Ebook Radiobiology for the radiologist (8/E): Part 1

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Library of Congress Cataloging-in-Publication Data

Names: Hall, Eric J., author | Giaccia, Amato J., author

Title: Radiobiology for the radiologist / Eric J Hall, Amato

J Giaccia

Description: Eighth edition | Philadelphia : Wolters Kluwer,

[2019] | Includes bibliographical references and index

Identifiers: LCCN 2017057791 | ISBN 9781496335418

Subjects: | MESH: Radiation Effects | Radiobiology | Radiotherapy

Classification: LCC R895 | NLM WN 600 | DDC 616.07/57—dc23 LC recordavailable at https://lccn.loc.gov/2017057791

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Preface to the First Edition

This book, like so many before it, grew out of a set of lecture notes The lectureswere given during the autumn months of 1969, 1970, and 1971 at the Columbia-Presbyterian Medical Center, New York City The audience consisted primarily

of radiology residents from Columbia, affiliated schools and hospitals, andvarious other institutions in and around the city

To plan a course in radiobiology involves a choice between, on the one hand,dealing at length and in depth with those few areas of the subject in which onehas personal expertise as an experimenter or, on the other hand, surveying thewhole field of interest to the radiologist, necessarily in less depth The formercourse is very much simpler for the lecturer and in many ways more satisfying; it

is, however, of very little use to the aspiring radiologist who, if this course isfollowed, learns too much about too little and fails to get an overall picture ofradiobiology Consequently, I opted in the original lectures, and now in thisbook, to cover the whole field of radiobiology as it pertains to radiology I haveendeavored to avoid becoming evangelical over those areas of the subject whichinterest me, those to which I have devoted a great deal of my life At the sametime I have attempted to cover, with as much enthusiasm as I could muster andfrom as much knowledge as I could glean, those areas in which I had noparticular expertise or personal experience

This book, then, was conceived and written for the radiologist—specifically,the radiologist who, motivated ideally by an inquiring mind or more realistically

by the need to pass an examination, elects to study the biological foundations ofradiology It may incidentally serve also as a text for graduate students in the lifesciences or even as a review of radiobiology for active researchers whoseviewpoint has been restricted to their own area of interest If the book servesthese functions, too, the author is doubly happy, but first and foremost, it isintended as a didactic text for the student of radiology

Radiology is not a homogenous discipline The diagnostician and therapisthave divergent interests; indeed, it sometimes seems that they come togetheronly when history and convenience dictate that they share a common course inphysics or radiobiology The bulk of this book will be of concern, and hopefully

of interest, to all radiologists The diagnostic radiologist is commendedparticularly to Chapters 11, 12, and 13 concerning radiation accidents, lateeffects, and the irradiation of the embryo and fetus A few chapters, particularly

Chapters 8, 9, 15, and 16, are so specifically oriented towards radiotherapy thatthe diagnostician may omit them without loss of continuity.

A word concerning reference material is in order The ideas contained in thisbook represent, in the author’s estimate, the consensus of opinion as expressed inthe scientific literature For ease of reading, the text has not been broken up with

a large number of direct references Instead, a selection of general references hasbeen included at the end of each chapter for the reader who wishes to pursue thesubject further

I wish to record the lasting debt that I owe my former colleagues at Oxfordand my present colleagues at Columbia, for it is in the daily cut and thrust ofdebate and discussion that ideas are formulated and views tested

Finally, I would like to thank the young men and women who have regularlyattended my classes Their inquiring minds have forced me to study hard andreflect carefully before facing them in a lecture room As each group of studentshas grown in maturity and understanding, I have experienced a teacher’ssatisfaction and joy in the belief that their growth was due in some smallmeasure to my efforts

E J H New York July 1972

The eighth edition is a significant revision of this textbook and includes newchapters that were not included in the seventh edition We have retained thesame format as the seventh edition, which divided the book into two parts.Section I contains 16 chapters and represents both a general introduction toradiation biology and a complete self-contained course in the subject, suitable forresidents in diagnostic radiology and nuclear medicine It follows the format ofthe syllabus in radiation biology prepared by the Radiological Society of NorthAmerica (RSNA) Section II consists of 12 chapters of more in-depth materialdesigned primarily for residents in radiation oncology

Dickens’s famous beginning to a Tale of Two Cities, “It was the best oftimes, it was the worst of times, it was the age of wisdom, it was the age offoolishness, it was the epoch of belief, it was the epoch of incredulity ,” verymuch applies to the current world order Although medical science andtechnology have made great advances in alleviating disease and suffering,irrational and unpredictable events occur quite frequently, instilling fear andapprehension about potential nuclear terrorism The eighth edition contains anew chapter (Chapter 9) on “Medical Countermeasures to Radiation Exposure”that summarizes the current therapies available to prevent or mitigate radiationdamage to normal tissues This chapter nicely complements Chapter 14 on

“Radiologic Terrorism.”

