Radiobiology for the Radiologist by Hall, Eric J. -- Read -- Imperial Library of Trantor

Index

Preface to the First Edition Preface Acknowledgments SECTION I For Students of Diagnostic Radiology, Nuclear Medicine, and Radiation Oncology 1 Physics and Chemistry of Radiation Absorption

TYPES OF IONIZING RADIATIONS

Electromagnetic Radiations Particulate Radiations

ABSORPTION OF X-RAYS DIRECT AND INDIRECT ACTION OF RADIATION ABSORPTION OF NEUTRONS ABSORPTION OF PROTONS AND HEAVIER IONS SUCH AS CARBON SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

2 Molecular Mechanisms of DNA and Chromosome Damage and Repair

GENERAL OVERVIEW OF DNA STRAND BREAKS MEASURING DNA STRAND BREAKS DNA REPAIR PATHWAYS

Base Excision Repair Nucleotide Excision Repair DNA Double-Strand Break Repair Nonhomologous End-Joining Homologous Recombination Repair Crosslink Repair Mismatch Repair

RELATIONSHIP BETWEEN DNA DAMAGE AND CHROMOSOME ABERRATIONS CHROMOSOMES AND CELL DIVISION THE ROLE OF TELOMERES RADIATION-INDUCED CHROMOSOME ABERRATIONS EXAMPLES OF RADIATION-INDUCED ABERRATIONS CHROMOSOME ABERRATIONS IN HUMAN LYMPHOCYTES SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

3 Cell Survival Curves

REPRODUCTIVE INTEGRITY THE IN VITRO SURVIVAL CURVE THE SHAPE OF THE SURVIVAL CURVE MECHANISMS OF CELL KILLING

DNA as the Target The Bystander Effect Apoptotic and Mitotic Death Autophagic Cell Death Senescence

SURVIVAL CURVES FOR VARIOUS MAMMALIAN CELLS IN CULTURE SURVIVAL CURVE SHAPE AND MECHANISMS OF CELL DEATH ONCOGENES AND RADIORESISTANCE GENETIC CONTROL OF RADIOSENSITIVITY INTRINSIC RADIOSENSITIVITY AND CANCER STEM CELLS EFFECTIVE SURVIVAL CURVE FOR A MULTIFRACTION REGIMEN CALCULATIONS OF TUMOR CELL KILL

Problem 1 Answer Problem 2 Answer Problem 3 Answer Problem 4 Answer

THE RADIOSENSITIVITY OF MAMMALIAN CELLS COMPARED WITH MICROORGANISMS SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

4 Radiosensitivity and Cell Age in the Mitotic Cycle

THE CELL CYCLE SYNCHRONOUSLY DIVIDING CELL CULTURES THE EFFECT OF X-RAYS ON SYNCHRONOUSLY DIVIDING CELL CULTURES MOLECULAR CHECKPOINT GENES THE EFFECT OF OXYGEN AT VARIOUS PHASES OF THE CELL CYCLE THE AGE-RESPONSE FUNCTION FOR A TISSUE IN VIVO VARIATION OF SENSITIVITY WITH CELL AGE FOR HIGH–LINEAR ENERGY TRANSFER RADIATIONS MECHANISMS FOR THE AGE-RESPONSE FUNCTION THE POSSIBLE IMPLICATIONS OF THE AGE-RESPONSE FUNCTION IN RADIOTHERAPY SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

5 Fractionated Radiation and the Dose-Rate Effect

OPERATIONAL CLASSIFICATIONS OF RADIATION DAMAGE

Potentially Lethal Damage Repair Sublethal Damage Repair

MECHANISM OF SUBLETHAL DAMAGE REPAIR REPAIR AND RADIATION QUALITY THE DOSE-RATE EFFECT EXAMPLES OF THE DOSE-RATE EFFECT IN VITRO AND IN VIVO THE INVERSE DOSE-RATE EFFECT THE DOSE-RATE EFFECT SUMMARIZED BRACHYTHERAPY OR ENDOCURIETHERAPY

Intracavitary Brachytherapy Permanent Interstitial Implants

SUMMARY OF PERTINENT CONCLUSIONS

Potentially Lethal Damage Repair Sublethal Damage Repair Dose-Rate Effect Brachytherapy

