A concise and updated guide to oncologic diseases. It covers both fundamentals (oncogenesis, molecular diagnostics and principles of every major type of therapy), and clinical information about every major type of oncologic disease. Plus it also delivers interesting topics with diagnostic tools (biostatistics) and clinical information regarding cancer in special populations, pain management and palliative care, cancer screening, nutritional support and counseling.
Contributing Authors viiPreface xxviiAcknowledgments xxixPART ONEMOLECULAR BIOLOGY OF CANCER1.The Cancer Genome . . . . . . . . . . . . . . . . . . . 2Yardena Samuels, Alberto Bardelli, and Carlos López-OtínCancer Genes and Their Mutations 2Identification of Cancer Genes 2Cancer Genome Investigation: Tools and Quality Controls 2Somatic Alteration Classes Detected by Cancer Genome Analysis 12Pathway-Oriented Models of Cancer Genome Analysis 14Networks of Cancer Genome Projects 16The Genomic Landscape of Cancers 18The Cancer Genome and the New Taxonomy of Tumors 18Cancer Genomics and Drug Resistance 20Perspectives of Cancer Genome Analysis 202.Mechanisms of Genomic Instability . . . . . . . 23David J. Gordon, David A. Barbie, Alan D. D’Andrea,and David PellmanBasic Defenses Against Genomic Instability 23Barriers to Genomic Instability 23Mutations in Cancer 26Mechanisms of Genome Destabilization in Human Tumors 29What Causes Chromosomal Instability and Whole-ChromosomeAneuploidy? 35Does Whole-Chromosome Aneuploidy Cause Cancer? 37Perspectives and Implications for Cancer Therapeutics 383.Epigenetics of Cancer . . . . . . . . . . . . . . . . . . 41Peter A. Jones and Karin B. MichelsEpigenetic Processes 41Epigenomic Changes in Cancer 43The Timing of Epigenetic Alterations 44Epigenetic Biomarkers for Early Detection of Cancer 44Epigenetic Therapies 45Problems with Epigenetic Therapies 464.Telomeres, Telomerase, and Cancer . . . . . . . 48Kwok-Kin Wong, Norman E. Sharpless, andRonald A. DePinhoTelomeres and Telomerase 48Senescence 50Telomere Maintenance and Cancer 535.Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Cell Signaling Growth Factors and TheirLewis C. Cantley, Chris L. Carpenter, William C. Hahn,and Matthew MeyersonSignal Transduction Systems 57Sensory Machinery: Ligands and Receptors 57Regulation of Protein Kinases 60Small-Molecule Second Messengers 63Efficiency and Specificity: Formation of Multiprotein SignalingComplexes 64Signaling Networks 666.Cell Cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . 68Steven I. ReedCell-Cycle Engine 68Induction of Cell-Cycle Phase Transitions 71Ubiquitin-Mediated Proteolysis 71Regulation of the Cell Cycle 72Cell Cycle and Cancer 76MicroRNAs, the Cell Cycle, and Cancer 79The Cell Cycle and Cancer Therapy 807.Mechanisms of Cell Death . . . . . . . . . . . . . . 82Vassiliki Karantza and Eileen WhiteApoptosis 82Autophagy 87Necrosis 898.Cancer Metabolism . . . . . . . . . . . . . . . . . . . 91Matthew G. Vander HeidenAltered Metabolism in Cancer Cells 91Energetics of Cell Proliferation 93Imaging Cancer Metabolism in Patients 94Genetic Events Important for Cancer Influence Metabolism 95Targeting Metabolism to Treat Cancer 999.Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . 101Robert S. Kerbel and Lee M. EllisIntroduction: Origins of the Concept of Antiangiogenic Therapy forCancer 101Sequential Steps Involved in the Formation of Blood Vessel Capillariesin Tumors 101Pericytes 102Dysfunctional Nature of the Tumor Vasculature 102Molecular Mediators of Tumor Angiogenesis: Angiogenic Stimulatorsand Their Receptors 103Endogenous Inhibitors of Tumor Angiogenesis 105A Cooperative Regulator of Tumor Angiogenesis: The Notch Receptor-DLL4 Signaling Pathway in Endothelial Cells 106Strategies for Development of Antiangiogenic Drugs 106Enhancement of Chemotherapy Efficacy and Other TherapeuticModalities by Antiangiogenic Drugs 107Resistance to Antiangiogenic Drugs or Treatments 108Biomarkers for Tumor Angiogenesis and Antiangiogenic Therapy 109Antiangiogenic/Anti-VEGF Drug-Based Clinical Trials 109Looking Ahead: New Targets, New Drugs, and New Strategies forAntiangiogenic Therapy 11110.Invasion and Metastasis . . . . . . . . . . . . . . . 113Andy J. Minn and Joan MassaguéThe Evolution and Pathogenesis of Metastasis 113An Integrated Model for Metastasis 115Selective Pressures at the Primary Tumor Driving Acquisition ofMetastasis Functions 117Coupling Tumorigenesis with Metastasis Initiation 119Coupling Tumorigenesis with Metastasis Progression 121From Metastasis Progression to Macrometastatic Colonization 122Micro-RNAs and Metastasis 12611.Cancer Stem Cells . . . . . . . . . . . . . . . . . . . 128Jean C. Y. Wang and John E. DickTumor Heterogeneity 128Leukemia Stem Cells 129CONTENTSxxxiCancer Stem Cells in Solid Tumors 130Genetic Diversity and Clonal Evolution in Cancer 133The Origins of Cancer Stem Cells 134Epithelial-Mesenchymal Transition 137Cancer Stem Cells: Targeted Therapy 13712.Biology of Personalized Cancer Medicine . . .141Raju KucherlapatiCancer Predisposition 141Familial Adenomatous Polyposis 141Lynch Syndrome 142Other Polyposis Syndromes 142Association Studies 142Breast Cancer 142Early Detection 143Tumor Classification and Patient Stratification 143Treatment 144Development of Resistance to Tyrosine Kinase Inhibitors 145Alternative Mechanisms of Resistance 145BRAF Inhibitors 146The Future 146Changing Face of Personalized Medicine 146Summary 146PART TWOETIOLOGY AND EPIDEMIOLOGYOF CANCERSection 1: Etiology of Cancer13. Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Stephen S. HechtEpidemiology of Tobacco and Cancer 150Tumor Induction in Laboratory Animals by Tobacco Products 152Carcinogens in Tobacco Products 153Overview of Mechanisms of Tumor Induction by Tobacco Products 156Tobacco Carcinogen and Toxicant Biomarkers 15714.Cancer Susceptibility Syndromes . . . . . . . . 161Alice Hawley Berger and Pier Paolo PandolfiPrinciples of Cancer Susceptibility 161Genetic Testing 163Cancer Susceptibility Syndromes 164Future Directions 17015.DNA Viruses . . . . . . . . . . . . . . . . . . . . . . . 173Peter M. Howley, Don Ganem, and Elliott KieffHistory of Viral Oncology 173Hepadnaviruses and Hepatocellular Carcinoma 174Papillomaviruses 176Epstein-Barr Virus 180Kaposi’s Sarcoma–Associated Herpesvirus 182Human Polyomaviruses 18416.RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . 186Gary L. Buchschacher, Jr. and Flossie Wong-StaalRetroviruses: Background, Replication Cycle, andMolecular Genetics 186Human T-Lymphotropic Virus Type 1 189Human T-Lymphotropic Virus Type 2 190Human Immunodeficiency Virus 190Hepatitis C Virus 19017.Inflammation . . . . . . . . . . . . . . . . . . . . . . . 193Giorgio TrinchieriTumor Immune Surveillance 193Inflammation and Tumorigenesis 194Mechanisms of Cell Transformation and Cancer Initiation in theInflammatory Environment 196Inflammatory Cells and Stromal Cells in the Initiation of Neoplasiaand in the Tumor Microenvironment 19818.Chemical Factors . . . . . . . . . . . . . . . . . . . . 203Stuart H. Yuspa and Peter G. ShieldsThe Nature of Chemical Carcinogens: Chemistryand Metabolism 203Animal Model Systems and Chemical Carcinogenesis 205DNA Repair Protects the Host from ChemicalCarcinogens 205Genetic Susceptibility to Chemical Carcinogenesis 205Molecular Epidemiology, Chemical Carcinogenesis, andCancer Risk in Human Populations 206Polyclic Aromatic Hydrocarbons as a Model for Gene-EnvironmentInteraction 20719.Physical Factors . . . . . . . . . . . . . . . . . . . . . 209Mats LjungmanIonizing Radiation 209Ultraviolet Light 212Radiofrequency and Microwave Radiation 214Electromagnetic Fields 214Asbestos 214Nanoparticles 21520.Dietary Factors . . . . . . . . . . . . . . . . . . . . . 217Karin B. Michels and Walter C. WillettMethodologic Challenges 217The Role of Individual Food and Nutrients inCancer Etiology 218Other Foods and Nutrients 222Dietary Patterns 224Diet During Early Phases of Life 224Summary 224Limitations 224Future Directions 225Recommendations 22521.Obesity and Physical Activity . . . . . . . . . . . 227Katherine D. Henderson, Yani Lu, and Leslie BernsteinBreast Cancer 227Colon and Rectal Cancer 228Endometrial Cancer 229Adenocarcinoma of the Esophagus 229Kidney/Renal Cell Cancer 230Pancreatic Cancer 230Gallbladder Cancer 230Non-Hodgkin Lymphoma 230Prostate Cancer 231Lung Cancer 231Ovarian Cancer 231Overview 231Section 2: Epidemiology of Cancer22.Epidemiologic Methods . . . . . . . . . . . . . . . 233Xiaomei Ma and Herbert YuAnalytical Studies 233Interpretation of Epidemiologic Findings 236Molecular Epidemiology 23723.Global Cancer Incidence and Mortality . . . 241Michael J. Thun, Ahmedin Jemal, and Elizabeth WardData Sources and Measurements 241Overall Cancer Risk 243Incidence and Mortality Patterns for Common Cancers 251Issues in Interpreting Temporal Trends 258Conclusion 259xxxiiContents24.Trends in Cancer Mortality . . . . . . . . . . . . 