Due to the strong request for including more information on moleculartechniques, we have included a new Chapter 17 on “Molecular Techniques inRadiology.” The techniques described in this chapter should be useful to both thenovice as well as the skilled practitioner in molecular biology

In this edition, we have eliminated the chapter on “Molecular Imaging.” Thebasis for this decision was that the subject matter covered in this chapter does notinvolve any radiobiologic principles, and in any case, there are several textbooksdevoted solely to the subject of molecular imaging For these reasons, we havedecided to remove this chapter from the eighth edition Overall, we believe thatthis new edition represents a well-balanced compilation of both traditional andmolecular radiation biology principles

The ideas contained in this book represent, we believe, the consensus ofopinion as expressed in the scientific literature We have followed the precedent

of previous editions, in that, the pages of text are unencumbered with

flyspeck-like numerals referring to footnotes or original publications, which are often toodetailed to be of much interest to the general reader On the other hand, there is

an extensive and comprehensive bibliography at the end of each chapter forthose readers who wish to pursue the subject further

We commend this new edition to residents in radiology, nuclear medicine,and radiation oncology, for whom it was conceived and written If it serves also

as a text for graduate students in the life sciences or even as a review of basicscience for active researchers or senior radiation oncologists, the authors will bedoubly happy

Eric J Hall Columbia University, New York

Amato J Giaccia Stanford University, California

October 2017

We would like to thank the many friends and colleagues who generously andwillingly gave permission for diagrams and illustrations from their publishedwork to be reproduced in this book

Although the ultimate responsibility for the content of this book must beours, we acknowledge with gratitude the help of several friends who readchapters relating to their own areas of expertise and made invaluable suggestionsand additions With each successive edition, this list grows longer and nowincludes Drs Ged Adams, Philip Alderson, Sally Amundson, Joel Bedford,Roger Berry, Max Boone, Victor Bond, David Brenner, J Martin Brown, EdBump, Denise Chan, Julie Choi, James Cox, Nicholas Denko, Bill Dewey, MarkDewhirst, Frank Ellis, Peter Esser, Stan Field, Greg Freyer, Charles Geard,Eugene Gerner, Julian Gibbs, George Hahn, Simon Hall, Ester Hammond, TomHei, Robert Kallman, Richard Kolesnick, Norman Kleiman, Gerhard Kraft,Adam Krieg, Edward LaGory, Dennis Leeper, Howard Lieberman, Philip Lorio,Edmund Malaise, Gillies McKenna, Mortimer Mendelsohn, George Merriam,Noelle Metting, Jim Mitchell, Thomas L Morgan, Anthony Nias, Ray Oliver,Stanley Order, Tej Pandita, Marianne Powell, Simon Powell, Julian Preston,Elaine Ron, Harald Rossi, Robert Rugh, Chang Song, Fiona Stewart, HermanSuit, Robert Sutherland, Roy Tishler, Len Tolmach, Liz Travis, Lou Wagner,John Ward, Barry Winston, Rod Withers, and Basil Worgul The principal creditfor this book must go to the successive classes of residents in radiology,radiation oncology, and nuclear medicine that we have taught over the years atColumbia and Stanford, as well as at American Society for Radiation Oncology(ASTRO) and RSNA refresher courses Their perceptive minds and searchingquestions have kept us on our toes Their impatience to learn what was needed ofradiobiology and to get on with being doctors has continually prompted us tosummarize and get to the point

We are deeply indebted to the U.S Department of Energy, the NationalCancer Institute, and the National Aeronautical and Space Administration, whichhave generously supported our work and, indeed, much of the researchperformed by numerous investigators that is described in this book

