Clinical Ophthalmic Oncology : Basic Principles [3 ed.] 9783030044893, 3030044890

Table of contents :
Preface
Acknowledgments
Contents
Contributors
1: Principles of Cancer Epidemiology
Introduction
Research Question
Outcome Measures
Prevalence
Incidence
Mortality
Time to Event
Surrogate Endpoints
Quality of Life
Measures of Association
Relative Risk
Hazard Ratio
Odds Ratio
Differences in Risk
Differences in Mean Score
Precision of the Estimate
Bias
Confounding
Selection Bias
Information Bias
Study Designs
Case Series
Cross-Sectional Study
Cohort Study
Randomized Controlled Trial
Case-Control Study
Pilot Study
Systematic Review
Conclusions
References
Further Readings
2: Etiology of Cancer
Introduction
Carcinogenic Agents
Chemical Carcinogens
Environmental Exposure
Behavioral Exposure
Tobacco
Alcohol
Electromagnetic Radiation
Ultraviolet Light
Ionizing Radiation (X-Rays and Gamma Rays)
Infections Agents
Viruses
Human Papillomavirus (HPV)
Epstein-Barr Virus
Kaposi Sarcoma Herpes Virus
Human T-Cell Lymphotropic Virus-1
Hepatitis B and C Virus
Bacteria
Helicobacter pylori
Chlamydia psittaci
Fungus
Parasites
Immune Evasion
Dietary Factors
Genetic Susceptibility
Iatrogenic Cancers
Immunosuppression
Chemotherapy
Radiation Therapy
Summary
References
3: Cancer Pathology
Introduction
Classification of Neoplasia
Benign Tumors
Malignant Tumors
Tumorigenesis
Genomic Instability and Mutations
Evading Immune Destruction
Proliferative Signaling and Reprogramming Energy Metabolism
Resisting Growth Suppressors
Escaping Cell Death
Replicative Immortality
Angiogenesis
Invasion and Metastasis
Box 3.1 Steps in Metastatic Process
The Tumor Microenvironment
Microscopic Features of Neoplasia
Cellular Proliferation
Cellular Pleomorphism
Cellular Differentiation
Nuclear Cytoplasmic Ratio
Invasion of Surrounding Tissues
Tumor Infiltration by Normal Cells
Tissue Sampling and Processing
Cytological Sampling
Exfoliative Cytology
Aspiration Cytology
Histopathologic Sampling and Processing
Diagnostic Techniques
Light Microscopy
Immunohistochemistry
Additional Techniques
References
4: Pathology Specimen: Handling Techniques
Introduction
Pathological Specimen Handling in Theatre Before Fixation
Multiple Biopsies from a Surgical Procedure
Orientation of Specimens
Conjunctival Mapping Biopsies
Tissue Handling for Frozen Sections
Sampling Fresh Tissue Prior to Fixation
Fixation of Ocular Pathology Specimens [1–7]
Surgical Tumour Specimens
Fine-Needle Aspiration (FNA) Specimens [8–13]
Vitrectomy Specimens [8–13]
Impression Cytology Samples
Specimens Requiring Electron Microscopy
The Ophthalmic Pathology Request Form [14]
Transporting Specimens to the Pathology Laboratory
Handling Ophthalmic Surgical Specimens in the Pathology Laboratory [1–7]
Eyelid Skin Tumour Resections
Mapping Biopsies
Frozen Tissue Handling
Local Resection of Intraocular Tumours
Enucleation Specimens for Intraocular Tumours
Exenteration Specimens for Tumours
Cytology Handling [8–13]
Impression Cytology
FNAs
Vitreous Samples
References
5: Cancer Angiogenesis
Introduction
Tumor Angiogenesis
Cooption
Angiogenic Switch
Steps in Angiogenesis
Tumor Vessels
Metastatic Cascade
Promotors of Angiogenesis
Vascular Endothelial Growth Factor
Functions
Subtypes (VEGF A)
VEGF Receptors
Regulation of VEGF
Hypoxia
Other Factors
Fibroblast Growth Factor
Angiopoietins
Matrix Metalloproteinases (MMPs)
Inhibitors of Angiogenesis
Endogenous
Thrombospondin
Angiostatin
Endostatin
Pharmaceutical
Anti-VEGF Agents
Bevacizumab (Avastin®)
Ranibizumab (Lucentis®)
Pegabtanib (Macugen®)
Aflibercept (Eylea®)
SU5416, Semaxanib
Cox-2 Inhibitors (Celecoxib, Nepafenac/Amfenac)
Trastuzumab (Herceptin®)
Interferon-α2a
Antiangiogenic Therapy in Clinical Practice
Angiogenic Aspects of Specific Ophthalmic Tumors
Retinoblastoma
Treatment
Uveal Melanoma
Pseudovascular Channels (Vasculogenic Mimicry)
Microvessel Density
Tumor Ingrowth into Blood Vessels
Indocyanine Green Angiographic Patterns
VEGF Expression
Metastatic Uveal Melanoma
Treatment
Radiation Retinopathy
Metastatic Uveal Melanoma
Von Hippel-Lindau Disease
Treatment
Hemangioma of the Eyelid
Treatment
Conjunctival Squamous Cell Carcinoma (SSC)
Treatment
Conclusions
References
6: Immunology of Ocular Tumors
Introduction
Innate and Specific Immune Responses
Immunological Escape
Immunological Aspects of Uveal Melanoma
Immune Responses Against UM in Humans
HLA Antigen Expression
Leukocyte Infiltrate
Previously Irradiated Tumors
Immunotherapy
Ipilimumab
Programmed Death-Ligand 1
Interferon Alpha-2b
Dendritic Cell Therapy
Immune-Related Response to Therapy
Conclusions
References
7: Cancer Genetics
Introduction
Proliferation and the Cell Cycle
Growth Factor Signaling Pathways
Rb-p16Ink4a-Cyclin D Pathway
MYC Family of Oncogenes
Apoptosis and Senescence
p53 and MDM2
Bcl-2
Telomere Maintenance
BRCA and BAP1
Splicing Factor Mutations
Angiogenesis
VEGF
HIF/VHL
Epigenetics
Conclusions
References
8: Cancer Staging
Introduction
History
Purposes of Staging
Prognostic Relevance
Therapeutic Relevance
Research Relevance
Summary
References
9: Principles of Cryotherapy
Introduction
Mechanism of Tissue Injury
Direct Effects
Indirect Effects
Technical Aspects
Tissue Temperature
Cooling Rate
Freeze-Thaw Cycle
Number of Repetitions
Indications
Eyelid Tumors
Conjunctival Tumors
Intraocular Tumors
Orbital Tumors
Techniques of Cryotherapy
Eyelid Tumors
Conjunctival Tumors
Intraocular Tumors
Complications
Conclusions
References
10: Principles of Laser Therapy
Introduction
Laser Effects on Tissues
Photothermal Effects
Photochemical Effects
Photomechanical Effects
Types of Ophthalmic Lasers
Treatment Variables
Laser Delivery Systems
Techniques of Ophthalmic Laser Therapy
Summary
References
11: Principles of Radiation Therapy
Introduction
Basic Principles
Dual Nature of Radiation
Electromagnetic Radiation
Particle Radiation
Radioactive Decay
Ionizing and Nonionizing Radiation
Teletherapy Sources
Cobalt-60 Unit
Linear Accelerator
Cyclotron
Radiation Parameters
Radiation Dose
Relative Biological Effectiveness
Cobalt Gray Equivalents
Treatment Parameters
Target Volume
Total Dose
Fractionation
Tissue Tolerance
Teletherapy Techniques
External Beam Therapy
Conformal Radiation Therapy
Three-Dimensional Conformal Therapy
Intensity-Modulated Radiation Therapy
Stereotactic Radiosurgery
Linac-Based Stereotactic Radiosurgery
Treatment Delivery
Gamma Knife Radiosurgery
Charged Particle Therapy
Brachytherapy
Summary
References
12: Ocular Complications of Radiotherapy
Introduction
Periorbital Skin
Conjunctiva
Cornea
Radiation-Induced Dry Eye and Keratitis
Treatment
Scleral Necrosis
Extraocular Muscles
Dose Relationship
Treatment
Iris
Radiation-Induced Iris Neovascularization and Neovascular Glaucoma
Treatment
Lens
Clinical Features
Dose Relationship
Treatment
Radiation Retinopathy
Clinical Features
Dose Relationship
Treatment
Preventive Strategies
Radiation Optic Neuropathy
Clinical Features
Dose Relationship
Treatment
Toxic Tumor Syndrome
Conclusions
Box 12.1. Salient Features of Radiation Retinopathy
References
13: Principles and Complications of Chemotherapy
Introduction