261Tim E. ByersCancer Surveillance Systems 261Making Sense of Cancer Trends 261Trends in Cancer Risk Factors 261Cancer Trends 263Predicting Future Cancer Trends 265PART THREEPRINCIPLES OF CANCER TREATMENT25.Surgical Oncology: General Issues . . . . . . . 268Steven A. RosenbergHistorical Perspective 268Anesthesia for Oncologic Surgery 268Determination of Operative Risk 270Roles for Surgery 272Surgical Oncologist 27426.Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . 277Surgical Oncology: LaparoscopicYoshinori Hosoya and Alan T. LeforNew Technology 277Physiology of Laparoscopy 278Laparoscopy in the Diagnosis of Malignancy 279Laparoscopy in the Staging of Malignancy 279Laparoscopy in the Treatment of Malignancy 281Laparoscopy in the Palliation of Malignancy 28727.Radiation Oncology . . . . . . . . . . . . . . . . . . 289Meredith A. Morgan, Randall K. Ten Haken, andTheodore S. LawrenceBiologic Aspects of Radiation Oncology 289Factors that Affect Radiation Response 294Drugs that Affect Radiation Sensitivity 296Radiation Physics 297Treatment Planning 301Other Treatment Modalities 303Clinical Applications of Radiation Therapy 304Treatment Intent 305Fractionation 306Adverse Effects 307Principles of Combining Anticancer Agents with Radiation Therapy 30828.Medical Oncology . . . . . . . . . . . . . . . . . . . 312Vincent T. DeVita, Jr. and Edward ChuIntroduction 312Biology of Drug Resistance 31629.Assessment of Clinical Response . . . . . . . . 322Antonio Tito Fojo and Susan Elaine BatesOverall Response Rate and Stable Disease 322Alternate Response Criteria 323Waterfall Plots 326Progression Free Survival and Time to Progression 326Overall Survival 327Kaplan-Meier Plots 328Hazard Ratios 329Forest Plots 329Meta-Analyses 329Quality of Life 329Novel End Points 32930.Cancer Immunotherapy . . . . . . . . . . . . . . . 332Steven A. Rosenberg, Paul F. Robbins, and Nicholas P. RestifoApproaches to the Identification of HumanTumor Antigens 332Categories of Tumor Antigens Can Be Defined by ExpressionPatterns 334Cancer Immunotherapies 33731.of Cancer Care . . . . . . . . . . . . . . . . . . . . . . 345Health Services Research and EconomicsCraig C. Earle and Deborah SchragStudies of Health Service Delivery in Cancer Medicine 345Patient-Reported Outcomes Assessment 350The Economics of Cancer Care 353Comparative Effectiveness Research 356PART FOURPHARMACOLOGY OF CANCERTHERAPEUTICSSection 1: Chemotherapy Agents32.Pharmacokinetics and Pharmacodynamics . . . .360Chris H. Takimoto, Chee M. Ng, and Thomas PuchalskiWhy Study Pharmacokinetics and Pharmacodynamics? 360Cancer Patients Present Unique Challenges 361Pharmacokinetic Concepts 361Pharmacodynamic Concepts 365Special Topics in Pharmacokinetics and Pharmacodynamics 365Population Pharmacokinetics/Pharmacodynamics 366Pharmacokinetics and Pharmacodynamics in Oncology DrugDevelopment 36633.Pharmacogenomics . . . . . . . . . . . . . . . . . . 369Anthony El-Khoueiry and Heinz Josef LenzDefinitions: Terms and Concepts 369Pharmacogenomics and Predictive Molecular Markers 369Pharmacogenomics and Prognostic Markers 372Current Challenges and Future Directions 37334.Alkylating Agents . . . . . . . . . . . . . . . . . . . . 375Kenneth D. TewPerspectives 375Chemistry 375Classification 375Clinical Pharmacokinetics/Pharmacodynamics 380Therapeutic Uses 381Toxicities 381Complications with High-Dose Alkylating AgentTherapy 383Alkylating Agent–Steroid Conjugates 383Drug Resistance and Modulation 383Recent Developments 38335.Platinum Analogs . . . . . . . . . . . . . . . . . . . . 386Eddie ReedCommon Features of Platinum Chemistry 387Clinical Pharmacology 388Determinants of Cellular Sensitivity and Resistance toPlatinum Agents 389Cellular Accumulation and Cytosolic Inactivationof Drug 390DNA Damage and Repair 39036.Antimetabolites . . . . . . . . . . . . . . . . . . . . . 393M. Wasif Saif and Edward ChuAntifolates 3935-Fluoropyrimidines 396Capecitabine 396Cytarabine 397ContentsxxxiiiGemcitabine 3976-Thiopurines 398Fludarabine 399Cladribine 399Clofarabine 40037.Topoisomerase-Interacting Agents . . . . . . . 402Zeshaan A. Rasheed and Eric H. RubinTopoisomerase Biology 402Camptothecins 402Anthracyclines 404Anthracenediones 409Epipodophyllotoxins 41038.Antimicrotubule Agents . . . . . . . . . . . . . . . 413Maysa M. Abu-Khalaf and Lyndsay N. HarrisMicrotubules 413Taxanes 413New Taxane Formulations 416Vinca Alkaloids 417Estramustine Phosphate 420Epothilones 420Novel Compounds Targeting Microtubules andMitotic Motor Proteins 42039.Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 422Targeted Therapy with Small Molecule KinaseCharles L. SawyersEarly Successes: Targeting Cancers with Well-Known KinaseMutations 422Targeting the PI3K Pathway Directly 431Combinations of Kinase Inhibitors 431Speculations on the Future Role of Kinase Inhibitors inCancer Medicine 43240.Demethylating Agents . . . . . . . . . . . . . . . . 434Histone Deacetylase Inhibitors andSteven D. Gore, Stephen B. Baylin, and James G. HermanEpigenetics and Gene Silencing 434Changes in DNA Methylation 434Histone Deacetylase Inhibitors 437Pharmacodynamic Observations 43941.Proteasome Inhibitors . . . . . . . . . . . . . . . . 441Michael G. Kauffman, Christopher J. Molineaux,Christopher J. Kirk, and Craig M. CrewsBiochemistry of the Ubiquitin-Proteasome Pathway 441Proteasome Inhibitors 441Preclinical Pharmacology of PIs 445Proteasome Inhibitors in Cancer 44542.Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 450Poly(ADP-Ribose) PolymeraseAlan AshworthCellular DNA Repair Pathways 450The Development of PARP Inhibitors 450BRCA1PARP1 Inhibition as a Synthetic Lethal Therapeutic Strategy for theTreatment of BRCA-Deficient Cancers 451Mechanisms of Resistance to PARP Inhibitors 452Initial Clinical Results Testing Synthetic Lethality 452The Use of PARP Inhibitors in Sporadic Cancerswith “BRCAness” 452Prospects 453and BRCA2 Mutations and DNA Repair 45143.Miscellaneous Chemotherapeutic Agents . . . 455M. Sitki Copur, Michal Rose, and Scott GettingerSirolimus and Temsirolimus 455Everolimus 455l-Asparaginase 456Bleomycin 456Procarbazine 457Thalidomide 458Lenalidomide 458Section 2: Biotherapeutics44.Interferons . . . . . . . . . . . . . . . . . . . . . . . . . 461Vernon K. Sondak, Jürgen C. Becker, and Axel HauschildInterferon Signaling Pathways 461Immunologic Effects of Interferon 463Nonimmunologic Antiangiogenic Effects of Interferon 464Direct Antitumor Effects of Interferons 464Clinical Toxicity of Interferon Administration 464Potential Drug Interactions 466Oncologic Applications of Interferons 46645.Interleukin Therapy . . . . . . . . . . . . . . . . . . 469Michael T. LotzeInterleukins as Therapeutics 469Interleukin-1 Family 469Interleukin 3, Interleukin 11, and Interleukin 34 470Interleukin-2 Family 470Interleukin 6 Family 477Interleukin 10 Family 48046.Antisense Agents . . . . . . . . . . . . . . . . . . . . 482Cy A. Stein and Harris S. SoiferOligonucleotide Stability and Efficacy: The Role ofPhosphorothioates 482Clinical Trials of G3139 (Oblimersen) in Chronic LymphocyticLeukemia 483Clinical Trials in Advanced Melanoma 48447.Antiangiogenesis Agents . . . . . . . . . . . . . . . 489Cindy H. Chau and William D. FiggUnderstanding the Angiogenic Process 489Drug Development of Angiogenesis Inhibitors 490Clinical Utility of Approved Antiangiogenic Agents inCancer Therapy 494Combination Therapies 496Surrogate Markers of Antiangiogenic Therapy 497Resistance to Antiangiogenic Therapy 49748.Monoclonal Antibodies . . . . . . . . . . . . . . . 499Matthew K. Robinson, Hossein Borghaei, Gregory P. Adams,and Louis M. WeinerImmunoglobulin Structure 499Modified Antibody-Based Molecules 499Factors Regulating Antibody-Based Tumor Targeting 500Unconjugated Antibodies 502Altering Signal Transduction 503Immunoconjugates 504Unconjugated Antibodies Approved for Use Against SolidTumors 505Antibodies Used in Hematologic Malignancies 50649.Endocrine Manipulation . . . . . . . . . . . . . . 508Matthew P. Goetz, Charles Erlichman, Manish Kohli, andCharles L. LoprinziSelective Estrogen Receptor Modulators 508Aromatase Inhibitors 513Gonadotropin-Releasing Hormone Analogues 514Gonadotropin-Releasing Hormone Antagonists 515Antiandrogens 515Novel Antiandrogens 516Other Sex Steroid Therapies 516Other Hormonal Therapies 518xxxivContentsPART FIVECANCER PREVENTION50.Preventive Cancer Vaccines. . . . . . . . . . . . . 522Douglas R. Lowy and John T. SchillerBackground 522Infectious Agents and Cancer 522Prophylactic Versus Therapeutic Vaccination 524Hepatitis B Virus 524Human Papillomavirus 525Helicobacter Pylori52751.Tobacco Dependence and Its Treatment . . . 529Ellen R. Gritz, Cho Y. Lam, Damon J. Vidrine, andMichelle Cororve FingeretNicotine and the Neurobiological Basis of Smoking 529Smoking Prevalence and Quit Rates 529Effects of Continued Smoking on Cancer Treatment Outcomes 530Cessation Treatment and Research 532Future Research and Clinical Opportunities 54052.Role of Surgery in Cancer Prevention . . . . . 