We owe an enormous debt of gratitude to Ms Sharon Clarke, who not onlytyped and formatted the chapter revisions but also played a major role in editingand proofreading Our publisher, Lauren Pecarich, guided our efforts at every

Finally, we thank our wives, Bernice Hall and Jeanne Giaccia, who havebeen most patient and have given us every encouragement with this work

1 Physics and Chemistry of Radiation Absorption

TYPES OF IONIZING RADIATIONS

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 CHROMOSOMEABERRATIONS

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

GENETIC CONTROL OF RADIOSENSITIVITY

INTRINSIC RADIOSENSITIVITY AND CANCER STEM CELLS

EFFECTIVE SURVIVAL CURVE FOR A MULTIFRACTIONREGIMEN

CALCULATIONS OF TUMOR CELL KILL

4 Radiosensitivity and Cell Age in the Mitotic Cycle

THE CELL CYCLE

SYNCHRONOUSLY DIVIDING CELL CULTURES

THE EFFECT OF X-RAYS ON SYNCHRONOUSLY DIVIDING CELLCULTURES

MOLECULAR CHECKPOINT GENES

THE EFFECT OF OXYGEN AT VARIOUS PHASES OF THE CELLCYCLE

THE AGE-RESPONSE FUNCTION FOR A TISSUE IN VIVO

VARIATION OF SENSITIVITY WITH CELL AGE FOR HIGH–LINEARENERGY TRANSFER RADIATIONS

MECHANISMS FOR THE AGE-RESPONSE FUNCTION

THE POSSIBLE IMPLICATIONS OF THE AGE-RESPONSEFUNCTION 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 OFTHE OXYGEN EFFECT

THE CONCENTRATION OF OXYGEN REQUIRED

CHRONIC AND ACUTE HYPOXIA

Chronic Hypoxia

Acute Hypoxia

THE FIRST EXPERIMENTAL DEMONSTRATION OF HYPOXICCELLS IN A TUMOR

PROPORTION OF HYPOXIC CELLS IN VARIOUS ANIMAL TUMORSEVIDENCE FOR HYPOXIA IN HUMAN TUMORS

TECHNIQUES TO MEASURE TUMOR OXYGENATION

Oxygen Probe Measurements

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 FRACTIONATEDDOSES

RELATIVE BIOLOGIC EFFECTIVENESS FOR DIFFERENT CELLSAND TISSUES

RELATIVE BIOLOGIC EFFECTIVENESS AS A FUNCTION OFLINEAR ENERGY TRANSFER

THE OPTIMAL LINEAR ENERGY TRANSFER

FACTORS THAT DETERMINE RELATIVE BIOLOGICEFFECTIVENESS

THE OXYGEN EFFECT AND LINEAR ENERGY TRANSFER

RADIATION WEIGHTING FACTOR

SUMMARY OF PERTINENT CONCLUSIONS

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 THEHEMATOPOIETIC SYNDROME

PULMONARY SYNDROME

CUTANEOUS RADIATION INJURY

SYMPTOMS ASSOCIATED WITH THE ACUTE RADIATIONSYNDROME

TREATMENT OF RADIATION ACCIDENT VICTIMS EXPOSED TODOSES CLOSE TO THE LD50/60

TRIAGE

SURVIVORS OF SERIOUS RADIATION ACCIDENTS IN THEUNITED 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 INRADIOTHERAPY

AMIFOSTINE AS A PROTECTOR AGAINST RADIATION-INDUCEDCANCER

A NEW FAMILY OF AMINOTHIOL RADIOPROTECTORS

CARCINOGENESIS: THE HUMAN EXPERIENCE

THE LATENT PERIOD

ASSESSING THE RISK

COMMITTEES CONCERNED WITH RISK ESTIMATES ANDRADIATION PROTECTION

RADIATION-INDUCED CANCER IN HUMAN POPULATIONS

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 DiseaseDOSE–RESPONSE RELATIONSHIP FOR RADIATIONCARCINOGENESIS AT HIGH DOSES