Basic Principles of Chemotherapy
The Cell Cycle
Mechanisms of Action
Dose Intensification of Chemotherapy
Clinical Pharmacology of Chemotherapeutic Agents
Pharmacokinetics
Drug-Drug Interactions
Chemotherapy Resistance
Multimodal Therapy
Adjuvant Chemotherapy
Neoadjuvant Chemotherapy
Commonly Used Chemotherapeutic Agents in Ophthalmologic Cancers
Systemic Treatment of Orbital Lymphoma
Systemic Treatment of Orbital Melanoma
Systemic Treatment of Retinoblastoma
Systemic Treatment of Orbital Rhabdomyosarcoma
Toxicities of Cytotoxic Chemotherapy
Summary
References
14: Ocular Complications of Targeted Therapy
Introduction
Specific Agents
Tyrosine Kinase Inhibitors
Epidermal Growth Factor Receptor Inhibitors
Inhibitors of Angiogenesis
mTOR Pathway Inhibitors
Anaplastic Lymphoma Kinase (ALK) Inhibitors
Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway
Immunotherapy
Conclusions
References
15: Counseling Patients with Cancer
Introduction
Challenges Faced by Patients with Eye Cancer
Emotions and Fears
Box 15.1 Patients’ Emotions and Fears When Informed of Their Diagnosis and Treatment
Coping Mechanisms
Patients’ Needs
Box 15.2 Patients’ Emotional Needs
Eliciting and Addressing Patients’ Emotional Needs
Communication
Box 15.3 Requirements for Effective Communication
Decision-Making
Psychological Support
Patient-Reported Outcome Measures (PROMs)
Self-Help
Family Support
Support from Patient Organisations
Children with Cancer: What Should They Be Told?
Conclusion
References
16: Tumor-Associated Cataract
Introduction
Surgical Treatment-Induced Cataract
Radiation-Induced Cataract
Chemotherapy- and Hormonal Therapy-Induced Cataract
Specific Entities
Medulloepithelioma
Retinal Lymphoma
Retinoblastoma
Uveal Melanoma
Uveal Metastases
Perioperative and Intraoperative Considerations
Summary
References
17: Tumor-Associated Glaucoma
Introduction
Pathogenesis
Open-Angle Glaucoma
Angle-Closure Glaucoma
Clinical Features
Diagnostic Evaluation
Specific Entities
Childhood Glaucoma
Sturge-Weber Syndrome
Neurofibromatosis Type 1
Von Hippel-Lindau Disease
Juvenile Xanthogranuloma
Medulloepithelioma
Adult Glaucoma
Iris Stromal Cysts
Melanocytoma
Fuchs Adenoma
Uveal Melanoma
Metastatic Tumors
Leukemia/Lymphoma
Myelodysplastic Syndrome/Multiple Myeloma
Treatment
Summary
References
18: Graft-Versus-Host Disease
Introduction
Etiology
Pathogenesis
Classification of GVHD
Acute GVHD
Chronic GVHD
Clinical Ophthalmic Features
Ocular Surface Manifestations
Symptoms and Signs
Target Tissues
Lacrimal Glands
Meibomian Glands
Conjunctiva
Cornea
Diagnostic Evaluation
Differential Diagnosis
Treatment of Systemic GVHD
Biomarkers in Serum and Tears
Prevention of Systemic GVHD
Treatment of Established Systemic GVHD
Treatment of Ocular GVHD
Topical Lubricants
Topical Corticosteroids
Topical Cyclosporine A
Tacrolimus
Autologous Serum Eye Drops
Contact Lenses
Cataract Surgery in cGVHD
Follow-Up
Prognosis of GVHD
Systemic GVHD
Ocular GVHD
References
19: Diagnostic Techniques: Angiography
Introduction
Basic Principles
Anterior Segment Tumors
Iris Tumors
Iris Hemangioma
Retinal Tumors
Retinoblastoma
Retinal Vascular Tumors
Retinal Hemangioblastoma (Retinal Capillary Hemangioma)
Retinal Vasoproliferative Tumor
Cavernous Hemangioma
Racemose Hemangioma (Retinal Arteriovenous Malformation)
Retinal Astrocytic Hamartoma
Retinal Pigment Epithelial Tumors
Choroidal Tumors
Choroidal Nevus
Choroidal Melanoma
Melanocytoma
Choroidal Hemangioma
Choroidal Osteoma
Choroidal Granuloma
Choroidal Metastatic Tumors
Choroidal Lymphoma and Vitreoretinal Lymphoma
Simulating Conditions
Coats’ Disease
Persistent Hyperplastic Primary Vitreous/Persistent Fetal Vasculature
Scleritis
Central Serous Chorioretinopathy (CSCR)
Polypoidal Choroidal Vasculopathy (PCV)
Uveal Effusion Syndrome
Paraneoplastic Disorders
Radiation Retinopathy
References
20: Diagnostic Techniques: OCT
Introduction
Enhanced Depth Imaging
Swept-Source OCT (SS-OCT)
Optical Coherence Tomography Angiography
Conjunctival and Corneal Tumors
Scleral Lesions
Anterior Uveal Tumors
Intraocular Tumors
Retinal Pigment Epithelial Tumors
Retinal Tumors
Retinal Astrocytic Hamartoma
Retinoblastoma
Primary Vitreoretinal Lymphoma
Retinal Cavernous Hemangioma
Retinal Capillary Hemangioma
Retinal Vasoproliferative Tumor
Wyburn-Mason Syndrome
Optic Disc Melanocytoma
Choroidal Tumors
Choroidal Nevus
Choroidal Melanoma
Choroidal Osteoma
Choroidal Metastasis
Choroidal Hemangioma
Conclusions
References
21: Diagnostic Techniques: Autofluorescence
Introduction
The Origin of Autofluorescence
Types of Autofluorescence
Short-Wavelength AF
Near-Infrared AF
Choroidal Melanocytic Tumors
Choroidal Nevus
Indeterminate Choroidal Melanocytic Tumor (Small Choroidal Melanoma)
Choroidal Melanoma
Choroidal Hemangioma
Choroidal Metastasis
Congenital Hypertrophy of the Retinal Pigment Epithelium
Neurofibromatosis Type 1 (NF1)
Vitreoretinal Lymphoma
Conclusions
References
22: Diagnostic Techniques: Ultrasonography
Introduction
Basic Physics
Instrumentation
Diagnostic A-Scan
B-Scan
Ultrasound Biomicroscopy (UBM)
Methods for Differentiation of Intraocular Tumors
Topographic Ultrasonography
Quantitative Ultrasonography
Reflectivity
Internal Structure
Sound Attenuation
Kinetic Ultrasonography
Mobility
Vascularity
Convection
Differentiation of Anterior Segment Tumors
Iridociliary Pigment Epithelial Cyst (IPE Cyst)
Iris and Ciliary Body Melanoma
Ciliary Body Melanocytoma
Differentiation of Retinal Tumors
Retinoblastoma
Topographic
Quantitative and Kinetic
Persistent Fetal Vasculature (PFV)
Retinopathy of Prematurity (ROP)
Coats’ Disease
Differentiation of Choroidal Tumors
Choroidal Nevus
Choroidal Melanoma
Topographic
Quantitative and Kinetic
Special Cases
Associated Hemorrhage
Extraocular Extension
Episcleral Brachytherapy
Choroidal Hemangioma
Topographic
Quantitative and Kinetic
Choroidal Metastasis
Topographic
Quantitative and Kinetic
Hemorrhagic Disciform Lesion
References
23: Diagnostic Techniques: FNAB
Introduction
Box 23.1 Intraocular biopsy
Surgical Technique
Iris Tumors
Ciliary Body and Pre-equatorial Tumors
Post-equatorial Tumors
Vitrectomy-Assisted Aspiration Biopsy
Sample Handling
Indications
Melanoma: Prognostic
Amelanotic Uveal Tumor (Primary Versus Metastasis)
Nevus Versus Melanoma (Indeterminate Melanocytic Lesions)
Melanoma: Diagnostic
Intraocular Lymphoma
Retinoblastoma and  Other Retinal Tumors
Orbital Tumors
Complications
False-Negative Biopsy
False-Positive Biopsy
Needle Tract Seeding
Hemorrhage
Retinal Detachment
Endophthalmitis
Conclusions
References
24: Diagnostic Techniques: Other Biopsy Techniques
Introduction
Box 24.1 Other Biopsy Techniques
Vitreous Cutter Aspiration Biopsy
Indications and Contraindications
Surgical Technique
Results and Complications
Incisional Biopsy
Indications and Contraindications
Surgical Technique
Results and Complications
Excisional Biopsy
Indications and Contraindications
Surgical Technique
Results and Complications
Laboratory Techniques
Transport
Laboratory Investigations
Discussion
References
Index

Citation preview

Clinical Ophthalmic Oncology Basic Principles Arun D. Singh Bertil E. Damato Editors