543José G. Guillem, Andrew Berchuck, Jeffrey F. Moley,Jeffrey Norton, and Sheryl G. A. GabramPatients at High Risk for Breast Cancer 543Hereditary Diffuse Gastric Cancer 545Surgical Prophylaxis of Hereditary Ovarian and EndometrialCancer 547Hereditary Endometrial Cancer (Lynch Syndrome) 548Multiple Endocrine Neoplasia Type 2 549Familial Adenomatous Polyposis,and Lynch Syndrome 552MYH-Associated Polyposis,53.Intervention . . . . . . . . . . . . . . . . . . . . . . . . 558Principles of Cancer Risk ReductionDean E. BrennerWhy Cancer Prevention as a Clinical Oncology Discipline? 558Defining Cancer Risk Reductive Intervention(Chemoprevention) 558Identifying Potential Cancer Risk Reductive Interventions 558Preclinical Development of Cancer Risk ReductiveInterventions 559Clinical Development of Cancer Risk Reductive Interventions 561Implementation of Cancer Risk Reductive Interventions in theCommunity 56254.Micronutrients in Cancer Prevention . . . . . 564Retinoids, Carotenoids, and OtherSusan T. Mayne, Edward Giovannucci, and Scott M. LippmanHead and Neck Cancer Chemoprevention 564Lung Cancer Chemoprevention 565Breast Cancer Chemoprevention 567Skin Cancer Chemoprevention 567Bladder Cancer Chemoprevention 568Cervical Cancer Chemoprevention 568Esophageal/Gastric Cancer Chemoprevention 569Colorectal Cancer Chemoprevention 569Prostate Cancer Chemoprevention 570Conclusions 57155.Reduction (Chemoprevention) . . . . . . . . . . 573Drugs and Nutritional Extracts for Cancer RiskMadhuri Kakarala and Dean E. BrennerAnti-Inflammatory Drugs 573Signal Transduction Modifiers 578Anti-Infectives 579PART SIXCANCER SCREENING56.Principles of Cancer Screening . . . . . . . . . . 582Jack S. Mandel and Robert SmithPrinciples of Screening 582Evaluating Screening Tests 583Developing and Evaluating a Cancer ScreeningProgram 58557.Early Detection Using Proteomics . . . . . . . . 587Virginia Espina, Claudio Belluco, Emanuel F. Petricoin III, andLance A. LiottaCellular Proteomics 587Biomarker Proteomics 59258.Screening for Gastrointestinal Cancers . . . . 596Timothy R. Church and Jack S. MandelHistory of Colorectal Cancer Screening 596Polyp Removal and Colorectal Cancer Prevention 597Methods of Screening for Colorectal Cancer 597Colorectal Cancer Screening for High-RiskPatients 600Other Gastrointestinal Cancers 600Screening 60159.Screening for Gynecologic Cancers . . . . . . 603Mary B. Daly and Janet S. RaderCervical Cancer 603Ovarian Cancer 606Endometrial Cancer 60760.Screening for Breast Cancer . . . . . . . . . . . . 610Laura J. Esserman and Chris I. FlowersThe Evidence of Mortality Benefit from Randomized Trials ofMammography Screening 610Changes in Systemic Therapies and Impact on Screening 610Optimizing the Organization of Screening 611Optimizing the Interpretation of Mammography 611Addressing the Potential Harms and Limitations ofScreening 612High-Risk Screening 614What has Biology Taught Us? 614Conclusion and Considerations for Screening 61561.Screening for Prostate Cancer . . . . . . . . . . 617Peter C. AlbertsenIs Prostate Cancer a Suitable Disease forScreening? 617Is Treatment for Prostate Cancer Effective? 618Is Prostate-Specific Antigen an Effective ScreeningTest? 620Recent Evidence from Randomized Trials 621Are there Substantial Risks Associated with Prostate-Specific AntigenScreening? 622How Should Physicians Advise their Patients? 62262.Screening for Lung Cancer . . . . . . . . . . . . . 625David E. Midthun and James R. JettThe Opportunity 625Chest Radiography and Sputum Cytology 625CT Screening 626The Problems with CT Screening 627Other Methods of Screening 629Future Directions 629Contentsxxxv63.Genetic Counseling . . . . . . . . . . . . . . . . . . 631Ellen T. Matloff and Danielle Campfield BonadiesWho is a Candidate for Cancer Genetic Counseling? 631Components of the Cancer Genetic Counseling Session 632Issues in Cancer Genetic Counseling 635Future Directions 637PART SEVENSPECIALIZED TECHNIQUES INCANCER MANAGEMENT64.Techniques . . . . . . . . . . . . . . . . . . . . . . . . . 640Vascular Access and SpecializedJames F. Pingpank, Jr.Catheter Types 640Catheter Selection 643Pediatric Patients 643Insertion Techniques 643Catheter-Related Complications 64565.Interventional Radiology . . . . . . . . . . . . . . 648Christos S. Georgiades and Jean-Francois H. GeschwindPulmonary 648Hepaticobiliary 649Cholangiocarcinoma 652Liver Metastases 655Genitourinary 657Musculoskeletal Cancer 659Special Topic: Inferior Vena Cava/Portal VeinOcclusion 66166.Functional Imaging . . . . . . . . . . . . . . . . . . 666Brian D. Ross, Craig J. Galbán, andAlnawaz RehemtullaDiffusion Magnetic Resonance Imaging 666Perfusion Magnetic Resonance Imaging 670Magnetic Resonance Spectroscopy 67267.Molecular Imaging . . . . . . . . . . . . . . . . . . . 676Steven M. Larson, Heiko Schöder, and Jan GrimmCharacterizing the Cancer Cell Phenotype 676Clinical Applications 680Optical Imaging 68368.Photodynamic Therapy . . . . . . . . . . . . . . . 686Keith A. Cengel, Smith Apisarnthanarax, andStephen M. HahnComponents of Photodynamic Therapy: Photosensitizers,Light, and Oxygen 686Mechanisms of Photodynamic Therapy Cytotoxicity 688Clinical Indications for Photodynamic Therapy for Early Stage Cancersin the Definitive Setting 689Clinical Indications for Photodynamic Therapy in the LocallyAdvanced and Palliative Settings 690Molecularly Targeted Photodynamic Therapy 69269.Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . 694Daniel F. HayesWhat is a Biomarker Used for? 694What are the Criteria to Incorporate a Tumor Marker intoClinical Practice? 695Prognosis Versus Prediction 698Pharmacogenomics: A Special Circumstance 698Markers that are Accepted for Routine Clinical Utility 700PART EIGHTPRACTICE OF ONCOLOGY70.Design and Analysis of Clinical Trials . . . . 704Richard SimonPhase 1 Clinical Trials 704Phase 2 Clinical Trials 706Design of Phase 3 Clinical Trials 711Factorial Designs 713Analysis of Phase 3 Clinical Trials 716Reporting Results of Clinical Trials 719False-Positive Reports in the Literature 720Meta-Analysis 720Section 1: Cancer of the Head and Neck71.Neck Cancers . . . . . . . . . . . . . . . . . . . . . . . 723Molecular Biology of Head andNishant Agrawal, Joseph Califano, andPatrick HaGenetic Susceptibility 723Molecular Networks Altered in HNSCC 724Epigenetics 727Loss of Heterozygosity and Risk of Malignant Progression 72772.Treatment of Head and Neck Cancer . . . . . 729William M. Mendenhall, John W. Werning, andDavid G. PfisterEpidemiology of Head and Neck Cancer 729Anatomy 729Pathology 729Natural History of Squamous Cell Carcinoma 729Diagnostic Evaluation 730Staging 731Principles of Treatment for Squamous Cell Carcinoma 731Management 731NECK 732Chemotherapy 734General Principles of Combining Modalities 738Chemotherapy as Part of Curative Treatment 738Follow-Up 744ORAL CAVITY 744Lip 744Floor of the Mouth 745Oral Tongue 747Buccal Mucosa 749Gingiva and Hard Palate (Including RetromolarTrigone) 750OROPHARYNX 752Anatomy 752LARYNX 756Anatomy 756Pathology 756Hypopharynx: Pharyngeal Walls, Pyriform Sinus, andPostcricoid Pharynx 761NASOPHARYNX 764Anatomy 764Pathology 764Patterns of Spread 765Clinical Picture 765Staging 765Treatment 766Nasal Vestibule, Nasal Cavity, and Paranasal Sinuses 766Paragangliomas 772Major Salivary Glands 774Minor Salivary Glands 777xxxviContents73.Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . .781Rehabilitation after Treatment of Head andDouglas B. Chepeha, Mark J. Haxer, and Teresa H. LydenPretreatment Counseling 781Support During Treatment and Rehabilitation of theChemoradiation Patient 781Resources for Rehabilitation of Head and Neck Cancer Patients 787Section 2: Cancer of the Thoracic Cavity74.Molecular Biology of Lung Cancer . . . . . . 789Jacob Kaufman, Leora Horn, and David CarboneSusceptibility to Lung Cancer: Genetic Susceptibility and Carcinogensin Tobacco Smoke 789Molecular Changes in Preneoplasia 789Genetic and Epigenetic Alterations in Lung Cancers 791Protooncogenes, Growth Factor Signaling, and Growth Factor TargetedTherapies 791Tumor Suppressor Genes and Growth Suppression 793Cyclins and Cell Cycle Regulatory Pathways 794Other Biologic Abnormalities in Lung Cancer 795Cancer Stem Cell Hypothesis 796Genomic Analysis of Lung Cancer 797Molecular Tools in the Lung Cancer Clinic 79775.Non–Small Cell Lung Cancer . . . . . . . . . . . 799David S. Schrump, Darryl Carter, Christopher R. Kelsey,Lawrence B. Marks, and Giuseppe GiacconeIncidence 799Etiology 799Pathology 802Molecular Markers of Prognosis 805Modes of Metastasis 806Clinical Manifestations 806Staging and Diagnosis 807Methods to Establish Tissue Diagnosis 811Overview of Invasive Lung Cancer Management:Treatment Modalities 813Specifics of Lung Cancer Management 820Superior Sulcus Tumors 829Unresectable or Medically Inoperable 829Locally Advanced 830Advanced Disease 833Investigational Agents in Development for NSCLC 843Personalized Medicine in NSCLC 843Local Therapies and Palliation 84476.the Lung. . . . . . . . . . . . . . . . . . . . . . . . . . . 