0; rret5count=0; rret6count=0; rret7count=0; rret8count=0; rre t9count=0; rret10count=0; rret11count=0; mesh_hist_ret_total=zeros(1,20801); for r1=1:sizer; for theta1=1:sizetheta; for phi1=1:sizephi; if (((rret(r1)*cos(phiret(phi1))*sin(thetaret(theta1)))^2+((rret(r1)*sin(phiret(phi1))* sin(thetaret(theta1))) 0.041)^2+(rret(r1)*cos(thetaret(theta1)))^2)<0.988^2) && (((rret(r1)*cos(phiret(phi1))*sin(thetaret(theta1)))+0.126)^2+((rret(r1)*cos(thetaret(theta1)))+0.056)^2>0.2) % ((xret(x1)^2+(yret(y1)+0.938)^2+zret(z1)^2)<0.9 88^2)&& ((xret+0.126)^2+(zret+0.056)^2>0.2) % equation in cartesian count=count+1; mesh_hist_ret_total(count)=meshret20mm6(r1,theta1,phi1)+meshret20mm5(r1,theta1,phi1)+meshret20mm7(r1,theta1,phi1); if r1 = = 1 retcount=retcount+ratioret(1); rret1count=rret1count+1; elseif r1 == 2 retcount=retcount+ratioret(2); rret2count=rret2count+1; elseif r1 == 3

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108 retcount=retcount+ratioret(3); rret3count=rret3count+1; elseif r1 == 4 retcount=retcount+ratioret(4); rret4count=rret4count+1; els eif r1 == 5 retcount=retcount+ratioret(5); rret5count=rret5count+1; elseif r1 == 6 retcount=retcount+ratioret(6); rret6count=rret6count+1; elseif r1 == 7 retcount=retcount+ratioret(7); rret7count=rret7count+1; elseif r1 == 8 retcount=retcount+ratioret(8); rret8count=rret8count+1; elseif r1 == 9 retcount=retcount+ratioret(9); rret9count=rret9count+1; elseif r1 == 10 retcount=retcount+ratioret(10); rret10count=rret10count+1; else retcount=retcount+ratioret(11); rret11count=rret11count+1; end end end end end rretcount1=rret1count; rretcount2=rretcount1+rret2count; rretcount3=r retcount2+rret3count; rretcount4=rretcount3+rret4count;

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109 rretcount5=rretcount4+rret5count; rretcount6=rretcount5+rret6count; rretcount7=rretcount6+rret7count; rretcount8=rretcount7+rret8count; rretcount9=rretcount8+rret9count; rretcount10=rretcount9+ rret10count; rretcount11=rretcount10+rret11count; retcounttotal=rretcount11; mesh_count_ret=retcount; % DVH Calculation of Ciliary Body, will change for different eye sizes ratiocb=zeros(1,20); for i=1:sizercb ratiocb(i)=((rcb(i+1))^3 (rcb(i ))^3)/((rcb(2))^3 (rcb(1))^3); end count=0; cbcount=0; rcb1count=0; rcb2count=0; rcb3count=0; rcb4count=0; rcb5count=0; rcb6count=0; rcb7count=0; rcb8count=0; rcb9count=0; rcb10count=0; rcb11count=0; rcb12count=0; rcb13count=0; rcb14count= 0; rcb15count=0; rcb16count=0; rcb17count=0;