Third Edition

123

Clinical Ophthalmic Oncology

Arun D. Singh  •  Bertil E. Damato Editors

Clinical Ophthalmic Oncology Basic Principles Third Edition

Editors Arun D. Singh Department of Ophthalmic Oncology Cole Eye Institute, Cleveland Clinic Cleveland, OH USA

Bertil E. Damato Nuffield Department of Clinical Neurosciences, University of Oxford John Radcliffe Hospital Oxford, UK

ISBN 978-3-030-04488-6    ISBN 978-3-030-04489-3 (eBook) https://doi.org/10.1007/978-3-030-04489-3 Library of Congress Control Number: 2019932849 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Ophthalmic tumors are rare and diverse so that their diagnosis can be quite complex. Treatment usually requires special expertise and equipment and in many instances is controversial. The field is advancing rapidly, because of accelerating progress in tumor biology, pharmacology, and instrumentation. Increasingly, the care of patients with an ocular or adnexal tumor is provided by a multidisciplinary team, consisting of ocular oncologists, general oncologists, radiotherapists, pathologists, psychologists, and other specialists. For all these reasons, we felt that there was a need for the new edition of the textbook providing a balanced view of current clinical practice. Although each section of Clinical Ophthalmic Oncology, 3rd Edition, now represents a stand-alone volume, each chapter has a similar layout with boxes that highlight the key features, tables that provide comparison, and flow diagrams that outline therapeutic approaches. The enormous task of editing a multiauthor, multivolume textbook could not have been possible without the support and guidance by the staff at Springer: Caitlin Prim, Melanie Zerah, ArulRonika Pathinathan, and Karthik Rajasekar. Michael D.  Sova kept the pressure on to meet the production deadlines. It is our sincere hope that our efforts will meet high expectation of the readers. Cleveland, OH, USA Oxford, UK

Arun D. Singh, MD Bertil E. Damato, MD, PhD, FRCOphth

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Acknowledgments

To my parents who educated me beyond their means, my wife Annapurna, and my children, Nakul and Rahul, who make all my efforts worthwhile. (ADS) To my family, Frankanne, Erika, Stephen, and Anna. (BED)  

Arun D Singh Bertil E Damato

vii

Contents

1 Principles of Cancer Epidemiology������������������������������������������������   1 Annette C. Moll, Michiel Robert de Boer, Lex M. Bouter, and Nakul Singh 2 Etiology of Cancer����������������������������������������������������������������������������  11 Brian T. Hill 3 Cancer Pathology ����������������������������������������������������������������������������  19 Gustav Stålhammar, Katarina Bartuma, Charlotta All-Eriksson, and Stefan Seregard 4 Pathology Specimen: Handling Techniques����������������������������������  33 Hardeep Singh Mudhar 5 Cancer Angiogenesis������������������������������������������������������������������������  49 Werner Wackernagel, Lisa Tarmann, Martin Weger, and Arun D. Singh 6 Immunology of Ocular Tumors������������������������������������������������������  71 Martine J. Jager and Inge H. G. Bronkhorst 7 Cancer Genetics ������������������������������������������������������������������������������  79 Elaine M. Binkley and Luke A. Wiley 8 Cancer Staging ��������������������������������������������������������������������������������  87 Claudine Bellerive and Arun D. Singh 9 Principles of Cryotherapy ��������������������������������������������������������������  93 Dan S. Gombos and Kayla Walter 10 Principles of Laser Therapy������������������������������������������������������������  99 Hatem Krema 11 Principles of Radiation Therapy���������������������������������������������������� 107 Abigail L. Stockham, Allan Wilkinson, and Arun D. Singh 12 Ocular Complications of Radiotherapy ���������������������������������������� 117 Mitchell Kamrava, James Lamb, Vidal Soberón, and Tara A. McCannel 13 Principles and Complications of Chemotherapy�������������������������� 129 Stacey Zahler, Nicola G. Ghazi, and Arun D. Singh

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14 Ocular Complications of Targeted Therapy���������������������������������� 143 Ashley Neiweem, Denis Jusufbegovic, and Arun D. Singh 15 Counseling Patients with Cancer���������������������������������������������������� 161 Bertil E. Damato 16 Tumor-Associated Cataract������������������������������������������������������������ 173 Carlos A. Medina Mendez, Mary E. Aronow, Guillermo Amescua, and Arun D. Singh 17 Tumor-Associated Glaucoma���������������������������������������������������������� 185 Reena Garg, Annapurna Singh, and Arun D. Singh 18 Graft-Versus-Host Disease�������������������������������������������������������������� 195 Edgar M. Espana, Lauren Jeang, and Arun D. Singh 19 Diagnostic Techniques: Angiography �������������������������������������������� 209 Kaan Gündüz and Yağmur Seda Yeşiltaş 20 Diagnostic Techniques: OCT���������������������������������������������������������� 235 Rubens Belfort and Arun D. Singh 21 Diagnostic Techniques: Autofluorescence�������������������������������������� 257 Edoardo Midena, Luisa Frizziero, Elisabetta Pilotto, and Raffaele Parrozzani 22 Diagnostic Techniques: Ultrasonography�������������������������������������� 271 Brandy H. Lorek, Mary E. Aronow, and Arun D. Singh 23 Diagnostic Techniques: FNAB�������������������������������������������������������� 295 Hassan A. Aziz, David Pelayes, Charles V. Biscotti, and Arun D. Singh 24 Diagnostic Techniques: Other Biopsy Techniques������������������������ 309 Bertil E. Damato, Armin Afshar, Sarah E. Coupland, Heinrich Heimann, and Carl Groenewald Index���������������������������������������������������������������������������������������������������������� 317

Contents

Contributors

Armin  Afshar, MD, MBA Ocular Oncology Service, Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA Charlotta  All-Eriksson, MD, PhD  Department of Ophthalmic Pathology and Oncology Service and Department of Clinical Neuroscience, St. Erik Eye Hospital and Karolinska Institutet, Stockholm, Sweden Guillermo  Amescua, MD Department of Cornea and External Diseases, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA Mary E. Aronow, MD  Department of Retina Service and Ocular Oncology, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, USA Hassan A. Aziz, MD  Clemenceau Medical Center, Beirut, Lebanon Katarina  Bartuma, MD, PhD  Department of Ophthalmic Pathology and Oncology Service and Department of Clinical Neuroscience, St. Erik Eye Hospital and Karolinska Institutet, Stockholm, Sweden Rubens  Belfort, MD, PhD Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina – Federal University of São Paulo, São Paulo, Brazil Claudine  Bellerive, MD, MSc Centre universitaire d’ophtalmologie, Hôpital Saint-Sacrement, Centre hospitalier universitaire de Québec, Québec, QC, Canada Elaine M. Binkley, MD  Department of Ophthalmology & Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Charles V. Biscotti, MD  Department of Anatomic Pathology and Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Lex  M.  Bouter, PhD  Department of Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands Inge H. G. Bronkhorst, MD  Department of Ophthalmology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands Sarah  E.  Coupland, MBBS, PhD  Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK xi

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Bertil E. Damato, MD, PhD, FRCOphth  Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK Michiel  Robert  de Boer, PhD Department of Health Sciences, VU Amsterdam, Amsterdam, The Netherlands Edgar M. Espana, MD  Department of Ophthalmology, University of South Florida, Tampa, USA Luisa Frizziero, MD  IRCCS – Fondazione Bietti, Rome, Italy Reena  Garg, MD Department of Ophthalmology, Emory University Hospital, Atlanta, GA, USA Nicola G. Ghazi, MD  Division of Ophthalmology and Vitreoretinal Service, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia Department of Ophthalmology, The University of Virginia, Charlottesville, VA, USA Dan  S.  Gombos, MD, FACS Section of Ophthalmology-Department of Head and Neck Surgery, MD Anderson Cancer Center, The Retinoblastoma Center of Houston (MD Anderson/Texas Children’s/Baylor/Methodist Hospital), Houston, TX, USA Carl Groenewald, MD  Liverpool Ocular Oncology Centre, St Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, UK Kaan  Gündüz, MD Department of Ophthalmology, Ankara University Faculty of Medicine, Ankara, Turkey Heinrich Heimann, MD  Liverpool Ocular Oncology Centre, St Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, UK Brian T. Hill, MD, PhD  Department of Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Martine  J.  Jager, MD, PhD Department of Ophthalmology, LUMC, Leiden, The Netherlands Lauren  Jeang, MD Department of Ophthalmology, New England Eye Center/Tufts Medical Center, Boston, MA, USA Denis Jusufbegovic, MD  Department of Ophthalmology, Indiana University School of Medicine/Glick Eye Institute, Indianapolis, IN, USA Mitchell Kamrava, MD  Department of Radiation Oncology, University of California, Los Angeles, CA, USA Hatem  Krema, MD, MSc, FRCS Ocular Oncology Service, Princess Margaret Cancer Center/ University Health Network, Toronto, ON, Canada James  Lamb, PhD Department of Radiation Oncology, University of California, Los Angeles, CA, USA Brandy H. Lorek, BS  Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

