DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology 11th Edition 2019
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CONTENTS
Contributing Authors.......................................................................................................................v
Preface ..........................................................................................................................................xxi
Acknowledgments........................................................................................................................xxiii
PART I
Molecular Biology of Cancer

1. The Cancer Genome ....................................................................................................................2
Yardena Samuels, Alberto Bardelli, Yochai Wolf, and Carlos López-Otin
Introduction 2
Cancer Genes and Their Mutations 2
Identification of Cancer Genes 2
Somatic Alteration Classes Detected by Cancer Genome Analysis 9
Pathway-Oriented Models of Cancer Genome Analysis 11
Networks of Cancer Genome Projects 13
The Genomic Landscape of Cancers 15
Integrative Analysis of Cancer Genomics 15
Immunogenomics 16
The Cancer Genome and the New Taxonomy of Tumors 17
Cancer Genomics and Drug Resistance 20
Perspectives of Cancer Genome Analysis 21
Acknowledgments 21

2. Molecular Methods in Cancer....................................................................................................25
Larissa V. Furtado, Jay L. Hess, and Bryan L. Betz
Applications of Molecular Diagnostics in Oncology 25
The Clinical Molecular Diagnostics Laboratory: Rules and Regulations 29
Specimen Requirements for Molecular Diagnostics 29
Molecular Diagnostics Testing Process 29
Targeted Mutation Analysis Methods 30
Whole-genome Analysis Methods 36
Immunohistochemistry for Tumor Biomarkers 39
Cell-Free DNA Technologies 40

3. Hallmarks of Cancer: An Organizing Principle for Cancer Medicine.......................................43
Douglas Hanahan and Robert A. Weinberg
Introduction 43
Hallmark Capabilities, in Essence 43
Two Ubiquitous Characteristics Facilitate the Acquisition of Hallmark Capabilities 53
The Constituent Cell Types of the Tumor Microenvironment 55
Therapeutic Targeting of the Hallmarks of Cancer 61
Conclusion and a Vision for the Future 61
Acknowledgment 62

4. Microbiome and Cancer.............................................................................................................66
Giorgio Trinchieri
Introduction 66
Cancer as a Disease of the Metaorganism 66
Bacteria as Cause of Cancer 66
Bacteria as Cancer Drugs 70
Microbiota and Drug Metabolism 70
Microbiota and Chemotherapy 71
Microbiota and Immunotherapy 71
Looking Forward 74

5. Cancer Susceptibility Syndromes..............................................................................................77
Alice Hawley Berger and Pier Paolo Pandolfi
Introduction 77
Principles of Cancer Susceptibility 77
Genetic Testing 80
Cancer Susceptibility Syndromes 80
Principles of Cancer Chemoprevention 85
Emerging Knowledge and New Lessons 85
Conclusion 87

PART II
Etiology and Epidemiology of Cancer

SECTION 1. ETIOLOGY OF CANCER

6. Tobacco......................................................................................................................................90
Richard J. O’Connor
Introduction 90
Epidemiology of Tobacco and Cancer 90
Carcinogens in Tobacco Products and Processes of Cancer Development 92
Conclusion 96

7. Oncogenic Viruses.....................................................................................................................98
Christopher B. Buck, Lee Ratner, and Giovanna Tosato
Principles of Tumor Virology 98
Papillomaviruses 100
Polyomaviruses 102
Epstein-Barr Virus 104
Kaposi Sarcoma Herpesvirus 105
Animal and Human Retroviruses 107
Hepatitis Viruses 109
Conclusion 111

8. Inflammation............................................................................................................................114
Michael D. Green and Weiping Zou
Introduction 114
Tumor-Intrinsic Inflammation 114
Tumor-Extrinsic Inflammation 114
Inflammatory Cell Subsets in the Cancer Microenvironment 115
Inflammatory Molecular Mediators in Cancer 116
Cellular Mechanisms of Inflammation in Cancer 118
Molecular Mechanisms of Inflammation in Cancer 118
Inflammation as a Therapeutic Target 119

9. Chemical Factors .....................................................................................................................120
Amanda K. Ashley and Christopher J. Kemp
Introduction 120
Initial Identification and Characterization of Carcinogens 120
Determining Carcinogenicity 121
Characteristics of Chemical Carcinogens 123
Outlook 124

10. Physical Factors.....................................................................................................................125
Mats Ljungman
Introduction 125
Ionizing Radiation 126
Ultraviolet Light 128
Radiofrequency and Microwave Radiation 130
Electromagnetic Fields 130
Asbestos 130
Nanoparticles 131

11. Dietary Factors.......................................................................................................................133
Karin B. Michels and Walter C. Willett
Introduction 133
Methodologic Challenges 133
The Role of Individual Food and Nutrients in Cancer Etiology 134
Other Foods and Nutrients 138
Dietary Patterns 140
Diet during Early Phases of Life 140
Diet after a Diagnosis of Cancer 141
The Microbiome 142
Summary 142
Limitations 142
Future Directions 143
Recommendations 143

12. Obesity and Physical Activity................................................................................................145
Justin C. Brown, Jeffrey A. Meyerhardt, and Jennifer A. Ligibel
Introduction 145
Obesity 145
Obesity and Cancer Risk 145
Obesity and Cancer Outcomes 145
Obesity and Cancer Treatment–Related Complications 146
Interventions 146
Physical Activity 147
Physical Activity and Cancer Risk 147
Physical Activity and Cancer Outcomes 148
Sedentary Behavior 148
Interventions 149
Mechanistic Data 149
Weight and Physical Activity Guidelines 149
American Society of Clinical Oncology Obesity Initiative 149
Conclusion 150

SECTION 2. EPIDEMIOLOGY OF CANCER

13. Epidemiologic Methods.........................................................................................................152
Xiaomei Ma and Herbert Yu
Introduction 152
Analytical Studies 152
Interpretation of Epidemiologic Findings 155
Cancer Outcomes Research 155
Molecular Epidemiology 156

14. Global Cancer Incidence and Mortality.................................................................................160
Ahmedin Jemal, Lindsey A. Torre, and Michael J. Thun
Introduction 160
Geographic and Temporal Variations in Risk 160
Data Sources 161
Measures of Burden 161
Measures of Risk 164
Demographic Factors that Affect Risk 165
Temporal Trends 170
Incidence and Mortality Patterns for Common Cancers 173
Issues in Interpreting Temporal Trends 180
Conclusion 181

PART III
Cancer Therapeutics

15. Precision Medicine in Oncology............................................................................................186
James H. Doroshow
Introduction 186
Approach to Precision Medicine in Oncology 186
Preclinical Models to Inform Precision Oncology 188
Role of Molecular Pharmacodynamics and Diagnostics in Precision Oncology 189
Precision Oncology Clinical Trials and Trial Designs 190
Imaging and Precision Oncology 193
Precision Prevention 194
Future Prospects 194

16. Essentials of Radiation Therapy ............................................................................................196
Meredith A. Morgan, Randall K. Ten Haken, and Theodore S. Lawrence
Introduction 196
Biologic Aspects of Radiation Oncology 196
Factors that Affect Radiation Response 201
Drugs that Affect Radiation Sensitivity 203
Radiation Physics 204
Treatment Planning 208
Other Treatment Modalities 210
Clinical Applications of Radiation Therapy 211
Treatment Intent 212
Fractionation 213
Adverse Effects 214
Principles of Combining Anticancer Agents with Radiation Therapy 215

17. Cancer Immunotherapy..........................................................................................................218
Jeffrey Weber and Iulia Giuroiu
Introduction 218
Interferon-a 218
Interleukin-2 219
Talimogene Laherparepvec 220
Granulocyte Macrophage Colony-stimulating Factor 220
Tumor-Infiltrating Lymphocytes 221
Checkpoint Inhibitors—Cytotoxic T-Lymphocyte Antigen 4 and Programmed Cell Death
Protein 1 221
Cytotoxic T-Lymphocyte Antigen 4 Blockade 223
Programmed Cell Death Protein 1 and Programmed Cell Death Protein Ligand 1
Blockade 223
Vaccines 227
Conclusion 227

18. Pharmacokinetics and Pharmacodynamics of Anticancer Drugs ..........................................231
Alex Sparreboom and Sharyn D. Baker
Introduction 231
Pharmacokinetic Concepts 231
Pharmacodynamic Concepts 232
Variability in Pharmacokinetics/ Pharmacodynamics 233
Dose Adaptation Using Pharmacokinetic/Pharmacodynamic Principles 238

19. Pharmacogenomics................................................................................................................239
Christine M. Walko and Howard L. McLeod
Introduction 239
Pharmacogenomics of Tumor Response 240
Pathway-Directed Anticancer Therapy 240
Genetic-Guided Therapy: Practical Issues in Somatic Analysis 242
Pharmacogenomics of Chemotherapy Drug Toxicity 243
Conclusions and Future Directions 244

20. Alkylating Agents..................................................................................................................246
Kenneth D. Tew
Historical Perspectives 246
Chemistry 246
Classification 246
Clinical Pharmacokinetics/Pharmacodynamics 250
Therapeutic Uses 251
Toxicities 252
Complications with High-Dose Alkylating Agent Therapy 253
Alkylating Agent–Steroid Conjugates 254
Drug Resistance and Modulation 254
Future Perspectives 254

21. Platinum Analogs...................................................................................................................256
Kim A. Reiss, A. Hilary Calvert, and Peter J. O’Dwyer
Introduction 256
History 256
Platinum Chemistry 257
Platinum Complexes after Cisplatin 257
Mechanism of Action 258
Cellular Responses to Platinum-Induced DNA Damage 259
Mechanisms of Resistance 260
Clinical Pharmacology 262