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110 rcb18count=0; rcb19count=0; rcb20count=0; mesh_hist_cb_total=zeros(1,39711); for r1=1:sizercb; for theta1=1:sizetheta; for phi1=1:sizephi; if ((((rcb(r1))*cos(phicb(phi1))*sin( thetacb(theta1)))^2+((rcb(r1))*sin(phicb(phi1))*sin(thetacb(theta1)))+1.180133)^2+(((rcb(r1))*cos(the tacb(theta1)))^2)<1.70655^2) && ((((rcb(r1))*cos(phicb(phi1))*sin(thetacb(theta1)))^2+(((rcb(r1))*sin(phicb(phi1))*sin(thetacb(theta1)))+2.20139)^2+((rcb(r 1))*cos(thet acb(theta1)))^2)<0.988^2) && ((((rcb(r1))*cos(phicb(phi1))*sin(thetacb(theta1)))^2+(((rcb(r1))*sin(phicb(phi1))*sin(thetacb(theta1)))+3.12439)^2+((rcb(r1) )*cos(thet acb(theta1)))^2)>0.542^2) && ((((rcb(r1))*cos(phicb(phi1))*sin(thetacb(theta1)) )^2+(((rcb(r1))*sin(phicb(phi1))*sin(thetacb(theta1)))+1.66639)^2+((rcb(r1))*cos(thet acb(theta1)))^2)<1.297^2); % ((xcb(x1)^2+(ycb(y1)+0.938)^2+zcb(z1)^2)<0.988^2)&& (xcb(x1)^2+(ycb(y1)+1.861)^2+zcb(z1)^2>0.542) && ((xcb(x1)^2+(ycb(y1) 0.0 83257)^2+zcb(z1)^2)<1.70655^2)&& ((xcb(x1)^2+(ycb(y1)+0.403)^2+zcb(z1)^2)<1.297^2)% equation in cartesian count=count+1; mesh_hist_cb_total(count)=meshcb20mm6(r1,theta1,phi1)+meshcb20mm5(r1,theta1,phi1)+meshcb20mm7(r1,thet a1,phi1); if r1 == 1 cbcount=cbcount+ratiocb(1); rcb1count=rcb1count+1; elseif r1 == 2 cbcount=cbcount+ratiocb(2); rcb2count=rcb2count+1; elseif r1 == 3 cbcount=cbcount+ratiocb(3); rcb3count=rcb3count+1; elseif r1 == 4 cbcount=cbcount+ratiocb(4); rcb4count=rcb4count+1; elseif r1 == 5 cbcount=cbcount+ratiocb(5); rcb5count=rcb5count+1; elseif r1 == 6 cbcount=cbcount+ratiocb(6); rcb6count=rcb6count+1;

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111 elseif r1 == 7 cbcount=cbcount+ratiocb(7); rcb7count=rcb7count+1; elseif r1 == 8 cbcount=cbcount+ratiocb(8); rcb8count=rcb8count+1; e lseif r1 == 9 cbcount=cbcount+ratiocb(9); rcb9count=rcb9count+1; elseif r1 == 10 cbcount=cbcount+ratiocb(10); rcb10count=rcb10count+1; els eif r1 == 11 cbcount=cbcount+ratiocb(11); rcb11count=rcb11count+1; elseif r1 == 12 cbcount=cbcount+ratiocb(12); rcb12count=rcb12count+1; e lseif r1 == 13 cbcount=cbcount+ratiocb(13); rcb13count=rcb13count+1; elseif r1 == 14 cbcount=cbcount+ratiocb(14); rcb14count=rcb14count+1; elseif r1 == 15 cbcount=cbcount+ratiocb(15); rcb15count=rcb15count+1; elseif r1 == 16 cbcount=cbcount+ratiocb(16); rcb16count=rcb16count+1; elseif r1 == 17 cbcount=cbcount+ratiocb(17); rcb17count=rcb17count+1; elseif r1 == 18 cbcount=cbcount+ratiocb(18);