Contributors

Contributors

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Tara  A.  McCannel, MD, PhD  Ophthalmic Oncology Center, Jules Stein Eye Institute, Department of Ophthalmology, University of California, Los Angeles, CA, USA Carlos  A.  Medina  Mendez, MD Retinal Consultants, Sacramento, CA, USA Edoardo Midena, MD, PhD  Department of Ophthalmology, University of Padova, Padova, Italy IRCCS – Fondazione Bietti, Rome, Italy Annette C. Moll, MD, PhD  Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands Hardeep  Singh  Mudhar, BSc, PhD, MBBChir, FRCPath National Specialist Ophthalmic Pathology Service (NSOPS), Department of Histopathology, E-Floor, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK Ashley  Neiweem, MD  Department of Ophthalmology, Indiana University School of Medicine/Glick Eye Institute, Indianapolis, IN, USA Raffaele Parrozzani, MD, PhD  Department of Ophthalmology, University of Padova, Padova, Italy David Pelayes, MD  Department of Ophthalmology, Buenos Aires University and Maimonides University, Buenos Aires, Argentina Elisabetta  Pilotto, MD Department of Ophthalmology, University of Padova, Padova, Italy Stefan  Seregard, MD PhD Department of Ophthalmic Pathology and Oncology Service and Department of Clinical Neuroscience, St. Erik Eye Hospital and Karolinska Institutet, Stockholm, Sweden Annapurna  Singh, MD Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Arun  D.  Singh, MD Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Nakul Singh, MS  School of Medicine, Case Western University, Cleveland, OH, USA Vidal  Soberón, MD Department of Retina/Oncology, Jules Stein Eye Institute, Los Angeles, CA, USA Gustav Stålhammar, MD, PhD  Department of Ophthalmic Pathology and Oncology Service and Department of Clinical Neuroscience, St. Erik Eye Hospital and Karolinska Institutet, Stockholm, Sweden Abigail  L.  Stockham, MD Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA Lisa  Tarmann, MD, PhD Department of Ophthalmology, Medical University Graz, Graz, Styria, Austria

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Werner  Wackernagel, MD Department of Ophthalmology, Medical University Graz, Graz, Styria, Austria Kayla Walter  UT McGovern School of Medicine, Houston, TX, USA Martin  Weger, MD Department of Ophthalmology, Medical University Graz, Graz, Styria, Austria Luke  A.  Wiley, PhD Department of Ophthalmology & Visual Sciences, Institute for Vision Research, University of Iowa, Iowa City, IA, USA Allan  Wilkinson, PhD Department of Radiation Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA Yağmur  Seda  Yeşiltaş, MD Department of Ophthalmology, Ankara University Faculty of Medicine, Ankara, Turkey Stacey  Zahler, DO, MS Department of Pediatric Hematology, Oncology and Blood & Marrow Transplantation, Cleveland Clinic Children’s Hospital, Cleveland, OH, USA

Contributors

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Principles of Cancer Epidemiology Annette C. Moll, Michiel Robert de Boer, Lex M. Bouter, and Nakul Singh

Introduction During the last decade, evidence-based medicine (EBM) has become a dominant approach in many medical fields, including ophthalmology [1, 2]. Clinical epidemiological studies provide evidence that can aid decision-making processes. An overwhelming amount of clinical epidemiological papers are being published every year, and critical appraisal of the findings can be challenging, especially for the busy clinician who is not formally trained in the field of clinical epidemiology. Therefore, the available evidence is increasingly bundled in clinical guidelines. The aim of this chapter is to provide readers with some basic knowledge to allow them to judge the value of clinical epidemiological papers and thus of the pillars of evidence-based clinical guidelines.

A. C. Moll (*) Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands e-mail: [email protected] M. R. de Boer Department of Health Sciences, VU Amsterdam, Amsterdam, The Netherlands L. M. Bouter Department of Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands N. Singh School of Medicine, Case Western University, Cleveland, OH, USA

Examples from ocular oncology will be used to illustrate the methodological principles.

Research Question A clinical epidemiological study should always start with a well-defined research question. Similarly, when reading a paper, one should always first identify the question(s) the authors wish to address (Fig.  1.1). Research questions can be aimed at explanation or description. Explanatory research examines causal relationships, while descriptive research is merely descriptive. In addition, research questions are also often being categorized as etiological, diagnostic, or prognostic (Table 1.1). For example, an explanatory research question related to etiology in the field of ocular oncology is as follows: are children born after in vitro fertilization at higher risk of developing retinoblastoma as compared to children born after natural conception? [3] A correct explanatory research question should contain information on the patients, interventions, contrast, and outcomes (PICO) at issue.

Outcome Measures Traditionally, prevalence, incidence, and mortality (survival) have been the outcome measures in clinical cancer epidemiology studies. More recently,

© Springer Nature Switzerland AG 2019 A. D. Singh, B. E. Damato (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-04489-3_1

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Research question(s)

•

Identify patients, interventions (exposures), controls and outcome (PICO)

• •

Descriptive or explanatory purpose Focus on aetiology (including prevention), diagnosis or prognosis (including therapy)

Design

Sample

Measurements

Case series Cross sectional Cohort study RCT Case control

Source population Target population Control population Sampling strategy Inclusion/Exclusion criteria

Outcome Potential confounders Validity, reproducibility and responsiveness Time to follow-up

Other considerations •

Ethical aspects

• •

Practical limitations Budget constraints

Fig. 1.1  Steps in designing a clinical epidemiological research Table 1.1  Types of epidemiological research Type of research Etiology (including prevention)

Diagnosis

Prognosis (including interventions)

Purpose To examine possible etiological factors for the occurrence of a disease To examine the usefulness of diagnostic tests for the disease To examine possible prognostic factors for the disease

Example Association between ultraviolet radiation and uveal melanoma Accuracy of magnetic resonance imaging in determining choroidal invasion of retinoblastoma Association between external beam therapy for retinoblastoma and the incidence of second malignant neoplasms

1  Principles of Cancer Epidemiology

quality of life measures have become increasingly popular. In ophthalmic oncology, visual acuity is also an important outcome measure.

Prevalence Prevalence refers to the proportion of the study population with the condition of interest. Usually prevalence is given for a specific moment in time (point prevalence), but sometimes it is estimated for a period of time (e.g., 1 year or lifetime prevalences). For example, the lifetime prevalence of uveal melanoma in a Caucasian population with oculo(dermal) melanocytosis is estimated to be 0.26% [4].

Incidence Whereas prevalence relates to existing cases, incidence relates to the proportion of new cases in the study population. It is important that the population under investigation is at risk of developing the condition. For example, persons with bilateral enucleation are no longer at risk of developing uveal melanoma. There are two different measures of incidence: cumulative incidence (CI) and incidence density (ID). CI is the proportion of new cases in a population at risk over a specified period of time. For example, the CI of second malignant neoplasms in hereditary retinoblastoma patients is 17% at the age of 35 years [5]. ID refers to the rate of developing the condition during follow-up, usually expressed as a proportion per person-year at risk.

Mortality Cancer is among the leading causes of mortality. In order to understand the processes that either hasten or delay this outcome, it is necessary to rigorously define the burden of disease. Clinical epidemiologists have created several concepts of mortality, all with their own definition, interpretation, and uses. Unfortunately, many of these concepts use similar nomenclature, so it is important to always clarify the definition of mortality at

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hand. Broadly speaking, mortality rate refers to the incidence of death, and survival rate is its complement, i.e., survival rate = 100 – mortality rate. Population mortality is the chance that a person in the general population will die from a specific disease over a specified time frame. It is a useful concept for measuring the burden of disease in a population. For example, the population mortality for heart disease was 197.2 per 100,000 population per year in 2015. Therefore, it is a measure more important for public health policymakers as opposed to clinicians. This measure is calculated from death certificates, where cause of death is known [6]. Overall mortality is the chance that a person with a disease will die within a time period after diagnosis. It is important to specify a time period for the mortality statistics – in the long run, mortality is 100% for any condition. Of note, this definition is indifferent to cause of death. Overall mortality is the most common measure of mortality in the literature and is often used to guide prognosis. This measure is helpful in identifying risk factors for poor prognosis, as well as measuring disparities between populations. The interpretation of this measure is complicated by biases, including lead time, length, and overdiagnosis biases. Cause-specific mortality is the chance that a person with a disease will die within a time period after diagnosis due to the disease. This is in contrast to overall survival, which does not distinguish between causes of death. Cause-specific mortality most closely measures the “deadliness” of a disease, but similar to overall mortality, it can be affected by lead time, length, and overdiagnosis bias. Relative mortality is a proportion that compares the overall mortality of people with a disease to that of an unaffected, but otherwise identical population. Relative mortality measures the excess mortality associated with a diagnosis compared to the general population. It is a convenient measure to calculate because it does not require cause of death to be recorded. It is also a helpful measure for understanding the deadliness of a disease that affects the elderly, where patients are at risk from dying from other causes. To calculate relative survival, overall survival of a

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cohort of patients is compared to life tables of the general population, matched by age, sex, race, and other important demographic features. Conditional mortality is another clinically informative measure of mortality, which measures the chance that a person with a disease will die within a specified time period after having already lived with the disease for a certain amount of time. It is a helpful measure to assess how prognosis changes over time. Conditional survival requires a cohort of patients where long-­ term follow-up is close to complete.