22. Antimetabolites......................................................................................................................265
James J. Lee and Edward Chu
Antifolates 265
5-Fluoropyrimidines 269
Capecitabine 271
Trifluridine/Tipiracil 271
Cytarabine 271
Gemcitabine 272
6-Thiopurines 273
Fludarabine 273
Cladribine 274
Clofarabine 274

23. Topoisomerase-Interacting Agents........................................................................................276
Anish Thomas, Khanh Do, Shivaani Kummar, James H. Doroshow, and Yves Pommier
Biochemical and Biologic Functions of Topoisomerases 276
Topoisomerase Inhibitors as Interfacial Poisons 276
Topoisomerase I Inhibitors: Camptothecins and Beyond 278
Topoisomerase II Inhibitors: Intercalators and Nonintercalators 281
Future Directions 285

24. Antimicrotubule Agents.........................................................................................................288
Christopher J. Hoimes
Microtubules 288
Taxanes 288
Vinca Alkaloids 292
Microtubule Antagonists 294
Mitotic Motor Protein Inhibitors 294
Mechanisms of Resistance to Microtubule Inhibitors 295
Summary 295

25. Kinase Inhibitors as Anticancer Drugs..................................................................................297
Gopa Iyer, Debyani Chakravarty, and David B. Solit
Introduction 297
Validating Mutated Kinases as Cancer Drug Targets—the Development of Imatinib for
Patients with Chronic Myelogenous Leukemia and Gastrointestinal Stromal Tumors
301
The Development of HER2-Targeted Therapies in Breast and Other Cancers 302
The Development of EGFR Tyrosine Kinase Inhibitors in Lung Cancer 303
Identifying Therapeutic Targets in EGFR Wildtype Lung Cancers 304
RAF and MEK Inhibitors for BRAF-Mutant Tumors 305
PI3 Kinase Pathway Inhibitors 307
One Target or Several: Multitargeted Kinase Inhibitor Therapy in Renal Cell Carcinoma
and Medullary Thyroid Cancer 308
CDK4/6 Inhibitors 308
Bruton Tyrosine Kinase Inhibitors 309
A Potential Pan Cancer Drug Target—TRK Inhibitors 309
Future Directions 310

26. Histone Deacetylase Inhibitors and Demethylating Agents ..................................................312
Stephen B. Baylin
Introduction 312
Epigenetic Abnormalities and Gene Expression Changes in Cancer 312
Histone Deacetylase Inhibitors 316
Epigenetic Therapy for Hematologic Malignancies 317
New Approaches to Epigenetic Therapy 318

27. Proteasome Inhibitors ............................................................................................................320
Ajay K. Nooka, Vikas A. Gupta, Christopher J. Kirk, and Lawrence H. Boise
Biochemistry of the Ubiquitin-Proteasome Pathway 320
Proteasome Inhibitors 320
Proteasome Inhibitors in Cancer 322

28. Poly(ADP-Ribose) Polymerase Inhibitors for Tumors with Defects in DNA Repair...........333
Alan Ashworth
Introduction 333
Cellular DNA Repair Pathways 333
BRCA1 and BRCA2 Mutations and DNA Repair 333
The Development of PARP Inhibitors 334
PARP-1 Inhibition as a Synthetic Lethal Therapeutic Strategy for the Treatment of
BRCA-Deficient Cancers 334
Initial Clinical Results Testing Synthetic Lethality of PARP Inhibitors and BRCA
Mutation 334
PARP Inhibitors Approved for Clinical Use 335
The Use of PARP Inhibitors in Non-BRCA Germline Mutant Cancers 335
Mechanisms of Resistance to PARP Inhibitors 335
Future Prospects 336

29. Miscellaneous Chemotherapeutic Agents..............................................................................337
M. Sitki Copur, Ryan Ramaekers, David Crockett, and Dron Gauchan
Homoharringtonine and Omacetaxine 337
L-Asparaginase 338
Bleomycin 338
Procarbazine 338
Dactinomycin 339
Vismodegib 339
Ado-Trastuzumab Emtansine 339
Sirolimus and Temsirolimus 340
Everolimus 340
Thalidomide, Lenalidomide, and Pomalidomide 341
Miscellaneous Agents with Potential for Repurposable Chemotherapeutic Use 342

30. Hormonal Agents...................................................................................................................347
Karthik V. Giridhar, Manish Kohli, and Matthew P. Goetz
Introduction 347
Selective Estrogen Receptor Modulators 347
Aromatase Inhibitors 351
Resistance to Endocrine-Targeted Therapy in Breast Cancer 352
Gonadotropin-Releasing Hormone Analogs 353
Antiandrogens 354
Resistance to Androgen Therapies in Prostate Cancer 355
Other Sex Steroid Therapies 356
Other Hormonal Therapies 356

31. Monoclonal Antibodies..........................................................................................................359
Hossein Borghaei, Matthew K. Robinson, Gregory P. Adams, and Louis M. Weiner
Introduction 359
Immunoglobulin Structure 359
Modified Antibody-Based Molecules 359
Factors Regulating Antibody-Based Tumor Targeting 359
Unconjugated Antibodies 361
Altering Signal Transduction 362
Immunoconjugates 362
Antibodies Approved for Use in Solid Tumors 363
Antibodies Used in Hematologic Malignancies 364
Conclusion 366

32. Immunotherapy Agents..........................................................................................................369
Jeffrey A. Sosman and Douglas B. Johnson
Introduction 369
Human Tumor Antigens 369
Tumor Vaccines 370
Oncolytic Viruses 377
Factors to Activate Immune Effector Cells 378
Signaling Modulation 379
Soluble Factors 380
Adenosine A2a Receptor Axis 380
Innate Immune Modulation 381
Bifunctional Fusion Proteins 381
PART IV
Cancer Prevention and Screening

33. Tobacco Use and the Cancer Patient .....................................................................................388
Graham W. Warren and Vani N. Simmons
Introduction 388
Tobacco Use Epidemiology, Addiction, and Tobacco Product Evolution 388
Electronic Nicotine Delivery Systems, or Electronic Cigarettes 388
Defining Tobacco Use by the Cancer Patient 389
Tobacco Use and Cessation by the Cancer Patient 390
Smoking Cessation in the Context of Lung Cancer Screening 390
The Clinical Effects of Smoking on Cancer Patients 390
Addressing Tobacco Use by the Cancer Patient 393
Research Considerations and the Future of Addressing Tobacco Use by Cancer Patients
398

34. Role of Surgery in Cancer Prevention ...................................................................................401
José G. Guillem, Andrew Berchuck, Jeffrey A. Norton, Preeti Subhedar, Kenneth P.
Seastedt, and Brian R. Untch
Introduction 401
Risk-Reducing Surgery in Breast Cancer 401
Hereditary Diffuse Gastric Cancer 403
Surgical Prophylaxis of Hereditary Ovarian and Endometrial Cancer 405
Multiple Endocrine Neoplasia Type 2 408
Hereditary Colorectal Cancer Syndromes: Familial Adenomatous Polyposis, MUTYHAssociated Polyposis, and Lynch Syndrome 412

35. Cancer Risk–Reducing Agents..............................................................................................419
Dean E. Brenner and Scott M. Lippman
Why Cancer Prevention as a Clinical Oncology Discipline 419
Defining Cancer Risk–Reducing Agents (Chemoprevention) 420
Identifying Potential Cancer Risk–Reducing Agents 421
Preclinical Development of Cancer Risk–Reducing Agents 421
Clinical Development of Cancer Risk–Reducing Agents 422
Micronutrients 424
Anti-Inflammatory Drugs 429
Posttranslational Pathway Targets 431
Diet-Derived Natural Products 435
Anti-Infectives 436

36. Prophylactic Cancer Vaccines ...............................................................................................444
John T. Schiller and Olivera J. Finn
Introduction 444
Overview of Infectious Agents in Cancer 445
Hepatitis B Vaccines 446
Human Papillomavirus Vaccines 447
Prospects for Prophylactic Vaccines against Other Oncogenic Microbes 448
Vaccines for Cancers of Noninfectious Etiology: Tumor-Specific and Tumor-Associated
Target Antigens 450
Therapeutic Cancer Vaccines Have Set the Stage for Preventative Cancer Vaccines 451
Prophylactic Vaccines for Cancers of Noninfectious Etiology 452

37. Cancer Screening ...................................................................................................................454
Otis W. Brawley and Howard L. Parnes
Introduction 454
Performance Characteristics of a Screening Test 455
Assessing a Screening Test 455
Screening Guidelines and Recommendations 457
Breast Cancer Screening 457
Gastrointestinal Tract Cancers 460
Gynecologic Cancer 462
Lung Cancer Screening 464
Prostate Cancer Screening 465
Skin Cancer Screening 467

38. Genetic Counseling................................................................................................................471
Danielle C. Bonadies, Meagan B. Farmer, and Ellen T. Matloff
Introduction 471
Who Is a Candidate for Cancer Genetic Counseling? 472
Components of the Cancer Genetic Counseling Session 473
Issues in Cancer Genetic Counseling 477
Future Directions 481
Conclusion 482

PART V
Practice of Oncology

39. Design and Analysis of Clinical Trials..................................................................................486
Richard M. Simon
Introduction 486
Phase I Clinical Trials 486
Phase II Clinical Trials 487
Design of Phase III Clinical Trials 491
Factorial Designs 495
Analysis of Phase III Clinical Trials 496
Reporting Results of Clinical Trials 498
False-positive Reports in the Literature 498
Meta-analysis 499

40. Assessment of Clinical Response ..........................................................................................501
Susan Bates and Tito Fojo
Introduction 501
Assessing Response 501
Determining Outcome 505