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112 rcb18count=rcb18count+1; elseif r1 == 19 cbcount=cbcount+ratiocb(19); rcb19count=rcb19count+1; else cbcount=cbcount+ratiocb(20); rcb20count=rcb20count+1; end end end end end rcbcount1=rcb1count; rcbcount2=rcbcount1+rcb2count; rcbcount3=rcbcount2+rcb3count; rcbcount4=rcbcount3+rcb4count; rcbcount5=rcbcount4+rcb5count; rcbcount6=rcbcount5+rcb6count; rcbcount7=rcbcount6+rcb7count ; rcbcount8=rcbcount7+rcb8count; rcbcount9=rcbcount8+rcb9count; rcbcount10=rcbcount9+rcb10count; rcbcount11=rcbcount10+rcb11count; rcbcount12=rcbcount11+rcb12count; rcbcount13=rcbcount12+rcb13count; rcbcount14=rcbcount13+rcb14count; rcbcount15=rcbc ount14+rcb15count; rcbcount16=rcbcount15+rcb16count; rcbcount17=rcbcount16+rcb17count; rcbcount18=rcbcount17+rcb18count; rcbcount19=rcbcount18+rcb19count; rcbcount20=rcbcount19+rcb20count; cbcounttotal=rcbcount20; mesh_count_cb=cbcount;

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113 % DVH Construction A=26.5; bins_mac_total=0:((A)/(1e4 1)):(A); number_bins=length(bins_mac_total); count=1; tally_mac_total=zeros(1,1e4); pvmactotal_20mm=zeros(1,1e4); tally_lens_total=zeros(1,1e4); pvlenstotal_20mm=zeros(1,1e4); tally_svlens_total=z eros(1,1e4); pvsvlenstotal_20mm=zeros(1,1e4); tally_cra_total=zeros(1,1e4); pvcratotal_20mm=zeros(1,1e4); tally_on1=zeros(1,1e4); tally_on2=zeros(1,1e4); tally_on3=zeros(1,1e4); tally_on4=zeros(1,1e4); tally_on_total=zeros(1,1e4); pvontotal_20mm=z eros(1,1e4); tally_ret_total=zeros(1,1e4); pvrettotal_20mm=zeros(1,1e4); tally_cb_total=zeros(1,1e4); pvcbtotal_20mm=zeros(1,1e4); %Macula DVH Construction for i=1:number_bins for count=1:mesh_count_mac if mesh_h ist_mac_total(count)>=bins_mac_total(i) tally_mac_total(i)=tally_mac_total(i)+1; end end pvmactotal_20mm(i)=(tally_mac_total(i)/mesh_count_mac)*100;

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114 %Lens DVH Construction for count=1:mesh_ count_lens if mesh_hist_lens_total(count)>=bins_mac_total(i) tally_lens_total(i)=tally_lens_total(i)+1; end end pvlenstotal_20mm(i)=(tally_lens_total(i)/mesh_count_lens)*100; %Senstive Volume Lens DVH Construction for count=1:mesh_count_svlens if mesh_hist_svlens_total(count)>=bins_mac_total(i) tally_svlens_total(i)=tally_svlens_total(i)+1; end end pvsvlenstotal_20mm(i)=(tally_svlens_total(i )/mesh_count_svlens)*100; %CRA DVH Construction for count=1:mesh_count_cra if mesh_hist_cra_total(count)>=bins_mac_total(i) tally_cra_total(i)=tally_cra_total(i)+1; end end pvcrato tal_20mm(i)=(tally_cra_total(i)/mesh_count_cra)*100; %Optic Nerve DVH Construction for count=1:mesh_count_on1 if mesh_hist_on1(count)>=bins_mac_total(i) tally_on1(i)=tally_on1(i)+1; end e nd for count=1:mesh_count_on2 if mesh_hist_on2(count)>=bins_mac_total(i) tally_on2(i)=tally_on2(i)+1; end