Time to Event

endpoints argue that they are preferable for reasons of feasibility, cost, and length of study, with possible expediency of the drug approval process. Critics of surrogate endpoints point out that the evidence base for surrogate endpoints correlating closely with clinical outcomes is often tenuous.

Quality of Life With increasing survival rates and with severe side effects of some treatment modalities, quality of life measures have become increasingly important in ophthalmic oncology. These measures encompass symptoms and physical, social, and psychological functioning from a patient’s perspective. Usually, quality of life is assessed with a structured questionnaire, and scores are summarized assuming an interval scale. Several questionnaires have recently been developed for patients with ocular diseases, such as the measure of outcome in ocular disease [MOOD]) [9].

Another class of outcomes that is of interest to clinical epidemiologists is time to event. Time to event measures the length of time that elapses from some start point to a defined endpoint, the most common time-to-event measure being survival, which is defined as time from diagnosis to death (not to be confused with survival rate). Other events can be used as the endpoint, such as relapse or radiographic progression. Time-to-­ event data is typically graphically presented with M  easures of Association a Kaplan-Meier plot, which displays a nonparametric estimation of the rate of survival in a pop- In epidemiological research, we are usually interulation as a function of time [7]. ested in how certain interventions or exposures are associated with outcomes; for example, is there an association between paternal age and Surrogate Endpoints retinoblastoma in the offspring? [10]. There are several statistical approaches that can be used to While overall mortality and cause-specific mor- quantify associations, either as a ratio or as a diftality are the two gold standard measures of mor- ference, depending upon the study design and tality when evaluating the efficacy of statistical method used (Table 1.2). interventions, other measures of efficacy are being proposed, such as surrogate endpoints, which are biomarkers that are intended to substi- Relative Risk tute for a clinical endpoint. Of note, these are not clinical quantities of interest but are correlated The ratio of cumulative incidences of exposed with them. Examples of surrogate endpoints and unexposed individuals (or between treated include evidence of radiographic progression, and untreated patients) is the relative risk (RR). biochemical markers, and physical signs [8]. For example, in the Netherlands, the RR of retiThese are controversial measures and are not uni- noblastoma in children conceived by in vitro ferformly accepted within the scientific and regula- tilization is between 4.9 and 7.2. This implies that tory community. Proponents of surrogate the risk of getting retinoblastoma is between 4.9

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Table 1.2  The relation between outcome, measures of association, study designs, and statistical methods Outcome Prevalence

Measure of association Prevalence rate

Odds of exposure

Prevalence difference Odds ratio

Cumulative incidence (CI) Incidence density (ID)

Relative risk Risk difference Hazard ratio Risk difference O/E ratio

Quality of life

Difference in mean score

Computation P1/P2

Study designs Cross-sectional

P1 − P2

Cross-sectional

Odds of exposure group 1/ odds of exposure group 2 CI1/CI2 CI1 − CI2 ID1/ID2

Case-control study (cohort study, RCT) Cohort study/RCT RCT Cohort study/RCT

ID1 − ID2 Observed ID/expected ID in general population X1 − X2

RCT Cohort study/registry study Cohort study/RCT

Statistical methods Chi-square test Logistic regression analysis Chi-square test Chi-square test Logistic regression Chi-square test Kaplan-Meier Cox regression Kaplan-Meier

Independent t-test Linear regression analyses

P1 prevalence group 1, P2 prevalence group 2, CI cumulative incidence, CI1 CI group 1, CI2 CI group 2, ID incidence density, ID1 ID group 1, ID2 ID group 2, O/E ratio observed to expected ratio, RCT randomized controlled trial, X1 = mean score group 1; X2 = mean score group 2

and 7.2 times higher for children conceived after IVF than naturally conceived children.

expected. This data can be expressed as standardized mortality ratio of 5.41 [11].

Hazard Ratio

Odds Ratio

The ratio of incidence densities of unexposed and exposed patients (or between treated and untreated patients) is the hazard ratio (HR), which has a similar interpretation as the RR. This measure is often used in relation to mortality, because we are generally interested not only in the proportion of patients that die but also in the time from baseline (diagnosis or start of treatment) until death. A special application of the HR is the ratio of the observed to the expected number of cases (O/E ratio). In this case the observed incidence density is calculated for the study population, and this is compared to the expected incidence density derived from a population registry (e.g., cancer registration). For example, in a study of lifetime risks of common cancers among 144 hereditary retinoblastoma survivors, 41 cancer deaths were observed, whereas only 7.58 deaths due to cancer were

The odds ratio (OR) is the most commonly reported measure of association in the literature, due to the fact that this is the statistic that can be derived from the popular logistic regression analysis. The OR is the ratio of the odds of outcome of interest between the exposed and the ­unexposed. Generally speaking, the OR is a good approximation of the RR or HR.

Differences in Risk Differences in risks (RD) are preferably reported as outcome in randomized controlled trials. The RD is easy to interpret and can be used to calculate the number of patients needed to treat (NNT) to prevent one extra event (e.g., death) compared to the standard treatment or placebo. The NNT can be calculated as inverse of RD (1/RD). A related

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c­oncept is that of the number needed to screen (NNS). This refers to the number of patients needed to screen to prevent one extra event compared to the situation without a screening program. The NNS thus depends on the predictive probability of the screening test as well as on the efficacy of treatment for people that are diagnosed with that screening test. The value of routine neuroimaging screening of pineoblastoma in retinoblastoma patients is uncertain and a point of discussion [12].

Therefore, interpretation of findings should never solely rely on statistical significance.

Differences in Mean Score

Confounding

For scores on interval scales, such as quality of life, differences in mean score between exposed and unexposed participants are the most important measure of interest. These can be derived from independent samples t-test of general linear models (e.g., linear regression analysis).

Confounding occurs when the association between exposure and outcome is influenced by a third variable that is related both to the exposure and the outcome (Fig. 1.2). A recent study found an association between cooking (as occupation) and the incidence of ocular melanoma [13]. It could be argued that as many cooks work at night, it is possible that they could have relatively high exposures to sunlight due to daytime leisure activities compared to people working during the daytime. It is implied that the association between cooking and ocular melanoma could potentially (in part) be explained by a higher exposure to sunlight by cooks.

Precision of the Estimate When interpreting an outcome, we do not only want to know the numerical value of the point estimate but also the precision with which it has been assessed. In other words, can we be confident that the outcome is not just a chance finding? The usual standard for accepting an outcome as being beyond chance is p (probability) 90% risk of developing retinoblastoma, as well as an increased risk for several other tumor types. In normal cells, cell-tocell contact mediates suppression of growth [1]. If normal cells lose the cell-to-cell contact, they undergo programmed cell death. This inhibitory signal is often lost in tumor cells. A set of cellsurface adhesion molecules, most notably the cadherins (E-cadherin and N-cadherin), are commonly altered in tumor cells enabling the tumor cell to let go and then reattach, thus serving as an important step in metastatic spread [14, 15].

Escaping Cell Death Apoptosis, the orderly conducted programmed cell death, can be triggered by environmental stress, elevated levels of oncogene signaling, telomere shortening, DNA damage, infection, and loss of attachment to other cells. It functions as a guardian against malignant genetic change [16]. By escaping programmed cell death, tumor cells manage to survive even though they harbor multiple genetic changes.

Replicative Immortality Normal cells are only able to replicate a limited number of times before they enter either senescence or cell death. Telomeres protect the ends of chromosomes and are intimately involved in replicative immortality [1]. While telomerase, a protein that adds repeat sequences to the end of telomeres and thereby elongates them, is barely expressed in normal cells, its overexpression in malignancies allows the cells to escape destruction [4, 17].

Angiogenesis Tumors must acquire new vasculature by angiogenesis to be able to grow beyond a size of approximately 2 mm3 (Chap. 5).