BIBLIOGRAPHY

6 Oxygen Effect and Reoxygenation

THE NATURE OF THE OXYGEN EFFECT THE TIME AT WHICH OXYGEN ACTS AND THE MECHANISM OF THE OXYGEN EFFECT THE CONCENTRATION OF OXYGEN REQUIRED CHRONIC AND ACUTE HYPOXIA

Chronic Hypoxia Acute Hypoxia

THE FIRST EXPERIMENTAL DEMONSTRATION OF HYPOXIC CELLS IN A TUMOR PROPORTION OF HYPOXIC CELLS IN VARIOUS ANIMAL TUMORS EVIDENCE FOR HYPOXIA IN HUMAN TUMORS TECHNIQUES TO MEASURE TUMOR OXYGENATION

Oxygen Probe Measurements Markers of Hypoxia

REOXYGENATION TIME SEQUENCE OF REOXYGENATION MECHANISM OF REOXYGENATION THE IMPORTANCE OF REOXYGENATION IN RADIOTHERAPY HYPOXIA AND CHEMORESISTANCE HYPOXIA AND TUMOR PROGRESSION SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

7 Linear Energy Transfer and Relative Biologic Effectiveness

THE DEPOSITION OF RADIANT ENERGY LINEAR ENERGY TRANSFER RELATIVE BIOLOGIC EFFECTIVENESS RELATIVE BIOLOGIC EFFECTIVENESS AND FRACTIONATED DOSES RELATIVE BIOLOGIC EFFECTIVENESS FOR DIFFERENT CELLS AND TISSUES RELATIVE BIOLOGIC EFFECTIVENESS AS A FUNCTION OF LINEAR ENERGY TRANSFER THE OPTIMAL LINEAR ENERGY TRANSFER FACTORS THAT DETERMINE RELATIVE BIOLOGIC EFFECTIVENESS THE OXYGEN EFFECT AND LINEAR ENERGY TRANSFER RADIATION WEIGHTING FACTOR SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

8 Acute Radiation Syndrome

ACUTE RADIATION SYNDROME EARLY LETHAL EFFECTS THE PRODROMAL RADIATION SYNDROME THE CEREBROVASCULAR SYNDROME THE GASTROINTESTINAL SYNDROME THE HEMATOPOIETIC SYNDROME THE FIRST AND MOST RECENT DEATHS FROM THE HEMATOPOIETIC SYNDROME PULMONARY SYNDROME CUTANEOUS RADIATION INJURY SYMPTOMS ASSOCIATED WITH THE ACUTE RADIATION SYNDROME TREATMENT OF RADIATION ACCIDENT VICTIMS EXPOSED TO DOSES CLOSE TO THE LD 50/60 50/60 TRIAGE SURVIVORS OF SERIOUS RADIATION ACCIDENTS IN THE UNITED STATES RADIATION EMERGENCY ASSISTANCE CENTER SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

9 Medical Countermeasures to Radiation Exposure

INTRODUCTION AND DEFINITIONS THE DISCOVERY OF RADIOPROTECTORS MECHANISM OF ACTION DEVELOPMENT OF MORE EFFECTIVE COMPOUNDS AMIFOSTINE (WR-2721) AS A RADIOPROTECTOR IN RADIOTHERAPY AMIFOSTINE AS A PROTECTOR AGAINST RADIATION-INDUCED CANCER A NEW FAMILY OF AMINOTHIOL RADIOPROTECTORS RADIATION MITIGATORS RADIONUCLIDE ELIMINATORS DIETARY SUPPLEMENTS AS COUNTERMEASURES TO RADIATION SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

10 Radiation Carcinogenesis

TISSUE REACTIONS (DETERMINISTIC EFFECTS) AND STOCHASTIC EFFECTS CARCINOGENESIS: THE HUMAN EXPERIENCE THE LATENT PERIOD ASSESSING THE RISK COMMITTEES CONCERNED WITH RISK ESTIMATES AND RADIATION PROTECTION RADIATION-INDUCED CANCER IN HUMAN POPULATIONS

Leukemia Thyroid Cancer Breast Cancer Lung Cancer Bone Cancer Skin Cancer

QUANTITATIVE RISK ESTIMATES FOR RADIATION-INDUCED CANCER DOSE AND DOSE-RATE EFFECTIVENESS FACTOR SUMMARY OF RISK ESTIMATES SECOND MALIGNANCIES IN RADIOTHERAPY PATIENTS

