Radiation Oncology Advances, 1st Edition

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Cancer Treatment and Research
Steven T. Rosen, M.D., Series Editor

Arnold, A.J. (ed.): Endocrine Neoplasms. 1997. ISBN 0-7923-4354-9.

Pollock, R.E. (ed.): Surgical Oncology. 1997. ISBN 0-7923-9900-5.
Verweij, J., Pinedo, H.M., Suit, H.D. (eds): Soft Tissue Sarcomas: Present Achievements
and Future Prospects. 1997. ISBN 0-7923-9913-7.
Walterhouse, D.O., Cohn, S. L. (eds): Diagnostic and Therapeutic Advances in Pediatric
Oncology. 1997. ISBN 0-7923-9978-1.
Mittal, B.B., Purdy, J.A., Ang, K.K. (eds): Radiation Therapy. 1998.
ISBN 0-7923-9981-1.
Foon, K.A., Muss, H.B. (eds): Biological and Hormonal Therapies of Cancer. 1998.
ISBN 0-7923-9997-8.
Ozols, R.F. (ed.): Gynecologic Oncology. 1998. ISBN 0-7923-8070-3.
Noskin, G.A. (ed.): Management of Infectious Complications in Cancer Patients. 1998.
ISBN 0-7923-8150-5.
Bennett, C.L. (ed.): Cancer Policy. 1998. ISBN 0-7923-8203-X.
Benson, A.B. (ed.): Gastrointestinal Oncology. 1998. ISBN 0-7923-8205-6.
Tallman, M.S., Gordon, L.I. (eds): Diagnostic and Therapeutic Advances in Hematologic
Malignancies. 1998. ISBN 0-7923-8206-4.
von Gunten, C.F. (ed.): Palliative Care and Rehabilitation of Cancer Patients. 1999.
ISBN 0-7923-8525-X.
Burt, R.K., Brush, M.M. (eds): Advances in Allogeneic Hematopoietic Stem Cell
Transplantation. 1999. ISBN 0-7923-7714-1.
Angelos, P. (ed.): Ethical Issues in Cancer Patient Care 2000. ISBN 0-7923-7726-5.
Gradishar, W.J., Wood, W.C. (eds): Advances in Breast Cancer Management. 2000.
ISBN 0-7923-7890-3.
Sparano, J.A. (ed.): HIV & HTLV-I Associated Malignancies. 2001.
ISBN 0-7923-7220-4.
Ettinger, D.S. (ed.): Thoracic Oncology. 2001. ISBN 0-7923-7248-4.
Bergan, R.C. (ed.): Cancer Chemoprevention. 2001. ISBN 0-7923-7259-X.
Raza, A., Mundle, S.D. (eds): Myelodysplastic Syndromes & Secondary Acute
Myelogenous Leukemia 2001. ISBN: 0-7923-7396.
Talamonti, M.S. (ed.): Liver Directed Therapy for Primary and Metastatic Liver Tumors.
2001. ISBN 0-7923-7523-8.
Stack, M.S., Fishman, D.A. (eds): Ovarian Cancer. 2001. ISBN 0-7923-7530-0.
Bashey, A., Ball, E.D. (eds): Non-Myeloablative Allogeneic Transplantation. 2002.
ISBN 0-7923-7646-3.
Leong, S.P.L. (ed.): Atlas of Selective Sentinel Lymphadenectomy for Melanoma, Breast
Cancer and Colon Cancer. 2002. ISBN 1-4020-7013-6.
Andersson, B., Murray, D. (eds): Clinically Relevant Resistance in Cancer
Chemotherapy. 2002. ISBN 1-4020-7200-7.
Beam, C. (ed.): Biostatistical Applications in Cancer Research. 2002.
ISBN 1-4020-7226-0.
Brockstein, B., Masters, G. (eds): Head and Neck Cancer. 2003. ISBN 1-4020-7336-4.
Frank, D.A. (ed.): Signal Transduction in Cancer. 2003. ISBN 1-4020-7340-2.
(continued after index)
Radiation Oncology
Advances

Edited by

Søren M. Bentzen, Ph.D., D.Sc.

Professor
Department of Human Oncology
University of Wisconsin School of Medicine
Madison, Wisconsin, USA

Paul M. Harari, M.D.

Jack Fowler Professor and Chairman
Department of Human Oncology
University of Wisconsin School of Medicine
Madison, Wisconsin, USA

Wolfgang A. Tomé, M.D., Ph.D

Associate Professor
Department of Human Oncology
University of Wisconsin School of Medicine
Madison, Wisconsin, USA

Minesh P. Mehta, M.D.