3  Cancer Pathology

Invasion and Metastasis

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obtained in uveal melanoma (and several other tumors) as tumor vessel counts have been associTumor metastases account for approximately ated with a poor prognosis [23]. Following 90% of tumor-related deaths [18]. By pinpoint- intravasation, the tumor cells must survive the ing the processes underlying metastasis, greater detachment from the supporting tumor matrix, understanding and treatment options will emerge the hemodynamic forces in the circulation, as [19]. The metastatic process is thought to start well as a hostile immune system. The process of with individual tumor cells dislodging from the extravasation begins when the cell attaches to the primary tumor and spreading by blood or lym- vessel wall in the target tissue. This is achieved phatic vessels. The timing of tumor dissemina- either by a tumor forming in the vessel wall, tion remains a subject of debate. There are two which eventually ruptures the vessel wall, or by major models: the linear progression model penetrating the endothelial cells and pericyte laywhere a cell acquires a set of characteristics ers and thereby establishing micrometastasis through stepwise alteration before dissemination (Box 3.1) [24]. Tumors originating within the eye and the parallel progression model where cells undergo hematogenous dissemination, because that are not yet fully neoplastic are circulating, there is no lymphatic drainage. Tumors originatsuggesting that they are disseminated from an ing in the orbit or eyelids may undergo either early malignant lesion [20, 21]. The invasion-­ hematogenous or lymphatic spread, depending metastasis cascade is a complex, multistep pro- on the tumor type and specific relation to the cess where tumor cells must be able to invade respective vascular system. locally through the extracellular matrix and stromal cell layers. The precisely organized architecture of surrounding normal epithelium serves Box 3.1 Steps in Metastatic Process as an effective barrier, which is overcome by invading tumor cells when the metastatic process starts [19]. The matrix metalloproteinases • Tumor cell epithelial-mesenchymal secreted by macrophages at the tumor periphery transition and invasion of local vessels contribute to the loss of the basement membrane • Tumor cell survival in the circulation by proteolysis, which facilitates invasion of the • Cellular extravasation and mesenchymal-­ stromal compartment [19, 22]. Invading cells epithelial transition must also become motile to escape the primary • Adaption to environment at distant site tumor; this is achieved by alterations in cell-surand establishment of a micrometastasis face proteins that promote migration. Alteration • Acquirement of supportive microenviof the cytoskeleton allows for movement along ronment including nutrient, growth facthe extracellular matrix and surface of other tor, and vascular supply for growth to cells. Further, the Ras family of GTPases alters macrometastasis actin and myosin activity, which promotes movement [1]. After leaving the primary tumor and invading Little is known about the predilection for parthe stroma, the tumor cells must intravasate into ticular metastatic targets, but two major theories blood or lymph vessels. Intravasation into blood have emerged: the mechanistic theory where vessels is facilitated by the insufficient pericyte tumor cells arrest within capillary beds due to coverage and weak endothelial interaction of size restrictions of the capillary vessels. The malignant blood vessels [19]. Acquiring an other theory describes receptor-ligand binding intrinsic vasculature, driven by secreted factors between tumor cells and capillaries, also known such as vascular endothelial growth factor as the “seed and soil” theory: the provision of a (VEGF), is important for primary tumors in order fertile environment in which compatible tumor to metastasize and for metastases to grow beyond cells can grow. Most likely the combination of a certain size. Indirect evidence for this has been both theories is true for the majority of metastatic

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malignancies. Some microenvironments seem to be more hospitable than others, exemplified by preferential dissemination by a wide range of different tumor types to the liver, bone marrow, and lung tissue [25]. Extravasation of tumor cells is more challenging than intravasation since intravasation occurs at the primary tumor site where the vasculature is already quite leaky and therefore easy to traverse [19]. After intravasation, the cancer cells must be able to adapt to a very different environment from that of the primary tumor. The process of metastasis is very inefficient. Indeed, it has been suggested that only 60 s), which can penetrate deeper to be absorbed by choroidal melanocytes and RPE. Transpupillary thermotherapy has been initially used as a primary sole treatment for small choroidal melanomas at the postequatorial fundus [25]. Nonetheless, the long-term tumor control rates for small melanoma were disappointing with 17% (8–56%) late recurrences at 3 years and reported cases of extraocular extension [26, 27]. The exact mechanism by which hyperthermia affects melanoma is unclear, though chemical and immunological theories were suggested [28]. Currently, TTT is used as an adjuvant treatment to radiotherapy for selected melanoma cases. TTT is applied for treatment of small edge

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recurrence of melanoma post radiotherapy, for ablation of small retinal or choroidal vascular tumors, and as a primary treatment for small retinoblastoma or post chemoreduction [29–31]. Photodynamic Therapy Photodynamic therapy (PDT) depends upon the photochemical property of laser. It utilizes a photosensitive intravenous drug, verteporfin, in combination with a low-power long-duration infrared laser, to treat vascular lesions of the retina and choroid [32]. Verteporfin is a benzoporphyrin derivative with a half-life of 5–6 h, which selectively collects in the abnormal blood vessels in the retina and choroid. Fifteen minutes after intravenous infusion of verteporfin (dose = 6 mg/m2 dose), a low-power 690  nm laser is applied with a slit lamp delivery system (standard dose of 50 J/cm2, intensity of 600 mW/cm2) over 83 s. Laser activation of verteporfin causes release of free radicals, which react with blood vessels’ endothelium inducing local increase of immune modulation factors as histamines, thromboxane, and TNF-α. The anti-inflammatory response can lead to series of events including vasoconstriction, thrombosis, increased vascular permeability, blood stasis, and hypoxia [33, 34]. This selective vascular toxicity has been utilized to treat choroidal neovascular membranes (CNVM) of wet age-related macular degeneration (AMD), polypoidal choroidal vasculopathy, and central serous chorioretinopathy [35–37]. In ophthalmic oncology, PDT is the treatment of choice for small- and medium-sized circumscribed choroidal hemangioma and retinal capillary hemangioma, particularly those in juxtapapillary location. Most of these vascular tumors are controlled by one treatment session, though few may require up to four sessions [38– 40]. PDT also can reduce SRF in symptomatic choroidal nevi with serous detachment at the macula [41]. PDT has been tried as a primary treatment for small choroidal melanoma, but similar to TTT, the long-term local control rates were unsatisfactory [42, 43].

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Summary Laser has been progressively utilized in multiple medical applications since the middle of the twentieth century. Stimulated emission is the physical principle of laser beam generation. Laser energy varies according to its wavelength. There are several types of ophthalmic lasers that can produce thermal, chemical, or mechanical effects on the ocular tissues. Several factors determine the impact of laser such as the degree of absorption of tissue pigments of a specific laser wavelength, laser power, the size of laser spot on the target tissue, the duration of application, and media clarity. Laser delivery systems can be attached to slit lamp and indirect ophthalmoscope, or laser can be delivered through a fiber-optic probe. Advanced delivery systems enabled for more tolerable, precise, and shorter treatment sessions. Techniques of ophthalmic laser therapy include laser photocoagulation, transpupillary thermotherapy, and photodynamic therapy. These laser techniques are used in ophthalmic oncology as a primary or adjuvant tumor treatment and as a treatment for some radiationinduced toxicities.

References 1. Einstein A.  On the quantum mechanics of radiation [in German]. Phys Z. 1917;18:121–8. 2. Schechter RJ.  An introduction to basic laser physics. In: Tasman W, Jaeger EA, eds. Duane’s clinical ophthalmology. 1992 Revised edition. Philadelphia: J.B. Lippincott Company; 1992. (1)69A:1–8. 3. Sramek C, Paulus Y, Nomoto H, et  al.  Dynamics of retinal photocoagulation and rupture. J Biomed Opt. 2009;14(3):034007. 4. LaMuraglia GM, Adili F, Karp SJ, et al. Photodynamic therapy inactivates extracellular matrix-basic fibroblast growth factor: insights to its effect on the vascular wall. J Vasc Surg. 1997;26(2):294–301. 5. Schmidt-Erfurth U, Miller J, Sickenberg M, et  al. Photodynamic therapy of subfoveal choroidal neovascularization: clinical and angiographic examples. Graefes Arch Clin Exp Ophthalmol. 1998;236(5):365–74. 6. Vogel A, Venugopalan V.  Mechanisms of pulsed laser ablation of biological tissues. Chem Rev. 2003;103(2):577–644.