848Small Cell and Neuroendocrine Tumors ofLee M. Krug, M. Catherine Pietanza, Mark G. Kris,Kenneth Rosenzweig, and William D. TravisSmall Cell Lung Cancer 848Typical Carcinoid and Atypical Carcinoid Tumors 863Large Cell Neuroendocrine Carcinoma 86777.Neoplasms of the Mediastinum . . . . . . . . . 871Robert B. Cameron, Patrick J. Loehrer, andCharles R. Thomas, Jr.Thymic Neoplasms 871Thymoma 871Thymic Carcinoma 872Thymic Carcinoid 878Thymolipoma 878Germ Cell Tumors 878Section 3: Cancers of the Gastrointestinal Tract78.Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . 882Molecular Biology of the Esophagus andAnil K. RustgiMolecular Biology of Esophageal Cancer 882Molecular Biology of Gastric Cancer 88479.Cancer of the Esophagus . . . . . . . . . . . . . . 887Mitchell C. Posner, Bruce D. Minsky, and David H. IlsonEpidemiology 887Etiologic Factors and Predisposing Conditions 887Applied Anatomy and Histology 891Natural History and Patterns of Failure 892Clinical Presentation 892Diagnostic Studies and Pretreatment Staging 893Pathologic Staging 894Treatment 895Stage-Directed Treatment Recommendations 92180.Cancer of the Stomach . . . . . . . . . . . . . . . . 924Itzhak Avital, Peter W.T. Pisters, David P. Kelsen, andChristopher G. WillettEpidemiology and Etiology 924Anatomic Considerations 926Pathology and Tumor Biology 927Histopathology 927Patterns of Spread 927Clinical Presentation and Pretreatment Evaluation 928Pretreatment Staging 929Staging, Classification, and Prognosis 930Gastric Cancer Nomograms: Predicting Individual Patient PrognosisAfter Potentially Curative Resection 933Treatment of Localized Disease 934Technical Treatment-Related Issues 944Treatment of Advanced Disease (Stage IV) 945Surgery in Treatment of Metastatic Gastric Cancer 952Radiation for Palliation 95281.Molecular Biology of Pancreas Cancer . . . . 955Scott E. Kern and Ralph H. HrubanCommon Molecular Changes 955Low-Frequency Genetic Changes 95882.Cancer of the Pancreas . . . . . . . . . . . . . . . . 961Richard E. Royal, Robert A. Wolff, and Christopher H. CraneIncidence and Etiology 961Anatomy and Pathology 964Screening 964Diagnosis and Staging 965Staging 967Treatment of Potentially Resectable Disease: American JointCommittee on Cancer Stage I and II 967Treatment of Locally Advanced Disease: American Joint Committee onCancer Stage III 975Treatment of Metastatic Disease: American Joint Committee on CancerStage IV 980Other Exocrine Neoplasms 98683.Molecular Biology of Liver Cancer . . . . . . 990Snorri S. Thorgeirsson and Joe W. GrishamAllelic Imbalance in Liver Cancer 990Classification and Prognostic Prediction of HepatocellularCarcinoma 991Comparative Functional Genomics 995Conclusion and Perspective 995Contentsxxxvii84.Cancer of the Liver . . . . . . . . . . . . . . . . . . 997David L. Bartlett, Adrian M. Di Bisceglie, andLaura A. DawsonEpidemiology 997Etiologic Factors 997Pathology 1001Staging 1002Clinical Features 1002Clinical Evaluation 1004Clinical Management 1008Adjuvant Therapy 1012Treatment of Other Primary Liver Tumors 101685.Cancer of the Biliary Tree . . . . . . . . . . . . 1019David L. Bartlett, Ramesh K. Ramanathan, andEdgar Ben-JosefCholangiocarcinomas 1019Tumors of the Gallbladder 103586.Cancer of the Small Intestine . . . . . . . . . . 1048Amer H. Zureikat, Matthew T. Heller, and Herbert J Zeh, IIISmall Bowel Cancer 1048Adenocarcinoma 1052Carcinoid Tumors 1053Intestinal Lymphoma 1055Gastrointestinal Stromal Tumors 1056Other Mesenchymal Tumors 105787.Gastrointestinal Stromal Tumor . . . . . . . . 1060George D. DemetriGIST as a Unique Clinicopathologic Subset of Sarcoma 1060GIST Cells are Related to the Mesenchymal Precursor Cellsthat Give Rise to Normal Interstitial Cells of Cajal:Aberrant Developmental Biology 1061The Development of a Molecular Understanding of GIST 1061Clinical Considerations 1062Prognostic Features of Gastrointestinal Stromal Tumor 1064Diagnostic Imaging of Patients with GastrointestinalStromal Tumors 1064Treatment Options and Management Decisions in the Era ofMolecularly Targeted Therapies for GIST 1065Extrapolation of Emerging Management Paradigms toEarly-Stage GIST 1070Adjuvant Therapy to Improve Outcomes for Patients withResected Early-Stage GIST 1070Special Considerations in GIST 1071New Challenges and Alternative Approaches 107188.Molecular Biology of Colorectal Cancer . 1074Ramesh A. ShivdasaniThe Adenoma–Carcinoma Sequence and Multistep Models ofColorectal Tumorigenesis 1074Early Events and Critical Pathways in Colorectal TumorigenesisHighlighted by Inherited Syndromes of Increased CancerRisk 1075Oncogene and Tumor Suppressor Gene Mutations in Colorectal CancerProgression 1079Infrequent Changes and Current Views of the MutationalLandscape of Colorectal Cancer 108289.Cancer of the Colon . . . . . . . . . . . . . . . . . 1084Steven K. Libutti, Leonard B. Saltz, and Christopher G. WillettEpidemiology 1084Etiology: Genetic and Environmental Risk Factors 1085Familial Colorectal Cancer 1086Anatomy of the Colon 1088Diagnosis of Colorectal Cancer 1089Screening for Colorectal Cancer 1089Staging and Prognosis of Colorectal Cancer 1090Approaches to Surgical Resection of Colon Cancer 1096Surgical Management of Complications from PrimaryColon Cancer 1098Polyps and Stage I Colon Cancer 1099Stage II and Stage III Colon Cancer 1099Treatment of Stage II Patients 1102Treatment Options for Stage III Patients 1104Radiation Therapy of Colon Cancer 1104Follow-Up After Management of Colon Cancer withCurative Intent 1106Surgical Management of Stage IV Disease 1108Management of Unresectable Metastatic Disease 1108Gene Therapy 1123Molecular Predictive Markers 1123Management of Synchronous Primary andMetastatic Disease 1123Unusual Colorectal Tumors 112490.Cancer of the Rectum . . . . . . . . . . . . . . . 1127Steven K. Libutti, Christopher G. Willett, and Leonard B. SaltzAnatomy 1127Staging 1128Surgery 1130Does Adjuvant Radiation Therapy ImpactSurvival? 1134Preoperative Radiation Therapy 1135Which Patients Should Receive Adjuvant Therapy? 1136Concurrent Chemotherapy 1137Synchronous Rectal Primary and Metastases 1138Management of Unresectable Primary and LocallyAdvanced Disease (T4) 1138Radiation Therapy Technique 113991.Cancer of the Anal Region . . . . . . . . . . . . 1142Yixing Jiang, David J. Beddy, Heidi Nelson, Lisa A. Kachnic,and Jaffer A. AjaniEpidemiology and Etiology 1142Pathology 1143Clinical Presentation and Staging 1144Prognostic Factors 1144Treatment of Localized Squamous Cell Carcinoma of theAnal Canal 1145Treatment of Other Sites and Pathologies 1151Section 4: Cancers of the Genitourinary System92.Molecular Biology of Kidney Cancer . . . . 1154W. Marston Linehan and Laura S. SchmidtVon Hippel-Lindau 1154Hereditary Papillary Renal Carcinoma Type 1 1155XP11.2 Translocation Renal Cell Cancer 1156Birt-Hogg-Dubé Syndrome 1156Hereditary Leiomyomatosis and Renal Cell Carcinoma 1157Familial Renal Cancer: Succinate Dehydrogenase Gene 1158Tuberous Sclerosis Complex 1159Conclusion 115993.Cancer of the Kidney . . . . . . . . . . . . . . . . 1161W. Marston Linehan, Brian I. Rini, and James C. YangHistologic Types of Renal Carcinoma 1161Hereditary Forms of Kidney Cancer 1161Transcription Factors and Kidney Cancer 1164Localized Renal Carcinoma 1169Metastatic Renal Carcinoma 117094.Molecular Biology of Bladder Cancer . . . 1183Margaret A. KnowlesMolecular Alterations in Superficial Urothelial Carcinoma 1183Carcinoma in Situ 1186Molecular Alterations in Invasive Urothelial Carcinoma 1186xxxviiiContentsInformation from Expression and Genomic MicroarrayProfiling 1188Signaling Pathways in Urothelial Carcinoma 1189Urothelial Tumor-Initiating Cells 1189Molecular Pathogenesis and Tumor Clonality 118995.Renal Pelvis . . . . . . . . . . . . . . . . . . . . . . . 1192Cancer of the Bladder, Ureter, andW. Scott McDougal, William U. Shipley, Donald S. Kaufman,Douglas M. Dahl, M. Dror Michaelson, andAnthony L. ZietmanUrothelial Cancers 1192Cancer of the Bladder 1194Cancers of the Renal Pelvis and Ureter 120596.Molecular Biology of Prostate Cancer . . . 1212Yu Chen, Vivek K. Arora, and Charles L. SawyersGenetic Predisposition 1212Genetic Landscape of Prostate Cancer 1212ETS Transcription Factors 121697.Cancer of the Prostate . . . . . . . . . . . . . . . 1220Michael J. Zelefsky, James A. Eastham, and A. Oliver SartorAnatomy of the Prostate 1220Prostate Zonal Anatomy 1220Histopathology 1220Gleason Score 1222Incidence, Epidemiology, and Risk Factors 1222Incidence and Mortality of Prostate Cancer 1223Clinical Risk Factors for Prostate Cancer 1223Genetic Alterations and Risk 1224Prostate Cancer Prevention 1224Disease Presentation and Diagnosis 1227Staging Workup 1228Prognostic Factors and the Assessment of Risk 1230Treating Clinically Localized Prostate Cancer 1231External-Beam Radiotherapy 1238Androgen Deprivation and Radiation Therapy 1249Adjuvant Radiation Therapy for High-Risk Patients After RadicalProstatectomy 1252Management of the Rising PSA After Definitive Local Therapy 1253Management of Metastatic Prostate Cancer 1258Castration-Resistant Prostate Cancer 126298.Cancer of the Urethra and Penis . . . . . . . . 