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115 end for count=1:mesh_count_on3 if mesh_hist_on3(count)>=bins_mac_total(i) tally_on 3(i)=tally_on3(i)+1; end end for count=1:mesh_count_on4 if mesh_hist_on4(count)>=bins_mac_total(i) tally_on4(i)=tally_on4(i)+1; end end tally_on_total(i)=(1.81147*tally_on1(i))+(1.514295*tally_on2 (i))+(1.243857*tally_on3(i))+tally_on4(i); pvontotal_20mm(i)=(tally_on_total(i)/(mesh_count_on_total))*100; %Retina DVH Construction for count=1:retcounttotal if mesh_hist_ret_total(count)>=bins_mac_total(i) if count <= rretcount1 tally_ret_total(i)=tally_ret_total(i)+ratioret(1); elseif rretcount1 < count && count <= rretcount2 tally_ret_total(i)=tally_ret_total(i)+ratioret(2); elseif rr etcount2 < count && count <= rretcount3 tally_ret_total(i)=tally_ret_total(i)+ratioret(3); elseif rretcount3 < count && count <= rretcount4 tally_ret_total(i)=tally_ret_total(i)+ratioret(4); else if rretcount4 < count && count <= rretcount5 tally_ret_total(i)=tally_ret_total(i)+ratioret(5); elseif rretcount5 < count && count <= rretcount6 tally_ret_total(i)=tally_ret_total(i)+ratioret(6); elseif rretcount6 < count && count <= rretcount7 tally_ret_total(i)=tally_ret_total(i)+ratioret(7); elseif rretcount7 < count && count <= rretcount8 tally_ret_total(i)=tally_ret_total(i)+ratioret(8); elseif rretcount8 < count && count <= rretcount9 tally_ret_total(i)=tally_ret_total(i)+ratioret(9);

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116 elseif rretcount9 < count && count <= rretcount10 tally_ret_total(i)=tally_ret_total(i)+ratioret(10 ); else tally_ret_total(i)=tally_ret_total(i)+ratioret(11); end end end pvrettotal_20mm(i)=(tally_ret_total(i)/mesh_count_ret)*100; %Ciliary Body DVH Const ruction for count=1:cbcounttotal if mesh_hist_cb_total(count)>=bins_mac_total(i) if count <= rcbcount1 tally_cb_total(i)=tally_cb_total(i)+1; elseif rcbcount1 < count && count <= rcbcount2 tally_cb_total(i)=tally_cb_total(i)+ratiocb(2); elseif rcbcount2 < count && count <= rcbcount3 tally_cb_total(i)=tally_cb_total(i)+ratiocb(3); elseif rcbcount3 < count && count <= rcbcount4 tally_cb_total(i)=tally_cb_total(i)+ratiocb(4); elseif rcbcount4 < count && count <= rcbcount5 tally_cb_total(i)=tally_cb_total(i)+ratiocb(5); elseif rcbcount5 < count && count <= rcbcount6 tally_cb_total(i)=tally_cb_total(i)+ratiocb(6); elseif rcbcount6 < count && count <= rcbcount7 tally_cb_total(i)=tally_cb_total(i)+ratiocb(7); elseif rcbcount7 < count && count <= rcbcount8 tally_cb_total(i)=tally_cb_total(i)+ratiocb(8); elseif rcbcount8 < count && count <= rcbcount9 tally_cb_total(i)=tally_cb_total(i)+ratiocb(9); elseif rcbcount9 < count && count<= rcbcount10 t ally_cb_total(i)=tally_cb_total(i)+ratiocb(10); elseif rcbcount10 < count && count <= rcbcount11 tally_cb_total(i)=tally_cb_total(i)+ratiocb(11); elseif rcbcount11 < count && count <= rcbcount12