H. Krema 7. Capon MR, Docchio F, Mellerio J.  Nd:YAG laser photodisruption: an experimental investigation on shielding and multiple plasma formation. Graefes Arch Clin Exp Ophthalmol. 1988;226(4):362–6. 8. Fankhauser F, Kwasniewska S.  Laser in ophthalmology. Basic, diagnostic and surgical aspects. The Hague: Kugler Publications; 2003. 9. Palanker DV, Blumenkranz MS, Marmor MF.  Fifty years of ophthalmic laser therapy. Arch Ophthalmol. 2011;129(12):1613–9. 10. Peyman GA, Raichand M, Zeimer RC. Ocular effects of various laser wavelengths. Surv Ophthalmol. 1984;28(5):391–404. 11. Pomerantzeff O, Kaneko H, Donovan RH, et al. Effect of the ocular media on the main wavelengths of argon laser emission. Invest Ophthalmol Vis Sci. 1976;15:70–7. 12. Al-Hussainy S, Dodson PM, Gibson JM.  Pain response and follow-up of patients undergoing panretinal laser photocoagulation with reduced exposure times. Eye (Lond). 2008;22:96–9. 13. Soleimani A, Rasta SH, Banaei T, et  al.  Effects of laser physical parameters on lesion size in retinal photocoagulation surgery: clinical OCT and experimental study. J Biomed Phys Eng. 2017;7(4):355–64. 14. Mainster MA, Crossman JL, Erickson PJ, et al. Retinal laser lenses: magnification, spot size, and field of view. Br J Ophthalmol. 1990;74(3):177–9. 15. Blumenkranz MS, Yellachich D, Andersen DE, et al. Semiautomated patterned scanning laser for retinal photocoagulation. Retina. 2006;26(3):370–6. 16. Verdaasdonk RM, van Swol CF. Laser light delivery systems for medical applications. Phys Med Biol. 1997;42(5):869–94. 17. Yadav NK, Jayadev C, Rajendran A, et  al.  Recent developments in retinal lasers and delivery systems. Indian J Ophthalmol. 2014;62(1):50–4. 18. L’Esperance FJ.  Ophthalmic lasers. St. Louis: CV Mosby; 1983. p. 340–50. 19. Brader HS, Young LH.  Subthreshold diode micropulse laser: a review. Semin Ophthalmol. 2016;31(1–2):30–9. 20. Finger PT, Kurli M. Laser photocoagulation for radiation retinopathy after ophthalmic plaque radiation therapy. Br J Ophthalmol. 2005;89(6):730–8. 21. Shields CL, Shields JA, Kiratli H, et al. Treatment of retinoblastoma with indirect ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol Strabismus. 1995;2(5):317–22. 22. Schmidt D, Natt E, Neumann HP. Long-term results of laser treatment for retinal angiomatosis in von Hippel-­ Lindau disease. Eur J Med Res. 2000;5(2):47–58. 23. SinghAD. Ocular phototherapy. Eye. 2013;27(2):190–8. 24. Wesley RE, Bond JB.  Carbon dioxide laser in ophthalmic plastic and orbital surgery. Ophthalmic Surg. 1985;16(10):631–3. 25. Oosterhuis JA, Journee-de Korver HG, Kakebeeke-­ Kemme HM, et  al.  Transpupillary thermotherapy in choroidal melanomas. Arch Ophthalmol. 1995;113(3):315–21.

10  Principles of Laser Therapy 26. Singh AD, Kivela T, Seregard S, et al. Primary transpupillary thermotherapy of “small” choroidal melanoma: is it safe? Br J Ophthalmol. 2008;92(6):727–8. 27. Singh AD, Rundle PA, Berry-Brincat A, et  al.  Extrascleral extension of choroidal malignant melanoma following transpupillary thermotherapy. Eye (Lond). 2004;18(1):91–3. 28. Dennaoui J, Bronkhorst IH, Ly LV, et al. Changes in immunological markers and influx of macrophages following trans-scleral thermotherapy of uveal melanoma. Acta Ophthalmol. 2011;89(3):268–73. 29. Shields CL, Cater J, Shields JA, et  al. Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients. Arch Ophthalmol. 2002;120(7):933–40. 30. Gunduz K. Transpupillary thermotherapy in the management of circumscribed choroidal hemangioma. Surv Ophthalmol. 2004;49(3):316–27. 31. Abramson DH, Schefler AC.  Transpupillary ther motherapy as initial treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology. 2004;111(5):984–99. 32. Schmidt-Erfurth U, Hasan T, Gragoudas E, et  al.  Vascular targeting in photodynamic occlusion of subretinal vessels. Ophthalmology. 1994;101(12):1953–61. 33. Kramer M, Miller JW, Michaud N, et al. Liposomal benzoporphyrin derivative verteporfin photodynamic therapy. Selective treatment of choroidal neovascularization in monkeys. Ophthalmology. 1996;103(3):427–38. 34. Woodburn KW, Engelman CJ, Blumenkranz MS.  Photodynamic therapy for choroidal neovascularization: a review. Retina. 2002;22(4):391–405. 35. Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal

105 choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol. 2001;119(2):198–207. 36. Erikitola OC, Crosby-Nwaobi R, Lotery AJ, et al. Photodynamic therapy for central serous chorioretinopathy. Eye. 2014;28(8):944–57. 37. Wong CW, Cheung CM, Mathur R, et al. Three-year results of polypoidal choroidal vasculopathy treated with photodynamic therapy: retrospective study and systematic review. Retina. 2015;35(8):1577–93. 38. Boixadera A, Garcia-Arumi J, Martinez-Castillo V, et  al. Prospective clinical trial evaluating the efficacy of photodynamic therapy for symptomatic circumscribed choroidal hemangioma. Ophthalmology. 2009;116:100–5. 39. Sachdeva R, Dadgostar H, Kaiser PK, et  al.  Verteporfin photodynamic therapy of six eyes with retinal capillary haemangioma. Acta Ophthalmol. 2010;88(8):e334–40. 40. Schmidt-Erfurth UM, Kusserow C, Barbazetto IA, et  al.  Benefits and complications of photodynamic therapy of papillary capillary hemangiomas. Ophthalmology. 2002;109(7):1256–66. 41. García-Arumí J, Amselem L, Gunduz K, et  al. Photodynamic therapy for symptomatic subretinal fluid related to choroidal nevus. Retina. 2012;32(5):936–41. 42. Fabian ID, Stacey AW, Harby LA, et al. Primary photodynamic therapy with verteporfin for pigmented posterior pole cT1a choroidal melanoma: a 3-year retrospective analysis. Br J Ophthalmol. 2018. pii: bjophthalmol-2017-311747. 43. Turkoglu EB, Pointdujour-Lim R, Mashayekhi A, et  al.  Photodynamic therapy as a primary treatment for small choroidal melanoma. Retina. 2018; https:// doi.org/10.1097/IAE.0000000000002169. [Epub ahead of print].

Principles of Radiation Therapy

11

Abigail L. Stockham, Allan Wilkinson, and Arun D. Singh

Introduction Radioactivity was first described by Henri Becquerel and Pierre and Marie Curie in the late 1890s. Wilhelm Roentgen discovered x-rays in 1895, and subsequent physics and biology research revealed the therapeutic properties of radiation. X-rays were first used to treat cancer in 1897. Soon after, the concept of brachytherapy was developed when radium was implanted into tumors for therapeutic effect. Low-voltage x-ray machines were built in the 1920s for the external treatment of superficial tumors. The first cyclotron (used to accelerate heavy particles such as protons, neutrons, and deuterons) was invented in 1932  in California. In 1951, the first clinical cobalt-60 unit was built in London, Ontario, Canada. It created a gamma-ray photon beam The authors would like to thank Dr. David J. Schwartz, V, for his editorial expertise and Dr. Roger Macklis for his assistance with previous editions. A. L. Stockham (*) Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA e-mail: [email protected] A. Wilkinson Department of Radiation Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA A. D. Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

from the emissions of a cobalt-60 source as it underwent nuclear decay. External beam radiation therapy was further refined in 1953 with the development of linear accelerators (linacs) that could produce megavoltage electron and x-ray photon beams using pulsed microwaves and an electron gun. With improvements in radiographic imaging techniques such as CT and MRI, conformal radiation therapy has been developed. Three-­ dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery, and charged particle therapy focus on the therapeutic dose while minimizing damage to surrounding normal structures. In this chapter we will review the basic principles of radiation therapy and its application in the definitive, adjuvant, salvage, and palliative management of a variety of ophthalmic cancers.

Basic Principles The unique characteristics of an individual element are determined by its atomic structure – the number and configuration of electrons, protons, and neutrons. Radiation therapy takes advantage of the energy created by the interaction of these fundamental particles with each other. This energy can break chemical bonds and create ions such as oxygen radicals.

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Dual Nature of Radiation

Radioactive Decay

Radiation can be in the form of electromagnetic waves, particles, or both.

Radioactive elements are in an unstable, high-­energy state and emit radiation to return to a stable, lowenergy state. This process is called nuclear decay. Three different types of radiation can be emitted from the nucleus during this process: alpha particles with a positive electrical charge (helium nucleus), beta particles with a negative charge (electrons), and gamma rays with no electrical charge. Radioactive decay is the process utilized in cobalt-60 machines and Gamma Knife radiotherapy.