CANCER RISKS IN NUCLEAR INDUSTRY WORKERS

EXTRAPOLATING CANCER RISKS FROM HIGH TO LOW DOSESMORTALITY PATTERNS IN RADIOLOGISTS

CHILDHOOD CANCER AFTER RADIATION EXPOSURE IN UTERONONNEOPLASTIC DISEASE AND RADIATION

SUMMARY OF PERTINENT CONCLUSIONS

BIBLIOGRAPHY

11 Heritable Effects of Radiation

GERM CELL PRODUCTION AND RADIATION EFFECTS ONFERTILITY

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 RADIOLOGICALPROTECTION ESTIMATES OF HEREDITARY RISKS

MUTATIONS IN THE CHILDREN OF THE A-BOMB SURVIVORSCHANGING CONCERNS FOR RISKS

EPIGENETICS

Imprinted Genes

SUMMARY OF PERTINENT CONCLUSIONS

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 HUMANSSUMMARY 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 CONTAMINATIONWITH RADIOACTIVE MATERIALS

Areas of High Natural Background

COMPARISON OF RADIATION DOSES FROM NATURAL SOURCESAND 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 WOMENIrradiation of Children

Irradiation of Pregnant Women

DOSES TO THE EMBRYO AND FETUS

RECOMMENDATIONS ON BREASTFEEDING INTERRUPTIONSSUMMARY

SUMMARY OF PERTINENT CONCLUSIONS

THE HISTORY OF THE CURRENT DOSE LIMITS

DOSE RANGES

SUMMARY OF PERTINENT CONCLUSIONS

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 AGEEXPOSURE OF MEMBERS OF THE PUBLIC (NONOCCUPATIONALLIMITS)

EXPOSURE TO INDOOR RADON

17 Molecular Techniques in Radiobiology

HISTORICAL PERSPECTIVES

THE STRUCTURE OF DNA

RNA AND DNA

TRANSCRIPTION AND TRANSLATION

THE GENETIC CODE

AMINO ACIDS AND PROTEINS

DNA-MEDIATED GENE TRANSFER

AGAROSE GEL ELECTROPHORESIS

POLYMERASE CHAIN REACTION

Polymerase Chain Reaction–mediated Site-directed MutagenesisGENE-CLONING STRATEGIES

GENOMIC ANALYSES

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 CRISPRAssociated 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

Immunoprecipitation-Microarrays to Assay Gene Expression

RNA-Seq to Assay Gene Expression

Far Western Blotting

DATABASES AND SEQUENCE ANALYSIS

SUMMARY OF PERTINENT CONCLUSIONS

MECHANISMS OF ONCOGENE ACTIVATION

Retroviral Integration through Recombination

DNA Mutation of Regulatory Sites

Gene Amplification

Chromosome Translocation

MUTATION AND INACTIVATION OF TUMOR SUPPRESSOR GENESThe 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 GENESDysregulated 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

RADIATION-INDUCED SIGNAL TRANSDUCTION

Early Response Genes

The Ceramide Pathway

T CELL CHECKPOINT THERAPY

SUMMARY OF PERTINENT CONCLUSIONS

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 CLONOGENICASSAYS IN NORMAL TISSUES

DOSE–RESPONSE RELATIONSHIPS FOR FUNCTIONAL ENDPOINTS

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 MULTIFRACTIONEXPERIMENTS 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: TISSUEARCHITECTURE

RADIATION PATHOLOGY OF TISSUES

CASARETT’S CLASSIFICATION OF TISSUE RADIOSENSITIVITYMICHALOWSKI’S H- AND F-TYPE POPULATIONS

Blood Cell Counts after Total Body Irradiation

Partial Body Irradiation

Radiation and Chemotherapy Agents

Lymphoid Tissue and the Immune System

Bone and Cartilage

QUANTITATIVE ANALYSIS OF NORMAL TISSUE EFFECTS IN THECLINIC

LATE EFFECTS OF NORMAL TISSUE AND SOMA

The SOMA Scoring System

APPLICATION OF STEM CELLS TO REGENERATE SENSITIVE ORGANS—SALIVARY GLAND REGENERATION

RADIATION-SUMMARY OF PERTINENT CONCLUSIONS

BIBLIOGRAPHY

21 Model Tumor Systems

TRANSPLANTABLE SOLID TUMOR SYSTEMS IN EXPERIMENTALANIMALS

APOPTOSIS IN TUMORS

TUMOR GROWTH MEASUREMENTS

TUMOR CURE (TCD50) ASSAY

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 OFTHE 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 ANIMALTUMORS

