9781451105452

Contributing Authors vii
Preface xxvii
Acknowledgments xxix
PART ONE
MOLECULAR BIOLOGY OF CANCER
1.
The Cancer Genome . . . . . . . . . . . . . . . . . . . 2Yardena Samuels, Alberto Bardelli, and Carlos López-Otín
Cancer Genes and Their Mutations 2
Identification of Cancer Genes 2
Cancer Genome Investigation: Tools and Quality Controls 2
Somatic Alteration Classes Detected by Cancer Genome Analysis 12
Pathway-Oriented Models of Cancer Genome Analysis 14
Networks of Cancer Genome Projects 16
The Genomic Landscape of Cancers 18
The Cancer Genome and the New Taxonomy of Tumors 18
Cancer Genomics and Drug Resistance 20
Perspectives of Cancer Genome Analysis 20
2.
Mechanisms of Genomic Instability . . . . . . . 23David J. Gordon, David A. Barbie, Alan D. D’Andrea,
and David Pellman
Basic Defenses Against Genomic Instability 23
Barriers to Genomic Instability 23
Mutations in Cancer 26
Mechanisms of Genome Destabilization in Human Tumors 29
What Causes Chromosomal Instability and Whole-Chromosome
Aneuploidy? 35
Does Whole-Chromosome Aneuploidy Cause Cancer? 37
Perspectives and Implications for Cancer Therapeutics 38
3.
Epigenetics of Cancer . . . . . . . . . . . . . . . . . . 41Peter A. Jones and Karin B. Michels
Epigenetic Processes 41
Epigenomic Changes in Cancer 43
The Timing of Epigenetic Alterations 44
Epigenetic Biomarkers for Early Detection of Cancer 44
Epigenetic Therapies 45
Problems with Epigenetic Therapies 46
4.
Telomeres, Telomerase, and Cancer . . . . . . . 48Kwok-Kin Wong, Norman E. Sharpless, and
Ronald A. DePinho
Telomeres and Telomerase 48
Senescence 50
Telomere Maintenance and Cancer 53
5.
Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Cell Signaling Growth Factors and TheirLewis C. Cantley, Chris L. Carpenter, William C. Hahn,
and Matthew Meyerson
Signal Transduction Systems 57
Sensory Machinery: Ligands and Receptors 57
Regulation of Protein Kinases 60
Small-Molecule Second Messengers 63
Efficiency and Specificity: Formation of Multiprotein Signaling
Complexes 64
Signaling Networks 66
6.
Cell Cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . 68Steven I. Reed
Cell-Cycle Engine 68
Induction of Cell-Cycle Phase Transitions 71
Ubiquitin-Mediated Proteolysis 71
Regulation of the Cell Cycle 72
Cell Cycle and Cancer 76
MicroRNAs, the Cell Cycle, and Cancer 79
The Cell Cycle and Cancer Therapy 80
7.
Mechanisms of Cell Death . . . . . . . . . . . . . . 82Vassiliki Karantza and Eileen White
Apoptosis 82
Autophagy 87
Necrosis 89
8.
Cancer Metabolism . . . . . . . . . . . . . . . . . . . 91Matthew G. Vander Heiden
Altered Metabolism in Cancer Cells 91
Energetics of Cell Proliferation 93
Imaging Cancer Metabolism in Patients 94
Genetic Events Important for Cancer Influence Metabolism 95
Targeting Metabolism to Treat Cancer 99
9.
Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . 101Robert S. Kerbel and Lee M. Ellis
Introduction: Origins of the Concept of Antiangiogenic Therapy for
Cancer 101
Sequential Steps Involved in the Formation of Blood Vessel Capillaries
in Tumors 101
Pericytes 102
Dysfunctional Nature of the Tumor Vasculature 102
Molecular Mediators of Tumor Angiogenesis: Angiogenic Stimulators
and Their Receptors 103
Endogenous Inhibitors of Tumor Angiogenesis 105
A Cooperative Regulator of Tumor Angiogenesis: The Notch Receptor-
DLL4 Signaling Pathway in Endothelial Cells 106
Strategies for Development of Antiangiogenic Drugs 106
Enhancement of Chemotherapy Efficacy and Other Therapeutic
Modalities by Antiangiogenic Drugs 107
Resistance to Antiangiogenic Drugs or Treatments 108
Biomarkers for Tumor Angiogenesis and Antiangiogenic Therapy 109
Antiangiogenic/Anti-VEGF Drug-Based Clinical Trials 109
Looking Ahead: New Targets, New Drugs, and New Strategies for
Antiangiogenic Therapy 111
10.
Invasion and Metastasis . . . . . . . . . . . . . . . 113Andy J. Minn and Joan Massagué
The Evolution and Pathogenesis of Metastasis 113
An Integrated Model for Metastasis 115
Selective Pressures at the Primary Tumor Driving Acquisition of
Metastasis Functions 117
Coupling Tumorigenesis with Metastasis Initiation 119
Coupling Tumorigenesis with Metastasis Progression 121
From Metastasis Progression to Macrometastatic Colonization 122
Micro-RNAs and Metastasis 126
11.
Cancer Stem Cells . . . . . . . . . . . . . . . . . . . 128Jean C. Y. Wang and John E. Dick
Tumor Heterogeneity 128
Leukemia Stem Cells 129
CONTENTS
xxxi
Cancer Stem Cells in Solid Tumors 130
Genetic Diversity and Clonal Evolution in Cancer 133
The Origins of Cancer Stem Cells 134
Epithelial-Mesenchymal Transition 137
Cancer Stem Cells: Targeted Therapy 137
12.
Biology of Personalized Cancer Medicine . . .141Raju Kucherlapati
Cancer Predisposition 141
Familial Adenomatous Polyposis 141
Lynch Syndrome 142
Other Polyposis Syndromes 142
Association Studies 142
Breast Cancer 142
Early Detection 143
Tumor Classification and Patient Stratification 143
Treatment 144
Development of Resistance to Tyrosine Kinase Inhibitors 145
Alternative Mechanisms of Resistance 145
BRAF Inhibitors 146
The Future 146
Changing Face of Personalized Medicine 146
Summary 146
PART TWO
ETIOLOGY AND EPIDEMIOLOGY
OF CANCER
Section 1: Etiology of Cancer
13. Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Stephen S. Hecht
Epidemiology of Tobacco and Cancer 150
Tumor Induction in Laboratory Animals by Tobacco Products 152
Carcinogens in Tobacco Products 153
Overview of Mechanisms of Tumor Induction by Tobacco Products 156
Tobacco Carcinogen and Toxicant Biomarkers 157
14.
Cancer Susceptibility Syndromes . . . . . . . . 161Alice Hawley Berger and Pier Paolo Pandolfi
Principles of Cancer Susceptibility 161
Genetic Testing 163
Cancer Susceptibility Syndromes 164
Future Directions 170
15.
DNA Viruses . . . . . . . . . . . . . . . . . . . . . . . 173Peter M. Howley, Don Ganem, and Elliott Kieff
History of Viral Oncology 173
Hepadnaviruses and Hepatocellular Carcinoma 174
Papillomaviruses 176
Epstein-Barr Virus 180
Kaposi’s Sarcoma–Associated Herpesvirus 182
Human Polyomaviruses 184
16.
RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . 186Gary L. Buchschacher, Jr. and Flossie Wong-Staal
Retroviruses: Background, Replication Cycle, and
Molecular Genetics 186
Human T-Lymphotropic Virus Type 1 189
Human T-Lymphotropic Virus Type 2 190
Human Immunodeficiency Virus 190
Hepatitis C Virus 190
17.
Inflammation . . . . . . . . . . . . . . . . . . . . . . . 193Giorgio Trinchieri
Tumor Immune Surveillance 193
Inflammation and Tumorigenesis 194
Mechanisms of Cell Transformation and Cancer Initiation in the
Inflammatory Environment 196
Inflammatory Cells and Stromal Cells in the Initiation of Neoplasia
and in the Tumor Microenvironment 198
18.
Chemical Factors . . . . . . . . . . . . . . . . . . . . 203Stuart H. Yuspa and Peter G. Shields
The Nature of Chemical Carcinogens: Chemistry
and Metabolism 203
Animal Model Systems and Chemical Carcinogenesis 205
DNA Repair Protects the Host from Chemical
Carcinogens 205
Genetic Susceptibility to Chemical Carcinogenesis 205
Molecular Epidemiology, Chemical Carcinogenesis, and
Cancer Risk in Human Populations 206
Polyclic Aromatic Hydrocarbons as a Model for Gene-Environment
Interaction 207
19.
Physical Factors . . . . . . . . . . . . . . . . . . . . . 209Mats Ljungman
Ionizing Radiation 209
Ultraviolet Light 212
Radiofrequency and Microwave Radiation 214
Electromagnetic Fields 214
Asbestos 214
Nanoparticles 215
20.
Dietary Factors . . . . . . . . . . . . . . . . . . . . . 217Karin B. Michels and Walter C. Willett
Methodologic Challenges 217
The Role of Individual Food and Nutrients in
Cancer Etiology 218
Other Foods and Nutrients 222
Dietary Patterns 224
Diet During Early Phases of Life 224
Summary 224
Limitations 224
Future Directions 225
Recommendations 225
21.
Obesity and Physical Activity . . . . . . . . . . . 227Katherine D. Henderson, Yani Lu, and Leslie Bernstein
Breast Cancer 227
Colon and Rectal Cancer 228
Endometrial Cancer 229
Adenocarcinoma of the Esophagus 229
Kidney/Renal Cell Cancer 230
Pancreatic Cancer 230
Gallbladder Cancer 230
Non-Hodgkin Lymphoma 230
Prostate Cancer 231
Lung Cancer 231
Ovarian Cancer 231
Overview 231
Section 2: Epidemiology of Cancer
22.
Epidemiologic Methods . . . . . . . . . . . . . . . 233Xiaomei Ma and Herbert Yu
Analytical Studies 233
Interpretation of Epidemiologic Findings 236
Molecular Epidemiology 237
23.
Global Cancer Incidence and Mortality . . . 241Michael J. Thun, Ahmedin Jemal, and Elizabeth Ward
Data Sources and Measurements 241
Overall Cancer Risk 243
Incidence and Mortality Patterns for Common Cancers 251
Issues in Interpreting Temporal Trends 258
Conclusion 259
xxxii
Contents24.
Trends in Cancer Mortality . . . . . . . . . . . . 261Tim E. Byers
Cancer Surveillance Systems 261
Making Sense of Cancer Trends 261
Trends in Cancer Risk Factors 261
Cancer Trends 263
Predicting Future Cancer Trends 265
PART THREE
PRINCIPLES OF CANCER TREATMENT
25.
Surgical Oncology: General Issues . . . . . . . 268Steven A. Rosenberg
Historical Perspective 268
Anesthesia for Oncologic Surgery 268
Determination of Operative Risk 270
Roles for Surgery 272
Surgical Oncologist 274
26.
Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Surgical Oncology: LaparoscopicYoshinori Hosoya and Alan T. Lefor
New Technology 277
Physiology of Laparoscopy 278
Laparoscopy in the Diagnosis of Malignancy 279
Laparoscopy in the Staging of Malignancy 279
Laparoscopy in the Treatment of Malignancy 281
Laparoscopy in the Palliation of Malignancy 287
27.