Second Cancers after Radiotherapy for Prostate Cancer Radiation Therapy for Carcinoma of the Cervix Second Cancers among Long-Term Survivors from Hodgkin Disease

DOSE–RESPONSE RELATIONSHIP FOR RADIATION CARCINOGENESIS AT HIGH DOSES CANCER RISKS IN NUCLEAR INDUSTRY WORKERS EXTRAPOLATING CANCER RISKS FROM HIGH TO LOW DOSES MORTALITY PATTERNS IN RADIOLOGISTS CHILDHOOD CANCER AFTER RADIATION EXPOSURE IN UTERO NONNEOPLASTIC DISEASE AND RADIATION SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

11 Heritable Effects of Radiation

GERM CELL PRODUCTION AND RADIATION EFFECTS ON FERTILITY REVIEW OF BASIC GENETICS MUTATIONS

Mendelian Chromosomal Changes Multifactorial

RADIATION-INDUCED HERITABLE EFFECTS IN FRUIT FLIES RADIATION-INDUCED HERITABLE EFFECTS IN MICE RADIATION-INDUCED HERITABLE EFFECTS IN HUMANS INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION ESTIMATES OF HEREDITARY RISKS MUTATIONS IN THE CHILDREN OF THE A-BOMB SURVIVORS CHANGING CONCERNS FOR RISKS EPIGENETICS

Imprinted Genes

SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

12 Effects of Radiation on the Embryo and Fetus

HISTORICAL PERSPECTIVE OVERVIEW OF RADIATION EFFECTS ON THE EMBRYO AND FETUS DATA FROM MICE AND RATS

Preimplantation Organogenesis The Fetal Period

EXPERIENCE IN HUMANS

Survivors of the A-Bomb Attacks on Hiroshima and Nagasaki Irradiated In Utero Exposure to Medical Radiation

COMPARISON OF HUMAN AND ANIMAL DATA CANCER IN CHILDHOOD AFTER IRRADIATION IN UTERO OCCUPATIONAL EXPOSURE OF WOMEN THE PREGNANT OR POTENTIALLY PREGNANT PATIENT SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

13 Radiation Cataractogenesis

CATARACTS OF THE OCULAR LENS LENS OPACIFICATION IN EXPERIMENTAL ANIMALS RADIATION CATARACTS IN HUMANS THE LATENT PERIOD DOSE–RESPONSE RELATIONSHIP FOR CATARACTS IN HUMANS SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

14 Radiologic Terrorism

POSSIBLE SCENARIOS FOR RADIOLOGIC TERRORISM AVAILABILITY OF RADIOACTIVE MATERIAL HEALTH EFFECTS OF RADIATION EXTERNAL EXPOSURE TO RADIATION AND CONTAMINATION WITH RADIOACTIVE MATERIALS EXTERNAL CONTAMINATION INTERNAL CONTAMINATION MEDICAL MANAGEMENT ISSUES IN THE EVENT OF RADIOLOGIC TERRORISM FURTHER INFORMATION SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

15 Doses and Risks in Diagnostic Radiology, Interventional Radiology and Cardiology, and Nuclear Medicine

DOSES FROM NATURAL BACKGROUND RADIATION

Cosmic Radiation Natural Radioactivity in the Earth’s Crust Internal Exposure Areas of High Natural Background

COMPARISON OF RADIATION DOSES FROM NATURAL SOURCES AND HUMAN ACTIVITIES DIAGNOSTIC RADIOLOGY

Dose Effective Dose Collective Effective Dose

INTERVENTIONAL RADIOLOGY AND CARDIOLOGY

Patient Doses and Effective Doses Dose to Personnel

NUCLEAR MEDICINE

Historical Perspective Effective Dose and Collective Effective Dose Principles in Nuclear Medicine Positron Emission Tomography The Therapeutic Use of Radionuclides

MEDICAL IRRADIATION OF CHILDREN AND PREGNANT WOMEN

Irradiation of Children Irradiation of Pregnant Women

DOSES TO THE EMBRYO AND FETUS RECOMMENDATIONS ON BREASTFEEDING INTERRUPTIONS SUMMARY SUMMARY OF PERTINENT CONCLUSIONS

Computed Tomography Effective Dose and Cancer Interventional Procedures Nuclear Medicine Medical Radiation of Children and Pregnant Women Summary