Professor
Department of Human Oncology
University of Wisconsin School of Medicine
Madison, Wisconsin, USA
Søren M. Bentzen, PhD
Paul M. Harari, MD
Wolfgang A. Tomé, PhD
Minesh P. Mehta, MD

University of Wisconsin
Department of Human Oncology
600 Highland Avenue, K4/310
Madison, WI 53792
USA

Series Editor:
Steven T. Rosen
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
Chicago, IL
USA

ISBN-13: 978-0387-36743-9 e-ISBN-13: 978-0387-36744-6

Library of Congress Control Number: 2007925437

© 2008 Springer Science + Business Media, LLC

All rights reserved. This work may not be translated or copied in whole or in part without the written
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The use in this publication of trade names, trademarks, service marks, and similar terms, even if they
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Printed on acid-free paper.

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Contents

1 Radiation Oncology Advances: An Introduction ..................................... 1

Søren M. Bentzen, Paul M. Harari, Wolfgang A. Tomé,
and Minesh P. Mehta
Advances in Imaging and Theragnostic Radiation Oncology ....................... 1
Advances in Molecular Biology and Targeted Therapies ............................. 2
Advances in Treatment Delivery and Planning ............................................. 3
Clinical Advances .......................................................................................... 4
References ...................................................................................................... 4

Section I. Advances in Imaging and Biologically-Based Treatment Planning

2 Advanced Image-Guided External Beam Radiotherapy ......................... 7

Thomas Rockwell Mackie and Wolfgang Tomé
Introduction .................................................................................................... 7
Image Guidance for Defining Target Volumes ......................................... 9
Image Guidance at the Time of Delivery ................................................... 13
Optical Guidance ....................................................................................... 14
Optical Tracking Systems .......................................................................... 15
Optical Tracking in Fractionated Stereotactic Radiotherapy,
Intracranial, and Head and Neck IMRT ..................................................... 16
Optically Guided Ultrasound ..................................................................... 18
In-Room CT Guidance ............................................................................... 20
Image Guidance and Organ Motion ........................................................... 27
Image Guidance for Follow-Up Imaging and Retreatments ...................... 29
Summary .................................................................................................... 31
References ...................................................................................................... 32

v
vi Contents

3 Dose Painting and Theragnostic Imaging: Towards the Prescription,

Planning and Delivery of Biologically Targeted Dose Distributions in
External Beam Radiation Oncology ........................................................ 40
Søren M. Bentzen
Radiation Theragnostics .............................................................................. 40
From Anatomical to Biological Targeting in Radiation Therapy ............... 41
From Target Selection and Delineation to 4D Dose Prescription ............... 42
The Case for Nonuniform Theragnostic Dose Distributions....................... 43
Precision Requirements ............................................................................... 46
Targeting Hypoxia Using EBRT: Are We Ready for Dose
Painting by Numbers?.................................................................................. 47
Hypoxia as a Cause of Clinical Failure of Radiation Therapy ................ 47
Hypoxia Imaging ..................................................................................... 49
Spatiotemporal Stability of the PET Hypoxia Map ................................. 52
Dose Painting by Numbers ...................................................................... 55
Dose Delivery and Expected Change in Outcome ................................... 56
Conclusion ................................................................................................... 56
References .................................................................................................... 57

4 Molecular and Functional Imaging in Radiation Oncology .................. 62

Robert Jeraj and M. Elizabeth Meyerand
Introduction .................................................................................................. 62
Molecular and Functional Imaging Modalities ........................................... 63
Positron Emission Tomography ............................................................... 63
Single Photon Emission Tomography ..................................................... 64
Dynamic Contrast Enhanced Computer Tomography (DCE-CT) ........... 64
Dynamic Contrast Enhanced Magnetic Resonance
Imaging (DCE-MRI) ................................................................................ 64
Magnetic Resonance Spectroscopy.......................................................... 65
Optical Imaging ....................................................................................... 65
Comparison Between Different Imaging Modalities ............................... 65
Molecular and Functional Imaging Targets................................................. 66
Cellular Metabolism................................................................................. 67
Cellular Proliferation ............................................................................... 71
Cellular Death .......................................................................................... 72
Cellular Regulation .................................................................................. 73
Tumor Microenvironment ........................................................................ 76
Future ........................................................................................................... 79
References .................................................................................................... 81
Contents vii