1272Edouard J. Trabulsi and Leonard G. GomellaCancer of the Male Urethra 1272Carcinoma of the Female Urethra 1273Cancer of the Penis 127499.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. ChagantiBackground: Incidence 1280Epidemiology 1280Risk Factors 1280Initial Presentation and Management 1280Histology 1281Biology 1282Immunohistochemical Markers 1284Staging 1284Management of Clinical Stage I Disease 1286Management of Clinical Stage II (Low Tumor Burden) 1290Management of Stage II and Stage III Disease(High Tumor Burden) 1291Management of Relapse and Refractory Disease 1296Treatment Sequelae 1298Long-Term Follow-Up 1299Midline Tumors of Uncertain Histogenesis 1299Other Testicular Tumors 1299Section 5: Gynecologic Cancers100.Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . 1302Molecular Biology of GynecologicKunle Odunsi, Tanja Pejovic, and Matthew L. AndersonOvarian Cancer 1302Endometrial Cancer 1306Cervix, Vaginal, and Vulvar Cancers 1307Gestational Trophoblastic Disease 1309101.Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311Cancer of the Cervix, Vagina, andPatricia J. Eifel, Jonathan S. Berek, and Maurie A. MarkmanCarcinoma of the Cervix 1311Carcinoma of the Vagina 1330Carcinoma of the Vulva 1335102.Cancers of the Uterine Body . . . . . . . . . . 1345Pedro T. Ramirez, Arno J. Mundt, and Franco M. MuggiaEndometrial Carcinoma 1345Uterine Sarcomas 1356103.Gestational Trophoblastic Neoplasms . . . 1363Donald P. Goldstein and Ross S. BerkowitzEpidemiology 1363Pathology and Natural History 1363Indications for Treatment 1363Measurement of hCG 1364Phantom hCG 1364Pretreatment Evaluation 1364Staging and Prognostic Score 1364Treatment 1364Placental Site Trophoblastic Tumors 1366Subsequent Pregnancy 1366Psychosocial Issues 1366104.Peritoneal Carcinoma . . . . . . . . . . . . . . . . . . .1368Ovarian Cancer, Fallopian Tube Carcinoma, andStephen A. Cannistra, David M. Gershenson, and Abram RechtEpithelial Ovarian Cancer 1368Borderline Tumors 1385Germ Cell Tumors of the Ovary 1386Sex Cord–Stromal Tumors 1387Primary Peritoneal Serous Carcinoma 1389Fallopian Tube Cancer 1389Section 6: Cancer of the Breast105.Molecular Biology of Breast Cancer . . . . 1392Erin Wysong Hofstatter, Gina G. Chung, and Lyndsay N. HarrisGenetics of Breast Cancer 1392Hereditary Breast Cancer 1392Somatic Changes in Breast Cancer 1393Gene Expression Patterns in Breast Cancer 1395Epigenetics of Breast Cancer 1396Protein/Pathway Alterations 1397106.Malignant Tumors of the Breast . . . . . . . 1401Harold J. Burstein, Jay R. Harris, and Monica MorrowAnatomy of the Breast 1401Risk Factors for Breast Cancer 1401Benign Breast Disease 1404Breast Density 1404Environmental Factors 1404Management of the High-Risk Patient 1404ContentsxxxixDiagnosis and Biopsy 1407Lobular CarcinomaDuctal CarcinomaTreatment of the Breast 1409Treatment of the Axilla 1411Endocrine Therapy 1411Staging 1411Pathology of Breast Cancer 1413Local Management of Invasive Cancer 1414Breast-Conserving Therapy 1414Mastectomy 1422Management of the Axilla 1423Local-Regional Therapy and Survival 1425Prognostic and Predictive Factors 1426Other Factors 1427Molecular and Genomic Factors 1427Adjuvant Systemic Therapy 1428Integration of Multimodality Primary Therapy 1434Follow-Up for Breast Cancer Survivors 1435Special Therapeutic Problems 1436Metastatic Disease 1439In Situ 1408In Situ 1409Section 7: Cancer of the Endocrine System107.Molecular Biology of Endocrine Tumors . 1447Samuel A. Wells, Jr.The Multiple Endocrine Neoplasia Syndromes 1447Application of Molecular Genetics to Clinical Medicine 1452Sporadic Thyroid Cancers 1453Future Directions 1455108.Thyroid Tumors . . . . . . . . . . . . . . . . . . . . . . .1457Tobias Carling and Robert UdelsmanThyroid Tumor Classification and Staging Systems 1457Epidemiology and Demographics 1458Etiology and Risk Factors 1458Evaluation of the Thyroid Nodule 1460Well-Differentiated Thyroid Carcinoma 1462Treatment of Well and Intermediately Differentiated ThyroidCarcinoma 1464Poorly Differentiated Thyroid Carcinoma 1468Medullary Thyroid Carcinoma 1469Treatment of Familial Medullary Thyroid Carcinoma 1470Thyroid Lymphoma 1470Metastatic Disease of the Thyroid 1471Children with Thyroid Carcinoma 1471109.Parathyroid Tumors . . . . . . . . . . . . . . . . . 1473Reza Rahbari and Electron KebebewEpidemiology 1473Pathology 1474Molecular Genetics 1475Clinical Manifestations 1475Diagnosis 1475Management of Parathyroid Cancer 1476Follow-Up and Natural History 1477Prognosis 1478110.Adrenal Tumors . . . . . . . . . . . . . . . . . . . . 1480Mio Kitano, Erin Patterson, and Electron KebebewAdrenocortical Cancer 1480Pediatric Adrenocortical Carcinoma 1484Pheochromocytoma 1484Adrenal Incidentaloma 1487111.Pancreatic Neuroendocrine Tumors . . . . . 1489James C. Yao, Guido Rindi, and Douglas B. EvansEpidemiology 1489Classification, Histopathology, and Molecular Genetics 1489Diagnosis and Management of Pancreatic Endocrine Tumors 1492Additional Clinical Considerations 1499Surgery Pitfalls 1500Emerging Therapeutic Options 1501112.Carcinoid Syndrome . . . . . . . . . . . . . . . . 1503Neuroendocrine (Carcinoid) Tumors and theGerard M. DohertyPathology and Tumor Histology 1503Molecular Pathogenesis 1506Clinical Features of Carcinoid Tumors 1506Carcinoid Syndrome 1506Treatment of the Carcinoid Tumor 1512113.Multiple Endocrine Neoplasias . . . . . . . . 1516Gerard M. DohertyMultiple Endocrine Neoplasia Type 1 1516Familial Medullary Thyroid Carcinoma and Multiple EndocrineNeoplasia Types 2A and 2B 1519Section 8: Sarcomas of Soft Tissue and Bone114.Molecular Biology of Soft Tissue Sarcoma 1522Samuel Singer, Torsten Nielsen, and Cristina R. AntonescuTranslocation-Associated Sarcomas 1522Simple Karyotype Tumors Associated with Mutations 1528Complex Sarcoma Types 1528Future Directions: Functional Screens and Next-GenerationSequencing 1531115.Soft Tissue Sarcoma . . . . . . . . . . . . . . . . . 1533Samuel Singer, Robert G. Maki, and Brian O’SullivanIncidence and Etiology 1533Anatomic and Age Distribution and Pathology 1535Diagnosis and Staging 1547Management by Presentation Status, Extent of Disease, and AnatomicLocation 1552Palliative Care 1574Future Directions 1576116.Sarcomas of Bone . . . . . . . . . . . . . . . . . . 1578Martin M. Malawer, Lee J. Helman, and Brian O’SullivanClassification and Types of Bone Tumor 1578Radiographic Evaluation and Diagnosis 1578Natural History 1579Staging Bone Tumors 1581Preoperative Radiographic Evaluation 1581Biopsy Technique and Timing 1585Restaging After Induction (Preoperative) Chemotherapy 1585Guidelines for Limb-Sparing Resection 1586Types of Skeletal Reconstruction 1586Limb-Sparing Surgery and Perioperative Pain Management 1587Amputations 1588Chemotherapy for Bone Sarcomas 1589Radiotherapy for Osteosarcoma 1594Malignant Bone Tumors 1595Section 9: Cancers of the Skin117.Cancer of the Skin . . . . . . . . . . . . . . . . . . 1610Anetta Reszko, Sumaira Z. Aasi, Lynn D. Wilson, andDavid J. LeffellNONMELANOMA SKIN CANCER 1610Diagnosis 1610General Approach to Management of Skin Cancer 1610Topical Therapy for Skin Cancer 1613Radiation Therapy for Skin Cancer 1614ACTINIC KERATOSES 1614xlContentsPathogenesis of AK 1615Clinical Features of AK 1615Treatment of AK 1615BASAL CELL CARCINOMA 1616Clinical Behavior of BCC 1617BCC Subtypes 1617Histology 1618Treatment 1619SQUAMOUS CELL CARCINOMA 1620Pathogenesis of SCC 1620Biologic Behavior of SCC 1620Clinical Features of SCC 1621Histology 1621Recurrence and Metastatic Risk 1621Treatment 1622Follow Up 1623Immunosuppression and Nonmelanoma Skin Cancer 1623ANGIOSARCOMA 1624Pathogenesis 1624Clinical Presentation and Prognosis 1624Histology 1625Treatment 1625DERMATOFIBROSARCOMA PROTUBERANS 1625Pathogenesis 1625Histology 1625Treatment 1625Recurrence and Metastatic Potential 1626MERKEL CELL CARCINOMA 1626Pathogenesis 1626Clinical Presentation 1626Histology 1626Treatment 1627Staging 1627Recurrence and Metastatic Risk 1627Prognosis 1628MICROCYSTIC ADNEXAL CARCINOMA 1628Pathogenesis 1629Clinical Presentation 1629Histology 1629Treatment 1629SEBACEOUS CARCINOMA 1629Histology 1630Treatment 1630ATYPICAL FIBROXANTHOMA AND MALIGNANTFIBROUS HISTIOCYTOMA 1630ATYPICAL FIBROXANTHOMA 1630Pathogenesis 1630Clinical Presentation 1630Histology 1631Treatment 1631MALIGNANT FIBROUS HISTIOCYTOMA 1631Clinical Presentation 1631Histology 1631Treatment and Prognosis 1631CARCINOMA METASTATIC TO SKIN 1631118.Melanoma . . . . . . . . . . . . . . . . . . . . . . . . 1634Molecular Biology of CutaneousLevi A. Garraway and Lynda ChinTheThe Retinoblastoma Pathway 1634The p53 Pathway 1635The MAP Kinase Pathway 1636The RAS Family: H-, N-, and K-RAS 1636The Phosphatidylinositol 3-Kinase Pathway 1638Receptor Tyrosine Kinases 1638Epidermal Growth Factor Receptor Family 1639The MITF Pathway 1639The WNT Pathway 1639The MC1R Pathway 1640The FAK Pathway 1640Cancer Stem Cells and Melanoma 1640Cancer Genomics and Translation 1640Looking Ahead 1641CDKN2A Locus 1634119.Cutaneous Melanoma . . . . . . . . . . . . . . . 