Electromagnetic Radiation Electromagnetic or photon radiation has a broad spectrum of wavelengths ranging from 107  m (radio waves) to 10−13 m (ultrahigh energy x-rays) (Fig. 11.1). Energy is propagated at the speed of light (c) with the frequency (ν) and wavelength (λ) being inversely related: c = νλ. Linear accelerators produce photon beams with wavelengths in the range of 10−11 to 10−13 m. Particle Radiation Particle radiation can be neutral (neutrons) or charged (protons, electrons). As the particles travel through space, they interact with matter and produce varying degrees of energy transfer to the medium. Linear accelerators and cyclotrons are used to produce this type of radiation.

Wavelength (m)

Frequency (cycles/s)

10–13

3 x 1021

Energy (eV) 1.24 x 107

Gamma rays, X-rays and Cosmic rays

10–8

3 x 1016

1.24 x 102

Ultra violet Visible light Infrared

10–3

3 x 1011

1.24 x 10–3

Microwaves

Radar 102

3 x 106

1.24 x 10–8

TV

Ionizing and Nonionizing Radiation Radiation has both ionizing and nonionizing effects on tissues. Ions are created when an atomic particle or photon with sufficient energy hits another atom resulting in loss of an electron, proton, or neutron. Both electromagnetic and particle radiation may directly damage the DNA molecule itself and impart single-strand breaks, double-strand breaks, or base-pair alterations. Much more common, however, is the indirect damage resulting from ionization of surrounding atoms that go on to ionize and damage the DNA.  Both direct and indirect DNA damages impair a cell’s ability to regenerate and duplicate. Nonionizing effects mainly consist of excitation of the outermost electrons of an atom and are of minimal clinical significance.

Teletherapy Sources Teletherapy is the process of delivering radiation from a remote distance. In modern clinical practice, a cobalt-60 unit, linear accelerator, or cyclotron is used to generate and deliver external beam photon therapy and particle radiotherapy.

Radio 107 3 x 101

1.24 x 10–13

Cobalt-60 Unit A cobalt-60 unit holds a radioactive cobalt source

Fig. 11.1  The electromagnetic spectrum. Therapeutic x-rays and gamma rays are in the high-frequency, high-­ that is emitting gamma radiation as it decays to energy range. Ranges are approximate nickel-60. The average energy of the gamma

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11  Principles of Radiation Therapy Electron percent depth dose 120 9 MeV

100 Percent dose

Fig. 11.2  Percent depth dose curves for commonly used electron beams. Divide the beam energy by 3 to estimate the depth in tissue of 80% of the maximum dose. Divide the beam energy by 2 to estimate the range of penetration

12 MeV 15 MeV

80

18 MeV 60 40 20 0

0

2

4

6

8

10

12

Wavelength (nm)

Linear Accelerator A linear accelerator uses high-frequency electromagnetic waves to accelerate electrons to high energies through a linear vacuum tube. The monoenergetic electron beam can be used to treat superficial tumors. Typical energies used range from 6 to 18 (MeV), with 80% of the maximum dose delivered to a depth of 2–6 cm and a relatively steep dose drop-off beyond (Fig. 11.2). When deeper tumors need to be treated, or the skin needs to be spared, the linear accelerator electron beam is directed at a target (usually tungsten). The resultant atomic interactions produce a range of high-energy x-rays, also called photons. Photons are characteristically more penetrating than electrons. As an example, a 6 MeV electron beam creates a photon beam with a maximum energy of 6 megavolts (MV). Typical energies of photon beams range from 6 to 18 MV, with the depth of maximum dose ranging from 1.5 to 3.5 cm and a more gradual dose drop-off beyond (Fig. 11.3).

Cyclotron A cyclotron is a heavy particle accelerator capable of producing neutron and proton beams.

100

Doss (%)

photon beam is 1.25 million electron volts (MeV), with the maximum dose being delivered to a depth of 0.5–1 cm.

Photon beam 6 MV 50

Modified PROTON beam 250 MeV Native PROTON beam 250 MeV

0

0

10 20 Depth in tissue (cm)

30

Fig. 11.3  The Bragg peak allows for low-energy deposition along the entrance pathway, very high-dose delivery over a narrow depth, with minimal exit dose. The spread-­ out Bragg peak allows for dose deposition over a greater distance for treatment of a larger volume of tissue (Reprinted from https://commons.wikimedia.org/wiki/ File:BraggPeak.png. With permission from Creative Commons License 3.0: https://creativecommons.org/ licenses/by-sa/3.0/deed.en)

Neutrons and protons have a higher linear energy transfer than photons, meaning they cause more damage as they pass through tissue. They cause direct damage to the nucleus of an atom, making them potentially more effective at treating hypoxic tumor cells because there is no dependence on the production of oxygen radicals. Proton beams have a unique dose distribution characteristic called the Bragg peak. There is a steep peak of maximal dose deposit with sharp distal drop-off (Fig. 11.3). This Bragg peak can be directed accurately and precisely onto the tumor [1]. The sharp distal drop-off and minimal

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scatter from proton beams translate into a less dose to surrounding normal tissues. Proton beam radiotherapy is used for treatment of uveal melanoma and retinoblastoma [2, 3]. Proton beam radiotherapy of uveal melanoma is discussed under uveal tumors.

ray beams. To facilitate comparisons to standard photon doses, the term cobalt gray equivalents (CGE) was developed: CGE = dose in proton or neutron gray x corresponding RBE value.

Radiation Parameters

Target Volume

Radiation Dose

Several target tissue volumes are considered when determining the prescription dose. Gross target volume (GTV) is the visible tumor extension or the surgical bed. Clinical target volume (CTV) is the GTV plus margin to cover microscopic tumor extension. Planning target volume (PTV), the volume ultimately treated, is CTV plus a safety margin accounting for setup variations and organ motion. An additional dosimetric margin is often added to the PTV to allow for physical dose buildup in tissue and therefore adequate dose delivery to the PTV.  The treatment margin beyond the GTV typically ranges from 0.5 to 2  cm, depending on the accuracy of the treatment machine, the immobilization device, and the tumor type.

Radiation-absorbed dose is defined in gray (Gy), which represents one joule of energy absorbed per kilogram of mass. Centigray (cGy) is also commonly used and it is 1/100th of a gray. The previous dose convention used the rad, defined as 100 ergs absorbed per gram. As a centigray is equivalent to a rad, this allows comparisons between older published reports and current data.

Relative Biological Effectiveness Relative biological effectiveness (RBE) is a measure of the efficiency of a specific radiation in producing a specific biological response. This can be expressed in the following equation, RBE = Ds/Dr, where Ds and Dr are the doses of standard radiation (250 kVp x-rays) and a test radiation (r) needed to produce an equivalent biological response (Table  11.1). Protons and neutrons have greater biological effectiveness than photons and electrons.

Cobalt Gray Equivalents

Treatment Parameters

Total Dose The total given dose depends on the tumor responsiveness, gross versus microscopic disease, and purpose of the radiation (curative or palliative).

Fractionation

The amount of absorbed dose from neutron and In general, total dose is broken into fractions delivproton beams is higher than with x-ray or gamma-­ ered over many weeks. Fractionation is used to minimize late radiation side effects. Conventional Table 11.1  Relative biological effectiveness (RBE) val- fractionation schemes comprise 180–200  cGy fractions delivered once per day, 5 days per week. ues of commonly used radiations For a given therapeutic dose, f­raction sizes Radiation RBE >200 cGy are associated with greater tendency for Standard (250 kVp x-rays) 1.0 Linac (6–15 MeV) ~0.8 late side effects such as severe dry eye, cataract, Cobalt-60 0.8–0.9 and optic neuropathy. Obversely, reducing the Protons ~1.1 fraction size diminishes the therapeutic effects of Neutrons (19 MeV) 1–2 radiation (tumor kill) when delivered in a conven-

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11  Principles of Radiation Therapy Table 11.2  External beam radiation therapy dose/fractionation schedules for common ophthalmic cancers

Disease Uveal melanoma

Retinoblastoma Uveal/orbital metastasis Orbital lymphoma Basal or squamous cell carcinoma of the eyelid Palliation

Dose per Total dose fraction 14–15 60–70 CGE CGE (protons) 40–50 Gy 2–2.5 Gy 40 Gy 2 Gy

Number of fractions 4–5

20–25 20

30 Gy 35– 42.5 Gy

2 Gy 15 4.25–7 Gy 5–10

30 Gy

3 Gy

10

Table 11.3  Normal tissue tolerance dose to external beam radiation (cGy) Complication rate at 5 years 5% 50% Clinical endpoint Organ Brain 6000 7500 Necrosis, infarction Optic nerve 5000 6500 Visual acuity