5 Prognostic and Predictive Markers in Radiation Therapy: Focus

on Prostate Cancer .................................................................................... 95
Mark A. Ritter
Introduction .................................................................................................. 95
The Need for Biomarkers of Radiation Response
in Prostate Cancer ........................................................................................ 95
Optimal Biomarkers and Patient Cohort Characteristics............................. 96
Evaluation of Candidate Markers ................................................................ 97
Biological Rationale................................................................................. 97
Biomarker Frequency............................................................................... 100
Biomarker Assessment Methods ................................................................. 100
Immunohistochemistry ................................................................................ 101
Clinical Correlative Data in Prostate Cancer............................................... 102
Markers of Cell Cycle Control, DNA Repair and Apoptosis .................. 103
Proliferation ............................................................................................. 103
Hypoxia .................................................................................................... 104
Limitations of Existing Studies ................................................................... 104
Future Studies and Directions...................................................................... 105
Large Prospective Clinical Trials............................................................. 105
Biomarker-Based Adaptive Therapy ....................................................... 106
Conclusion ................................................................................................... 107
References .................................................................................................... 107

Section II. Advances in Molecular Biology and Targeted Therapies

6 Overview of Cancer Molecular Radiobiology ......................................... 115

Jann N. Sarkaria and Robert G. Bristow
Introduction .................................................................................................. 115
Interaction of Radiation with Living Cells .................................................. 115
Cellular Response to Ionizing Radiation ..................................................... 116
Cell Cycle Arrest ......................................................................................... 116
DNA Repair ................................................................................................. 118
Apoptosis ..................................................................................................... 119
Cell Survival Signaling ................................................................................ 120
Ras Signaling ........................................................................................... 120
Receptor Tyrosine Kinases ...................................................................... 121
mTOR Signaling ...................................................................................... 121
Targeting Housekeeping Proteins ................................................................ 122
HSP90 Inhibitors ...................................................................................... 123
HDAC Inhibitors ...................................................................................... 124
Proteosome Inhibitors .............................................................................. 126
Conclusion ................................................................................................... 127
References .................................................................................................... 128
viii Contents

7 Clinical Application of EGFR Inhibitors in Head and Neck

Squamous Cell Cancer .............................................................................. 132
Igor Astsaturov, Roger B. Cohen, and Paul M. Harari
Introduction .................................................................................................. 132
EGFR Biology ............................................................................................. 133
Anti-EGFR Monoclonal Antibodies ............................................................ 135
Radiation Plus Cetuximab For Locoregionally Advanced HNSCC ........ 135
Cetuximab, Cisplatin, and Radiation in Locoregionally
Advanced HNSCC ................................................................................... 137
Cetuximab ± Chemotherapy in Recurrent
and/or Metastatic HNSCC ....................................................................... 138
Cetuximab with Chemotherapy in the First-Line Treatment
of Patients with Recurrent and/or Metastatic HNSCC ............................ 139
EGFR Tyrosine Kinase Inhibitors (TKIs) ................................................... 140
TKI Monotherapy in HNSCC .................................................................. 141
TKIs in Combination with Radiation Therapy ........................................ 141
TKIs with Dual Specificity ...................................................................... 142
Patient Selection .......................................................................................... 142
Conclusions .................................................................................................. 143
References .................................................................................................... 144

8 Advancement of Antiangiogenic and Vascular Disrupting Agents

Combined with Radiation ......................................................................... 150
Deborah Citrin and Kevin Camphausen
Introduction .................................................................................................. 150
Tumor Vasculature ...................................................................................... 150
Targeting the Tumor Vasculature ................................................................ 152
Antiangiogenic Agents ................................................................................ 152
Vascular Disrupting Agents ......................................................................... 155
Combining Antiangiogenic and Vascular Disrupting Agents
with Radiation .............................................................................................. 157
Antiangiogenic Agents and Radiation in the Laboratory ............................ 157
Angiogenesis Inhibitors and Radiation in the Clinic ............................... 159
Vascular Disrupting Agents and Radiation in the Laboratory ................. 160
Vascular Disrupting Agents with Radiation in the Clinic ....................... 161
Future Directions ......................................................................................... 162
Conclusion ................................................................................................... 163
References .................................................................................................... 164

9 Overcoming Therapeutic Resistance in Malignant Gliomas: Current

Practices and Future Directions ............................................................... 169
Arnab Chakravarti and Kamalakannan Palanichamy
Introduction .................................................................................................. 169
Signal Transduction Pathways Involved in Treatment Resistance ............. 169
Angiogenesis Pathways ............................................................................... 171
Contents ix