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 STANDARDDOSE SYSTEM

PROLIFERATION AS A FACTOR IN NORMAL TISSUES

THE SHAPE OF THE DOSE–RESPONSE RELATIONSHIP FOREARLY- AND LATE-RESPONDING TISSUES

A POSSIBLE EXPLANATION FOR THE DIFFERENCE IN SHAPE OFDOSE–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 CALCULATEEFFECTIVE 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

Bone Metastases

Breast

Lung

Recurrent Vaginal Metastases

SUMMARY OF PERTINENT CONCLUSIONSAnimal Studies

The Hammersmith Neutron Experience

The United States Neutron Experience

BORON NEUTRON CAPTURE THERAPYBoron Compounds

Scattering and Fragmentation

Positron Emission Tomography Verification of Treatment Plans

Reasons for the Choice of Carbon Ions

SUMMARY OF PERTINENT CONCLUSIONS

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 ofHypoxia

Nicotinamide and Carbogen Breathing

HYPOXIC CYTOTOXINS

Tirapazamine

Clinical Trials with Tirapazamine and New Bioreductive Drugs

TARGETING TUMOR METABOLISM TO KILL HYPOXIC CELLSTargeting Tumor Metabolism to Enhance the Efficacy of RadiotherapySUMMARY OF PERTINENT CONCLUSIONS

Hypoxia-Inducible Factor

The Unfolded Protein Response

Radiosensitizing Hypoxic Cells

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 CYTOTOXINSDRUG RESISTANCE AND CANCER STEM CELLS

COMPARISON OF CHEMOTHERAPEUTIC AGENTS WITHRADIATION

ADJUNCT USE OF CHEMOTHERAPEUTIC AGENTS WITHRADIATION

ASSAYS FOR SENSITIVITY OF INDIVIDUAL TUMORS

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 CLINICALHYPERTHERMIA

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 OFHYPERTHERMIA FOR ENHANCING RADIATION THERAPY

CLINICAL TRIALS ASSESSING THE BENEFIT OF HYPERTHERMIA

IN COMBINATION WITH CHEMOTHERAPEUTIC AGENTS

Development and Evaluation of “Thermosensitive” Liposomes forImproved 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 HumanTumors

BIBLIOGRAPHY

Glossary

Index

For Students of Diagnostic Radiology, Nuclear Medicine, and

Radiation Oncology

Absorption of Protons and Heavier Ions Such as Carbon

Summary of Pertinent Conclusions

Bibliography

n 1895, the German physicist Wilhelm Conrad Röntgen discovered “a newkind of ray,” emitted by a gas discharge tube, that could blackenphotographic film contained in light-tight containers He called these rays

“x-rays” in his first announcement in December 1895—the x representingthe unknown In demonstrating the properties of x-rays at a public lecture,Röntgen asked Rudolf Albert von Kölliker, a prominent Swiss professor ofanatomy, to put his hand in the beam and so produced the first publiclytaken radiograph (Fig 1.1)

FIGURE 1.1 The first publicly taken radiograph of a living object, taken in

January 1896, just a few months after the discovery of x-rays (Courtesy ofRöntgen Museum, Würzburg, Germany.)

The first medical use of x-rays was reported in the Lancet of January 23,

1896 In this report, x-rays were used to locate a piece of a knife in the backbone

of a drunken sailor, who was paralyzed until the fragment was removedfollowing its location The new technology spread rapidly through Europe andthe United States, and the field of diagnostic radiology was born There is somedebate about who first used x-rays therapeutically, but by 1896, Leopold Freund,

an Austrian surgeon, demonstrated before the Vienna Medical Society thedisappearance of a hairy mole following treatment with x-rays Antoine HenriBecquerel discovered radioactivity emitted by uranium compounds in 1896, and

2 years later, Pierre and Marie Curie isolated the radioactive elements poloniumand radium Within a few years, radium was used for the treatment of cancer.The first recorded biologic effect of radiation was due to Becquerel, whoinadvertently left a radium container in his vest pocket He subsequentlydescribed the skin erythema that appeared 2 weeks later and the ulceration thatdeveloped and that required several weeks to heal It is said that Pierre Curierepeated this experience in 1901 by deliberately producing a radium “burn” onhis own forearm (Fig 1.2) From these early beginnings, at the turn of thecentury, the study of radiobiology began