BIBLIOGRAPHY

16 Radiation Protection

DE MINIMIS DOSE AND NEGLIGIBLE INDIVIDUAL DOSE RADIATION DETRIMENT NATIONAL COUNCIL ON RADIATION PROTECTION AND MEASUREMENTS AND THE INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION COMPARED THE HISTORY OF THE CURRENT DOSE LIMITS DOSE RANGES SUMMARY OF PERTINENT CONCLUSIONS GLOSSARY OF TERMS BIBLIOGRAPHY THE ORIGINS OF RADIATION PROTECTION ORGANIZATIONS QUANTITIES AND UNITS

Dose Radiation Weighting Factor Equivalent Dose Effective Dose Committed Equivalent Dose Committed Effective Dose Collective Equivalent Dose Collective Effective Dose Collective Committed Effective Dose Summary of Quantities and Units

TISSUE REACTIONS AND STOCHASTIC EFFECTS PRINCIPLES OF RADIATION PROTECTION BASIS FOR EXPOSURE LIMITS LIMITS FOR OCCUPATIONAL EXPOSURE

Stochastic Effects Tissue Reactions (Formerly Known as Deterministic Effects)

AS LOW AS REASONABLY ACHIEVABLE PROTECTION OF THE EMBRYO/FETUS EMERGENCY OCCUPATIONAL EXPOSURE EXPOSURE OF PERSONS YOUNGER THAN 18 YEARS OF AGE EXPOSURE OF MEMBERS OF THE PUBLIC (NONOCCUPATIONAL LIMITS) EXPOSURE TO INDOOR RADON

SECTION II For Students of Radiation Oncology 17 Molecular Techniques in Radiobiology

HISTORICAL PERSPECTIVES THE STRUCTURE OF DNA RNA AND DNA TRANSCRIPTION AND TRANSLATION THE GENETIC CODE AMINO ACIDS AND PROTEINS RESTRICTION ENDONUCLEASES VECTORS

Plasmids Bacteriophage λ Bacterial Artificial Chromosomes Viruses

LIBRARIES

Genomic Library cDNA Library

HOSTS

Escherichia Coli Yeast Mammalian Cells

DNA-MEDIATED GENE TRANSFER AGAROSE GEL ELECTROPHORESIS POLYMERASE CHAIN REACTION

Polymerase Chain Reaction–mediated Site-directed Mutagenesis

GENE-CLONING STRATEGIES GENOMIC ANALYSES

Mapping

Contiguous Mapping

DNA Sequence Analyses Polymorphisms or Mutations

Restriction Fragment Length Polymorphisms

Comparative Genome Hybridization

GENE KNOCKOUT STRATEGIES

Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR Associated Protein Homologous Recombination to Knockout Genes Knockout Mice

GENE EXPRESSION ANALYSIS

Northern Blotting RNA Interference Reverse Transcription Polymerase Chain Reaction Quantitative Real-Time Polymerase Chain Reaction Genetic Reporters Promoter Bashing Chromatin Immunoprecipitation Protein–DNA Interaction Arrays (Chromatin Immunoprecipitation-Chips) Microarrays to Assay Gene Expression RNA-Seq to Assay Gene Expression Chromatin Immunoprecipitation-Seq

PROTEIN ANALYSIS

Western Blotting Antibody Production Immunoprecipitation Far Western Blotting Fluorescent Proteins Two-Hybrid Screening Split Luciferase Complementation Assay Proteomics Two-Dimensional Electrophoresis

DATABASES AND SEQUENCE ANALYSIS SUMMARY OF PERTINENT CONCLUSIONS GLOSSARY OF TERMS BIBLIOGRAPHY

18 Cancer Biology

MECHANISMS OF CARCINOGENESIS ONCOGENES MECHANISMS OF ONCOGENE ACTIVATION

Retroviral Integration through Recombination DNA Mutation of Regulatory Sites Gene Amplification Chromosome Translocation

MUTATION AND INACTIVATION OF TUMOR SUPPRESSOR GENES

The Retinoblastoma Paradigm The Li–Fraumeni Paradigm Familial Breast Cancer, BRCA1 and BRCA2