41. Vascular Access.....................................................................................................................513
Mohammad S. Jafferji and Stephanie L. Goff
Introduction 513
Catheter Types 513
External Catheters 513
Implantable Devices 514
Catheter Selection 516
Pediatric Patients 516
Insertion Techniques 516
Catheter-Related Complications 517

42. Endoscopic and Robotic Surgery...........................................................................................519
Jeremy L. Davis, R. Taylor Ripley, and Jonathan M. Hernandez
Introduction 519
Physiologic Effects of Endoscopic Surgery 520
Applications of Endoscopic and Robotic Surgery 520
Special Topics 522
Gastrointestinal and Hepatopancreatobiliary Cancers 524
Genitourinary and Gynecologic Oncology 525
Emerging Techniques 526
Conclusion 526

43. Tumor Biomarkers.................................................................................................................528
Corey W. Speers and Daniel F. Hayes
Introduction 528
Uses for Tumor Biomarker Tests 528
What Are the Criteria to Incorporate a Tumor Biomarker Test into Clinical Practice? 530
Tumor Biomarker Tests that Are Accepted for Routine Clinical Utility 534
Special Circumstances 534
Tumor Biomarker Tests of Radiation Response 534
Conclusion 534

SECTION 1. CANCER OF THE HEAD AND NECK

44. The Molecular Biology of Head and Neck Cancers..............................................................536
Thomas E. Carey, Mark E. Prince, and J. Chad Brenner
Incidence, Risk Factors, and Etiology 536
Oral Tongue Cancer in Young Patients 536
High-Risk HPV in Oropharyngeal Cancer 536
Molecular Mechanisms in HNSCC 537
The Cancer Genome Atlas Project 538
Inhibition of HNSCC Immune Escape 539
Cancer Stem Cells 539

45. Cancer of the Head and Neck ................................................................................................542
William M. Mendenhall, Peter T. Dziegielewski, and David G. Pfister
Incidence and Etiology 542
Anatomy and Pathology 542
Natural History 543
Diagnosis 543
Staging 544
Principles of Treatment for Squamous Cell Carcinoma 545
Management 545
NECK 546
Clinically Negative Neck 546
Clinically Positive Neck Lymph Nodes 547
Chemotherapy 547
General Principles of Combining Modalities 550
Chemotherapy as Part of Curative Treatment 551
Follow-up 556
ORAL CAVITY 556
Lip 556
Floor of the Mouth 557
Oral Tongue 559
Buccal Mucosa 560
Gingiva and Hard Palate (Including Retromolar Trigone) 561
OROPHARYNX 563
Anatomy 563
Pathology 563
Patterns of Spread 563
Clinical Picture 564
Staging 564
Treatment: Tonsillar Fossa 564
Results of Treatment: Tonsillar Area 566
Complications of Treatment: Tonsillar Area 567
Treatment: Base of Tongue 567
Results of Treatment: Base of Tongue 567
Follow-up: Base of Tongue 568
Complications of Treatment: Base of Tongue 568
Treatment: Soft Palate 568
Results of Treatment: Soft Palate 568
Complications of Treatment: Soft Palate 568
LARYNX 569
Anatomy 569
Pathology 569
Patterns of Spread 569
Clinical Picture 569
Differential Diagnosis and Staging 570
Treatment: Vocal Cord Carcinoma 570
Treatment: Supraglottic Larynx Carcinoma 572
Treatment: Subglottic Larynx Carcinoma 572
Treatment: Supraglottic Larynx Cancer 573
HYPOPHARYNX: PHARYNGEAL WALLS, PYRIFORM SINUS, AND
POSTCRICOID PHARYNX 574
Anatomy 574
Pathology 574
Patterns of Spread 574
Clinical Picture 575
Staging 575
Treatment 575
Results of Treatment 576
Complications of Treatment 577
NASOPHARYNX 577
Anatomy 577
Pathology 577
Patterns of Spread 577
Clinical Picture 577
Staging 578
Treatment 578
Results of Treatment 579
Follow-up 579
Complications of Treatment 579
NASAL VESTIBULE, NASAL CAVITY, AND PARANASAL SINUSES 579
Anatomy 579
Pathology 580
Patterns of Spread 580
Clinical Picture 581
Staging 581
Treatment 582
Results of Treatment 583
Complications of Treatment 583
PARAGANGLIOMAS 584
Anatomy 584
Pathology 584
Patterns of Spread 584
Staging 584
Treatment 584
Results of Treatment 584
Complications of Treatment 584
MAJOR SALIVARY GLANDS 585
Anatomy 585
Pathology 585
Patterns of Spread 586
Clinical Picture 586
Differential Diagnosis 586
Staging 586
Treatment 586
Results of Treatment 587
Complications of Treatment 588
MINOR SALIVARY GLANDS 588
Anatomy 588
Pathology 588
Patterns of Spread 589
Clinical Picture 589
Treatment 589
Results of Treatment 589

46. Rehabilitation after Treatment of Head and Neck Cancer.....................................................598
Douglas B. Chepeha and Teresa H. Lyden
Introduction 598
Pretreatment Counseling 598
Support during Treatment and Rehabilitation of the Chemoradiation Patient 598
Resources for Rehabilitation of Head and Neck Cancer Patients 605
SECTION 2. CANCER OF THE THORACIC CAVITY

47. The Molecular Biology of Lung Cancer................................................................................607
Jill E. Larsen and John D. Minna
Introduction 607
Genomics: Tools for Identification, Prediction, and Prognosis 607
Functional Genomics in Lung Cancer 609
Genetic and Epigenetic Alterations in Lung Cancer 610
Metastasis and the Tumor Microenvironment 614
Lung Cancers Stem Cells 615
Telomerase-Mediated Cellular Immortality in Lung Cancer 615
Clinical Translation of Molecular Data 615

48. Non–small-cell Lung Cancer.................................................................................................618
Anne Chiang, Frank C. Detterbeck, Tyler Stewart, Roy H. Decker, and Lynn Tanoue
Introduction 618
Incidence and Etiology 618
Anatomy and Pathology 622
Screening and Prevention 626
Diagnosis 628
Stage Evaluation 629
Management by Stage 631
Special Clinical Situations 654
Palliative Care 657
Conclusion 659

49. Small Cell and Neuroendocrine Tumors of the Lung............................................................671
Christine L. Hann, M. Abraham Wu, Natasha Rekhtman, and Charles M. Rudin
Introduction 671
Small Cell Lung Cancer 671
Typical Carcinoid and Atypical Carcinoid Tumors 687
Large Cell Neuroendocrine Carcinoma 690

50. Neoplasms of the Mediastinum .............................................................................................700
Robert B. Cameron, Patrick J. Loehrer Sr., Alexander Marx, and Percy P. Lee
Thymic Neoplasms 700
Thymoma 700
Thymic Carcinoma 702
Germ Cell Tumors 707

SECTION 3. CANCERS OF THE GASTROINTESTINAL TRACT

51. Molecular Biology of the Esophagus and Stomach...............................................................713
Anil K. Rustgi
Introduction 713
Molecular Biology of Esophageal Cancer 713
Molecular Biology of Gastric Cancer 715

52. Cancer of the Esophagus........................................................................................................718
Mitchell C. Posner, Karyn A. Goodman, and David H. Ilson
Introduction 718
Epidemiology 718
Etiologic Factors and Predisposing Conditions 718
Applied Anatomy and Histology 721
Natural History and Patterns of Failure 723
Clinical Presentation 723
Diagnostic Studies and Pretreatment Staging Tools 723
Staging Guidelines 724
Treatment 724
Predictors of Treatment Response 743
Palliation of Esophageal Cancer with Radiation Therapy 746
Radiotherapy Techniques 746
Treatment of Metastatic Disease 749
Stage-Directed Treatment Recommendations 753

53. Cancer of the Stomach...........................................................................................................762
Itzhak Avital, Aviram Nissan, Talia Golan, Yaacov Richard Lawrence, and Alexander
Stojadinovic
Introduction 762
Anatomic Considerations 762
Pathology and Tumor Biology 763
Histopathology 763
Molecular Classification of Gastric Cancer 764
Patterns of Spread 764
Clinical Presentation and Pretreatment Evaluation 765
Pretreatment Staging 766
Staging, Classification, and Prognosis 767
Gastric Cancer Nomograms: Predicting Individual Patient Prognosis after Potentially
Curative Resection 770
Treatment of Localized Disease 772
Technical Treatment-Related Issues 781
Treatment of Advanced Disease (Stage IV) 782
Surgery in Treatment of Metastatic Gastric Cancer 788
Gastric Cancer in the Elderly 789

54. The Molecular Biology of Pancreas Cancer..........................................................................797
Scott E. Kern and Ralph H. Hruban
Introduction 797
Common Genetic Changes in Pancreatic Ductal Adenocarcinoma 797
Less-Prevalent Genetic Changes in Pancreatic Ductal Adenocarcinoma 800
Other Neoplastic Lesions 801

55. Cancer of the Pancreas...........................................................................................................804
Jordan M. Winter, Jonathan R. Brody, Ross A. Abrams, James A. Posey, and Charles J.
Yeo
Incidence and Etiology 804
Anatomy and Pathology 805
Exocrine Pancreatic Cancers 805
Endocrine Pancreatic Cancers 809
Pancreatic Ductal Adenocarcinoma: Screening 809
Pancreatic Ductal Adenocarcinoma: Diagnosis 810
Pancreatic Ductal Adenocarcinoma: Staging 811
Stages I and II: Localized Pancreatic Ductal Adenocarcinoma 811
Stage III: Locally Advanced Disease 820
Emerging Role of Stereotactic Body Radiotherapy 824
Stage IV: Metastatic Disease 824
Future Directions and Challenges 829
Conclusion 830