1643Craig L. Slingluff Jr., Keith Flaherty, Steven A. Rosenberg, andPaul W. ReadCutaneous Melanoma Biology 1643Epidemiology 1644Changes in Incidence 1645Gender and Age Distribution 1645Melanoma in Children, Infants, and Neonates 1645Anatomic Distribution 1646Etiology and Risk Factors 1646Pregnancy and Estrogen Use 1646Prevention and Screening 1647Diagnosis of Primary Melanoma 1648General Considerations in Clinical Management of a Newly DiagnosedCutaneous Melanoma (Stage I–II) 1652Wide Local Excision for Clinical Stage I–II Melanoma: GeneralConsiderations 1653Clinical Trials to Define Margins of Excision for PrimaryCutaneous Melanomas 1653Surgical Staging of Regional Nodes 1655Management of Clinically Localized Melanoma 1658Management of Thin Primary Melanoma (Clinical T1a) 1658Management of Clinical T2a, T2b Melanomas 1660Management of Clinical T3a Melanomas (Clinical Stage IIA) 1660Management of Clinical T3b Melanomas (Clinical Stage IIB) 1660Management of Thick Melanomas (T4a, T4b, Greater than4 mm Thick) 1660Special Considerations in Management of Primary Melanomas 1661The Role of Radiation Therapy in the Management of PrimaryMelanoma Lesions 1662Clinical Follow-Up for Intermediate-Thickness and Thick Melanomas(Stage IB–IIC) 1662Regionally Metastatic Melanoma (Stage III): Lymph Node Metastasis,Satellite Lesions, and In-Transit Metastases 1662Management of Regional Metastases in Patients withVisceral or Other Distant Disease 1666Adjuvant Systemic Therapy (Stages IIB, IIC, and III) 1667Management of Distant Metastases of Melanoma (Stage IV) 1672Combination Chemotherapy 1678Experimental and Developing Immunologic Therapies forStage IV Melanoma 1682Rationale for Targeted Therapy in Melanoma 1684Radiation Therapy for Metastatic Melanoma (Stage IV) 1687Section 10: Neoplasms of theCentral Nervous System120.System Tumors . . . . . . . . . . . . . . . . . . . . . 1692Molecular Biology of Central NervousC. David James, David N. Louis, and Webster K. CaveneeNeurologic Tumor Syndromes 1692CNS Tumor Histopathology and Molecular Correlates 1692Current Basis of CNS Tumor Treatment andResponse to Therapy 1698121.Neoplasms of the Central Nervous System 1700Minesh Mehta, Michael A. Vogelbaum, Susan Chang, andNeha PatelEpidemiology of Brain Tumors 1700Anatomic Location and Clinical Considerations 1702Neurodiagnostic Tests 1705Surgery 1706Radiation Therapy 1708Chemotherapy and Targeted Agents 1710Specific Central Nervous System Neoplasms 1712Gliomatosis Cerebri 1720Optic, Chiasmal, and Hypothalamic Gliomas 1720Brainstem Gliomas 1722Cerebellar Astrocytomas 1723Gangliogliomas 1723Ependymoma 1724ContentsxlixliiContentsMeningiomas 1727Primitive Neuroectodermal or Embryonal Central NervousSystem Neoplasms 1730Pineal Region Tumors and Germ Cell Tumors 1733Pituitary Adenomas 1735Craniopharyngiomas 1737Vestibular Schwannomas 1738Glomus Jugulare Tumors 1740Hemangioblastomas 1741Chordomas and Chondrosarcomas 1742Choroid Plexus Tumors 1744Spinal Axis Tumors 1745Section 11: Cancers of Childhood122.Molecular Biology of Childhood Cancers . . .1750Lee J. Helman and David MalkinTumor Suppressor Genes 1750Retinoblastoma: The Paradigm 1752Wilms Tumor: Three Distinct Loci 1753Neurofibromatoses 1753Neuroblastoma 1754Ewing Sarcoma Family of Tumors 1755Rhabdomyosarcoma 1755Hereditary Syndromes Associated with Tumors of Childhood 1756Malignant Rhabdoid Tumors 1757Predictive Testing for Germ Line Mutations and ChildhoodCancers 1757Molecular Therapeutics 1758123.Solid Tumors of Childhood . . . . . . . . . . . 1760Lisa L. Wang, Jason Yustein, Chrystal Louis, Heidi V. Russell,Alberto S. Pappo, Arnold Paulino, Jed G. Nuchtern, andMurali ChintagumpalaThe Importance of Multidisciplinary Management Teams in PediatricSolid Tumors 1760Neuroblastoma 1760Wilms’ Tumor 1766Retinoblastoma 1769Pediatric Bone Sarcomas: Osteosarcoma and Ewing’s Sarcoma 1771Rhabdomyosarcoma 1780Liver Tumors 1784Germ Cell Tumors 1786124.Childhood . . . . . . . . . . . . . . . . . . . . . . . . 1793Leukemias and Lymphomas ofJudith F. Margolin, Karen R. Rabin, and David G. PoplackLeukemias 1793Lymphomas 1801Supportive Care 1804Long-Term, Palliative, and Hospice Care in Pediatric Oncology 1804Section 12: Lymphomas in Adults125.Molecular Biology of Lymphomas . . . . . . 1806Urban Novak, Laura Pasqualucci, and Riccardo Dalla-FaveraThe Cell of Origin of Lymphoma 1806General Mechanisms of Genetic Lesion in Lymphoma 1807Molecular Pathogenesis of B-Cell Non-Hodgkin’s Lymphoma 1810Molecular Pathogenesis of T-Cell NHL 1816Molecular Pathogenesis of HL 1817126.Hodgkin Lymphoma . . . . . . . . . . . . . . . . 1819Andreas Engert, Dennis A. Eichenauer, Nancy Lee Harris,Peter M. Mauch, and Volker DiehlHistory of Hodgkin Lymphoma 1819Etiology and Epidemiology 1819Biology and Cell of Origin 1820Immunology of Hodgkin Lymphoma 1820Diagnosis and Staging of Hodgkin Lymphomas 1825Clinical Presentation of Hodgkin Lymphomas 1827Treatment Methods for Hodgkin Lymphoma 1827Choice of Treatment 1829Treatment for Early Favorable Hodgkin Lymphoma 1832Early Unfavorable Hodgkin Lymphoma 1834Advanced Stages of Hodgkin Lymphoma 1836Progressive and Relapsed Disease 1840Lymphocyte-Predominant Hodgkin Lymphoma 1844Special Populations 1846Treatment-Related Late Side Effects 1848Quality of Life 1850New Drugs in Hodgkin Lymphoma 1851127.Non-Hodgkin Lymphomas . . . . . . . . . . . 1855Jonathan W. Friedberg, Peter M. Mauch, Lisa Rimsza, andRichard I. FisherEpidemiology 1855Etiology 1855Biologic Background for Classification of Lymphoid Neoplasms 1857B- and T-Cell Differentiation 1857Immunophenotyping of Lymphoid Cells 1862Chromosomal Translocations and OncogeneRearrangements 1863Use of Immunophenotyping and Genetic Studies in theDiagnosis of Lymphoid Neoplasms 1864Principles of the World Health Organization Classification ofLymphoid Neoplasms 1864Principles of Management of Non-Hodgkin Lymphoma 1867Specific Disease Entities 1869Mature T-Cell and NK Cell Neoplasms 1884Special Clinical Situations 1889128.Cutaneous Lymphomas . . . . . . . . . . . . . . 1894Francine M. Foss, Richard L. Edelson, and Lynn D. WilsonMycosis Fungoides and the Sézary Syndrome 1894Diagnosis and Staging 1896Clinical Evaluation of Patients with CutaneousLymphoma 1898Principles of Therapy of Mycosis Fungoides and theSézary Syndrome 1899Systemic Therapy for Mycosis Fungoides and theSézary Syndrome 1902Other Cutaneous Lymphomas 1905129.Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . 1908Primary Central Nervous SystemLisa M. DeAngelis and Joachim YahalomClinical Features 1908Diagnostic Tests 1909Pathology 1909Management and Therapy 1910Section 13: Leukemias and Plasma Cell Tumors130.Leukemias . . . . . . . . . . . . . . . . . . . . . . . . 1916Molecular Biology of AcuteGlen D. Raffel and Jan CernyLeukemic Stem Cell 1916Elucidation of Genetic Events in Acute Leukemia 1916Recurring Chromosomal Abnormalities in Acute Leukemia 1917Chromosomal Translocations that Target Core-Binding Factor 1917Chromosomal Translocations that Target the RetinoicAcid Receptor Alpha Gene 1919Chromosomal Translocations that Target HOX FamilyMembers 1920Chromosomal Translocations that Target theChromosomal Translocations that Involve Transcriptional Coactivatorsand Chromatin Remodeling Proteins 1921MLL Gene 1920Contentsxliiit(1;22) Translocation Associated with Infant AcuteMegakaryoblastic Leukemia 1921Deletions and Numeric Abnormalities in Acute Leukemias 1921Chromosomal Translocations that Result in Overexpression ofOtherwise Normal Genes 1922Chromosomal Translocations Involving the T-Cell Receptor 1922Point Mutations in Acute Leukemia 1922Mutation in Tumor Suppressor Genes 1924Activating Mutations of NOTCH 1924Mutations Altering Localization of NPM1 1925Loss-of-Function Point Mutations inMutation of Lymphoid Development Genes in ALL 1925Mutational Complementation Groups in Acute Leukemias 1925Conclusion 1926AML1,C/EBP, and GATA-1 1925131.Management of Acute Leukemias . . . . . . 1928Partow Kebriaei, Richard Champlin, Marcos de Lima, andElihu EsteyAcute Myelogenous Leukemia 1929Acute Lymphoblastic Leukemia 1946132.Leukemias . . . . . . . . . . . . . . . . . . . . . . . . 1955Molecular Biology of ChronicAnupriya Agarwal, John C. Byrd, and Michael W. DeiningerChronic Myeloid Leukemia 1955Chronic Lymphocytic Leukemia 1958133.Chronic Myelogenous Leukemia . . . . . . . 1962Brian J. Druker and Stephanie J. LeeEpidemiology 1962Pathogenesis 1962Diagnosis 1963Clinical Course and Prognosis 1964Treatment of Chronic Phase Disease 1965Tyrosine Kinase Inhibitors 1965Hematopoietic Cell Transplantation 1968Advanced Phase Disease 1970Future Directions 1971134.Chronic Lymphocytic Leukemias . . . . . . . 1973William G. Wierda and Susan O’BrienMolecular Biology 1973Immune Abnormalities 1975Diagnosis 1975Clinical Manifestations 1975Treatment and Response Criteria 1977New and Novel Agents for Treatment of Chronic LymphocyticLeukemia 1984Second Malignancies and Transformation 1985Prolymphocytic Leukemia 1985Large Granular Lymphocyte Leukemia 1985Hairy Cell Leukemia 1986135.Myelodysplastic Syndromes . . . . . . . . . . . 