SOMATIC HOMOZYGOSITY THE MULTISTEP NATURE OF CANCER FUNCTION OF ONCOGENES AND TUMOR SUPPRESSOR GENES

Dysregulated Proliferation Failure to Respond to Growth-Restrictive Signals Failure to Commit Suicide (Apoptosis) Escaping Senescence Angiogenesis Invasion and Metastasis

THE CONCEPT OF GATEKEEPERS AND CARETAKERS MISMATCH REPAIR HERITABLE SYNDROMES THAT AFFECT RADIOSENSITIVITY, GENOMIC INSTABILITY, AND CANCER

Ataxia-Telangiectasia Seckel Syndrome Mouse versus Human Severe Combined Immunodeficiency Ataxia-Telangiectasia–Like Disorder Nijmegen Breakage Syndrome Fanconi Anemia Homologues of RecQ—Bloom Syndrome, Werner Syndrome, and Rothmund–Thompson Syndrome

RADIATION-INDUCED SIGNAL TRANSDUCTION

Early Response Genes The Ceramide Pathway

T CELL CHECKPOINT THERAPY SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

Signal Transduction Heritable Syndromes that Affect Radiosensitivity, Genomic Instability, and Cancer Oncogenes and Tumor Suppressor Genes Cancer Genetics Multistep Nature of Cancer and Mismatch Repair Genes and Ionizing Radiation

19 Dose–Response Relationships for Model Normal Tissues

DOSE–RESPONSE RELATIONSHIPS

Therapeutic Ratio (Therapeutic Index)

TYPES OF CELL DEATH: HOW AND WHY CELLS DIE ASSAYS FOR DOSE–RESPONSE RELATIONSHIPS CLONOGENIC END POINTS

Clones Regrowing In Situ

Skin Colonies Crypt Cells of the Mouse Jejunum Testes Stem Cells Kidney Tubules

Cells Transplanted to Another Site

Bone Marrow Stem Cells Mammary and Thyroid Cells

SUMMARY OF DOSE–RESPONSE CURVES FOR CLONOGENIC ASSAYS IN NORMAL TISSUES DOSE–RESPONSE RELATIONSHIPS FOR FUNCTIONAL END POINTS

Pig Skin Rodent Skin Early and Late Response of the Lung Based on Breathing Rate Spinal Cord Myelopathy

Latency Fractionation and Protraction Volume Effects Retreatment after Long Time Intervals

INFERRING THE RATIO α / β FROM MULTIFRACTION EXPERIMENTS IN NONCLONOGENIC SYSTEMS SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

20 Clinical Response of Normal Tissues

CELLS AND TISSUES EARLY (ACUTE) AND LATE EFFECTS FUNCTIONAL SUBUNITS IN NORMAL TISSUES THE VOLUME EFFECT IN RADIOTHERAPY: TISSUE ARCHITECTURE RADIATION PATHOLOGY OF TISSUES CASARETT’S CLASSIFICATION OF TISSUE RADIOSENSITIVITY MICHALOWSKI’S H- AND F-TYPE POPULATIONS GROWTH FACTORS SPECIFIC TISSUES AND ORGANS

Skin

Skin Appendages: A Special Case

Hematopoietic System

Blood Cell Counts after Total Body Irradiation Partial Body Irradiation Radiation and Chemotherapy Agents

Lymphoid Tissue and the Immune System Digestive Tract

Oral Mucosa Esophagus Stomach Small and Large Intestines

Lungs Kidneys Liver Bladder Epithelium Central and Peripheral Nervous Systems

Brain Spinal Cord Peripheral Nerves

Testes Ovaries Female Genitalia Blood Vessels and the Vascular System Heart Bone and Cartilage

QUANTITATIVE ANALYSIS OF NORMAL TISSUE EFFECTS IN THE CLINIC LATE EFFECTS OF NORMAL TISSUE AND SOMA

The SOMA Scoring System

APPLICATION OF STEM CELLS TO REGENERATE RADIATION-SENSITIVE ORGANS—SALIVARY GLAND REGENERATION SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