56. Molecular Biology of Liver Cancer.......................................................................................837
Jens U. Marquardt and Snorri S. Thorgeirsson
Introduction 837
Genetic Alterations in Liver Cancer 837
Epigenetic Alterations in Liver Cancer 838
Mutational Landscape of Genetic Alterations—the Next Generation 839
The Microenvironment of Liver Cancer 839
Classification and Prognostic Prediction of Hepatocellular Carcinoma 841
Molecular Basis of Cholangiocarcinoma 842
Conclusion and Perspective 842

57. Cancer of the Liver ................................................................................................................844
Yuman Fong, Damian E. Dupuy, Mary Feng, and Ghassan Abou-Alfa
Introduction 844
Epidemiology 845
Etiologic Factors 845
Diagnosis 846
Staging 846
Treatment of Hepatocellular Carcinoma 847
Adjuvant and Neoadjuvant Therapy 850
Treatment of Other Primary Liver Tumors 861

58. Cancer of the Biliary Tree......................................................................................................865
Tushar Patel and Kabir Mody
Introduction 865
Anatomy of the Biliary Tract 865
Cholangiocarcinoma 866
Gallbladder Cancer 877
Acknowledgments 881

59. Small Bowel Cancer ..............................................................................................................884
Ronald Chamberlain, Nasrin Ghalyaie, and Sachin Patil
Introduction 884
Small Bowel Adenocarcinoma 886
Carcinoid Tumors 889
Small Bowel Lymphoma 891
Gastrointestinal Stromal Tumor 892
Metastatic Cancer to the Small Bowel 892

60. Gastrointestinal Stromal Tumor.............................................................................................895
Paolo G. Casali, Angelo Paolo Dei Tos, and Alessandro Gronchi
Introduction 895
Incidence and Etiology 895
Anatomy and Pathology 895
Screening 898
Diagnosis 898
Staging 899
Management by Stage 900
Palliative Care 905

61. Molecular Biology of Colorectal Cancer...............................................................................907
Ramesh A. Shivdasani
Introduction 907
Multistep Models of Colorectal Cancer and Genetic Instability 907
Mutational and Epigenetic Landscapes in Colorectal Cancer 909
Insights from Mouse Intestinal Crypts and Human Colorectal Cancers Lead to a Coherent
Model for Colorectal Cancer Initiation and Progression 910
Inherited Syndromes of Increased Cancer Risk Highlight Early Events and Critical
Pathways in Colorectal Tumorigenesis 911
Oncogene and Tumor Suppressor Gene Mutations in Colorectal Cancer Progression 914

62. Cancer of the Colon ...............................................................................................................918
Steven K. Libutti, Leonard B. Saltz, Christopher G. Willett, and Rebecca A. Levine
Introduction 918
Epidemiology 918
Etiology: Genetic, Environmental, and Other Risk Factors 919
Familial Colorectal Cancer 922
Anatomy of the Colon 923
Diagnosis of Colorectal Cancer 924
Screening for Colorectal Cancer 925
Staging and Prognosis of Colorectal Cancer 926
Approaches to Surgical Resection of Colon Cancer 933
Surgical Management of Complications from Primary Colon Cancer 935
Laparoscopic Colon Resection 936
Polyps and Stage I Colon Cancer 937
Stage II and Stage III Colon Cancer 937
Treatment of Stage II Patients 940
Treatment Options for Stage III Patients 942
Investigational Adjuvant Approaches 943
Follow-up after Management of Colon Cancer with Curative Intent 944
Surgical Management of Stage IV Disease 946
Management of Unresectable Metastatic Disease 946
Molecular Predictive Markers 961

63. Cancer of the Rectum.............................................................................................................970
Steven K. Libutti, Christopher G. Willett, Leonard B. Saltz, and Rebecca A. Levine
Introduction 970
Anatomy 970
Staging 971
Surgery 974
Does Adjuvant Radiation Therapy Impact Survival? 981
Preoperative Radiation Therapy 982
Which Patients Should Receive Adjuvant Therapy? 984
Support of Nonoperative Management 985
Total Neoadjuvant Therapy 985
Concurrent Chemotherapy 987
Synchronous Rectal Primary and Metastases 989
Management of Unresectable Primary and Locally Advanced Disease (T4) 989
Management of Locally Recurrent Disease 990
Reirradiation in Recurrent Disease 990
Radiation Therapy Technique 990
Radiation Fields 991

64. Cancer of the Anal Region.....................................................................................................997
Brian G. Czito, Shahab Ahmed, Matthew F. Kalady, and Cathy Eng
Introduction 997
Epidemiology and Etiology 997
Screening and Prevention 998
Pathology 999
Clinical Presentation and Staging 1000
Prognostic Factors 1002
Treatment of Localized Squamous Cell Carcinoma 1002
Treatment of Other Sites and Pathologies 1009

SECTION 4. CANCERS OF THE GENITOURINARY SYSTEM

65. Molecular Biology of Kidney Cancer..................................................................................1014
W. Marston Linehan and Laura S. Schmidt
Introduction 1014
Clear Cell Renal Cell Carcinoma 1014
Papillary Renal Cell Carcinoma 1015
Chromophobe Renal Cell Carcinoma 1018
Additional Types of Renal Cell Carcinoma 1018
Conclusion 1019

66. Cancer of the Kidney ...........................................................................................................1020
Andres F. Correa, Brian R. Lane, Brian I. Rini, and Robert G. Uzzo
Introduction 1020
Epidemiology, Demographics, and Risk Factors 1020
Pathology of Renal Cell Carcinoma 1020
Differential Diagnosis and Staging 1021
Hereditary Kidney Cancer Syndromes, Genetics, and Molecular Biology 1023
Treatment of Localized Renal Cell Carcinoma 1024
Treatment of Locally Advanced Renal Cell Carcinoma 1029
Surgical Management of Advanced Renal Cell Carcinoma 1031
Systemic Therapy for Advanced Renal Cell Carcinoma 1034
Conclusion and Future Directions 1038
Acknowledgments 1038

67. Molecular Biology of Bladder Cancer.................................................................................1042
Carolyn D. Hurst and Margaret A. Knowles
Introduction 1042
Mutational Landscape 1042
Heterogeneity and Clonal Evolution 1045
Molecular Subtypes 1046
Therapeutic Opportunities and Future Outlook 1048

68. Cancer of the Bladder, Ureter, and Renal Pelvis.................................................................1050
Adam S. Feldman, Richard J. Lee, David T. Miyamoto, Douglas M. Dahl, and Jason A.
Efstathiou
Introduction 1050
Cancer of the Bladder 1053
Cancers of the Renal Pelvis and Ureter 1067

69. The Molecular Biology of Prostate Cancer .........................................................................1076
Charles Dai and Nima Sharifi
Introduction 1076
The Genomic Landscape of Prostate Cancer 1076
The Molecular Subtypes of Primary Prostate Cancer 1077
The Clonal Evolution of Lethal Metastatic Prostate Cancer 1078
Genetic Basis of Prostate Cancer Heritability 1078
Androgen Signaling in Prostate Cancer 1079
Other Signaling Pathways in Prostate Cancer 1082
Areas of Ongoing Research and Emerging Therapeutic Approaches 1083
Conclusion 1083

70. Cancer of the Prostate ..........................................................................................................1087
Michael J. Zelefsky, Michael J. Morris, and James A. Eastham
Introduction 1087
Incidence and Etiology 1087
Anatomy and Pathology 1089
Diagnosis, Risk Assessment, and State Assignment 1093
Management by Clinical States 1097
Palliation 1126
Future Directions 1127

71. Cancer of the Urethra and Penis ..........................................................................................1136
J. Ryan Mark, Mark Hurwitz, and Leonard G. Gomella
Introduction 1136
Urethral Cancer in the Male 1136
Urethral Cancer in the Female 1138
Penile Cancer 1140

72. Cancer of the Testis .............................................................................................................1145
Matthew T. Campbell, Jose A. Karam, and Christopher J. Logothetis
Introduction 1145
Incidence and Epidemiology 1145
Initial Presentation and Management 1145
Histology 1146
Biology 1147
Immunohistochemical Markers 1149
Staging 1149
Management of Clinical Stage I Disease 1152
Management of Clinical Stage II Disease (Low Tumor Burden) 1154
Management of Stage II Disease with High Tumor Burden and Stage III Disease 1154
Management of Recurrent Disease 1157
Treatment Sequelae 1157
Long-term Follow-up 1158
Midline Tumors of Uncertain Histogenesis 1159
Other Testicular Tumors 1159

SECTION 5. GYNECOLOGIC CANCERS

73. Molecular Biology of Gynecologic Cancers........................................................................1163
Tanja Pejovic, Adam J. Krieg, and Kunle Odunsi
Introduction 1163
Ovarian Cancer 1163
Endometrial Cancer 1167
Cervix, Vaginal, and Vulvar Cancers 1168

74. Cancer of the Cervix, Vagina, and Vulva ............................................................................1171
Patricia J. Eifel, Ann H. Klopp, Jonathan S. Berek, and Panagiotis A. Konstantinopoulos
Carcinoma of the Cervix 1171
Carcinoma of the Vagina 1193
Carcinoma of the Vulva 1198

75. Cancer of the Uterine Body .................................................................................................1211
Kaled M. Alektiar, Nadeem R. Abu-Rustum, and Gini F. Fleming
Endometrial Carcinoma 1211
Uterine Sarcomas 1222