1988Stefan Faderl and Hagop M. KantarjianEpidemiology and Etiology 1988Presentation and Diagnosis 1988Cytogenetic-Molecular Abnormalities and MDS Pathogenesis 1990Classification 1991Therapy 1992Outlook 1995136.Plasma Cell Neoplasms . . . . . . . . . . . . . . 1997Nikhil C. Munshi and Kenneth C. AndersonHistory 1997Epidemiology 1998Etiology 1998Pathogenesis 1999Drug Resistance 2004Clinical Manifestations 2005Treatment 2015Section 14: Other Cancers137.Cancer of Unknown Primary Site . . . . . . . 2033F. Anthony Greco and John D. HainsworthPathologic Evaluation 2033Clinical Features and Evaluation 2038Treatment 2040Special Issues in Carcinoma of Unknown Primary Site 2048Unknown Primary Cancer in Children 2049Future Directions and Changing Treatment Paradigm 2050138.Benign and Malignant Mesothelioma . . . 2052Harvey I. Pass, Nicholas J. Vogelzang, Steven M. Hahn, andMichele CarboneMechanism of Asbestos-Carcinogenesis 2052Overview of Molecular Mechanisms in Mesothelioma 2054Alterations of Oncogenesin Mesothelioma 2054Pathology of Mesothelioma 2056Epidemiology and Clinical Presentation 2058Diagnostic Approach for Presumed Mesothelioma 2062Natural History 2064Treatment 2066Pleurectomy 2068Radiotherapy for Mesothelioma 2069Multimodality Treatment 2071Novel Intrapleural Approaches: New Techniques withNew/Old Agents 2072Chemotherapy and Newer Agents 2074Novel Treatment Approaches 2076Other Agents 2077139.Peritoneal Surface Malignancy . . . . . . . . . 2081Marcello Deraco, Dominique Elias, Olivier Glehen,Cyril W. Helm, Paul H. Sugarbaker, and Vic J. VerwaalRationale for a Combined Treatment for Peritoneal SurfaceMalignancy 2081Validated Quantitative Prognostic Indicators 2081Appendiceal Malignancy 2083Colorectal Carcinomatosis: Curative Treatment and Prevention 2084Diffuse Malignant Peritoneal Mesothelioma 2085Gastric Cancer 2086Peritoneal Carcinomatosis in Ovarian Cancer 2087Sarcomatosis 2087140.Intraocular Melanoma . . . . . . . . . . . . . . . 2090Daniel M. Albert and Amol D. KulkarniIncidence and Etiology 2090Anatomy and Pathology 2090Diagnosis 2091Metastatic Workup 2093Staging 2093Management 2093Prognostic and Predictive Factors 2096Posttreatment Quality of Life 2097Section 15: Immunosuppression-RelatedMalignancies141.AIDS-Related Malignancies . . . . . . . . . . . 2099Robert Yarchoan, Thomas S. Uldrick, and Richard F. LittleCancer and HIV: Incidence and Etiology 2099Kaposi Sarcoma 2101KSHV-Associated Multicentric Castleman Disease 2104AIDS-Associated Lymphomas 2104Hodgkin’s Lymphoma 2110HPV-Associated Cancer in HIV Infection 2110Cervical Cancer 2110Anal Cancer 2110Future Directions 2111xlivContents142.Transplantation-Related Malignancies . . . 2113Smita Bhatia and Ravi BhatiaMyelodysplasia and Acute Myeloid Leukemia 2113Lymphomas 2119Solid Tumors 2120Section 16: Oncologic Emergencies143.Superior Vena Cava Syndrome . . . . . . . . . 2123Joachim YahalomAnatomy and Pathophysiology 2123Etiology and Natural History 2123Diagnostic Procedures 2124Management 2125Small Cell Lung Cancer 2125Non–Small Cell Lung Cancer 2125Non−Hodgkin’s Lymphoma 2125Nonmalignant Causes 2126Catheter-Induced Obstruction 2126Treatment 2126Areas of Uncertainty 2127Recommendations 2128144.Increased Intracranial Pressure . . . . . . . . . 2130Kevin P. Becker and Joachim M. BaehringPathophysiological Considerations 2130Epidemiology and Pathogenesis 2131Clinical Presentation 2131Diagnosis 2133Treatment 2134145.Spinal Cord Compression . . . . . . . . . . . . 2136Kevin P. Becker and Joachim M. BaehringEpidemiology 2136Pathophysiology 2136Clinical Presentation 2138Differential Diagnosis 2138Diagnosis 2139Treatment 2139Prognosis 2140146.Metabolic Emergencies . . . . . . . . . . . . . . 2142Antonio Tito FojoTumor Lysis Syndrome 2142Hyperuricemia 2144Cancer and Hyponatremia 2147Lactic Acidosis and Cancer 2148Hypercalcemia and Cancer 2148Cancer-Related Hemolytic Uremic Syndrome 2150Section 17: Treatment of Metastatic Cancer147.Metastatic Cancer to the Brain . . . . . . . . 2153David A. Larson, James L. Rubenstein, Michael W. McDermott,and Igor BaraniBrain Metastasis 2153Carcinomatous Meningitis 2162148.Metastatic Cancer to the Lung . . . . . . . . . . . .2165King F. Kwong and Robert TimmermanRationale for Local Therapies forLung Metastases 2165Modes of Metastatic Spread 2165Diagnosis 2165149.Metastatic Cancer to the Liver . . . . . . . . . 2177H. Richard Alexander Jr., Jordan Berlin, and Fred MoesleinNatural History of Liver Metastases 2177Imaging of Liver Metastases 2179Resection of Liver Metastases 2179Results of Hepatic Resection for CRC 2180Results of Resection for Noncolorectal Cancers 2181Adjuvant Therapy for Resectable CRC LiverMetastases 2181Neoadjuvant Chemotherapy for CRC Liver Metastases 2183Regional Therapies for Unresectable IsolatedLiver Metastases 2184Radiation Therapy for Liver Metastases 2188Conclusions 2190150.Metastatic Cancer to the Bone . . . . . . . . . 2192Edward Chow, Joel A. Finkelstein, Arjun Sahgal, andRobert E. ColemanPresentation 2192Pathophysiology 2192Diagnostic Evaluation 2192Therapeutic Modalities 2193New Targeted Therapies in the Treatment of MetastaticBone Disease 2194External-Beam Radiation Therapy 2195Systemic Radionuclides 2197Radiotherapy for Complications of Bone Metastases: LocalizedExternal Beam Radiotherapy for Pathological Fractures andSpinal Cord Compression 2198Mechanical Stability and Fracture Risk 2199151.the Pericardium . . . . . . . . . . . . . . . . . . . . 2205Malignant Effusions of the Pleura andKing F. Kwong and Dao M. NguyenMalignant Pleural Effusion 2205Malignant Pericardial Effusion 2209152.Malignant Ascites . . . . . . . . . . . . . . . . . . 2214Udai S. KammulaPathophysiology 2214Diagnosis and Workup 2215Treatment of Malignant Ascites 2216153.Paraneoplastic Syndromes . . . . . . . . . . . . 2220Michael Boyiadzis, Frank S. Lieberman, Larisa J. Geskin, andKenneth A. FoonEndocrinologic Manifestations of Cancer 2220Hematologic Manifestations of Cancer 2222Renal Manifestations 2223Cutaneous Manifestations of Cancer 2224Disorders of Epidermal Proliferation and Keratinization(Papulosquamous Disorders) 2224Disorders of Cutaneous Discoloration and Deposition 2225Neutrophilic Dermatoses 2226Vascular Abnormalities 2226Endocrine and Metabolic Disorders 2226Bullous Disorders 2226Collagen-Vascular Diseases 2227Disorders of Hair 2227Skin Neoplasms Associated with Internal Malignancy 2227Miscellaneous Lesions 2229Neurologic Manifestations of Cancer 2229Limbic Encephalitis 2229Autonomic Neuropathy 2231Progressive Cerebellar Degeneration 2231Paraneoplastic Visual Loss 2231Opsoclonus-Myoclonus 2232Paraneoplastic Motor Neuron Disorders 2232Paraneoplastic Peripheral Neuropathies 2233Neuromuscular Junction Disorders 2233ContentsxlvParaneoplastic Syndromes with Muscle Rigidity 2234Dermatomyositis 2234Movement Disorders 2234Approach to the Patient with ParaneoplasticNeurologic Disease 2234Section 18: Stem Cell Transplantation154.Autologous Stem Cell Transplantation . . . 2236John Magenau, Dale Bixby, and James FerraraHistory 2236Stem Cell Mobilization 2236Inadequate Mobilization of Stem Cells 2237Tumor Contamination 2237Indication and Timing of Autologous Hematopoietic Stem CellTransplantation 2237Standard Infection Prophylaxis 2238High-Dose Conditioning Regimens 2239Complications of Autologous Hematopoietic Stem CellTransplantation 2239Recent Developments in Autologous Hematopoietic Stem CellTransplantation 2241Future Directions 2241155.Allogeneic Stem Cell Transplantation . . . . 2244Richard W. ChildsConditioning Regimens 2244Graft-Versus-Leukemia Effect 2245Mechanisms of Graft-Versus-Leukemia Effect 2246Complications of Allogeneic Hematopoietic Stem CellTransplantation 2247Veno-Occlusive Disease 2247Epstein-Barr Virus Lymphoproliferative Disorder 2248Sources of Allogeneic Hematopoietic Stem Cells 2251Results of Conventional Allogeneic Transplantation forHematologic Malignancies 2254Future Prospects 2260Section 19: Management of AdverseEffects of Treatment156.Infections in the Cancer Patient . . . . . . . . 2262Juan Gea-Banacloche and Brahm H. SegalRISK FACTORS FOR INFECTIONS INPATIENTS WITH CANCER AND ANTIMICROBIALPROPHYLAXIS 2262Risk Factors for Infection 2262Prevention of Infections 2266DIAGNOSIS AND MANAGEMENT OF INFECTIOUS DISEASESSYNDROMES 2272Fever and Neutropenia 2272SELECTED PATHOGENS OF INTEREST IN ONCOLOGY 2291Selected Bacterial Infections in Patients with Cancer 2291157.Leukopenia and Thrombocytopenia . . . . . 