Conventional Chemotherapeutic Agents in Malignant Gliomas ................. 173

Biotherapeutic Strategies ............................................................................. 178
Antiepidermal Growth Factor Receptor (EGFR) Strategies .................... 178
mTor Pathway Inhibition: CCI-779 ............................................................. 180
Antiangiogenic Strategies ............................................................................ 181
Summary ...................................................................................................... 182
References .................................................................................................... 182

Section III. Advances in Treatment Delivery and Planning

10 Advances in Intensity-Modulated Radiotherapy Delivery .................... 189

John D. Fenwick, Stephen W. Riley, and Alison J.D. Scott
Introduction .................................................................................................. 189
Background .................................................................................................. 189
Fixed-Field IMRT ........................................................................................ 190
Direct Aperture Optimisation and Jaws-Only
Linear Accelerator IMRT ........................................................................ 195
Tomotherapy ................................................................................................ 195
Axial Tomotherapy .................................................................................. 196
Helical Tomotherapy ............................................................................... 197
Future Developments ............................................................................... 202
CyberKnife ................................................................................................... 204
Summary ...................................................................................................... 205
References .................................................................................................... 206

11 Image-Based Modeling of Normal Tissue Complication Probability

for Radiation Therapy ............................................................................... 211
Joseph O. Deasy and Issam El Naqa
Introduction .................................................................................................. 211
NTCP Models: Tools or Toys? ................................................................ 212
Why Image-Based NTCP Analysis? ........................................................ 214
Tissue Dose–Response Classification ......................................................... 215
The Concepts of “Serial” and “Parallel” Tissue Dose–Response ............ 215
Local vs. Global Organ Injuries ............................................................... 217
NTCP Models .............................................................................................. 218
The Generalized Equivalent Uniform Dose Equation ............................. 219
Basic Mathematical Features of Common NTCP Functions ................... 221
Cluster Models ......................................................................................... 223
A Data-Mining/Data-Driven Approach to NTCP Modeling ................... 223
Selection of Relevant Input Variables ..................................................... 227
Selection of Model Functional Form ........................................................... 228
Selection of Model Order ............................................................................ 229
Model Order Based on Information Theory ............................................ 229
Model Order Based on Cross-validation Methods................................... 231
Model Variable Stability .......................................................................... 231
x Contents

Model Parameter Fitting .......................................................................... 231

Image-Based Factors and Radiosensitivity Predictors ............................. 232
Some Critical NTCP Endpoints ................................................................... 233
Late Rectal Toxicity Due to External Beam Prostate
Cancer Treatment ..................................................................................... 233
Radiation Pneumonitis Due to Thoracic Irradiation for
Lung Cancer ............................................................................................. 234
Xerostomia Due to Head and Neck Cancer Treatment ............................ 236
Drawbacks to Treatment Planning Based on Dose–Volume Limits ....... 239
Uncertainties in NTCP Models ................................................................ 240
Incorporating Fractionation Sensitivity ................................................... 241
Summary ...................................................................................................... 244
References .................................................................................................... 244

12 Optimization of Radiotherapy Using Biological Parameters ................ 253

Yusung Kim and Wolfgang Tomé
Introduction .................................................................................................. 253
The Need for Optimization Based on Biological Parameters .................. 255
Radiobiological Models ........................................................................... 256
Biological Optimization ............................................................................... 260
Subvolume-Based Radiobiological Models ............................................. 260
Impact of Diagnostic Accuracy on Biological Optimization ...................... 266
Functional Imaging in Oncology ............................................................. 266
Theragnostic Imaging in Risk-Adaptive Radiotherapy ........................... 266
The Impact of Imaging Sensitivity on Risk-Adaptive Radiotherapy....... 267
Clinical Parameters Necessary for Biological Optimization ................... 268
Summary ...................................................................................................... 270
References .................................................................................................... 271

Section IV. Clinical Advances

13 Combined Chemoradiotherapy Advances .............................................. 277

Gordon Wong and Minesh P. Mehta
Introduction .................................................................................................. 277
Head and Neck Cancers ............................................................................... 278
Nonsmall Cell Lung Carcinoma .................................................................. 284
Cervical Carcinoma ..................................................................................... 288
Esophageal Carcinoma ................................................................................ 290
Rectal Adenocarcinoma ............................................................................... 292
Anal Squamous Cell Carcinoma.................................................................. 294
Muscle Invasive Bladder Cancer ................................................................. 295
Conclusion ................................................................................................... 296
References .................................................................................................... 296
Contents xi