76. Gestational Trophoblastic Neoplasia ...................................................................................1227
Donald P. Goldstein, Ross S. Berkowitz, and Neil S. Horowitz
Introduction 1227
Incidence 1227
Pathology and Natural History 1227
Indications for Treatment 1227
Measurement of Human Chorionic Gonadotropin 1227
Pretreatment Evaluation 1228
Staging and Prognostic Score 1228
Treatment 1229
Placental Site or Epithelioid Trophoblastic Tumors 1230
Subsequent Pregnancy after Treatment for Gestational Trophoblastic Neoplasia 1230

77. Ovarian Cancer ....................................................................................................................1232
Krishnansu S. Tewari, Richard T. Penson, and Bradley J. Monk
Incidence and Etiology 1232
Anatomy and Pathology 1233
Screening and Prevention 1234
Diagnosis 1235
Presentation and Evaluation of Advanced Disease 1236
International Federation of Gynecology and Obstetrics Staging 1237
Management by Stage 1238
Management of Newly Diagnosed Advanced-Stage Disease 1239
Management of Recurrent Disease 1244
Antiangiogenesis Therapy 1246
PARP Inhibitors 1248
Clinical Implications of BRCA1/2 Mutation Status 1248
Olaparib 1249
Rucaparib 1250
Niraparib 1251
Veliparib 1252
Talazoparib 1252
BRCA1/2 Reversion Mutations 1252
Tolerability of PARP Inhibitors 1252
Immunotherapy 1253
Therapeutic Vaccines 1254
Toll-Like Receptors 1254
Oncolytic Viruses 1254
Chimeric Antigen Receptors 1254
Bispecific T-Cell Engagers 1255
Immune-Mediated Toxicity 1255
Immune-Related Response Criteria 1255

SECTION 6. CANCER OF THE BREAST

78. Molecular Biology of Breast Cancer ...................................................................................1259
Ana T. Nunes, Tara Berman, and Lyndsay Harris
Introduction 1259
Genetics of Breast Cancer 1259
Somatic Alterations in Breast Cancer 1261
Protein/Pathway Alterations 1265

79. Malignant Tumors of the Breast ..........................................................................................1269
Reshma Jagsi, Tari A. King, Constance Lehman, Monica Morrow, Jay R. Harris, and
Harold J. Burstein
Incidence and Etiology 1269
Management of the High-Risk Patient 1271
Anatomy and Pathology 1272
Diagnosis and Biopsy 1277
Staging 1277
Management by Stage: Ductal Carcinoma In Situ 1281
Management by Stage: Primary Operable Invasive Breast Cancer 1283
Management by Stage: Adjuvant Systemic Therapy 1293
Management by Stage: Special Considerations 1299
Management by Stage: Metastatic Disease 1303

SECTION 7. CANCER OF THE ENDOCRINE SYSTEM

80. Molecular Biology of Endocrine Tumors............................................................................1317
Zeyad T. Sahli, Brittany A. Avin, and Martha A. Zeiger
Endocrine Syndromes 1317
Adrenal Gland 1319
Parathyroid Gland 1321
Pituitary Gland 1322
Thyroid Gland 1322
Acknowledgments 1324

81. Thyroid Tumors...................................................................................................................1326
Anupam Kotwal, Caroline J. Davidge-Pitts, and Geoffrey B. Thompson
Anatomy and Physiology 1326
Thyroid Nodules 1326
Thyroid Tumor Classification and Staging Systems 1327
Differentiated Thyroid Cancer 1328
Treatment of Differentiated Thyroid Cancer 1329
Anaplastic Thyroid Carcinoma 1333
Medullary Thyroid Cancer 1333
Thyroid Lymphoma 1335
Children with Thyroid Carcinoma 1335

82. Parathyroid Tumors .............................................................................................................1338
Anupam Kotwal and Geoffrey B. Thompson
Incidence and Etiology 1338
Anatomy and Pathology 1338
Clinical Manifestations and Screening 1339
Diagnosis 1339
Staging 1340
Management of Parathyroid Cancer 1340
Follow-up and Natural History 1341
Prognosis 1341

83. Adrenal Tumors...................................................................................................................1343
Antonio M. Lerario, Dipika R. Mohan, Roy Lirov, Tobias Else, and Gary D. Hammer
Introduction 1343
Incidence and Etiology 1343
Anatomy and Pathology 1344
Screening 1346
Diagnosis 1346
Staging 1349
Management 1349
Palliative Care 1351

84. Pancreatic Neuroendocrine Tumors.....................................................................................1352
James C. Yao, Callisia N. Clarke, and Douglas B. Evans
Introduction 1352
Incidence and Etiology 1353
Classification, Histopathology, and Molecular Genetics 1353
Diagnosis and Management of Pancreatic Neuroendocrine Tumors 1356
Cytotoxic Chemotherapy 1359
Functional Tumors 1361
Additional Clinical Considerations 1363
Small, Nonfunctioning, Sporadic Pancreatic Neuroendocrine Tumors 1365

85. Carcinoid Tumors and the Carcinoid Syndrome .................................................................1368
Jeffrey A. Norton
Incidence and Etiology 1368
Anatomy and Pathology 1368
General Principles of Neuroendocrine Tumor Diagnosis, Staging, and Management 1368
Diagnosis, Staging, and Management by Primary Tumor Site 1370
Diagnosis and Management of Carcinoid Syndrome 1372
Antitumor Management 1373
Management of Liver Metastases 1375
Conclusions 1376

86. Multiple Endocrine Neoplasia .............................................................................................1377
Jeffrey A. Norton
Introduction 1377
Multiple Endocrine Neoplasia Type 1 1377
Multiple Endocrine Neoplasia Types 2 and 3 and Familial Medullary Thyroid Cancer
1380
Multiple Endocrine Neoplasia Type 4 1382

SECTION 8. SARCOMAS OF SOFT TISSUE AND BONE

87. Molecular Biology of Sarcomas ..........................................................................................1384
Samuel Singer and Cristina R. Antonescu
Introduction 1384
Soft Tissue Sarcomas 1384
Bone and Cartilaginous Tumors 1393
Future Directions: Next-Generation Sequencing and Functional Screens 1394

88. Soft Tissue Sarcoma ............................................................................................................1400
Samuel Singer, William D. Tap, David G. Kirsch, and Aimee M. Crago
Introduction 1400
Incidence and Etiology 1400
Anatomic and Age Distribution and Pathology 1402
Clinical and Pathologic Features of Specific Soft Tissue Tumor Types 1403
Diagnosis and Staging 1414
Management by Presentation Status, Extent of Disease, and Anatomic Location 1418
Palliative Care 1438
Future Directions 1438

89. Sarcomas of Bone ................................................................................................................1450
Richard J. O’Donnell, Steven G. DuBois, and Daphne A. Haas-Kogan
Introduction 1450
Incidence and Etiology 1451
Anatomy and Pathology 1451
Screening 1452
Diagnosis 1452
Staging 1456
Management by Diagnosis and Stage 1456
Continuing Care: Surveillance and Palliation 1468

SECTION 9. CANCERS OF THE SKIN

90. Cancer of the Skin................................................................................................................1475
Sean R. Christensen, Lynn D. Wilson, and David J. Leffell
General Approach to Nonmelanoma Skin Cancer 1475
Basal Cell Carcinoma 1478
Squamous Cell Carcinoma and Actinic Keratosis 1483
Merkel Cell Carcinoma 1489
Dermatofibrosarcoma Protuberans 1491
Angiosarcoma 1493
Microcystic Adnexal Carcinoma 1494
Sebaceous Carcinoma 1494
Extramammary Paget Disease 1495
Atypical Fibroxanthoma 1495

91. Molecular Biology of Cutaneous Melanoma.......................................................................1500
Michael A. Davies
Introduction 1500
The Cancer Genome Atlas Effort in Cutaneous Melanoma 1500
The RAS-RAF-MAPK Pathway 1501
Additional Oncogenic Pathways 1503
Melanin Synthesis Pathway 1506
Summary and Future Directions 1507

92. Cutaneous Melanoma...........................................................................................................1510
Antoni Ribas, Paul Read, and Craig L. Slingluff Jr.
Introduction 1510
Molecular Biology of Melanoma 1510
Epidemiology 1512
Changes in Incidence 1514
Sex and Age Distribution 1514
Melanoma in Children, Infants, and Neonates 1515
Anatomic Distribution 1515
Etiology and Risk Factors 1516
Prevention and Screening 1516
Diagnosis of Primary Melanoma 1518
General Considerations in Clinical Management of a Newly Diagnosed Cutaneous
Melanoma (Stages I and II) 1522
Clinical Trials to Define Margins of Excision for Primary Cutaneous Melanomas 1523
Surgical Staging of Regional Nodes 1524
Selection of Patients for Sentinel Node Biopsy 1527
Management 1527
Thick Melanomas (T4A, T4B, >4 mm Thick) 1530
Special Considerations in Management of Primary Melanomas 1530
Primary Melanomas of the Fingers and Toes 1531
The Role of Radiation Therapy in the Management of Primary Melanoma Lesions 1531
Clinical Follow-up for Intermediate-Thickness and Thick Melanomas (Stage IB to IIC)
1531
Regionally Metastatic Melanoma (Stage III): Lymph Node Metastasis, Satellite Lesions,
and In-Transit Metastases 1532
Management of Regional Metastases in Patients with Visceral or Other Distant Disease
1536
Adjuvant Systemic Therapy (Stages IIB, IIC, and III) 1537
Management of Distant Metastases of Melanoma (Stage IV) 1540
Radiation Therapy for Metastatic Melanoma (Stage IV) 1553