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117 tally_cb_total(i)=tally_cb_total(i)+ratiocb(12); elseif rcbcount12 < count && count <= rcbcount13 tally_cb_total(i)=tally_cb_total(i)+ratiocb(13); elseif rcbcount13 < count && count <= rcbcount14 tally_cb_total(i)=tally_cb_total(i)+ratiocb(14); elseif rcbcount14 < count && count <= rcbcount15 tally_cb_total(i)=tally_cb_total(i)+ratiocb(15); elseif rcbcount15 < count && count <= rcbcount16 tally_cb_total(i)=tally_cb_total(i)+ratiocb(16); elseif rcbcount16 < count && count <= rcbcount17 tally_cb_total(i)=tally_cb_total(i)+ratiocb(17); elseif rcbcount17 < count && count <= rcbcount18 tally_cb_total(i)=tally_cb_total(i)+ratiocb(18); elseif rcbcount18 < count && count <= rcbcount19 tally_cb_total(i)=tally_cb_total(i)+ratiocb(19); else tally_cb_total(i)=tally_ cb_total(i)+ratiocb(20); end end end pvcbtotal_20mm(i)=(tally_cb_total(i)/mesh_count_cb)*100; end save('Dose20mm','bins_mac_total',' ASCII',' tabs'); save('DVHMacula20mm','pvmactotal_20mm',' ASCII',' tabs '); save('DVHLens20mm','pvlenstotal_20mm',' ASCII',' tabs'); save('DVHsvLens20mm','pvsvlenstotal_20mm',' ASCII',' tabs'); save('DVHCRA20mm','pvcratotal_20mm',' ASCII',' tabs'); save('DVHOpticNerve20mm','pvontotal_20mm',' ASCII',' tabs'); save('DVHReti na20mm','pvrettotal_20mm',' ASCII',' tabs'); save('DVHCiliaryBody20mm','pvcbtotal_20mm',' ASCII',' tabs'); D1=round(0.01/bins_mac_total(2)); % Entry corresponding to Dose of 0.01Gy D2=round(0.10/bins_mac_total(2)); % Entry corresponding to Dose of 0.1Gy D3=round(0.25/bins_mac_total(2)); % Entry corresponding to Dose of 0.25Gy