Radiation Oncology . . . . . . . . . . . . . . . . . . 289Meredith A. Morgan, Randall K. Ten Haken, and
Theodore S. Lawrence
Biologic Aspects of Radiation Oncology 289
Factors that Affect Radiation Response 294
Drugs that Affect Radiation Sensitivity 296
Radiation Physics 297
Treatment Planning 301
Other Treatment Modalities 303
Clinical Applications of Radiation Therapy 304
Treatment Intent 305
Fractionation 306
Adverse Effects 307
Principles of Combining Anticancer Agents with Radiation Therapy 308
28.
Medical Oncology . . . . . . . . . . . . . . . . . . . 312Vincent T. DeVita, Jr. and Edward Chu
Introduction 312
Biology of Drug Resistance 316
29.
Assessment of Clinical Response . . . . . . . . 322Antonio Tito Fojo and Susan Elaine Bates
Overall Response Rate and Stable Disease 322
Alternate Response Criteria 323
Waterfall Plots 326
Progression Free Survival and Time to Progression 326
Overall Survival 327
Kaplan-Meier Plots 328
Hazard Ratios 329
Forest Plots 329
Meta-Analyses 329
Quality of Life 329
Novel End Points 329
30.
Cancer Immunotherapy . . . . . . . . . . . . . . . 332Steven A. Rosenberg, Paul F. Robbins, and Nicholas P. Restifo
Approaches to the Identification of Human
Tumor Antigens 332
Categories of Tumor Antigens Can Be Defined by Expression
Patterns 334
Cancer Immunotherapies 337
31.
of Cancer Care . . . . . . . . . . . . . . . . . . . . . . 345
Health Services Research and EconomicsCraig C. Earle and Deborah Schrag
Studies of Health Service Delivery in Cancer Medicine 345
Patient-Reported Outcomes Assessment 350
The Economics of Cancer Care 353
Comparative Effectiveness Research 356
PART FOUR
PHARMACOLOGY OF CANCER
THERAPEUTICS
Section 1: Chemotherapy Agents
32.
Pharmacokinetics and Pharmacodynamics . . . .360Chris H. Takimoto, Chee M. Ng, and Thomas Puchalski
Why Study Pharmacokinetics and Pharmacodynamics? 360
Cancer Patients Present Unique Challenges 361
Pharmacokinetic Concepts 361
Pharmacodynamic Concepts 365
Special Topics in Pharmacokinetics and Pharmacodynamics 365
Population Pharmacokinetics/Pharmacodynamics 366
Pharmacokinetics and Pharmacodynamics in Oncology Drug
Development 366
33.
Pharmacogenomics . . . . . . . . . . . . . . . . . . 369Anthony El-Khoueiry and Heinz Josef Lenz
Definitions: Terms and Concepts 369
Pharmacogenomics and Predictive Molecular Markers 369
Pharmacogenomics and Prognostic Markers 372
Current Challenges and Future Directions 373
34.
Alkylating Agents . . . . . . . . . . . . . . . . . . . . 375Kenneth D. Tew
Perspectives 375
Chemistry 375
Classification 375
Clinical Pharmacokinetics/Pharmacodynamics 380
Therapeutic Uses 381
Toxicities 381
Complications with High-Dose Alkylating Agent
Therapy 383
Alkylating Agent–Steroid Conjugates 383
Drug Resistance and Modulation 383
Recent Developments 383
35.
Platinum Analogs . . . . . . . . . . . . . . . . . . . . 386Eddie Reed
Common Features of Platinum Chemistry 387
Clinical Pharmacology 388
Determinants of Cellular Sensitivity and Resistance to
Platinum Agents 389
Cellular Accumulation and Cytosolic Inactivation
of Drug 390
DNA Damage and Repair 390
36.
Antimetabolites . . . . . . . . . . . . . . . . . . . . . 393M. Wasif Saif and Edward Chu
Antifolates 393
5-Fluoropyrimidines 396
Capecitabine 396
Cytarabine 397
Contents
xxxiiiGemcitabine 397
6-Thiopurines 398
Fludarabine 399
Cladribine 399
Clofarabine 400
37.
Topoisomerase-Interacting Agents . . . . . . . 402Zeshaan A. Rasheed and Eric H. Rubin
Topoisomerase Biology 402
Camptothecins 402
Anthracyclines 404
Anthracenediones 409
Epipodophyllotoxins 410
38.
Antimicrotubule Agents . . . . . . . . . . . . . . . 413Maysa M. Abu-Khalaf and Lyndsay N. Harris
Microtubules 413
Taxanes 413
New Taxane Formulations 416
Vinca Alkaloids 417
Estramustine Phosphate 420
Epothilones 420
Novel Compounds Targeting Microtubules and
Mitotic Motor Proteins 420
39.
Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Targeted Therapy with Small Molecule KinaseCharles L. Sawyers
Early Successes: Targeting Cancers with Well-Known Kinase
Mutations 422
Targeting the PI3K Pathway Directly 431
Combinations of Kinase Inhibitors 431
Speculations on the Future Role of Kinase Inhibitors in
Cancer Medicine 432
40.
Demethylating Agents . . . . . . . . . . . . . . . . 434
Histone Deacetylase Inhibitors andSteven D. Gore, Stephen B. Baylin, and James G. Herman
Epigenetics and Gene Silencing 434
Changes in DNA Methylation 434
Histone Deacetylase Inhibitors 437
Pharmacodynamic Observations 439
41.
Proteasome Inhibitors . . . . . . . . . . . . . . . . 441Michael G. Kauffman, Christopher J. Molineaux,
Christopher J. Kirk, and Craig M. Crews
Biochemistry of the Ubiquitin-Proteasome Pathway 441
Proteasome Inhibitors 441
Preclinical Pharmacology of PIs 445
Proteasome Inhibitors in Cancer 445
42.
Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Poly(ADP-Ribose) PolymeraseAlan Ashworth
Cellular DNA Repair Pathways 450
The Development of PARP Inhibitors 450
BRCA1
PARP1 Inhibition as a Synthetic Lethal Therapeutic Strategy for the
Treatment of BRCA-Deficient Cancers 451
Mechanisms of Resistance to PARP Inhibitors 452
Initial Clinical Results Testing Synthetic Lethality 452
The Use of PARP Inhibitors in Sporadic Cancers
with “BRCAness” 452
Prospects 453
and BRCA2 Mutations and DNA Repair 45143.
Miscellaneous Chemotherapeutic Agents . . . 455M. Sitki Copur, Michal Rose, and Scott Gettinger
Sirolimus and Temsirolimus 455
Everolimus 455
l-Asparaginase 456
Bleomycin 456
Procarbazine 457
Thalidomide 458
Lenalidomide 458
Section 2: Biotherapeutics
44.
Interferons . . . . . . . . . . . . . . . . . . . . . . . . . 461Vernon K. Sondak, Jürgen C. Becker, and Axel Hauschild
Interferon Signaling Pathways 461
Immunologic Effects of Interferon 463
Nonimmunologic Antiangiogenic Effects of Interferon 464
Direct Antitumor Effects of Interferons 464
Clinical Toxicity of Interferon Administration 464
Potential Drug Interactions 466
Oncologic Applications of Interferons 466
45.
Interleukin Therapy . . . . . . . . . . . . . . . . . . 469Michael T. Lotze
Interleukins as Therapeutics 469
Interleukin-1 Family 469
Interleukin 3, Interleukin 11, and Interleukin 34 470
Interleukin-2 Family 470
Interleukin 6 Family 477
Interleukin 10 Family 480
46.
Antisense Agents . . . . . . . . . . . . . . . . . . . . 482Cy A. Stein and Harris S. Soifer
Oligonucleotide Stability and Efficacy: The Role of
Phosphorothioates 482
Clinical Trials of G3139 (Oblimersen) in Chronic Lymphocytic
Leukemia 483
Clinical Trials in Advanced Melanoma 484
47.
Antiangiogenesis Agents . . . . . . . . . . . . . . . 489Cindy H. Chau and William D. Figg
Understanding the Angiogenic Process 489
Drug Development of Angiogenesis Inhibitors 490
Clinical Utility of Approved Antiangiogenic Agents in
Cancer Therapy 494
Combination Therapies 496
Surrogate Markers of Antiangiogenic Therapy 497
Resistance to Antiangiogenic Therapy 497
48.
Monoclonal Antibodies . . . . . . . . . . . . . . . 499Matthew K. Robinson, Hossein Borghaei, Gregory P. Adams,
and Louis M. Weiner
Immunoglobulin Structure 499
Modified Antibody-Based Molecules 499
Factors Regulating Antibody-Based Tumor Targeting 500
Unconjugated Antibodies 502
Altering Signal Transduction 503
Immunoconjugates 504
Unconjugated Antibodies Approved for Use Against Solid
Tumors 505
Antibodies Used in Hematologic Malignancies 506
49.
Endocrine Manipulation . . . . . . . . . . . . . . 508Matthew P. Goetz, Charles Erlichman, Manish Kohli, and
Charles L. Loprinzi
Selective Estrogen Receptor Modulators 508
Aromatase Inhibitors 513
Gonadotropin-Releasing Hormone Analogues 514
Gonadotropin-Releasing Hormone Antagonists 515
Antiandrogens 515
Novel Antiandrogens 516
Other Sex Steroid Therapies 516
Other Hormonal Therapies 518
xxxiv
ContentsPART FIVE
CANCER PREVENTION
50.
Preventive Cancer Vaccines. . . . . . . . . . . . . 522Douglas R. Lowy and John T. Schiller
Background 522
Infectious Agents and Cancer 522
Prophylactic Versus Therapeutic Vaccination 524
Hepatitis B Virus 524
Human Papillomavirus 525
Helicobacter Pylori
52751.
Tobacco Dependence and Its Treatment . . . 529Ellen R. Gritz, Cho Y. Lam, Damon J. Vidrine, and
Michelle Cororve Fingeret
Nicotine and the Neurobiological Basis of Smoking 529
Smoking Prevalence and Quit Rates 529
Effects of Continued Smoking on Cancer Treatment Outcomes 530
Cessation Treatment and Research 532
Future Research and Clinical Opportunities 540
52.
Role of Surgery in Cancer Prevention . . . . . 543José G. Guillem, Andrew Berchuck, Jeffrey F. Moley,
Jeffrey Norton, and Sheryl G. A. Gabram
Patients at High Risk for Breast Cancer 543
Hereditary Diffuse Gastric Cancer 545
Surgical Prophylaxis of Hereditary Ovarian and Endometrial
Cancer 547
Hereditary Endometrial Cancer (Lynch Syndrome) 548
Multiple Endocrine Neoplasia Type 2 549
Familial Adenomatous Polyposis,
and Lynch Syndrome 552
MYH-Associated Polyposis,53.
Intervention . . . . . . . . . . . . . . . . . . . . . . . . 558
Principles of Cancer Risk ReductionDean E. Brenner
Why Cancer Prevention as a Clinical Oncology Discipline? 558
Defining Cancer Risk Reductive Intervention
(Chemoprevention) 558
Identifying Potential Cancer Risk Reductive Interventions 558
Preclinical Development of Cancer Risk Reductive
Interventions 559
Clinical Development of Cancer Risk Reductive Interventions 561
Implementation of Cancer Risk Reductive Interventions in the
Community 562
54.
Micronutrients in Cancer Prevention . . . . . 564
Retinoids, Carotenoids, and OtherSusan T. Mayne, Edward Giovannucci, and Scott M. Lippman
Head and Neck Cancer Chemoprevention 564
Lung Cancer Chemoprevention 565
Breast Cancer Chemoprevention 567
Skin Cancer Chemoprevention 567
Bladder Cancer Chemoprevention 568
Cervical Cancer Chemoprevention 568
Esophageal/Gastric Cancer Chemoprevention 569
Colorectal Cancer Chemoprevention 569
Prostate Cancer Chemoprevention 570
Conclusions 571
55.
Reduction (Chemoprevention) . . . . . . . . . . 573
Drugs and Nutritional Extracts for Cancer RiskMadhuri Kakarala and Dean E. Brenner
Anti-Inflammatory Drugs 573
Signal Transduction Modifiers 578
Anti-Infectives 579
PART SIX
CANCER SCREENING
56.
Principles of Cancer Screening . . . . . . . . . . 582Jack S. Mandel and Robert Smith
Principles of Screening 582
Evaluating Screening Tests 583
Developing and Evaluating a Cancer Screening
Program 585
57.
Early Detection Using Proteomics . . . . . . . . 587Virginia Espina, Claudio Belluco, Emanuel F. Petricoin III, and
Lance A. Liotta
Cellular Proteomics 587
Biomarker Proteomics 592
58.
Screening for Gastrointestinal Cancers . . . . 596Timothy R. Church and Jack S. Mandel
History of Colorectal Cancer Screening 596
Polyp Removal and Colorectal Cancer Prevention 597
Methods of Screening for Colorectal Cancer 597
Colorectal Cancer Screening for High-Risk
Patients 600
Other Gastrointestinal Cancers 600
Screening 601
59.
Screening for Gynecologic Cancers . . . . . . 603Mary B. Daly and Janet S. Rader
Cervical Cancer 603
Ovarian Cancer 606
Endometrial Cancer 607
60.
Screening for Breast Cancer . . . . . . . . . . . . 610Laura J. Esserman and Chris I. Flowers
The Evidence of Mortality Benefit from Randomized Trials of
Mammography Screening 610
Changes in Systemic Therapies and Impact on Screening 610
Optimizing the Organization of Screening 611
Optimizing the Interpretation of Mammography 611
Addressing the Potential Harms and Limitations of
Screening 612
High-Risk Screening 614
What has Biology Taught Us? 614
Conclusion and Considerations for Screening 615
61.
Screening for Prostate Cancer . . . . . . . . . . 617Peter C. Albertsen
Is Prostate Cancer a Suitable Disease for
Screening? 617
Is Treatment for Prostate Cancer Effective? 618
Is Prostate-Specific Antigen an Effective Screening
Test? 620
Recent Evidence from Randomized Trials 621
Are there Substantial Risks Associated with Prostate-Specific Antigen
Screening? 622
How Should Physicians Advise their Patients? 622
62.
Screening for Lung Cancer . . . . . . . . . . . . . 625David E. Midthun and James R. Jett
The Opportunity 625
Chest Radiography and Sputum Cytology 625
CT Screening 626
The Problems with CT Screening 627
Other Methods of Screening 629
Future Directions 629
Contents
xxxv63.
Genetic Counseling . . . . . . . . . . . . . . . . . . 631Ellen T. Matloff and Danielle Campfield Bonadies
Who is a Candidate for Cancer Genetic Counseling? 631
Components of the Cancer Genetic Counseling Session 632
Issues in Cancer Genetic Counseling 635
Future Directions 637
PART SEVEN
SPECIALIZED TECHNIQUES IN
CANCER MANAGEMENT
64.
Techniques . . . . . . . . . . . . . . . . . . . . . . . . . 640
Vascular Access and SpecializedJames F. Pingpank, Jr.
Catheter Types 640
Catheter Selection 643
Pediatric Patients 643
Insertion Techniques 643
Catheter-Related Complications 645
65.
Interventional Radiology . . . . . . . . . . . . . . 648Christos S. Georgiades and Jean-Francois H. Geschwind
Pulmonary 648
Hepaticobiliary 649
Cholangiocarcinoma 652
Liver Metastases 655
Genitourinary 657
Musculoskeletal Cancer 659
Special Topic: Inferior Vena Cava/Portal Vein
Occlusion 661
66.
Functional Imaging . . . . . . . . . . . . . . . . . . 666Brian D. Ross, Craig J. Galbán, and
Alnawaz Rehemtulla
Diffusion Magnetic Resonance Imaging 666
Perfusion Magnetic Resonance Imaging 670
Magnetic Resonance Spectroscopy 672
67.
Molecular Imaging . . . . . . . . . . . . . . . . . . . 676Steven M. Larson, Heiko Schöder, and Jan Grimm
Characterizing the Cancer Cell Phenotype 676
Clinical Applications 680
Optical Imaging 683
68.
Photodynamic Therapy . . . . . . . . . . . . . . . 686Keith A. Cengel, Smith Apisarnthanarax, and
Stephen M. Hahn
Components of Photodynamic Therapy: Photosensitizers,
Light, and Oxygen 686
Mechanisms of Photodynamic Therapy Cytotoxicity 688
Clinical Indications for Photodynamic Therapy for Early Stage Cancers
in the Definitive Setting 689
Clinical Indications for Photodynamic Therapy in the Locally
Advanced and Palliative Settings 690
Molecularly Targeted Photodynamic Therapy 692
69.
Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . 694Daniel F. Hayes
What is a Biomarker Used for? 694
What are the Criteria to Incorporate a Tumor Marker into
Clinical Practice? 695
Prognosis Versus Prediction 698
Pharmacogenomics: A Special Circumstance 698
Markers that are Accepted for Routine Clinical Utility 700
PART EIGHT
PRACTICE OF ONCOLOGY
70.
Design and Analysis of Clinical Trials . . . . 704Richard Simon
Phase 1 Clinical Trials 704
Phase 2 Clinical Trials 706
Design of Phase 3 Clinical Trials 711
Factorial Designs 713
Analysis of Phase 3 Clinical Trials 716
Reporting Results of Clinical Trials 719
False-Positive Reports in the Literature 720
Meta-Analysis 720
Section 1: Cancer of the Head and Neck
71.
Neck Cancers . . . . . . . . . . . . . . . . . . . . . . . 723
Molecular Biology of Head andNishant Agrawal, Joseph Califano, and
Patrick Ha
Genetic Susceptibility 723
Molecular Networks Altered in HNSCC 724
Epigenetics 727
Loss of Heterozygosity and Risk of Malignant Progression 727
72.
Treatment of Head and Neck Cancer . . . . . 729William M. Mendenhall, John W. Werning, and
David G. Pfister
Epidemiology of Head and Neck Cancer 729
Anatomy 729
Pathology 729
Natural History of Squamous Cell Carcinoma 729
Diagnostic Evaluation 730
Staging 731
Principles of Treatment for Squamous Cell Carcinoma 731
Management 731
NECK 732
Chemotherapy 734
General Principles of Combining Modalities 738
Chemotherapy as Part of Curative Treatment 738
Follow-Up 744
ORAL CAVITY 744
Lip 744
Floor of the Mouth 745
Oral Tongue 747
Buccal Mucosa 749
Gingiva and Hard Palate (Including Retromolar
Trigone) 750
OROPHARYNX 752
Anatomy 752
LARYNX 756
Anatomy 756
Pathology 756
Hypopharynx: Pharyngeal Walls, Pyriform Sinus, and
Postcricoid Pharynx 761
NASOPHARYNX 764
Anatomy 764
Pathology 764
Patterns of Spread 765
Clinical Picture 765
Staging 765
Treatment 766
Nasal Vestibule, Nasal Cavity, and Paranasal Sinuses 766
Paragangliomas 772
Major Salivary Glands 774
Minor Salivary Glands 777
xxxvi
Contents73.
Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . .781
Rehabilitation after Treatment of Head andDouglas B. Chepeha, Mark J. Haxer, and Teresa H. Lyden
Pretreatment Counseling 781
Support During Treatment and Rehabilitation of the
Chemoradiation Patient 781
Resources for Rehabilitation of Head and Neck Cancer Patients 787
Section 2: Cancer of the Thoracic Cavity
74.
Molecular Biology of Lung Cancer . . . . . . 789Jacob Kaufman, Leora Horn, and David Carbone
Susceptibility to Lung Cancer: Genetic Susceptibility and Carcinogens
in Tobacco Smoke 789
Molecular Changes in Preneoplasia 789
Genetic and Epigenetic Alterations in Lung Cancers 791
Protooncogenes, Growth Factor Signaling, and Growth Factor Targeted
Therapies 791
Tumor Suppressor Genes and Growth Suppression 793
Cyclins and Cell Cycle Regulatory Pathways 794
Other Biologic Abnormalities in Lung Cancer 795
Cancer Stem Cell Hypothesis 796
Genomic Analysis of Lung Cancer 797
Molecular Tools in the Lung Cancer Clinic 797
75.
Non–Small Cell Lung Cancer . . . . . . . . . . . 799David S. Schrump, Darryl Carter, Christopher R. Kelsey,
Lawrence B. Marks, and Giuseppe Giaccone
Incidence 799
Etiology 799
Pathology 802
Molecular Markers of Prognosis 805
Modes of Metastasis 806
Clinical Manifestations 806
Staging and Diagnosis 807
Methods to Establish Tissue Diagnosis 811
Overview of Invasive Lung Cancer Management:
Treatment Modalities 813
Specifics of Lung Cancer Management 820
Superior Sulcus Tumors 829
Unresectable or Medically Inoperable 829
Locally Advanced 830
Advanced Disease 833
Investigational Agents in Development for NSCLC 843
Personalized Medicine in NSCLC 843
Local Therapies and Palliation 844
76.
the Lung. . . . . . . . . . . . . . . . . . . . . . . . . . . 848
Small Cell and Neuroendocrine Tumors ofLee M. Krug, M. Catherine Pietanza, Mark G. Kris,
Kenneth Rosenzweig, and William D. Travis
Small Cell Lung Cancer 848
Typical Carcinoid and Atypical Carcinoid Tumors 863
Large Cell Neuroendocrine Carcinoma 867
77.
Neoplasms of the Mediastinum . . . . . . . . . 871Robert B. Cameron, Patrick J. Loehrer, and
Charles R. Thomas, Jr.
Thymic Neoplasms 871
Thymoma 871
Thymic Carcinoma 872
Thymic Carcinoid 878
Thymolipoma 878
Germ Cell Tumors 878
Section 3: Cancers of the Gastrointestinal Tract
78.
Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . 882
Molecular Biology of the Esophagus andAnil K. Rustgi
Molecular Biology of Esophageal Cancer 882
Molecular Biology of Gastric Cancer 884
79.
Cancer of the Esophagus . . . . . . . . . . . . . . 887Mitchell C. Posner, Bruce D. Minsky, and David H. Ilson
Epidemiology 887
Etiologic Factors and Predisposing Conditions 887
Applied Anatomy and Histology 891
Natural History and Patterns of Failure 892
Clinical Presentation 892
Diagnostic Studies and Pretreatment Staging 893
Pathologic Staging 894
Treatment 895
Stage-Directed Treatment Recommendations 921
80.
Cancer of the Stomach . . . . . . . . . . . . . . . . 924Itzhak Avital, Peter W.T. Pisters, David P. Kelsen, and
Christopher G. Willett
Epidemiology and Etiology 924
Anatomic Considerations 926
Pathology and Tumor Biology 927
Histopathology 927
Patterns of Spread 927
Clinical Presentation and Pretreatment Evaluation 928
Pretreatment Staging 929
Staging, Classification, and Prognosis 930
Gastric Cancer Nomograms: Predicting Individual Patient Prognosis
After Potentially Curative Resection 933
Treatment of Localized Disease 934
Technical Treatment-Related Issues 944
Treatment of Advanced Disease (Stage IV) 945
Surgery in Treatment of Metastatic Gastric Cancer 952
Radiation for Palliation 952
81.
Molecular Biology of Pancreas Cancer . . . . 955Scott E. Kern and Ralph H. Hruban
Common Molecular Changes 955
Low-Frequency Genetic Changes 958
82.
Cancer of the Pancreas . . . . . . . . . . . . . . . . 961Richard E. Royal, Robert A. Wolff, and Christopher H. Crane
Incidence and Etiology 961
Anatomy and Pathology 964
Screening 964
Diagnosis and Staging 965
Staging 967
Treatment of Potentially Resectable Disease: American Joint
Committee on Cancer Stage I and II 967
Treatment of Locally Advanced Disease: American Joint Committee on
Cancer Stage III 975
Treatment of Metastatic Disease: American Joint Committee on Cancer
Stage IV 980
Other Exocrine Neoplasms 986
83.
Molecular Biology of Liver Cancer . . . . . . 990Snorri S. Thorgeirsson and Joe W. Grisham
Allelic Imbalance in Liver Cancer 990
Classification and Prognostic Prediction of Hepatocellular
Carcinoma 991
Comparative Functional Genomics 995
Conclusion and Perspective 995
Contents
xxxvii84.
Cancer of the Liver . . . . . . . . . . . . . . . . . . 997David L. Bartlett, Adrian M. Di Bisceglie, and
Laura A. Dawson
Epidemiology 997
Etiologic Factors 997
Pathology 1001
Staging 1002
Clinical Features 1002
Clinical Evaluation 1004
Clinical Management 1008
Adjuvant Therapy 1012
Treatment of Other Primary Liver Tumors 1016
85.
Cancer of the Biliary Tree . . . . . . . . . . . . 1019David L. Bartlett, Ramesh K. Ramanathan, and
Edgar Ben-Josef
Cholangiocarcinomas 1019
Tumors of the Gallbladder 1035
86.
Cancer of the Small Intestine . . . . . . . . . . 1048Amer H. Zureikat, Matthew T. Heller, and Herbert J Zeh, III
Small Bowel Cancer 1048
Adenocarcinoma 1052
Carcinoid Tumors 1053
Intestinal Lymphoma 1055
Gastrointestinal Stromal Tumors 1056
Other Mesenchymal Tumors 1057
87.
Gastrointestinal Stromal Tumor . . . . . . . . 1060George D. Demetri
GIST as a Unique Clinicopathologic Subset of Sarcoma 1060
GIST Cells are Related to the Mesenchymal Precursor Cells
that Give Rise to Normal Interstitial Cells of Cajal:
Aberrant Developmental Biology 1061
The Development of a Molecular Understanding of GIST 1061
Clinical Considerations 1062
Prognostic Features of Gastrointestinal Stromal Tumor 1064
Diagnostic Imaging of Patients with Gastrointestinal
Stromal Tumors 1064
Treatment Options and Management Decisions in the Era of
Molecularly Targeted Therapies for GIST 1065
Extrapolation of Emerging Management Paradigms to
Early-Stage GIST 1070
Adjuvant Therapy to Improve Outcomes for Patients with
Resected Early-Stage GIST 1070
Special Considerations in GIST 1071
New Challenges and Alternative Approaches 1071
88.
Molecular Biology of Colorectal Cancer . 1074Ramesh A. Shivdasani
The Adenoma–Carcinoma Sequence and Multistep Models of
Colorectal Tumorigenesis 1074
Early Events and Critical Pathways in Colorectal Tumorigenesis
Highlighted by Inherited Syndromes of Increased Cancer
Risk 1075
Oncogene and Tumor Suppressor Gene Mutations in Colorectal Cancer
Progression 1079
Infrequent Changes and Current Views of the Mutational
Landscape of Colorectal Cancer 1082
89.
Cancer of the Colon . . . . . . . . . . . . . . . . . 1084Steven K. Libutti, Leonard B. Saltz, and Christopher G. Willett
Epidemiology 1084
Etiology: Genetic and Environmental Risk Factors 1085
Familial Colorectal Cancer 1086
Anatomy of the Colon 1088
Diagnosis of Colorectal Cancer 1089
Screening for Colorectal Cancer 1089
Staging and Prognosis of Colorectal Cancer 1090
Approaches to Surgical Resection of Colon Cancer 1096
Surgical Management of Complications from Primary
Colon Cancer 1098
Polyps and Stage I Colon Cancer 1099
Stage II and Stage III Colon Cancer 1099
Treatment of Stage II Patients 1102
Treatment Options for Stage III Patients 1104
Radiation Therapy of Colon Cancer 1104
Follow-Up After Management of Colon Cancer with
Curative Intent 1106
Surgical Management of Stage IV Disease 1108
Management of Unresectable Metastatic Disease 1108
Gene Therapy 1123
Molecular Predictive Markers 1123
Management of Synchronous Primary and
Metastatic Disease 1123
Unusual Colorectal Tumors 1124
90.
Cancer of the Rectum . . . . . . . . . . . . . . . 1127Steven K. Libutti, Christopher G. Willett, and Leonard B. Saltz
Anatomy 1127
Staging 1128
Surgery 1130
Does Adjuvant Radiation Therapy Impact
Survival? 1134
Preoperative Radiation Therapy 1135
Which Patients Should Receive Adjuvant Therapy? 1136
Concurrent Chemotherapy 1137
Synchronous Rectal Primary and Metastases 1138
Management of Unresectable Primary and Locally
Advanced Disease (T4) 1138
Radiation Therapy Technique 1139
91.
Cancer of the Anal Region . . . . . . . . . . . . 1142Yixing Jiang, David J. Beddy, Heidi Nelson, Lisa A. Kachnic,
and Jaffer A. Ajani
Epidemiology and Etiology 1142
Pathology 1143
Clinical Presentation and Staging 1144
Prognostic Factors 1144
Treatment of Localized Squamous Cell Carcinoma of the
Anal Canal 1145
Treatment of Other Sites and Pathologies 1151
Section 4: Cancers of the Genitourinary System
92.
Molecular Biology of Kidney Cancer . . . . 1154W. Marston Linehan and Laura S. Schmidt
Von Hippel-Lindau 1154
Hereditary Papillary Renal Carcinoma Type 1 1155
XP11.2 Translocation Renal Cell Cancer 1156
Birt-Hogg-Dubé Syndrome 1156
Hereditary Leiomyomatosis and Renal Cell Carcinoma 1157
Familial Renal Cancer: Succinate Dehydrogenase Gene 1158
Tuberous Sclerosis Complex 1159
Conclusion 1159
93.
Cancer of the Kidney . . . . . . . . . . . . . . . . 1161W. Marston Linehan, Brian I. Rini, and James C. Yang
Histologic Types of Renal Carcinoma 1161
Hereditary Forms of Kidney Cancer 1161
Transcription Factors and Kidney Cancer 1164
Localized Renal Carcinoma 1169
Metastatic Renal Carcinoma 1170
94.
Molecular Biology of Bladder Cancer . . . 1183Margaret A. Knowles
Molecular Alterations in Superficial Urothelial Carcinoma 1183
Carcinoma in Situ 1186
Molecular Alterations in Invasive Urothelial Carcinoma 1186
xxxviii
ContentsInformation from Expression and Genomic Microarray
Profiling 1188
Signaling Pathways in Urothelial Carcinoma 1189
Urothelial Tumor-Initiating Cells 1189
Molecular Pathogenesis and Tumor Clonality 1189
95.
Renal Pelvis . . . . . . . . . . . . . . . . . . . . . . . 1192
Cancer of the Bladder, Ureter, andW. Scott McDougal, William U. Shipley, Donald S. Kaufman,
Douglas M. Dahl, M. Dror Michaelson, and
Anthony L. Zietman
Urothelial Cancers 1192
Cancer of the Bladder 1194
Cancers of the Renal Pelvis and Ureter 1205
96.
Molecular Biology of Prostate Cancer . . . 1212Yu Chen, Vivek K. Arora, and Charles L. Sawyers
Genetic Predisposition 1212
Genetic Landscape of Prostate Cancer 1212
ETS Transcription Factors 1216
97.
Cancer of the Prostate . . . . . . . . . . . . . . . 1220Michael J. Zelefsky, James A. Eastham, and A. Oliver Sartor
Anatomy of the Prostate 1220
Prostate Zonal Anatomy 1220
Histopathology 1220
Gleason Score 1222
Incidence, Epidemiology, and Risk Factors 1222
Incidence and Mortality of Prostate Cancer 1223
Clinical Risk Factors for Prostate Cancer 1223
Genetic Alterations and Risk 1224
Prostate Cancer Prevention 1224
Disease Presentation and Diagnosis 1227
Staging Workup 1228
Prognostic Factors and the Assessment of Risk 1230
Treating Clinically Localized Prostate Cancer 1231
External-Beam Radiotherapy 1238
Androgen Deprivation and Radiation Therapy 1249
Adjuvant Radiation Therapy for High-Risk Patients After Radical
Prostatectomy 1252
Management of the Rising PSA After Definitive Local Therapy 1253
Management of Metastatic Prostate Cancer 1258
Castration-Resistant Prostate Cancer 1262
98.
Cancer of the Urethra and Penis . . . . . . . . 1272Edouard J. Trabulsi and Leonard G. Gomella
Cancer of the Male Urethra 1272
Carcinoma of the Female Urethra 1273
Cancer of the Penis 1274
99.
Cancer of the Testis . . . . . . . . . . . . . . . . . 1280George J. Bosl, Darren R. Feldman, Dean F. Bajorin,
Joel Sheinfeld, Robert J. Motzer, Victor E. Reuter,
Marisa A. Kollmeier, and Raju S. K. Chaganti
Background: Incidence 1280
Epidemiology 1280
Risk Factors 1280
Initial Presentation and Management 1280
Histology 1281
Biology 1282
Immunohistochemical Markers 1284
Staging 1284
Management of Clinical Stage I Disease 1286
Management of Clinical Stage II (Low Tumor Burden) 1290
Management of Stage II and Stage III Disease
(High Tumor Burden) 1291
Management of Relapse and Refractory Disease 1296
Treatment Sequelae 1298
Long-Term Follow-Up 1299
Midline Tumors of Uncertain Histogenesis 1299
Other Testicular Tumors 1299
Section 5: Gynecologic Cancers
100.
Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . 1302
Molecular Biology of GynecologicKunle Odunsi, Tanja Pejovic, and Matthew L. Anderson
Ovarian Cancer 1302
Endometrial Cancer 1306
Cervix, Vaginal, and Vulvar Cancers 1307
Gestational Trophoblastic Disease 1309
101.
Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311
Cancer of the Cervix, Vagina, andPatricia J. Eifel, Jonathan S. Berek, and Maurie A. Markman
Carcinoma of the Cervix 1311
Carcinoma of the Vagina 1330
Carcinoma of the Vulva 1335
102.
Cancers of the Uterine Body . . . . . . . . . . 1345Pedro T. Ramirez, Arno J. Mundt, and Franco M. Muggia
Endometrial Carcinoma 1345
Uterine Sarcomas 1356
103.
Gestational Trophoblastic Neoplasms . . . 1363Donald P. Goldstein and Ross S. Berkowitz
Epidemiology 1363
Pathology and Natural History 1363
Indications for Treatment 1363
Measurement of hCG 1364
Phantom hCG 1364
Pretreatment Evaluation 1364
Staging and Prognostic Score 1364
Treatment 1364
Placental Site Trophoblastic Tumors 1366
Subsequent Pregnancy 1366
Psychosocial Issues 1366
104.
Peritoneal Carcinoma . . . . . . . . . . . . . . . . . . .1368
Ovarian Cancer, Fallopian Tube Carcinoma, andStephen A. Cannistra, David M. Gershenson, and Abram Recht
Epithelial Ovarian Cancer 1368
Borderline Tumors 1385
Germ Cell Tumors of the Ovary 1386
Sex Cord–Stromal Tumors 1387
Primary Peritoneal Serous Carcinoma 1389
Fallopian Tube Cancer 1389
Section 6: Cancer of the Breast
105.
Molecular Biology of Breast Cancer . . . . 1392Erin Wysong Hofstatter, Gina G. Chung, and Lyndsay N. Harris
Genetics of Breast Cancer 1392
Hereditary Breast Cancer 1392
Somatic Changes in Breast Cancer 1393
Gene Expression Patterns in Breast Cancer 1395
Epigenetics of Breast Cancer 1396
Protein/Pathway Alterations 1397
106.
Malignant Tumors of the Breast . . . . . . . 1401Harold J. Burstein, Jay R. Harris, and Monica Morrow
Anatomy of the Breast 1401
Risk Factors for Breast Cancer 1401
Benign Breast Disease 1404
Breast Density 1404
Environmental Factors 1404
Management of the High-Risk Patient 1404
Contents
xxxixDiagnosis and Biopsy 1407
Lobular Carcinoma
Ductal Carcinoma
Treatment of the Breast 1409
Treatment of the Axilla 1411
Endocrine Therapy 1411
Staging 1411
Pathology of Breast Cancer 1413
Local Management of Invasive Cancer 1414
Breast-Conserving Therapy 1414
Mastectomy 1422
Management of the Axilla 1423
Local-Regional Therapy and Survival 1425
Prognostic and Predictive Factors 1426
Other Factors 1427
Molecular and Genomic Factors 1427
Adjuvant Systemic Therapy 1428
Integration of Multimodality Primary Therapy 1434
Follow-Up for Breast Cancer Survivors 1435
Special Therapeutic Problems 1436
Metastatic Disease 1439
In Situ 1408In Situ 1409Section 7: Cancer of the Endocrine System
107.
Molecular Biology of Endocrine Tumors . 1447Samuel A. Wells, Jr.
The Multiple Endocrine Neoplasia Syndromes 1447
Application of Molecular Genetics to Clinical Medicine 1452
Sporadic Thyroid Cancers 1453
Future Directions 1455
108.
Thyroid Tumors . . . . . . . . . . . . . . . . . . . . . . .1457Tobias Carling and Robert Udelsman
Thyroid Tumor Classification and Staging Systems 1457
Epidemiology and Demographics 1458
Etiology and Risk Factors 1458
Evaluation of the Thyroid Nodule 1460
Well-Differentiated Thyroid Carcinoma 1462
Treatment of Well and Intermediately Differentiated Thyroid
Carcinoma 1464
Poorly Differentiated Thyroid Carcinoma 1468
Medullary Thyroid Carcinoma 1469
Treatment of Familial Medullary Thyroid Carcinoma 1470
Thyroid Lymphoma 1470
Metastatic Disease of the Thyroid 1471
Children with Thyroid Carcinoma 1471
109.
Parathyroid Tumors . . . . . . . . . . . . . . . . . 1473Reza Rahbari and Electron Kebebew
Epidemiology 1473
Pathology 1474
Molecular Genetics 1475
Clinical Manifestations 1475
Diagnosis 1475
Management of Parathyroid Cancer 1476
Follow-Up and Natural History 1477
Prognosis 1478
110.
Adrenal Tumors . . . . . . . . . . . . . . . . . . . . 1480Mio Kitano, Erin Patterson, and Electron Kebebew
Adrenocortical Cancer 1480
Pediatric Adrenocortical Carcinoma 1484
Pheochromocytoma 1484
Adrenal Incidentaloma 1487
111.
Pancreatic Neuroendocrine Tumors . . . . . 1489James C. Yao, Guido Rindi, and Douglas B. Evans
Epidemiology 1489
Classification, Histopathology, and Molecular Genetics 1489
Diagnosis and Management of Pancreatic Endocrine Tumors 1492
Additional Clinical Considerations 1499
Surgery Pitfalls 1500
Emerging Therapeutic Options 1501
112.
Carcinoid Syndrome . . . . . . . . . . . . . . . . 1503
Neuroendocrine (Carcinoid) Tumors and theGerard M. Doherty
Pathology and Tumor Histology 1503
Molecular Pathogenesis 1506
Clinical Features of Carcinoid Tumors 1506
Carcinoid Syndrome 1506
Treatment of the Carcinoid Tumor 1512
113.
Multiple Endocrine Neoplasias . . . . . . . . 1516Gerard M. Doherty
Multiple Endocrine Neoplasia Type 1 1516
Familial Medullary Thyroid Carcinoma and Multiple Endocrine
Neoplasia Types 2A and 2B 1519
Section 8: Sarcomas of Soft Tissue and Bone
114.
Molecular Biology of Soft Tissue Sarcoma 1522Samuel Singer, Torsten Nielsen, and Cristina R. Antonescu
Translocation-Associated Sarcomas 1522
Simple Karyotype Tumors Associated with Mutations 1528
Complex Sarcoma Types 1528
Future Directions: Functional Screens and Next-Generation
Sequencing 1531
115.
Soft Tissue Sarcoma . . . . . . . . . . . . . . . . . 1533Samuel Singer, Robert G. Maki, and Brian O’Sullivan
Incidence and Etiology 1533
Anatomic and Age Distribution and Pathology 1535
Diagnosis and Staging 1547
Management by Presentation Status, Extent of Disease, and Anatomic
Location 1552
Palliative Care 1574
Future Directions 1576
116.
Sarcomas of Bone . . . . . . . . . . . . . . . . . . 1578Martin M. Malawer, Lee J. Helman, and Brian O’Sullivan
Classification and Types of Bone Tumor 1578
Radiographic Evaluation and Diagnosis 1578
Natural History 1579
Staging Bone Tumors 1581
Preoperative Radiographic Evaluation 1581
Biopsy Technique and Timing 1585
Restaging After Induction (Preoperative) Chemotherapy 1585
Guidelines for Limb-Sparing Resection 1586
Types of Skeletal Reconstruction 1586
Limb-Sparing Surgery and Perioperative Pain Management 1587
Amputations 1588
Chemotherapy for Bone Sarcomas 1589
Radiotherapy for Osteosarcoma 1594
Malignant Bone Tumors 1595
Section 9: Cancers of the Skin
117.
Cancer of the Skin . . . . . . . . . . . . . . . . . . 1610Anetta Reszko, Sumaira Z. Aasi, Lynn D. Wilson, and
David J. Leffell
NONMELANOMA SKIN CANCER 1610
Diagnosis 1610
General Approach to Management of Skin Cancer 1610
Topical Therapy for Skin Cancer 1613
Radiation Therapy for Skin Cancer 1614
ACTINIC KERATOSES 1614
xl
ContentsPathogenesis of AK 1615
Clinical Features of AK 1615
Treatment of AK 1615
BASAL CELL CARCINOMA 1616
Clinical Behavior of BCC 1617
BCC Subtypes 1617
Histology 1618
Treatment 1619
SQUAMOUS CELL CARCINOMA 1620
Pathogenesis of SCC 1620
Biologic Behavior of SCC 1620
Clinical Features of SCC 1621
Histology 1621
Recurrence and Metastatic Risk 1621
Treatment 1622
Follow Up 1623
Immunosuppression and Nonmelanoma Skin Cancer 1623
ANGIOSARCOMA 1624
Pathogenesis 1624
Clinical Presentation and Prognosis 1624
Histology 1625
Treatment 1625
DERMATOFIBROSARCOMA PROTUBERANS 1625
Pathogenesis 1625
Histology 1625
Treatment 1625
Recurrence and Metastatic Potential 1626
MERKEL CELL CARCINOMA 1626
Pathogenesis 1626
Clinical Presentation 1626
Histology 1626
Treatment 1627
Staging 1627
Recurrence and Metastatic Risk 1627
Prognosis 1628
MICROCYSTIC ADNEXAL CARCINOMA 1628
Pathogenesis 1629
Clinical Presentation 1629
Histology 1629
Treatment 1629
SEBACEOUS CARCINOMA 1629
Histology 1630
Treatment 1630
ATYPICAL FIBROXANTHOMA AND MALIGNANT
FIBROUS HISTIOCYTOMA 1630
ATYPICAL FIBROXANTHOMA 1630
Pathogenesis 1630
Clinical Presentation 1630
Histology 1631
Treatment 1631
MALIGNANT FIBROUS HISTIOCYTOMA 1631
Clinical Presentation 1631
Histology 1631
Treatment and Prognosis 1631
CARCINOMA METASTATIC TO SKIN 1631
118.
Melanoma . . . . . . . . . . . . . . . . . . . . . . . . 1634
Molecular Biology of CutaneousLevi A. Garraway and Lynda Chin
The
The Retinoblastoma Pathway 1634
The p53 Pathway 1635
The MAP Kinase Pathway 1636
The RAS Family: H-, N-, and K-RAS 1636
The Phosphatidylinositol 3-Kinase Pathway 1638
Receptor Tyrosine Kinases 1638
Epidermal Growth Factor Receptor Family 1639
The MITF Pathway 1639
The WNT Pathway 1639
The MC1R Pathway 1640
The FAK Pathway 1640
Cancer Stem Cells and Melanoma 1640
Cancer Genomics and Translation 1640
Looking Ahead 1641
CDKN2A Locus 1634119.
Cutaneous Melanoma . . . . . . . . . . . . . . . 1643Craig L. Slingluff Jr., Keith Flaherty, Steven A. Rosenberg, and
Paul W. Read
Cutaneous Melanoma Biology 1643
Epidemiology 1644
Changes in Incidence 1645
Gender and Age Distribution 1645
Melanoma in Children, Infants, and Neonates 1645
Anatomic Distribution 1646
Etiology and Risk Factors 1646
Pregnancy and Estrogen Use 1646
Prevention and Screening 1647
Diagnosis of Primary Melanoma 1648
General Considerations in Clinical Management of a Newly Diagnosed
Cutaneous Melanoma (Stage I–II) 1652
Wide Local Excision for Clinical Stage I–II Melanoma: General
Considerations 1653
Clinical Trials to Define Margins of Excision for Primary
Cutaneous Melanomas 1653
Surgical Staging of Regional Nodes 1655
Management of Clinically Localized Melanoma 1658
Management of Thin Primary Melanoma (Clinical T1a) 1658
Management of Clinical T2a, T2b Melanomas 1660
Management of Clinical T3a Melanomas (Clinical Stage IIA) 1660
Management of Clinical T3b Melanomas (Clinical Stage IIB) 1660
Management of Thick Melanomas (T4a, T4b, Greater than
4 mm Thick) 1660
Special Considerations in Management of Primary Melanomas 1661
The Role of Radiation Therapy in the Management of Primary
Melanoma Lesions 1662
Clinical Follow-Up for Intermediate-Thickness and Thick Melanomas
(Stage IB–IIC) 1662
Regionally Metastatic Melanoma (Stage III): Lymph Node Metastasis,
Satellite Lesions, and In-Transit Metastases 1662
Management of Regional Metastases in Patients with
Visceral or Other Distant Disease 1666
Adjuvant Systemic Therapy (Stages IIB, IIC, and III) 1667
Management of Distant Metastases of Melanoma (Stage IV) 1672
Combination Chemotherapy 1678
Experimental and Developing Immunologic Therapies for
Stage IV Melanoma 1682
Rationale for Targeted Therapy in Melanoma 1684
Radiation Therapy for Metastatic Melanoma (Stage IV) 1687
Section 10: Neoplasms of the
Central Nervous System
120.
System Tumors . . . . . . . . . . . . . . . . . . . . . 1692
Molecular Biology of Central NervousC. David James, David N. Louis, and Webster K. Cavenee
Neurologic Tumor Syndromes 1692
CNS Tumor Histopathology and Molecular Correlates 1692
Current Basis of CNS Tumor Treatment and
Response to Therapy 1698
121.
Neoplasms of the Central Nervous System 1700Minesh Mehta, Michael A. Vogelbaum, Susan Chang, and
Neha Patel
Epidemiology of Brain Tumors 1700
Anatomic Location and Clinical Considerations 1702
Neurodiagnostic Tests 1705
Surgery 1706
Radiation Therapy 1708
Chemotherapy and Targeted Agents 1710
Specific Central Nervous System Neoplasms 1712
Gliomatosis Cerebri 1720
Optic, Chiasmal, and Hypothalamic Gliomas 1720
Brainstem Gliomas 1722
Cerebellar Astrocytomas 1723
Gangliogliomas 1723
Ependymoma 1724
Contents
xlixlii
ContentsMeningiomas 1727
Primitive Neuroectodermal or Embryonal Central Nervous
System Neoplasms 1730
Pineal Region Tumors and Germ Cell Tumors 1733
Pituitary Adenomas 1735
Craniopharyngiomas 1737
Vestibular Schwannomas 1738
Glomus Jugulare Tumors 1740
Hemangioblastomas 1741
Chordomas and Chondrosarcomas 1742
Choroid Plexus Tumors 1744
Spinal Axis Tumors 1745
Section 11: Cancers of Childhood
122.
Molecular Biology of Childhood Cancers . . .1750Lee J. Helman and David Malkin
Tumor Suppressor Genes 1750
Retinoblastoma: The Paradigm 1752
Wilms Tumor: Three Distinct Loci 1753
Neurofibromatoses 1753
Neuroblastoma 1754
Ewing Sarcoma Family of Tumors 1755
Rhabdomyosarcoma 1755
Hereditary Syndromes Associated with Tumors of Childhood 1756
Malignant Rhabdoid Tumors 1757
Predictive Testing for Germ Line Mutations and Childhood
Cancers 1757
Molecular Therapeutics 1758
123.
Solid Tumors of Childhood . . . . . . . . . . . 1760Lisa L. Wang, Jason Yustein, Chrystal Louis, Heidi V. Russell,
Alberto S. Pappo, Arnold Paulino, Jed G. Nuchtern, and
Murali Chintagumpala
The Importance of Multidisciplinary Management Teams in Pediatric
Solid Tumors 1760
Neuroblastoma 1760
Wilms’ Tumor 1766
Retinoblastoma 1769
Pediatric Bone Sarcomas: Osteosarcoma and Ewing’s Sarcoma 1771
Rhabdomyosarcoma 1780
Liver Tumors 1784
Germ Cell Tumors 1786
124.
Childhood . . . . . . . . . . . . . . . . . . . . . . . . 1793
Leukemias and Lymphomas ofJudith F. Margolin, Karen R. Rabin, and David G. Poplack
Leukemias 1793
Lymphomas 1801
Supportive Care 1804
Long-Term, Palliative, and Hospice Care in Pediatric Oncology 1804
Section 12: Lymphomas in Adults
125.
Molecular Biology of Lymphomas . . . . . . 1806Urban Novak, Laura Pasqualucci, and Riccardo Dalla-Favera
The Cell of Origin of Lymphoma 1806
General Mechanisms of Genetic Lesion in Lymphoma 1807
Molecular Pathogenesis of B-Cell Non-Hodgkin’s Lymphoma 1810
Molecular Pathogenesis of T-Cell NHL 1816
Molecular Pathogenesis of HL 1817
126.
Hodgkin Lymphoma . . . . . . . . . . . . . . . . 1819Andreas Engert, Dennis A. Eichenauer, Nancy Lee Harris,
Peter M. Mauch, and Volker Diehl
History of Hodgkin Lymphoma 1819
Etiology and Epidemiology 1819
Biology and Cell of Origin 1820
Immunology of Hodgkin Lymphoma 1820
Diagnosis and Staging of Hodgkin Lymphomas 1825
Clinical Presentation of Hodgkin Lymphomas 1827
Treatment Methods for Hodgkin Lymphoma 1827
Choice of Treatment 1829
Treatment for Early Favorable Hodgkin Lymphoma 1832
Early Unfavorable Hodgkin Lymphoma 1834
Advanced Stages of Hodgkin Lymphoma 1836
Progressive and Relapsed Disease 1840
Lymphocyte-Predominant Hodgkin Lymphoma 1844
Special Populations 1846
Treatment-Related Late Side Effects 1848
Quality of Life 1850
New Drugs in Hodgkin Lymphoma 1851
127.
Non-Hodgkin Lymphomas . . . . . . . . . . . 1855Jonathan W. Friedberg, Peter M. Mauch, Lisa Rimsza, and
Richard I. Fisher
Epidemiology 1855
Etiology 1855
Biologic Background for Classification of Lymphoid Neoplasms 1857
B- and T-Cell Differentiation 1857
Immunophenotyping of Lymphoid Cells 1862
Chromosomal Translocations and Oncogene
Rearrangements 1863
Use of Immunophenotyping and Genetic Studies in the
Diagnosis of Lymphoid Neoplasms 1864
Principles of the World Health Organization Classification of
Lymphoid Neoplasms 1864
Principles of Management of Non-Hodgkin Lymphoma 1867
Specific Disease Entities 1869
Mature T-Cell and NK Cell Neoplasms 1884
Special Clinical Situations 1889
128.
Cutaneous Lymphomas . . . . . . . . . . . . . . 1894Francine M. Foss, Richard L. Edelson, and Lynn D. Wilson
Mycosis Fungoides and the Sézary Syndrome 1894
Diagnosis and Staging 1896
Clinical Evaluation of Patients with Cutaneous
Lymphoma 1898
Principles of Therapy of Mycosis Fungoides and the
Sézary Syndrome 1899
Systemic Therapy for Mycosis Fungoides and the
Sézary Syndrome 1902
Other Cutaneous Lymphomas 1905
129.
Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . 1908
Primary Central Nervous SystemLisa M. DeAngelis and Joachim Yahalom
Clinical Features 1908
Diagnostic Tests 1909
Pathology 1909
Management and Therapy 1910
Section 13: Leukemias and Plasma Cell Tumors
130.
Leukemias . . . . . . . . . . . . . . . . . . . . . . . . 1916
Molecular Biology of AcuteGlen D. Raffel and Jan Cerny
Leukemic Stem Cell 1916
Elucidation of Genetic Events in Acute Leukemia 1916
Recurring Chromosomal Abnormalities in Acute Leukemia 1917
Chromosomal Translocations that Target Core-
Binding Factor 1917
Chromosomal Translocations that Target the Retinoic
Acid Receptor Alpha Gene 1919
Chromosomal Translocations that Target HOX Family
Members 1920
Chromosomal Translocations that Target the
Chromosomal Translocations that Involve Transcriptional Coactivators
and Chromatin Remodeling Proteins 1921
MLL Gene 1920Contents
xliiit(1;22) Translocation Associated with Infant Acute
Megakaryoblastic Leukemia 1921
Deletions and Numeric Abnormalities in Acute Leukemias 1921
Chromosomal Translocations that Result in Overexpression of
Otherwise Normal Genes 1922
Chromosomal Translocations Involving the T-Cell Receptor 1922
Point Mutations in Acute Leukemia 1922
Mutation in Tumor Suppressor Genes 1924
Activating Mutations of NOTCH 1924
Mutations Altering Localization of NPM1 1925
Loss-of-Function Point Mutations in
Mutation of Lymphoid Development Genes in ALL 1925
Mutational Complementation Groups in Acute Leukemias 1925
Conclusion 1926
AML1,C/EBP, and GATA-1 1925131.
Management of Acute Leukemias . . . . . . 1928Partow Kebriaei, Richard Champlin, Marcos de Lima, and
Elihu Estey
Acute Myelogenous Leukemia 1929
Acute Lymphoblastic Leukemia 1946
132.
Leukemias . . . . . . . . . . . . . . . . . . . . . . . . 1955
Molecular Biology of ChronicAnupriya Agarwal, John C. Byrd, and Michael W. Deininger
Chronic Myeloid Leukemia 1955
Chronic Lymphocytic Leukemia 1958
133.
Chronic Myelogenous Leukemia . . . . . . . 1962Brian J. Druker and Stephanie J. Lee
Epidemiology 1962
Pathogenesis 1962
Diagnosis 1963
Clinical Course and Prognosis 1964
Treatment of Chronic Phase Disease 1965
Tyrosine Kinase Inhibitors 1965
Hematopoietic Cell Transplantation 1968
Advanced Phase Disease 1970
Future Directions 1971
134.
Chronic Lymphocytic Leukemias . . . . . . . 1973William G. Wierda and Susan O’Brien
Molecular Biology 1973
Immune Abnormalities 1975
Diagnosis 1975
Clinical Manifestations 1975
Treatment and Response Criteria 1977
New and Novel Agents for Treatment of Chronic Lymphocytic
Leukemia 1984
Second Malignancies and Transformation 1985
Prolymphocytic Leukemia 1985
Large Granular Lymphocyte Leukemia 1985
Hairy Cell Leukemia 1986
135.
Myelodysplastic Syndromes . . . . . . . . . . . 1988Stefan Faderl and Hagop M. Kantarjian
Epidemiology and Etiology 1988
Presentation and Diagnosis 1988
Cytogenetic-Molecular Abnormalities and MDS Pathogenesis 1990
Classification 1991
Therapy 1992
Outlook 1995
136.
Plasma Cell Neoplasms . . . . . . . . . . . . . . 1997Nikhil C. Munshi and Kenneth C. Anderson
History 1997
Epidemiology 1998
Etiology 1998
Pathogenesis 1999
Drug Resistance 2004
Clinical Manifestations 2005
Treatment 2015
Section 14: Other Cancers
137.
Cancer of Unknown Primary Site . . . . . . . 2033F. Anthony Greco and John D. Hainsworth
Pathologic Evaluation 2033
Clinical Features and Evaluation 2038
Treatment 2040
Special Issues in Carcinoma of Unknown Primary Site 2048
Unknown Primary Cancer in Children 2049
Future Directions and Changing Treatment Paradigm 2050
138.
Benign and Malignant Mesothelioma . . . 2052Harvey I. Pass, Nicholas J. Vogelzang, Steven M. Hahn, and
Michele Carbone
Mechanism of Asbestos-Carcinogenesis 2052
Overview of Molecular Mechanisms in Mesothelioma 2054
Alterations of Oncogenesin Mesothelioma 2054
Pathology of Mesothelioma 2056
Epidemiology and Clinical Presentation 2058
Diagnostic Approach for Presumed Mesothelioma 2062
Natural History 2064
Treatment 2066
Pleurectomy 2068
Radiotherapy for Mesothelioma 2069
Multimodality Treatment 2071
Novel Intrapleural Approaches: New Techniques with
New/Old Agents 2072
Chemotherapy and Newer Agents 2074
Novel Treatment Approaches 2076
Other Agents 2077
139.
Peritoneal Surface Malignancy . . . . . . . . . 2081Marcello Deraco, Dominique Elias, Olivier Glehen,
Cyril W. Helm, Paul H. Sugarbaker, and Vic J. Verwaal
Rationale for a Combined Treatment for Peritoneal Surface
Malignancy 2081
Validated Quantitative Prognostic Indicators 2081
Appendiceal Malignancy 2083
Colorectal Carcinomatosis: Curative Treatment and Prevention 2084
Diffuse Malignant Peritoneal Mesothelioma 2085
Gastric Cancer 2086
Peritoneal Carcinomatosis in Ovarian Cancer 2087
Sarcomatosis 2087
140.
Intraocular Melanoma . . . . . . . . . . . . . . . 2090Daniel M. Albert and Amol D. Kulkarni
Incidence and Etiology 2090
Anatomy and Pathology 2090
Diagnosis 2091
Metastatic Workup 2093
Staging 2093
Management 2093
Prognostic and Predictive Factors 2096
Posttreatment Quality of Life 2097
Section 15: Immunosuppression-Related
Malignancies
141.
AIDS-Related Malignancies . . . . . . . . . . . 2099Robert Yarchoan, Thomas S. Uldrick, and Richard F. Little
Cancer and HIV: Incidence and Etiology 2099
Kaposi Sarcoma 2101
KSHV-Associated Multicentric Castleman Disease 2104
AIDS-Associated Lymphomas 2104
Hodgkin’s Lymphoma 2110
HPV-Associated Cancer in HIV Infection 2110
Cervical Cancer 2110
Anal Cancer 2110
Future Directions 2111
xliv
Contents142.
Transplantation-Related Malignancies . . . 2113Smita Bhatia and Ravi Bhatia
Myelodysplasia and Acute Myeloid Leukemia 2113
Lymphomas 2119
Solid Tumors 2120
Section 16: Oncologic Emergencies
143.
Superior Vena Cava Syndrome . . . . . . . . . 2123Joachim Yahalom
Anatomy and Pathophysiology 2123
Etiology and Natural History 2123
Diagnostic Procedures 2124
Management 2125
Small Cell Lung Cancer 2125
Non–Small Cell Lung Cancer 2125
Non−Hodgkin’s Lymphoma 2125
Nonmalignant Causes 2126
Catheter-Induced Obstruction 2126
Treatment 2126
Areas of Uncertainty 2127
Recommendations 2128
144.
Increased Intracranial Pressure . . . . . . . . . 2130Kevin P. Becker and Joachim M. Baehring
Pathophysiological Considerations 2130
Epidemiology and Pathogenesis 2131
Clinical Presentation 2131
Diagnosis 2133
Treatment 2134
145.
Spinal Cord Compression . . . . . . . . . . . . 2136Kevin P. Becker and Joachim M. Baehring
Epidemiology 2136
Pathophysiology 2136
Clinical Presentation 2138
Differential Diagnosis 2138
Diagnosis 2139
Treatment 2139
Prognosis 2140
146.
Metabolic Emergencies . . . . . . . . . . . . . . 2142Antonio Tito Fojo
Tumor Lysis Syndrome 2142
Hyperuricemia 2144
Cancer and Hyponatremia 2147
Lactic Acidosis and Cancer 2148
Hypercalcemia and Cancer 2148
Cancer-Related Hemolytic Uremic Syndrome 2150
Section 17: Treatment of Metastatic Cancer
147.
Metastatic Cancer to the Brain . . . . . . . . 2153David A. Larson, James L. Rubenstein, Michael W. McDermott,
and Igor Barani
Brain Metastasis 2153
Carcinomatous Meningitis 2162
148.
Metastatic Cancer to the Lung . . . . . . . . . . . .2165King F. Kwong and Robert Timmerman
Rationale for Local Therapies for
Lung Metastases 2165
Modes of Metastatic Spread 2165
Diagnosis 2165
149.
Metastatic Cancer to the Liver . . . . . . . . . 2177H. Richard Alexander Jr., Jordan Berlin, and Fred Moeslein
Natural History of Liver Metastases 2177
Imaging of Liver Metastases 2179
Resection of Liver Metastases 2179
Results of Hepatic Resection for CRC 2180
Results of Resection for Noncolorectal Cancers 2181
Adjuvant Therapy for Resectable CRC Liver
Metastases 2181
Neoadjuvant Chemotherapy for CRC Liver Metastases 2183
Regional Therapies for Unresectable Isolated
Liver Metastases 2184
Radiation Therapy for Liver Metastases 2188
Conclusions 2190
150.
Metastatic Cancer to the Bone . . . . . . . . . 2192Edward Chow, Joel A. Finkelstein, Arjun Sahgal, and
Robert E. Coleman
Presentation 2192
Pathophysiology 2192
Diagnostic Evaluation 2192
Therapeutic Modalities 2193
New Targeted Therapies in the Treatment of Metastatic
Bone Disease 2194
External-Beam Radiation Therapy 2195
Systemic Radionuclides 2197
Radiotherapy for Complications of Bone Metastases: Localized
External Beam Radiotherapy for Pathological Fractures and
Spinal Cord Compression 2198
Mechanical Stability and Fracture Risk 2199
151.
the Pericardium . . . . . . . . . . . . . . . . . . . . 2205
Malignant Effusions of the Pleura andKing F. Kwong and Dao M. Nguyen
Malignant Pleural Effusion 2205
Malignant Pericardial Effusion 2209
152.
Malignant Ascites . . . . . . . . . . . . . . . . . . 2214Udai S. Kammula
Pathophysiology 2214
Diagnosis and Workup 2215
Treatment of Malignant Ascites 2216
153.
Paraneoplastic Syndromes . . . . . . . . . . . . 2220Michael Boyiadzis, Frank S. Lieberman, Larisa J. Geskin, and
Kenneth A. Foon
Endocrinologic Manifestations of Cancer 2220
Hematologic Manifestations of Cancer 2222
Renal Manifestations 2223
Cutaneous Manifestations of Cancer 2224
Disorders of Epidermal Proliferation and Keratinization
(Papulosquamous Disorders) 2224
Disorders of Cutaneous Discoloration and Deposition 2225
Neutrophilic Dermatoses 2226
Vascular Abnormalities 2226
Endocrine and Metabolic Disorders 2226
Bullous Disorders 2226
Collagen-Vascular Diseases 2227
Disorders of Hair 2227
Skin Neoplasms Associated with Internal Malignancy 2227
Miscellaneous Lesions 2229
Neurologic Manifestations of Cancer 2229
Limbic Encephalitis 2229
Autonomic Neuropathy 2231
Progressive Cerebellar Degeneration 2231
Paraneoplastic Visual Loss 2231
Opsoclonus-Myoclonus 2232
Paraneoplastic Motor Neuron Disorders 2232
Paraneoplastic Peripheral Neuropathies 2233
Neuromuscular Junction Disorders 2233
Contents
xlvParaneoplastic Syndromes with Muscle Rigidity 2234
Dermatomyositis 2234
Movement Disorders 2234
Approach to the Patient with Paraneoplastic
Neurologic Disease 2234
Section 18: Stem Cell Transplantation
154.
Autologous Stem Cell Transplantation . . . 2236John Magenau, Dale Bixby, and James Ferrara
History 2236
Stem Cell Mobilization 2236
Inadequate Mobilization of Stem Cells 2237
Tumor Contamination 2237
Indication and Timing of Autologous Hematopoietic Stem Cell
Transplantation 2237
Standard Infection Prophylaxis 2238
High-Dose Conditioning Regimens 2239
Complications of Autologous Hematopoietic Stem Cell
Transplantation 2239
Recent Developments in Autologous Hematopoietic Stem Cell
Transplantation 2241
Future Directions 2241
155.
Allogeneic Stem Cell Transplantation . . . . 2244Richard W. Childs
Conditioning Regimens 2244
Graft-Versus-Leukemia Effect 2245
Mechanisms of Graft-Versus-Leukemia Effect 2246
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation 2247
Veno-Occlusive Disease 2247
Epstein-Barr Virus Lymphoproliferative Disorder 2248
Sources of Allogeneic Hematopoietic Stem Cells 2251
Results of Conventional Allogeneic Transplantation for
Hematologic Malignancies 2254
Future Prospects 2260
Section 19: Management of Adverse
Effects of Treatment
156.
Infections in the Cancer Patient . . . . . . . . 2262Juan Gea-Banacloche and Brahm H. Segal
RISK FACTORS FOR INFECTIONS IN
PATIENTS WITH CANCER AND ANTIMICROBIAL
PROPHYLAXIS 2262
Risk Factors for Infection 2262
Prevention of Infections 2266
DIAGNOSIS AND MANAGEMENT OF INFECTIOUS DISEASES
SYNDROMES 2272
Fever and Neutropenia 2272
SELECTED PATHOGENS OF INTEREST IN ONCOLOGY 2291
Selected Bacterial Infections in Patients with Cancer 2291
157.
Leukopenia and Thrombocytopenia . . . . . 2300Carla Kurkjian and Howard Ozer
Overview of Hematopoiesis and Hematopoietic
Growth Factors 2300
Erythropoietin 2300
Granulocyte Colony-Stimulating Factor 2301
Granulocyte-Macrophage Colony-Stimulating Factor 2304
Interleukin-11 2304
Thrombopoietin Agents 2305
Clinical Use of Erythropoietin-Stimulating Agents in
Cancer Therapy 2305
Clinical Use of Recombinant Granulocyte Colony-Stimulating
Factors in Cancer Therapy 2307
Use of Colony-Stimulating Factors in other Oncology Settings 2309
Clinical Use of Thrombopoietin Agents 2311
158.
Cancer-Associated Thrombosis . . . . . . . . . . .2314Agnes Y. Y. Lee and Alok A. Khorana
Mechanisms of Cancer-Associated Thrombosis 2314
Epidemiology of Cancer-Associated Thrombosis 2314
Prevention of Cancer-Associated Thrombosis 2316
Treatment of Cancer-Associated Thrombosis 2317
159.
Nausea and Vomiting . . . . . . . . . . . . . . . . 2321Elizabeth M. Blanchard and Paul J. Hesketh
Nausea and Vomiting Syndromes 2321
Pathophysiology of Treatment-Induced Nausea and Vomiting 2321
Defining the Risk of Nausea and Vomiting 2322
Antiemetic Agents 2323
Antiemetic Treatment by Clinical Setting 2326
Special Chemotherapy-Induced Nausea and Vomiting Problems 2326
Radiotherapy-Induced Nausea and Vomiting 2327
160.
Diarrhea and Constipation . . . . . . . . . . . . 2329Nathan I. Cherny
Diarrhea 2329
Constipation 2333
161.
Oral Complications . . . . . . . . . . . . . . . . . 2337Eliezer Soto, Jane M. Fall-Dickson, and Ann M. Berger
Oral Mucositis 2337
Chemotherapy-Induced Stomatitis 2337
Radiation-Induced Stomatitis 2337
Radiation Therapy-Related Complications 2338
Pathogenesis of Chemotherapy- and Radiation-Induced
Oral Mucositis 2338
Chronic Graft-Versus-Host Disease Oral Manifestations 2339
Sequelae of Oral Complications 2339
Strategies for Prevention and Treatment of Oral Complications 2340
Treatment Strategies 2340
Radioprotectors 2342
Biological Response Modifiers 2343
Treatment for Oral Chronic Graft-Versus-Host Disease 2344
Symptom Management 2345
162.
Pulmonary Toxicity . . . . . . . . . . . . . . . . . 2348Diane E. Stover and Robert J. Kaner
Radiation-Induced Pulmonary Toxicity 2348
Chemotherapy-Induced Pulmonary Toxicity 2351
163.
Cardiac Toxicity . . . . . . . . . . . . . . . . . . . . 2360Joachim Yahalom and Carol S. Portlock
Anthracyclines 2360
Cyclophosphamide 2362
Ifosfamide 2362
Taxanes 2362
Trastuzumab 2363
Fluoropyrimidines 2363
Tyrosine Kinase Inhibitors 2364
Radiation-Induced Heart Disease 2364
Future Directions 2367
164.
Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . 2368Joyson J. Karakunnel and Ann M. Berger
Anatomy and Physiology 2368
Classification 2368
Diagnosis 2369
Treatment 2369
165.
Gonadal Dysfunction . . . . . . . . . . . . . . . . 2372John M. Norian, Eve C. Feinberg, Alan H. DeCherney, and
Alicia Y. Armstrong
Effects of Cytotoxic Agents on Adult Men 2372
Effects of Cytotoxic Agents on Adult Women 2374
xlvi
ContentsEffects of Cytotoxic Agents on Children 2378
Gonadal Dysfunction After Cranial Irradiation 2378
Preservation of Fertility, Hormone Levels, and
Sexual Function 2378
Pharmacologic Attempts at Preserving Fertility in Men 2382
Pharmacologic Attempts at Preserving Fertility in
Women 2382
Fertility Preservation in Women with Cervical Cancer 2384
Evaluation of Fertility After Treatment 2384
Hormone Replacement Therapy 2384
Prevention and Management of Erectile and Ejaculatory
Dysfunction 2384
Genetic Concerns 2385
166.
Fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . . 2387Sandra A. Mitchell and Ann M. Berger
Definition and Etiology of Cancer-Related Fatigue 2387
Current Theories of Cancer-Related Fatigue 2387
Evaluation of the Patient with Cancer-Related
Fatigue 2388
Interventions for Fatigue 2389
167.
Second Primary Cancers . . . . . . . . . . . . . . 2393Lois B. Travis, Smita Bhatia, James M. Allan,
Kevin C. Oeffinger, and Andrea Ng
Methods to Assess Second Cancer Risk 2393
Carcinogenicity of Individual Treatment Modalities 2394
Genetic Susceptibility to Second Primary Cancers 2396
Risk of Second Malignancy in Patients with Selected
Primary Cancers 2398
Pediatric Malignancies 2406
Comment 2409
168.
Neurocognitive Effects . . . . . . . . . . . . . . . 2411Paul D. Brown, Nadia N. I. Laack, and Jeffrey S. Wefel
Assessment of Neurocognitive Function 2411
Impact of Treatment 2412
Impact of Tumor 2415
Treatment of Cognitive Dysfunction 2415
169.
Cancer Survivorship . . . . . . . . . . . . . . . . . 2418Wendy Landier, Craig C. Earle, Smita Bhatia,
Melissa M. Hudson, Kevin Oeffinger, Patricia A. Ganz, and
Louis S. Constine
Definition of Survivorship and Scope of the Problem 2418
Goals of Survivorship Health Care 2419
Care Plans 2422
Delivery of Follow-Up Care and Best-Practice Models 2423
Educational Considerations 2423
Enhancing Research 2423
Survivorship Advocacy 2424
Section 20: Supportive Care and Quality of Life
170.
Management of Cancer Pain . . . . . . . . . . 2426Amy Abernathy and Kathleen M. Foley
Epidemiology 2426
Definition of Pain 2427
Common Pain Syndromes 2429
Management of Cancer Pain 2432
Psychological Approaches 2442
Anesthetic and Neurosurgical Approaches 2442
Neuropharmacologic Approaches 2445
Neuroablative and Neurostimulatory Procedures for the
Relief of Pain 2445
Trigger Point Injection and Acupuncture 2445
Physiatric Approaches 2446
Algorithm for Cancer Pain Management 2446
Future Directions 2446
171.
Nutritional Support . . . . . . . . . . . . . . . . . 2448Alessandro Laviano, Robert A. Meguid, and
Michael M. Meguid
Anorexia 2448
Changes in Host Metabolism: Weight Loss and
Cachexia 2449
Nutrition Therapy for Cancer Cachexia 2450
Nutrition and Tumor Growth 2450
Nutritional Assessment of the Cancer Patient 2451
Parenteral Versus Enteral Nutrition in
Cancer Patients 2451
Ethical and Legal Aspects of Nutrition Therapy 2454
172.
Sexual Problems . . . . . . . . . . . . . . . . . . . . 2456Veronica Sanchez Varela, Christian J. Nelson, and
Sharon L. Bober
Cancer in Men 2456
Cancers that Affect Men and Women 2458
Cancer in Women 2460
Cancer in Children and Young Adults 2463
Relevant Sociocultural Considerations 2463
Disruption of Intimacy and Relational
Considerations 2464
173.
Psychological Issues in Cancer . . . . . . . . . 2467David Spiegel and Michelle B. Riba
Understanding Cancer as a Trauma 2467
Common Psychiatric Conditions 2467
Screening for Psychological Problems 2467
Coping 2469
Treatment Interventions 2469
Outcome 2472
Implications for Cancer Progression and
Mortality 2472
Survivorship 2472
Psychotropic Medication 2473
174.
Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . 2477
Communicating News to the CancerEric J. Cassell
Preventing Illness 2477
Communication 2477
Explanations 2478
Uncomfortable Questions 2479
Information 2479
Meaning 2479
Cafeteria Explanations 2480
175.
Specialized Care of the Terminally Ill . . . . 2481Kristen G. Schaefer, Kathy Selvaggi, and Janet L. Abrahm
Discussing Prognosis 2481
Discussing End of Life 2481
Hope 2482
Healing Versus Curing 2482
How to Tell the Children 2482
Cultural and Religious Considerations 2482
Care without Chemotherapy 2483
Palliative Care Programs 2483
Hospice Programs 2483
Relief of Suffering 2483
The Final Days 2488
After the Death 2488
Grief and Bereavement 2488
176.
Community Resources . . . . . . . . . . . . . . . 2491Bonnie A. Indeck and Nora Rightmer
Community Resources for the Cancer Patient and Family 2491
The Cancer Patient 2491
Social and Emotional Support 2491
Informational Support 2492
Contributing Authors
xlviiInstrumental Support 2493
Common Community Resources 2493
Internet Resources 2496
Language Resources 2498
Legal Resources 2498
Palliative Care 2498
Personal Websites that Facilitate Communication 2498
Survivorship 2498
Transportation 2498
Wish Foundations 2499
177.
Rehabilitation of the Cancer Patient . . . . 2500Michael D. Stubblefield
The Rehabilitation Team 2500
Complications of Cancer and its Treatment 2501
Neuromuscualr Complications of Cancer and Cancer Treatment 2503
Musculoskeletal Complications of Cancer and Cancer
Treatment 2510
Radiation Fibrosis Syndrome 2513
Lymphedema 2518
Rehabilittion Interventions 2519
Nonpharmacologic Pain Management 2521
Section 21: Societal Issues in Oncology
178.
Regulatory Issues . . . . . . . . . . . . . . . . . . . 2523Ann T. Farrell, Grant A. Williams, and Richard Pazdur
The History of Food and Drug Administration Regulation of
Drugs and Biologics 2523
Food and Drug Administration Oversight of Clinical Trials for
Drugs and Biologics 2523
The Basis for Cancer Drug Approval 2525
Drug Safety Reporting and Evaluation 2527
Expanded Access to Investigational Drugs 2527
Regulation of Devices for Cancer Treatment and Diagnosis 2528
179.
Health Disparities in Cancer . . . . . . . . . . 2532Harold P. Freeman
Race and Cancer 2534
Relationships Between Culture and Cancer 2535
Poverty as a Cause of Cancer Disparities 2535
Patient Navigation 2535
The Harlem Breast Cancer Experience 2536
Discussion 2538
What Must be Done to Diminish Cancer Disparities 2538
180.
Cancer Information on the Internet . . . . . 2540Sherri L. Place and J. Robert Beck
Background 2540
Tools for Finding Information 2540
Evaluating Information 2541
Search Strategies 2543
Useful Tools for Keeping Up 2544
Section 22: Complementary, Alternative, and
Integrative Therapies
181.
Therapies in Cancer Care . . . . . . . . . . . . . 2550
Complementary, Alternative, and IntegrativeCatherine Ulbricht, Lorenzo Cohen, and Richard Lee
Background 2550
Establishing an Integrative Oncology Approach with Patients 2550
Standardization and Quality 2555
Specific Complementary and Alternative Medicine
Therapies 2556
Index 2563

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DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology

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