SECTION 10. NEOPLASMS OF THE CENTRAL NERVOUS SYSTEM

93. Molecular Biology of Central Nervous System Tumors .....................................................1561
Mark W. Youngblood, Jennifer Moliterno Günel, and Murat Günel
Introduction 1561
Pediatric Brain Tumors 1561
Adult Brain Tumors 1564
Summary 1566
Acknowledgments 1566

94. Neoplasms of the Central Nervous System .........................................................................1568
Susan M. Chang, Minesh P. Mehta, Michael A. Vogelbaum, Michael D. Taylor, and
Manmeet S. Ahluwalia
Epidemiology of Brain Tumors 1568
Classification 1569
Anatomic Location and Clinical Considerations 1571
Neurodiagnostic Tests 1572
Surgery 1574
Radiation Therapy 1575
Chemotherapy and Targeted Agents 1578
Specific Central Nervous System Neoplasms 1578
Gliomatosis Cerebri 1587
Optic, Chiasmal, and Hypothalamic Gliomas 1587
Brain Stem Gliomas 1589
Cerebellar Astrocytomas 1590
Gangliogliomas 1591
Ependymoma 1592
Meningiomas 1593
Primitive Neuroectodermal or Embryonal Central Nervous System Neoplasms 1595
Pineal Region Tumors and Germ Cell Tumors 1598
Pituitary Adenomas 1600
Craniopharyngiomas 1601
Vestibular Schwannomas 1602
Glomus Jugulare Tumors 1604
Hemangioblastomas 1605
Chordomas and Chondrosarcomas 1606
Choroid Plexus Tumors 1607
Spinal Axis Tumors 1608

SECTION 11. CANCERS IN ADOLESCENTS AND YOUNG ADULTS

95. Adolescents and Young Adults with Cancer .......................................................................1617
Archie Bleyer, Andrea Ferrari, Jeremy Whelan, and Ronald Barr
Epidemiology 1617
Etiology and Biology 1617
Signs, Symptoms, and Delays in Diagnosis 1620
Prevention and Screening 1622
Diagnosis 1623
Management 1623
Progress 1627
Future Challenges 1630

SECTION 12. LYMPHOMAS IN ADULTS

96. Molecular Biology of Lymphoma .......................................................................................1632
Nicolò Compagno, Laura Pasqualucci, and Riccardo Dalla-Favera
Introduction 1632
The Cell of Origin of Lymphoma 1632
General Mechanisms of Genetic Alterations in Lymphoma 1634
Molecular Pathogenesis of B-Cell Non-Hodgkin Lymphoma 1635
Molecular Pathogenesis of T-Cell Non-Hodgkin Lymphoma 1642
Molecular Pathogenesis of Hodgkin Lymphoma 1643

97. Hodgkin Lymphoma ............................................................................................................1648
Anas Younes, Ahmet Dogan, Peter Johnson, Joachim Yahalom, John Kuruvilla, and
Stephen Ansell
Introduction 1648
Pathology of Hodgkin Lymphoma 1648
Early-Stage Hodgkin Lymphoma 1654
Advanced-Stage Hodgkin Lymphoma 1657
Special Circumstances 1661

98. Non-Hodgkin Lymphoma....................................................................................................1671
Arnold S. Freedman, Caron A. Jacobson, Andrea Ng, and Jon C. Aster
Introduction 1671
Incidence and Etiology 1671
Biology and Pathology 1672
Lymphoma Classification: the Principles of the World Health Organization Classification
of Lymphoid Neoplasms 1676
Diagnosis, Staging, and Management 1677
Specific Disease Entities 1679
Mature T-Cell and Natural Killer Cell Neoplasms 1695

99. Cutaneous Lymphomas........................................................................................................1708
Francine M. Foss, Michael Girardi, and Lynn D. Wilson
Introduction 1708
Mycosis Fungoides and the Sézary Syndrome 1708
Epidemiology and Etiology 1708
Pathobiology 1708
Diagnosis and Staging 1710
The Sézary Syndrome 1710
Staging and Prognosis of Mycosis Fungoides and the Sézary Syndrome 1710
Clinical Evaluation of Patients with Cutaneous Lymphoma 1712
Principles of Therapy of Mycosis Fungoides and the Sézary Syndrome 1712
Skin-Directed Therapy 1714
Systemic Therapy for Mycosis Fungoides and the Sézary Syndrome 1715
Other Cutaneous Lymphomas 1717

100. Primary Central Nervous System Lymphoma ...................................................................1721
Tracy T. Batchelor and Catherine H. Han
Epidemiology 1721
Histopathology and Molecular Profile 1722
Diagnosis 1722
Prognostic Models 1723
Management of Newly Diagnosed Primary Central Nervous System Lymphoma 1723
Treatment in the Elderly 1725
Management of Refractory/Relapsed Primary Central Nervous System Lymphoma 1725
Monitoring and Follow-up 1726
Neurotoxicity 1726

SECTION 13. LEUKEMIAS AND PLASMA CELL TUMORS

101. Molecular Biology of Acute Leukemias............................................................................1729
Glen D. Raffel and Jan Cerny
Introduction 1729
Leukemic Stem Cell 1729
Elucidation of Genetic Events in Acute Leukemia 1729
Mutations Affecting Transcription Factors 1732
Mutations of Epigenetic Modifiers 1735
Mutations Affecting Signaling 1737
Mutations in Tumor Suppressor Genes 1738
Activating Mutations of NOTCH 1738
Mutations Altering Localization of NPM1 1739
Mutations in Cohesin Complex Genes 1739
Mutations in Splicing Machinery 1739
Mutational Complementation Groups in Acute Leukemias 1739
Conclusion 1740

102. Management of Acute Leukemias.....................................................................................1742
Partow Kebriaei, Farhad Ravandi, Marcos de Lima, and Richard Champlin
Introduction 1742
Acute Myeloid Leukemia 1743
Acute Lymphoblastic Leukemia 1751

103. Molecular Biology of Chronic Leukemias ........................................................................1764
Christopher A. Eide, James S. Blachly, and Anupriya Agarwal
Introduction 1764
Chronic Myeloid Leukemia 1764
Chronic Lymphocytic Leukemia 1767
Acknowledgments 1770

104. Chronic Myeloid Leukemia ...............................................................................................1773
Carlo Gambacorti-Passerini and Philipp le Coutre
Introduction 1773
Epidemiology and Pathogenesis 1773
Diagnosis 1774
Differential Diagnosis and Staging 1775
Prognostic Factors 1775
Therapy 1776
Assessment of Response to Tyrosine-Kinase Inhibitors 1778
Therapy of Chronic Phase Chronic Myeloid Leukemia 1778
Treatment of Advanced Disease 1781
Future Directions 1781
Acknowledgments 1782

105. Chronic Lymphocytic Leukemias......................................................................................1785
William G. Wierda and Susan M. O’Brien
Introduction 1785
Immunophenotype 1785
Molecular Biology 1785
Immune Abnormalities 1786
Diagnosis 1787
Clinical Manifestations 1787
Laboratory Findings 1787
Autoimmune Complications 1788
Staging 1788
Indications for Treatment and Response Criteria 1789
Treatments for Chronic Lymphocytic Leukemia 1790
Management Recommendations 1796
Prolymphocytic Leukemia 1797
Large Granular Lymphocyte Leukemia 1798
Hairy Cell Leukemia 1798

106. Myelodysplastic Syndromes..............................................................................................1802
Rami S. Komrokji, Eric Padron, and Alan F. List
Introduction 1802
Historical Perspective 1802
Epidemiology 1802
Etiology 1802
Pathology 1803
Pathogenesis 1806
Clinical Presentation 1808
Risk Assessment and Prognosis 1808
Management of Myelodysplastic Syndromes 1810

107. Plasma Cell Neoplasms......................................................................................................1818
S. Vincent Rajkumar and Shaji Kumar
Introduction 1818
Multiple Myeloma 1818
Pathogenesis 1820
Cytogenetic Classification 1822
Clinical Features 1823
Diagnostic Tests 1823
Differential Diagnosis 1825
Staging and Risk Stratification 1825
Prognosis 1825
Treatment 1826
Supportive Care 1837
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE 1839
Introduction 1839
Incidence and Prevalence 1839
Clinical Features 1839
Differential Diagnosis 1839
Prognosis 1839
Risk Stratification 1841
Management 1841
SMOLDERING MULTIPLE MYELOMA 1841
Introduction 1841
Prevalence 1841
Clinical Features 1841
Differential Diagnosis 1841
Prognosis 1842
Risk Stratification 1842
Management 1842
Waldenström Macroglobulinemia 1844
Diagnosis 1844
Prognosis 1844
Treatment 1844
Systemic AL (Immunoglobulin Light Chain) Amyloidosis 1845
Diagnosis 1846
Prognosis 1847
Treatment 1847
Solitary Plasmacytoma 1848
Diagnosis and Prognosis 1848
Treatment 1848
POEMS Syndrome 1848

SECTION 14. OTHER CANCERS

108. Cancer of Unknown Primary .............................................................................................1856
Sarah Yentz, Manali Bhave, Erin Cobain, and Laurence Baker
Introduction 1856
Pathology Evaluation 1856
Additional Pathologic Diagnostic Tests in Cancers of Unknown Primary 1856
Use of Next-Generation Sequencing 1858
Clinical Features and Evaluation 1859
Prognostic Factors 1862