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118 D4=round(0.50/bins_mac_total(2)); % Entry corresponding to Dose of 0.5Gy D5=round(0.75/bins_mac_total(2)); % Entry corresponding to Dose of 0.75Gy D6=round(1.00/bins _mac_total(2)); % Entry corresponding to Dose of 1Gy D7=round(2.00/bins_mac_total(2)); % Entry corresponding to Dose of 2Gy D8=round(5.00/bins_mac_total(2)); % Entry corresponding to Dose of 5Gy D9=round(10.0/bins_mac_total(2)); % Entry correspo nding to Dose of 10Gy D10=round(15.0/bins_mac_total(2)); % Entry corresponding to Dose of 15Gy D11=round(20.0/bins_mac_total(2)); % Entry corresponding to Dose of 20Gy D12=round(24.0/bins_mac_total(2)); % Entry corresponding to Dose of 24Gy len s_20mm=[pvlenstotal_20mm(D1),pvlenstotal_20mm(D2),pvlenstotal_20mm(D3),pvlenstotal_20mm(D4),pvlenstotal_20mm(D5),p vlenstotal_20mm(D6),pvlenstotal_20mm(D7),pvlenstotal_20mm(D8),pvlenstotal_20mm(D9),pvlenstotal_20mm(D10),pvlenstotal_20 mm(D11),pvlenstotal_20m m(D12)]; svlens_20mm=[pvsvlenstotal_20mm(D1),pvsvlenstotal_20mm(D2),pvsvlenstotal_20mm(D3),pvsvlenstotal_20mm(D4),pvsvlenstotal _20mm(D5),pvsvlenstotal_20mm(D6),pvsvlenstotal_20mm(D7),pvsvlenstotal_20mm(D8),pvsvlenstotal_20mm(D9),pvsvlenstotal_20 mm(D10),pv svlenstotal_20mm(D11),pvsvlenstotal_20mm(D12)]; cra_20mm=[pvcratotal_20mm(D1),pvcratotal_20mm(D2),pvcratotal_20mm(D3),pvcratotal_20mm(D4),pvcratotal_20mm(D5),pvcrato tal_20mm(D6),pvcratotal_20mm(D7),pvcratotal_20mm(D8),pvcratotal_20mm(D9),pvcratotal_20mm(D 10),pvcratotal_20mm(D11),pv cratotal_20mm(D12)]; on_20mm=[pvontotal_20mm(D1),pvontotal_20mm(D2),pvontotal_20mm(D3),pvontotal_20mm(D4),pvontotal_20mm(D5),pvontotal_ 20mm(D6),pvontotal_20mm(D7),pvontotal_20mm(D8),pvontotal_20mm(D9),pvontotal_20mm(D10),pvontot al_20mm(D11),pvontotal _20mm(D12)]; ret_20mm=[pvrettotal_20mm(D1),pvrettotal_20mm(D2),pvrettotal_20mm(D3),pvrettotal_20mm(D4),pvrettotal_20mm(D5),pvrettotal_ 20mm(D6),pvrettotal_20mm(D7),pvrettotal_20mm(D8),pvrettotal_20mm(D9),pvrettotal_20mm(D10),pvrettota l_20mm(D11),pvrettota l_20mm(D12)]; cb_20mm=[pvcbtotal_20mm(D1),pvcbtotal_20mm(D2),pvcbtotal_20mm(D3),pvcbtotal_20mm(D4),pvcbtotal_20mm(D5),pvcbtotal_2 0mm(D6),pvcbtotal_20mm(D7),pvcbtotal_20mm(D8),pvcbtotal_20mm(D9),pvcbtotal_20mm(D10),pvcbtotal_20mm(D11), pvcbtotal_2 0mm(D12)]; save('DVHLens20mmTable','lens_20mm',' ASCII',' tabs'); save('DVHsvLens20mmTable','svlens_20mm',' ASCII',' tabs'); save('DVHCRA20mmTable','cra_20mm',' ASCII',' tabs'); save('DVHOpticNerve20mmTable','on_20mm',' ASCII',' tabs'); s ave('DVHRetina20mmTable','ret_20mm',' ASCII',' tabs'); save('DVHCiliaryBody20mmTable','cb_20mm',' ASCII',' tabs'); plot(bins_mac_total,pvmactotal_20mm,bins_mac_total,pvlenstotal_20mm,bins_mac_total,pvsvlenstotal_20mm,bins_mac_total,pvcr atotal_20mm,bins _mac_total,pvontotal_20mm,bins_mac_total,pvrettotal_20mm,bins_mac_total,pvcbtotal_20mm) title('Absorbed Dose to Macula and Non Targeted Tissues 20mm Eye') xlabel('Absorbed Dose (Gy)') ylabel('Volume (%)') legend('Macula','Lens','SV Lens','CRA','Optic N erve','Retina','Ciliary Body')

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119 LIST OF REFERENCES Ahmed F, Brown KM, Stephan DA, Morrison JC, Johnson EC, et al. 2004 Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. Invest Ophthalmo l Vis Sci. 45 :1247 1258. radiotherapy in macular degeneration: Our technique, dosimetric calculation, and preliminary results. Int. J. Radiat. Oncol., Biol., Phys. 40 :923 927. Anderson MG, Libby RT, Gou ld DB, Smith RS, John SW. 2005 High dose radiation with bone marrow transfer prevents neurodegeneration in an inherited glaucoma. Proc Natl Acad Sci U S A. 102 :4566 4571. Archerz DB and Gardiner TA. 1994 Ionizing radiation and the retina. Curr. Opin. O phthalmol. 5 :59 65. Avila MP, Farah ME, Santos A, et al. 2009a Twelve month short term safety and visual acuity results from a multicenter prospective study of epiretinal strontium 90 brachytherapy with bevacizumab for the treatment of subfoveal choroid al neovascularization secondary to age related macular degeneration. Br J Ophthalmol. 93 :305 309. Avila MP, Farah ME, Santos A, et al. 2009b Twelve month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation the rapy for the treatment of subfoveal CNV secondary to AMD. Retina. 29 :157 169. Avila MP, Farah ME, Santos A, et al. 2012 Three year safety and visual acuity results of epimacular (90)strontium/(90)yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age related macular degeneration. Retina. 32: 10 18. Behrens R, Dietze G, Zankl M 2009 Dose conversion coefficients for photon exposure of the human eye lens. Phys Med Biol. 54 :4069 4087. Berson A M, Finger PT, Sherr DL, Emery R, Alfieri AA, and Bosworth JL. 1996 Radiotherapy for age related macular degeneration: Preliminary results of a potentially new treatment. Int. J. Radiat. Oncol., Biol., Phys. 36 :861 865. Block ML, Zecca L and Hong JS. 20 07 Microglia mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 8 :57 69. Bolch WE, Eckerman KF, Sgouros G, and Thomas SR. 2009 MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetry standardization of n omenclature. J Nucl Med. 50 :477 484.

