Radiation Oncology Advances

About this book

Radiation Oncology Advances provides a comprehensive overview of the exciting developments shaping the current and future practice of radiation oncology. Advances in treatment planning and delivery, in biological targeted therapies combined with radiation, and in functional and molecular imaging are all covered. The contributors are leaders in the field offering a critical evaluation of their clinical practice and its relevance.

Series editor's comments: "Advances in radiation oncology have transformed the current management of cancer patients. Key scientific discoveries and application of modern techniques are reviewed. A spectrum of topics is covered, including imaging and biologically-based treatment planning; molecular biology and targeted therapies; treatment delivery; and clinical accomplishments."

Steven T. Rosen
Series Editor

Written for:

Radiation oncologists, medical physicists, radiation therapy technicians, scientists, radiologists, nurses, oncologists

Table of contents

1 Radiation Oncology Advances: An Introduction - 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 - 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

3 Dose Painting and Theragnostic Imaging: Towards the Prescription, Planning and Delivery of Biologically Targeted Dose Distributions in External Beam Radiation Oncology - 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 - 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

5 Prognostic and Predictive Markers in Radiation Therapy: Focus on Prostate Cancer - 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 - 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

7 Clinical Application of EGFR Inhibitors in Head and Neck Squamous Cell Cancer - 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 - 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 - Arnab Chakravarti and Kamalakannan Palanichamy

Introduction .................................................................................................. 169
Signal Transduction Pathways Involved in Treatment Resistance .............. 169
Angiogenesis Pathways ............................................................................... 171
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 - 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 - 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
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 - 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 - 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

14 Cytoprotection for Radiation-Associated Normal Tissue Injury - 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