109. Benign and Malignant Mesothelioma................................................................................1863
Harvey I. Pass, Michele Carbone, Lee M. Krug, and Kenneth E. Rosenzweig
Introduction 1863
Epidemiology 1863
Mechanism of Asbestos Carcinogenesis 1863
Mechanism of Asbestos Pathogenicity 1864
Overview of Molecular Mechanisms in Mesothelioma 1864
Genetic Predisposition to Mesothelioma: BAP1 1866
Pathology of Mesothelioma 1866
Clinical Presentation 1867
Diagnostic Approach for Presumed Mesothelioma 1871
Natural History 1871
Treatment 1874
Palliation or Macroscopic Complete Resection 1875
Chemotherapy 1878
Novel Therapeutic Approaches 1880
Radiotherapy for Mesothelioma 1882

110. Peritoneal Metastases and Peritoneal Mesothelioma.........................................................1889
Alvaro Arjona-Sanchez, Marcello Deraco, Olivier Glehen, David Morris, and Paul H.
Sugarbaker
Introduction 1889
Natural History Studies Document the Importance of Local-Regional Progression 1890
Patient Selection Using Quantitative Prognostic Indicators 1890
Appendiceal Malignancy 1892
Colorectal Peritoneal Metastases: Curative Treatment and Prevention 1893
Malignant Peritoneal Mesothelioma 1894
Gastric Cancer 1895
Peritoneal Metastases in Ovarian Cancer 1895
Sarcomatosis 1896

111. Intraocular Melanoma........................................................................................................1899
Paul T. Finger and Anna C. Pavlick
Introduction 1899
Incidence and Etiology 1899
Anatomy and Pathology 1899
Ophthalmic Diagnosis 1900
Staging 1902
Management of Primary Uveal Melanoma 1902
Overview: Treatment of Uveal Melanoma 1902
Treatment for Special Cases 1904
Diagnosis of Metastasis 1904
Biomarkers: Prognostic and Predictive Factors 1907
Summary 1908

SECTION 15. ONCOLOGIC EMERGENCIES

112. Superior Vena Cava Syndrome..........................................................................................1910
Andreas Rimner and Joachim Yahalom
Introduction 1910
Anatomy and Pathophysiology 1910
Clinical Presentation and Etiology 1910
Diagnostic Workup 1912
Disease-Specific Management and Outcomes 1912
Small-cell Lung Cancer 1912
Non–small-cell Lung Cancer 1913
Non-Hodgkin Lymphoma 1913
Nonmalignant Causes 1913
Catheter-Induced Obstruction 1913
Treatment 1913
Areas of Uncertainty 1914
Recommendations 1914

113. Increased Intracranial Pressure ..........................................................................................1915
Ashley M. Roque and Joachim M. Baehring
Introduction 1915
Pathophysiologic Considerations 1916
Epidemiology and Pathogenesis 1916
Clinical Presentation 1917
Diagnosis 1918
Treatment 1920

114. Spinal Cord Compression ..................................................................................................1921
Nicholas Szerlip, Whitney H. Beeler, and Daniel E. Spratt
Incidence and Etiology 1921
Anatomy and Pathophysiology 1922
Clinical Presentation 1922
Differential Diagnosis 1922
Diagnosis 1922
Grading 1923
Management by Stage 1923

115. Metabolic Emergencies......................................................................................................1928
Stacey Stein and Hari A. Deshpande
Introduction 1928
Tumor Lysis Syndrome and Hyperuricemia 1928
Hyponatremia 1929
Hypercalcemia 1930
Lactic Acidosis 1931
Hyperammonemia 1931
Summary 1932

SECTION 16. TREATMENT OF METASTATIC CANCER

116. Metastatic Cancer to the Brain...........................................................................................1934
John H. Suh, Rupesh Kotecha, Manmeet S. Ahluwalia, and Michael A. Vogelbaum
Introduction 1934
Epidemiology 1934
Clinical Presentation 1934
Imaging and Diagnosis 1934
Prognosis 1934
Symptom Management 1935
Treatment Options 1936
Leptomeningeal Metastases 1941

117. Metastatic Cancer to the Lung ...........................................................................................1946
John Yonge and Jessica Donington
Introduction 1946
Presentation and Diagnosis of Pulmonary Metastases 1946
Surgical Metastasectomy 1947
Ablative Therapies 1950
Treatment Concerns and Outcomes for Individual Histologies 1951
Conclusion 1954

118. Metastatic Cancer to the Liver...........................................................................................1957
Clifford S. Cho, Sam Lubner, and Dawn Owen
Introduction 1957
Hepatic Colorectal Adenocarcinoma Metastases 1960
Hepatic Neuroendocrine Carcinoma Metastases 1965
Noncolorectal Nonneuroendocrine Hepatic Metastases 1967

119. Metastatic Cancer to the Bone ...........................................................................................1970
Edward Chow, Joel A. Finkelstein, Arjun Sahgal, and Robert E. Coleman
Introduction 1970
Presentation 1970
Pathophysiology 1970
Diagnostic Evaluation 1970
Therapeutic Modalities 1970
Optimum Use of Bone-Targeted Agents in Metastatic Bone Disease 1971
New Targeted Therapies in the Treatment of Metastatic Bone Disease 1972
External-Beam Radiation Therapy 1972
Systemic Radionuclides 1974
Radiotherapy for Complications of Bone Metastases: Localized External-Beam
Radiotherapy for Pathologic Fractures 1974

120. Malignant Pleural and Pericardial Effusions .....................................................................1983
R. Taylor Ripley
Malignant Pleural Effusions 1983
Treatment Algorithm 1987
Malignant Pericardial Effusions 1987
Summary 1989

121. Malignant Ascites ............................................................................................................. 1991
Thuy B. Tran and Ajay V. Maker
Incidence and Etiology 1991
Anatomy and Pathology 1991
Diagnosis 1991
Management 1992

122. Paraneoplastic Syndromes.................................................................................................1998
Daniel Morgensztern, Saiama N. Waqar, and Ramaswamy Govindan
Introduction 1998
Paraneoplastic Neurologic Syndromes 1998
Paraneoplastic Endocrinology Syndromes 2000
Paraneoplastic Hematologic Syndromes 2003
Paraneoplastic Dermatologic Manifestations 2004
Paraneoplastic Rheumatologic Manifestations 2005

SECTION 17. STEM CELL TRANSPLANTATION

123. Autologous Hematopoietic Cell Transplantation...............................................................2008
Hillard M. Lazarus, Mehdi Hamadani, and Parameswaran N. Hari
Introduction 2008
Autologous Hematopoietic Progenitor Cell Collection 2008
Autologous Hematopoietic Cell Transplantation Toxicities and Supportive Care 2008
Autologous Hematopoietic Cell Transplantation for Plasma Cell Myeloma 2009
Older Patients and Those with Comorbidities 2012
Maintenance Therapy after Hematopoietic Cell Transplantation 2012
Tandem Autologous Hematopoietic Cell Transplantation 2012
Response and Minimal Residual Disease after HCT 2012
Unique Considerations for Hematopoietic Progenitor Cell Collection in Myeloma 2012
Salvage Second or Third Transplants at Relapse 2013
Future Directions in Autologous Hematopoietic Cell Transplantation for Myeloma 2013
Autologous Hematopoietic Cell Transplantation for Rare Plasma Cell Dyscrasias 2013
Autologous Hematopoietic Cell Transplantation for Lymphomas 2013
Hematopoietic Cell Transplantation for Follicular Lymphoma 2013
Hematopoietic Cell Transplantation for Mantle Cell Lymphoma 2015
Hematopoietic Cell Transplantation for Waldenström Macroglobulinemia 2015
Hematopoietic Cell Transplantation for Marginal Zone and Small Lymphocytic
Lymphoma 2015
Hematopoietic Cell Transplantation for Diffuse Large B-Cell Lymphoma 2015
Hematopoietic Cell Transplantation for Burkitt Lymphoma 2015
Hematopoietic Cell Transplantation for Hodgkin Lymphoma 2016
Hematopoietic Cell Transplantation for T-Cell Lymphomas 2016
Unique Considerations for Hematopoietic Cell Transplantation Mobilization in
Lymphomas 2016
Tumor Cell Contamination in Autograft 2016
Posttransplantation Maintenance Therapies for Lymphoid Malignancies 2016
Functional Imaging and Autologous Hematopoietic Cell Transplantation Outcomes 2016
Autologous Hematopoietic Cell Transplantation for Acute Myeloid Leukemia 2016
Autologous Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia
2017
Autologous Hematopoietic Cell Transplantation for Germ Cell Tumors 2017
Late Complications after Autologous Hematopoietic Cell Transplantation 2017

124. Allogeneic Stem Cell Transplantation...............................................................................2019
Stanley R. Riddell and Edus H. Warren
Introduction 2019
Conditioning Regimens 2019
Stem Cell Sources 2020
Immunobiology of Allogeneic Hematopoietic Cell Transplantation 2023
Complications of Allogeneic Hematopoietic Cell Transplantation and Their Management
2024
Graft Failure 2028
Outcome of Allogeneic Hematopoietic Cell Transplantation for Hematologic
Malignancies and Solid Tumors 2028
Management of Posttransplant Relapse 2032
Future Directions 2032

SECTION 18. MANAGEMENT OF ADVERSE EFFECTS OF TREATMENT

125. Infections in the Cancer Patient .........................................................................................2036
Tara N. Palmore, Mark Parta, Jennifer Cuellar-Rodriguez, and Juan C. Gea-Banacloche
RISK FACTORS FOR INFECTIONS IN PATIENTS WITH CANCER AND
ANTIMICROBIAL PROPHYLAXIS 2036
Risk Factors for Infection 2036
Prevention of Infections 2041
DIAGNOSIS AND MANAGEMENT OF INFECTIOUS DISEASES SYNDROMES
2043
Fever and Neutropenia 2043
Multidrug-Resistant Organisms of Interest in Oncology 2059