14 Cytoprotection for Radiation-Associated Normal

Tissue Injury .............................................................................................. 302
Jingfang Mao, Oluwatoyosi A. Fatunase, and Lawrence B. Marks
Biologic Rationale of Cytoprotectors .......................................................... 302
Assessment of Amifostine in Patients with Head and Neck Cancer........... 304
Assessment of Amifostine in Patients with Thoracic Tumors .................... 304
Lung Injury .............................................................................................. 304
Esophageal Injury .................................................................................... 307
Assessment of Amifostine in Patients with Pelvic Tumors ........................ 307
Assessment of Amifostine in Patients with Tumors at Other Sites ............ 307
Impact of Amifostine on Tumor Control and Survival ............................... 309
Amifostine-Related Toxicity ....................................................................... 309
Administration of Amifostine ...................................................................... 309
Other Cytoprotectors.................................................................................... 316
Conclusion ................................................................................................... 318
References .................................................................................................... 318

Index .................................................................................................................. 323

Contributors

Igor Astsaturov, MD
Department of Medical Oncology
Division of Medical Science
Fox Chase Cancer Center
Philadelphia, PA, USA

Søren M. Bentzen, PhD, DSc

Department of Human Oncology and Department
of Medical Physics
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA

Robert G. Bristow, MD, PhD, FRCPC

Department of Radiation Oncology
Princess Margaret Hospital – University Health Network
Toronto, ON, Canada M5G 2M9

Kevin Camphausen, MD
Radiation Oncology Branch
National Cancer Institute
Bethesda, MD, USA

Arnab Chakravarti, MD
Laboratory of Cellular and Molecular Neuro-Radiation Oncology
Department of Radiation Oncology
Massachusetts General Hospital/Harvard Medical School
Boston, MA, USA

Deborah Citrin, MD
Radiation Oncology Branch
National Cancer Institute
Bethesda, MD, USA

xiii
xiv Contributors

Roger B. Cohen, MD
Department of Medical Oncology
Division of Medical Science
Fox Chase Cancer Center
Philadelphia, PA, USA

Joseph O. Deasy, PhD

Department of Radiation Oncology
Division of Bioinformatics and Outcomes Research
Washington University School of Medicine
St. Louis, MO, USA

Issam El Naqa, PhD

Department of Radiation Oncology
Division of Bioinformatics and Outcomes Research
Washington University School of Medicine
St. Louis, MO, USA

Oluwatoyosi A. Fatunase, BA
Department of Radiation Oncology
Duke University Medical Center
Durham, NC, USA

John D. Fenwick, PhD

Medical Physics
Clatterbridge Centre for Oncology
Bebington, Wirral, UK

Paul M. Harari, MD
Department of Human Oncology
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA

Robert Jeraj, PhD

Department of Medical Physics
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA

Yusung Kim, PhD

Department of Human Oncology and Department
of Medical Physics
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA
Contributors xv

Thomas Rockwell Mackie, PhD

Department of Human Oncology and Department
of Medical Physics
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA
and
TomoTherapy, Inc.
Madison, WI, USA

Jingfang Mao, MD
Department of Radiation Oncology
Duke University Medical Center
Durham, NC, USA
and
Department of Radiation Oncology
Cancer Hospital, Fudan University
Shanghai, People’s Republic of China

Lawrence B. Marks, MD
Department of Radiation Oncology
Duke University Medical Center
Durham, NC, USA

Minesh P. Mehta, MD
Department of Human Oncology
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA

M. Elizabeth Meyerand, PhD

Department of Medical Physics
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA

Kamalakannan Palanichamy, PhD

Department of Radiation Oncology
Massachusetts General Hospital
Boston, MA, USA

Stephen W. Riley, MSc

Medical Physics
Clatterbridge Centre for Oncology
Bebington, Wirral, UK
xvi Contributors

Mark A. Ritter, MD, PhD

Department of Human Oncology
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA

Jann N. Sarkaria, MD
Mayo Clinic
Department of Radiation Oncology
Rochester, MN, USA

Alison J. D. Scott, MSc

Medical Physics
Clatterbridge Centre for Oncology
Bebington, Wirral, UK

Wolfgang A. Tomé, PhD

Department of Human Oncology and Department
of Medical Physics
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA

Gordon Wong, MD
Department of Human Oncology
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA