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DeVita, Hellman, and Rosenberg's Cancer

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Contributing Authors vii Preface xxvii Acknowledgments xxix PART ONE MOLECULAR BIOLOGY OF CANCER 1. The Cancer Genome ... 2Yardena Samuels, Alberto Bardelli, and Carlos Lopez-Otin 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 Massague 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, Jurgen 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 ... 543Jose 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. Galban, and Alnawaz Rehemtulla Diffusion Magnetic Resonance Imaging 666 Perfusion Magnetic Resonance Imaging 670 Magnetic Resonance Spectroscopy 672 67. Molecular Imaging ... 676Steven M. Larson, Heiko Schoder, 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-Dube 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 Sezary Syndrome 1894 Diagnosis and Staging 1896 Clinical Evaluation of Patients with Cutaneous Lymphoma 1898 Principles of Therapy of Mycosis Fungoides and the Sezary Syndrome 1899 Systemic Therapy for Mycosis Fungoides and the Sezary 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 The

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