2300Carla Kurkjian and Howard OzerOverview of Hematopoiesis and HematopoieticGrowth Factors 2300Erythropoietin 2300Granulocyte Colony-Stimulating Factor 2301Granulocyte-Macrophage Colony-Stimulating Factor 2304Interleukin-11 2304Thrombopoietin Agents 2305Clinical Use of Erythropoietin-Stimulating Agents inCancer Therapy 2305Clinical Use of Recombinant Granulocyte Colony-StimulatingFactors in Cancer Therapy 2307Use of Colony-Stimulating Factors in other Oncology Settings 2309Clinical Use of Thrombopoietin Agents 2311158.Cancer-Associated Thrombosis . . . . . . . . . . .2314Agnes Y. Y. Lee and Alok A. KhoranaMechanisms of Cancer-Associated Thrombosis 2314Epidemiology of Cancer-Associated Thrombosis 2314Prevention of Cancer-Associated Thrombosis 2316Treatment of Cancer-Associated Thrombosis 2317159.Nausea and Vomiting . . . . . . . . . . . . . . . . 2321Elizabeth M. Blanchard and Paul J. HeskethNausea and Vomiting Syndromes 2321Pathophysiology of Treatment-Induced Nausea and Vomiting 2321Defining the Risk of Nausea and Vomiting 2322Antiemetic Agents 2323Antiemetic Treatment by Clinical Setting 2326Special Chemotherapy-Induced Nausea and Vomiting Problems 2326Radiotherapy-Induced Nausea and Vomiting 2327160.Diarrhea and Constipation . . . . . . . . . . . . 2329Nathan I. ChernyDiarrhea 2329Constipation 2333161.Oral Complications . . . . . . . . . . . . . . . . . 2337Eliezer Soto, Jane M. Fall-Dickson, and Ann M. BergerOral Mucositis 2337Chemotherapy-Induced Stomatitis 2337Radiation-Induced Stomatitis 2337Radiation Therapy-Related Complications 2338Pathogenesis of Chemotherapy- and Radiation-InducedOral Mucositis 2338Chronic Graft-Versus-Host Disease Oral Manifestations 2339Sequelae of Oral Complications 2339Strategies for Prevention and Treatment of Oral Complications 2340Treatment Strategies 2340Radioprotectors 2342Biological Response Modifiers 2343Treatment for Oral Chronic Graft-Versus-Host Disease 2344Symptom Management 2345162.Pulmonary Toxicity . . . . . . . . . . . . . . . . . 2348Diane E. Stover and Robert J. KanerRadiation-Induced Pulmonary Toxicity 2348Chemotherapy-Induced Pulmonary Toxicity 2351163.Cardiac Toxicity . . . . . . . . . . . . . . . . . . . . 2360Joachim Yahalom and Carol S. PortlockAnthracyclines 2360Cyclophosphamide 2362Ifosfamide 2362Taxanes 2362Trastuzumab 2363Fluoropyrimidines 2363Tyrosine Kinase Inhibitors 2364Radiation-Induced Heart Disease 2364Future Directions 2367164.Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . 2368Joyson J. Karakunnel and Ann M. BergerAnatomy and Physiology 2368Classification 2368Diagnosis 2369Treatment 2369165.Gonadal Dysfunction . . . . . . . . . . . . . . . . 2372John M. Norian, Eve C. Feinberg, Alan H. DeCherney, andAlicia Y. ArmstrongEffects of Cytotoxic Agents on Adult Men 2372Effects of Cytotoxic Agents on Adult Women 2374xlviContentsEffects of Cytotoxic Agents on Children 2378Gonadal Dysfunction After Cranial Irradiation 2378Preservation of Fertility, Hormone Levels, andSexual Function 2378Pharmacologic Attempts at Preserving Fertility in Men 2382Pharmacologic Attempts at Preserving Fertility inWomen 2382Fertility Preservation in Women with Cervical Cancer 2384Evaluation of Fertility After Treatment 2384Hormone Replacement Therapy 2384Prevention and Management of Erectile and EjaculatoryDysfunction 2384Genetic Concerns 2385166.Fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . . 2387Sandra A. Mitchell and Ann M. BergerDefinition and Etiology of Cancer-Related Fatigue 2387Current Theories of Cancer-Related Fatigue 2387Evaluation of the Patient with Cancer-RelatedFatigue 2388Interventions for Fatigue 2389167.Second Primary Cancers . . . . . . . . . . . . . . 2393Lois B. Travis, Smita Bhatia, James M. Allan,Kevin C. Oeffinger, and Andrea NgMethods to Assess Second Cancer Risk 2393Carcinogenicity of Individual Treatment Modalities 2394Genetic Susceptibility to Second Primary Cancers 2396Risk of Second Malignancy in Patients with SelectedPrimary Cancers 2398Pediatric Malignancies 2406Comment 2409168.Neurocognitive Effects . . . . . . . . . . . . . . . 2411Paul D. Brown, Nadia N. I. Laack, and Jeffrey S. WefelAssessment of Neurocognitive Function 2411Impact of Treatment 2412Impact of Tumor 2415Treatment of Cognitive Dysfunction 2415169.Cancer Survivorship . . . . . . . . . . . . . . . . . 2418Wendy Landier, Craig C. Earle, Smita Bhatia,Melissa M. Hudson, Kevin Oeffinger, Patricia A. Ganz, andLouis S. ConstineDefinition of Survivorship and Scope of the Problem 2418Goals of Survivorship Health Care 2419Care Plans 2422Delivery of Follow-Up Care and Best-Practice Models 2423Educational Considerations 2423Enhancing Research 2423Survivorship Advocacy 2424Section 20: Supportive Care and Quality of Life170.Management of Cancer Pain . . . . . . . . . . 2426Amy Abernathy and Kathleen M. FoleyEpidemiology 2426Definition of Pain 2427Common Pain Syndromes 2429Management of Cancer Pain 2432Psychological Approaches 2442Anesthetic and Neurosurgical Approaches 2442Neuropharmacologic Approaches 2445Neuroablative and Neurostimulatory Procedures for theRelief of Pain 2445Trigger Point Injection and Acupuncture 2445Physiatric Approaches 2446Algorithm for Cancer Pain Management 2446Future Directions 2446171.Nutritional Support . . . . . . . . . . . . . . . . . 2448Alessandro Laviano, Robert A. Meguid, andMichael M. MeguidAnorexia 2448Changes in Host Metabolism: Weight Loss andCachexia 2449Nutrition Therapy for Cancer Cachexia 2450Nutrition and Tumor Growth 2450Nutritional Assessment of the Cancer Patient 2451Parenteral Versus Enteral Nutrition inCancer Patients 2451Ethical and Legal Aspects of Nutrition Therapy 2454172.Sexual Problems . . . . . . . . . . . . . . . . . . . . 2456Veronica Sanchez Varela, Christian J. Nelson, andSharon L. BoberCancer in Men 2456Cancers that Affect Men and Women 2458Cancer in Women 2460Cancer in Children and Young Adults 2463Relevant Sociocultural Considerations 2463Disruption of Intimacy and RelationalConsiderations 2464173.Psychological Issues in Cancer . . . . . . . . . 2467David Spiegel and Michelle B. RibaUnderstanding Cancer as a Trauma 2467Common Psychiatric Conditions 2467Screening for Psychological Problems 2467Coping 2469Treatment Interventions 2469Outcome 2472Implications for Cancer Progression andMortality 2472Survivorship 2472Psychotropic Medication 2473174.Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . 2477Communicating News to the CancerEric J. CassellPreventing Illness 2477Communication 2477Explanations 2478Uncomfortable Questions 2479Information 2479Meaning 2479Cafeteria Explanations 2480175.Specialized Care of the Terminally Ill . . . . 2481Kristen G. Schaefer, Kathy Selvaggi, and Janet L. AbrahmDiscussing Prognosis 2481Discussing End of Life 2481Hope 2482Healing Versus Curing 2482How to Tell the Children 2482Cultural and Religious Considerations 2482Care without Chemotherapy 2483Palliative Care Programs 2483Hospice Programs 2483Relief of Suffering 2483The Final Days 2488After the Death 2488Grief and Bereavement 2488176.Community Resources . . . . . . . . . . . . . . . 2491Bonnie A. Indeck and Nora RightmerCommunity Resources for the Cancer Patient and Family 2491The Cancer Patient 2491Social and Emotional Support 2491Informational Support 2492Contributing AuthorsxlviiInstrumental Support 2493Common Community Resources 2493Internet Resources 2496Language Resources 2498Legal Resources 2498Palliative Care 2498Personal Websites that Facilitate Communication 2498Survivorship 2498Transportation 2498Wish Foundations 2499177.Rehabilitation of the Cancer Patient . . . . 2500Michael D. StubblefieldThe Rehabilitation Team 2500Complications of Cancer and its Treatment 2501Neuromuscualr Complications of Cancer and Cancer Treatment 2503Musculoskeletal Complications of Cancer and CancerTreatment 2510Radiation Fibrosis Syndrome 2513Lymphedema 2518Rehabilittion Interventions 2519Nonpharmacologic Pain Management 2521Section 21: Societal Issues in Oncology178.Regulatory Issues . . . . . . . . . . . . . . . . . . . 2523Ann T. Farrell, Grant A. Williams, and Richard PazdurThe History of Food and Drug Administration Regulation ofDrugs and Biologics 2523Food and Drug Administration Oversight of Clinical Trials forDrugs and Biologics 2523The Basis for Cancer Drug Approval 2525Drug Safety Reporting and Evaluation 2527Expanded Access to Investigational Drugs 2527Regulation of Devices for Cancer Treatment and Diagnosis 2528179.Health Disparities in Cancer . . . . . . . . . . 2532Harold P. FreemanRace and Cancer 2534Relationships Between Culture and Cancer 2535Poverty as a Cause of Cancer Disparities 2535Patient Navigation 2535The Harlem Breast Cancer Experience 2536Discussion 2538What Must be Done to Diminish Cancer Disparities 2538180.Cancer Information on the Internet . . . . . 2540Sherri L. Place and J. Robert BeckBackground 2540Tools for Finding Information 2540Evaluating Information 2541Search Strategies 2543Useful Tools for Keeping Up 2544Section 22: Complementary, Alternative, andIntegrative Therapies181.Therapies in Cancer Care . . . . . . . . . . . . . 2550Complementary, Alternative, and IntegrativeCatherine Ulbricht, Lorenzo Cohen, and Richard LeeBackground 2550Establishing an Integrative Oncology Approach with Patients 2550Standardization and Quality 2555Specific Complementary and Alternative MedicineTherapies 2556
Index 2563