21 Model Tumor Systems

TRANSPLANTABLE SOLID TUMOR SYSTEMS IN EXPERIMENTAL ANIMALS APOPTOSIS IN TUMORS TUMOR GROWTH MEASUREMENTS TUMOR CURE (TCD 50 ) ASSAY 50 DILUTION ASSAY TECHNIQUE LUNG COLONY ASSAY IN VIVO / IN VITRO ASSAY XENOGRAFTS OF HUMAN TUMORS PATIENT-DERIVED XENOGRAFTS MODELS AUTOCHTHONOUS AND TRANSGENIC TUMOR MODELS SPHEROIDS: AN IN VITRO MODEL TUMOR SYSTEM SPHEROIDS OF HUMAN TUMOR CELLS ORGANOID MODELS OF HUMAN TUMORS COMPARISON OF THE VARIOUS MODEL TUMOR SYSTEMS SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

22 Cell, Tissue, and Tumor Kinetics

THE CELL CYCLE CYCLINS AND KINASES CHECKPOINT PATHWAYS QUANTITATIVE ASSESSMENT OF THE CONSTITUENT PARTS OF THE CELL CYCLE THE PERCENT-LABELED MITOSES TECHNIQUE EXPERIMENTAL MEASUREMENTS OF CELL CYCLE TIMES IN VIVO AND IN VITRO PULSED FLOW CYTOMETRY THE GROWTH FRACTION POTENTIAL DOUBLING TIME CELL LOSS DETERMINATIONS OF CELL LOSS IN EXPERIMENTAL ANIMAL TUMORS GROWTH KINETICS OF HUMAN TUMORS SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

23 Time, Dose, and Fractionation in Radiotherapy

THE INTRODUCTION OF FRACTIONATION THE FOUR Rs OF RADIOBIOLOGY THE STRANDQUIST PLOT AND THE ELLIS NOMINAL STANDARD DOSE SYSTEM PROLIFERATION AS A FACTOR IN NORMAL TISSUES THE SHAPE OF THE DOSE–RESPONSE RELATIONSHIP FOR EARLY- AND LATE-RESPONDING TISSUES A POSSIBLE EXPLANATION FOR THE DIFFERENCE IN SHAPE OF DOSE–RESPONSE RELATIONSHIPS FOR EARLY- AND LATE-RESPONDING TISSUES FRACTION SIZE AND OVERALL TREATMENT TIME: INFLUENCE ON EARLY- AND LATE-RESPONDING TISSUES ACCELERATED REPOPULATION THE IMPORTANCE OF OVERALL TREATMENT TIME MULTIPLE FRACTIONS PER DAY HYPOFRACTIONATION: RENEWED INTEREST USING THE LINEAR-QUADRATIC CONCEPT TO CALCULATE EFFECTIVE DOSES IN RADIOTHERAPY

Choice of α/β Model Calculations Allowance for Tumor Proliferation

Calculations Suggested by Fowler Pragmatic Approach of Peters and Colleagues

SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

24 Retreatment after Radiotherapy: The Possibilities and the Perils

THE NATURE OF THE PROBLEM EARLY- AND LATE-RESPONDING TISSUES PRECLINICAL DATA CLINICAL STUDIES

Spinal Cord Brain Head and Neck Rectum Bone Metastases Breast Lung Recurrent Vaginal Metastases

SUMMARY OF PERTINENT CONCLUSIONS

Animal Studies Clinical Studies

BIBLIOGRAPHY

Reviews Preclinical (Animal Studies) Clinical

25 Alternative Radiation Modalities

FAST NEUTRONS

Rationale The Hammersmith Neutron Experience The United States Neutron Experience

BORON NEUTRON CAPTURE THERAPY

Boron Compounds Neutron Sources Clinical Trials

PROTONS

Depth-Dose Patterns and the Bragg Peak Advantages of Protons

CARBON ION RADIOTHERAPY

Depth-Dose Profiles Radiobiologic Properties Design of a Carbon Ion Beam for Clinical Use Scattering and Fragmentation Positron Emission Tomography Verification of Treatment Plans Reasons for the Choice of Carbon Ions

SUMMARY OF PERTINENT CONCLUSIONS

Hadron Therapy Neutrons Boron Neutron Capture Therapy Protons Carbon Ion Radiotherapy

BIBLIOGRAPHY

26 The Biology and Exploitation of Tumor Hypoxia

HYPOXIA-INDUCIBLE FACTOR

Oxygen-Dependent Regulation of Hypoxia-Inducible Factor Cancer Mutations that Activate Hypoxia-Inducible Factor Important Roles of Hypoxia-Inducible Factor in Tumors