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126 Rosenfeld PJ, Moshfeghi AA, Puliafito CA. 2005 Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age related macular degeneration. Ophthalmic Surg Lasers Imaging. 36 :331 335. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, et al. 2006 Ranibizumab for neovascular age related macular degeneration N Engl J Med. 355 :1419 1431. Sari B, Siki J, Katusi D, and Vukojevi N. 2001 Brachytherapy Optional treatment for choroidal neovascularization secondary to age related macular degeneration. Coll. Antropol. 25 :89 96. Schmidt Erfurth UM, Richard G, Augustin A, et al. 2007 Guidance for the treatment of neovascular age related macular degeneration. Acta Ophthalmol Scand. 85 :486 494. Schulte RW, Fargo RA, Meinass HJ, Slater JD, and Slater JM. 2000 Analysis of head motion prior to and during proton beam therapy. Int. J. Radiat. Oncol., Biol., Phys. 47 :1105 1110. Shah PK, Selvaraj U, Narendran V, et al. 2013 Indigenous 125 I brachytherapy sourc e for the management of intraocular melanomas in India. Cancer Biotherapy and Radiopharmaceuticals. 28 :21 28 Singh RP, Moshfeghi AA, Shusterman EM, McDormick SA, Gertner M. 2008 Evaluation of transconjunctival collimated external beam radiation for age related macular degeneration (abstract). Presented at: American Academy of Ophthalmology Annual Meeting; November 8 11, Atlanta, GA. Sivagnanavel V, Evans JR, Ockrim Z, and Chong V. 2004 Radiotherapy for neovascular age related macular degeneration. Co chrane Database Syst. Rev. 18 (4):CD004004. Soto I, Oglesby E, Buckingham BP, Son JL, Roberson ED, et al. 2008 Retinal ganglion cells down regulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. J Neurosci. 2 8 :548 561. Staar S, Krott R, Mueller RP, Bartz Schmidt KU, and Heimann K. 1999 External beam radiotherapy for subretinal neovascularization in age related macular degeneration: Is this treatment efficient? Int. J. Radiat. Oncol., Biol., Phys. 45 :467 473 Stalmans P, Leys A, and Van LE. 1997 External beam radiotherapy (20 Gy, 2 Gy fractions) fails to control the growth of choroidal neovascularization in age related macular degeneration: A review of 111 cases. Retina 17 (6)481 492.

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128 BIOGRAPHICAL SKETCH Justin L. Cantley was born in Charleston, WV, on September 28, 1983. He graduated from South Charlest on High School with an International Baccalaureate diploma in 2002. He attended Haverford College, where he met his wife Eli zabeth, and earned his B.S. in physics and a stronomy in 2006. After taking time off from his studies, Justin returned to academics and earned his M.S. in physics from Central Michigan University. In 2010, Justin enrolled in the University of Florida to earn his Ph.D. Since the summer of 2010, he has worked under the supervision of Dr. Wesley Bolch doing research in computational m edical physics. His research has been focused upon computational eye dosimetry, working closely with Oraya Therapeutics, Inc. Justin will complete his Ph.D. at the University of Florida in August 2013.