126. Neutropenia and Thrombocytopenia..................................................................................2068
Lodovico Balducci, Bijal Shah, and Kenneth Zuckerman
Introduction 2068

127. Nausea and Vomiting.........................................................................................................2077
Elizabeth M. Blanchard and Paul J. Hesketh
Introduction 2077
Nausea and Vomiting Syndromes 2077
Pathophysiology of Treatment-Induced Nausea and Vomiting 2077
Defining the Risk of Nausea and Vomiting 2078
Antiemetic Agents 2079
Lower Therapeutic Index 2082
Antiemetic Treatment by Clinical Setting 2082
Special Chemotherapy-Induced Nausea and Vomiting Problems 2083
Radiotherapy-Induced Nausea and Vomiting 2083

128. Diarrhea and Constipation .................................................................................................2085
Nathan I. Cherny and Batsheva Werman
Introduction 2085
Diarrhea 2085
Neutropenic Colitis 2086
Ischemic Colitis (Nonneutropenic Enterocolitis) 2087
Targeted Therapy–Associated Diarrhea 2087
Immunotherapy-Associated Diarrhea 2087
Radiotherapy-Induced Diarrhea 2087
Other Causes of Treatment-Related Diarrhea 2087
Assessment 2088
General Principles in the Management of Diarrhea 2088
Antidiarrhea Medications 2088
Specific Management Guidelines 2089
Radiation Therapy–Induced Diarrhea 2089
Immunotherapy-Induced Diarrhea and Colitis 2089
Management of Neutropenic Enterocolitis 2090
Diarrhea Prophylaxis 2090
Constipation 2090
Conclusion 2093

129. Oral Complications............................................................................................................2094
Jane M. Fall-Dickson, Stefan Cordes, and Ann M. Berger
Introduction 2094
Oral Mucositis 2094
Radiation Therapy–Related Complications 2095
Pathogenesis of Chemotherapy- and Radiation Therapy–Induced Oral Mucositis 2095
Chronic Graft-Versus-Host Disease Oral Manifestations 2096
Sequelae of Oral Complications 2097
Strategies for Prevention and Treatment of Oral Complications 2097
Treatment Strategies 2098
Radioprotectors 2099
Biologic Response Modifiers 2100
Treatment for Oral Chronic Graft-Versus-Host Disease 2103
Symptom Management 2103

130. Pulmonary Toxicity ...........................................................................................................2109
Diane E. Stover, Michael T. Bender, Manju V. Pillai, and Robert J. Kaner
Introduction 2109
Radiation-Induced Pulmonary Toxicity 2109
Chemotherapy-Induced Pulmonary Toxicity 2111
Additional Resources 2118

131. Cardiac Toxicity.................................................................................................................2119
Joachim Yahalom and Matthew A. Lunning
Introduction 2119
Chemotherapeutics 2119
Radiotherapy-Associated Cardiac Sequelae 2123
Conclusion 2126

132. Hair Loss and Other Hair Changes....................................................................................2128
Hoyoung M. Maeng and Ann M. Berger
Introduction 2128
Anatomy and Physiology of Hair 2128
Classification of Hair Loss 2129
Diagnosis of Hair Loss 2129
Treatment and Prevention of Chemotherapy-Induced Hair Loss 2130
Radiation-Induced Hair Changes 2131
Other Hair-Associated Changes 2131
Future Considerations 2132

133. Gonadal Dysfunction .........................................................................................................2133
George Patounakis, Alicia Y. Christy, and Alan H. DeCherney
Introduction 2133
Effects of Cytotoxic Agents on Adult Men 2134
Effects of Cytotoxic Agents on Adult Women 2137
Effects of Cytotoxic Agents on Children 2139
Gonadal Dysfunction after Cranial Irradiation 2139
Preservation of Fertility, Hormone Levels, and Sexual Function 2140
Pharmacologic Attempts at Preserving Fertility in Men 2143
Pharmacologic Attempts at Preserving Fertility in Women 2143
Fertility Preservation in Women with Cervical Cancer 2143
Genetic Concerns 2144
Acknowledgments 2145

134. Fatigue................................................................................................................................2148
Sandra A. Mitchell and Ann M. Berger
Introduction 2148
Definition, Risk Factors, and Mechanisms of Cancer-Related Fatigue 2148
Screening and Evaluation of the Patient with Cancer-Related Fatigue 2150
Interventions for Cancer-Related Fatigue 2150
Pharmacologic Interventions 2151
Nonpharmacologic Interventions 2152
Complementary and Integrative Therapies 2152
Summary 2153

135. Second Cancers..................................................................................................................2155
Chunkit Fung, Smita Bhatia, James M. Allan, Kevin C. Oeffinger, Andrea Ng, and Lois B. Travis
Introduction 2155
Carcinogenicity of Individual Treatment Modalities 2155
Genetic Susceptibility to Second Primary Cancers 2157
Risk of Second Malignancy in Patient with Selected Primary Cancers 2159
Pediatric Malignancies 2163
Comment 2169

136. Neurocognitive Effects ......................................................................................................2174
Paul D. Brown, Alissa M. Butts, Michael W. Parsons, and Jane H. Cerhan
Introduction 2174
Assessment of Cognitive Function 2174
Neurocognitive Effects of Central Nervous System Tumors and Treatment 2174
Neurocognitive Effects in Non–Central Nervous System Cancer 2176
Treatment of Cognitive Dysfunction 2178
Conclusion 2178

137. Cancer Survivorship...........................................................................................................2180
Wendy Landier, Michelle Shayne, Kevin C. Oeffinger, Smita Bhatia, and Louis S. Constine
Introduction 2180
Definition of Survivorship and Scope of the Problem 2180
Goals of Survivorship Health Care 2181
Care Plans 2183
Delivery of Follow-up Care and Best Practice Models 2184
Educational Considerations 2185
Enhancing Research 2185
Survivorship Advocacy 2185
Conclusion 2186

PART VI

Palliative and Alternative Care

SECTION 1. SUPPORTIVE CARE AND QUALITY OF LIFE

138. Management of Cancer Pain..............................................................................................2190
Thomas W. Leblanc and Arif H. Kamal
Introduction 2190
Epidemiology 2190
Definition of Pain 2191
Types of Pain 2191
Temporal Aspects of Pain 2191
Intensity of Pain 2192
Measurement Schemas 2192
Patient-Reported Outcome Measures 2192
Common Pain Syndromes 2193
Clinical Assessment of Pain 2193
Management of Cancer Pain 2195
Pharmacologic Management of Cancer Pain 2195
Adjuvant Drugs 2202
Adjuvants to Treat Side Effects 2205
Psychological Approaches 2205
Anesthetic and Neurosurgical Approaches 2205
Neuropharmacologic Approaches 2207
Neuroablative and Neurostimulatory Procedures for the Relief of Pain 2207
Trigger Point Injection and Acupuncture 2208
Physiatric Approaches 2208
Algorithm for Cancer Pain Management 2208
Future Directions 2208
Acknowledgments 2208

139. Nutrition Support ...............................................................................................................2212
David A. August, Mihir M. Shah, and Maureen B. Huhmann
Background 2212
Causes of Malnutrition in Cancer Patients 2212
Cancer Cachexia Syndrome 2213
Nutrition Screening and Assessment 2214
Pharmacotherapy of Cancer-Associated Weight Loss and Malnutrition 2215
Nutrition Support of Cancer Patients 2215

140. Sexual Problems.................................................................................................................2220
Eric S. Zhou and Sharon L. Bober
Introduction 2220
Cancer in Men 2220
Cancers that Affect Men and Women 2221
Cancer in Women 2222
Cancer in Children and Young Adults 2224
Relevant Sociocultural Considerations 2225
Disruption of Intimacy and Relational Considerations 2225
Communication About Sexual Problems 2225

141. Psychological Issues ..........................................................................................................2229
David Spiegel and Michelle B. Riba
Introduction 2229
Common Psychiatric Conditions 2229
Screening for Psychological Problems 2230
Coping 2230
Treatment Interventions 2231
Implications for Cancer Progression and Mortality 2233
Psychotropic Medication 2233
Conclusion 2236

142. Communicating News to the Cancer Patient .....................................................................2238
Eric J. Cassell
Introduction 2238
Preventing Illness 2238
Communication 2239
Explanations 2240
Uncomfortable Questions 2240
Information 2240
Meaning 2241
Cafeteria Explanations 2241

143. Specialized Care of the Terminally Ill...............................................................................2242
Robert S. Krouse and Arif H. Kamal
Introduction 2242
Early Specialist Palliative Care 2242
Communication 2242
Specific Problems in the Setting of Advanced Cancer 2242
Impending Death 2245
Conclusions 2246

144. Rehabilitation of the Cancer Patient ..................................................................................2248
Michael D. Stubblefield
Introduction 2248
The Rehabilitation Team 2249
Complications of Cancer and Its Treatment 2250
Neuromuscular Complications of Cancer and Cancer Treatment 2251
Musculoskeletal Complications of Cancer and Cancer Treatment 2257
Radiation Fibrosis Syndrome 2258
Head and Neck Cancer 2261
Lymphedema 2263
Rehabilitation Interventions 2264

SECTION 2. COMPLEMENTARY, ALTERNATIVE, AND INTEGRATIVE THERAPIES

145. Complementary, Alternative, and Integrative Therapies in Cancer Care..........................2269
Catherine E. Ulbricht, Oliver Grundmann, Eunji Michelle Ko, and Nikhil Sangave
Background 2269
Establishing an Integrative Oncology Approach with Patients 2269
Standardization and Quality 2271
Specific Complementary and Integrative Medicine Therapies 2272

Index ..........................................................................................................................................2285