Tumor Angiogenesis Tumor Metabolism Tumor Metastasis

Hypoxia-Inducible Factor and Radiotherapy

UNFOLDED PROTEIN RESPONSE RADIOSENSITIZING HYPOXIC CELLS

Hyperbaric Oxygen Improving the Oxygen Supply to Tumors Hypoxic Cell Radiosensitizers

Misonidazole Etanidazole and Nimorazole

Overgaard’s Meta-analysis of Clinical Trials Addressing the Problem of Hypoxia Nicotinamide and Carbogen Breathing

HYPOXIC CYTOTOXINS

Tirapazamine Clinical Trials with Tirapazamine and New Bioreductive Drugs

TARGETING TUMOR METABOLISM TO KILL HYPOXIC CELLS

Targeting Tumor Metabolism to Enhance the Efficacy of Radiotherapy

SUMMARY OF PERTINENT CONCLUSIONS

Hypoxia-Inducible Factor The Unfolded Protein Response Radiosensitizing Hypoxic Cells Hypoxic Cytotoxins

BIBLIOGRAPHY

27 Chemotherapeutic Agents from the Perspective of the Radiation Biologist

BIOLOGIC BASIS OF CHEMOTHERAPY CLASSES OF AGENTS AND THEIR MODE OF ACTION

Alkylating Agents

Procarbazine Cis -Platinum

Antibiotics Antimetabolites

5-Fluorouracil Hydroxyurea

Nucleoside Analogues Vinca Alkaloids Taxanes Hormone Targeted Therapies Topoisomerase Inhibitors Targeted Therapy

Cetuximab (Erbitux) Bevacizumab (Avastin) Poly Adenosine Diphosphate-Ribose Polymerase Inhibitors

Immune Checkpoint Therapies

DOSE–RESPONSE RELATIONSHIPS SUBLETHAL AND POTENTIALLY LETHAL DAMAGE REPAIR THE OXYGEN EFFECT AND CHEMOTHERAPEUTIC AGENTS RESISTANCE TO CHEMOTHERAPY AND HYPOXIC CYTOTOXINS DRUG RESISTANCE AND CANCER STEM CELLS COMPARISON OF CHEMOTHERAPEUTIC AGENTS WITH RADIATION ADJUNCT USE OF CHEMOTHERAPEUTIC AGENTS WITH RADIATION ASSAYS FOR SENSITIVITY OF INDIVIDUAL TUMORS SECOND MALIGNANCIES SUMMARY OF PERTINENT CONCLUSIONS BIBLIOGRAPHY

28 Hyperthermia

HISTORICAL RESPONSE TO HEAT AT CYTOTOXIC TEMPERATURES

Dose Response Sensitivity to Heat as a Function of Cell Age in the Mitotic Cycle Hypoxia and Hyperthermia Effect of pH and Nutrient Deficiency on Sensitivity to Heat Response of Normal Tissues to Heat Thermotolerance Heat and Tumor Vasculature

METHODS OF HEATING AND THE IMPACT ON CLINICAL HYPERTHERMIA

Methods of Heating in Experimental Systems Methods of Heating in Patients Thermal Ablation

RESPONSE TO HEAT AT NONCYTOTOXIC TEMPERATURES

Reoxygenation Immunologic Effects of Hyperthermia

THERMAL ENHANCEMENT RATIO HEAT AND THE THERAPEUTIC GAIN FACTOR MEASURING THERMAL DOSE IN PATIENTS PHASE III CLINICAL TRIALS TESTING BENEFITS OF HYPERTHERMIA FOR ENHANCING RADIATION THERAPY CLINICAL TRIALS ASSESSING THE BENEFIT OF HYPERTHERMIA IN COMBINATION WITH CHEMOTHERAPEUTIC AGENTS

Development and Evaluation of “Thermosensitive” Liposomes for Improved Tumor Targeting of Chemotherapy

METHODS OF TUMOR HEATING

Magnetic Hyperthermia

CLINICAL THERMOMETRY

Invasive Thermometry Methods Progress toward Clinically Achievable Noninvasive Thermometry

SUMMARY OF PERTINENT CONCLUSIONS

Hyperthermia at Cytotoxic Temperatures (42° to 45° C) Hyperthermia at Modest Temperatures that Can Be Achieved in Human Tumors

BIBLIOGRAPHY

Glossary Index

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