Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures (eBook)

Contents 6
Contributors 9
Part I Chemotherapy 14
1 Plant-Derived Natural Products as Anticancer Agents 15
1.1 Introduction and Scope 15
1.2 Podophyllotoxin Derivatives 15
1.2.1 Introduction 15
1.2.2 History 15
1.2.3 Chemistry 16
1.2.4 Activity in In Vitro and In Vivo Assay Systems 17
1.2.5 Structure-Activity Studies and Mechanism of Action 17
1.2.6 Pharmacology 18
1.2.7 Clinical Single Agent Activity 18
1.2.8 Clinical Combination Therapy 19
1.2.9 Toxicity 19
1.2.10 New Analogs in Development 19
1.2.11 Conclusion 20
1.3 Paclitaxel 20
1.3.1 Introduction 20
1.3.2 History 21
1.3.3 Mechanism of Action 21
1.3.4 The Paclitaxel-Tubulin Interaction 22
1.3.5 Paclitaxel Analogs 23
1.3.6 Mechanisms of Resistance 24
1.3.7 Formulation of Paclitaxel and Docetaxel 24
1.3.8 Paclitaxel Metabolism 24
1.3.9 Cancer Therapy with Paclitaxel and Docetaxel 25
1.3.9.1 Ovarian Cancer 25
1.3.9.2 Breast Cancer 25
1.3.9.3 Lung Cancer 25
1.3.9.4 AIDS-Related Kaposi's Sarcoma 25
1.3.10 Summary 25
1.4 Camptothecin and Analogs 25
1.4.1 Introduction 25
1.4.2 Mechanism of Action 26
1.4.2.1 Inhibition of Topoisomerase I 26
1.4.2.2 Other Biochemical Effects of Camptothecin 26
1.4.3 Mechanisms of Resistance 27
1.4.4 Camptothecin Supply 27
1.4.5 Synthetic Studies 27
1.4.6 Medicinal Chemistry 27
1.4.7 Camptothecin Analogs in Clinical Use 27
1.4.7.1 Topotecan 27
1.4.7.2 Irinotecan 28
1.4.8 Camptothecin Analogs in Clinical Trial or Preclinical Development 29
1.4.9 Conclusions 29
References 30
2 The Vinca Alkaloids 36
2.1 Introduction 36
2.2 Chemistry 36
2.3 Mechanism of Action 36
2.4 Clinical Use 38
2.5 Mechanisms of Resistance 38
2.6 Pharmacokinetics 39
2.7 Doses and Schedules 41
2.7.1 Vincristine 41
2.7.2 Vinblastine 42
2.7.3 Vindesine 42
2.7.4 Vinorelbine 42
2.8 Toxicity 42
2.9 Drug Interactions 44
References 44
3 Taxanes and Epothilones in Cancer Treatment 49
3.1 Introduction 49
3.2 Microtubules 49
3.3 Taxanes 50
3.3.1 Background 50
3.3.2 Mechanism of Action 51
3.3.2.1 Mechanism of Resistance 52
3.3.3 Pharmacology 54
3.3.4 Dose and Schedule 55
3.3.5 Toxicity 56
3.3.6 Spectrum of Antitumor Activity 56
3.3.6.1 Breast Cancer 57
3.3.6.2 Prostate Cancer 58
3.3.6.3 Lung Cancer 59
3.3.6.4 Other Cancers 59
3.4 Epothilones 60
3.5 Clinical Activity of Epothiones 61
3.5.1 Ixabepilone (Ixempra) 61
3.5.2 Patupilone (EPO906) 62
3.5.3 BMS-310705 63
3.5.4 KOS-862 (Epothilone D) 63
3.5.5 Sagopilone (ZK-EPO) 64
References 64
4 Alkylating Agents 71
4.1 Introduction 71
4.2 Mechanism of Action 71
4.3 Types of Agent 72
4.3.1 Nitrogen Mustards 72
4.3.2 Aziridines 73
4.3.3 Epoxides 76
4.3.4 Alkyl Sulfonate 77
4.3.5 Nitrosoureas 77
4.3.6 Triazene Compounds 79
4.3.7 Prodrugs of Alkylating Agents 80
4.3.7.1 Glutathione S-Transferase-Activated Prodrug 80
4.3.7.2 Antibody- and Gene-Directed Enzyme Prodrug Therapy 81
4.3.8 Alkylating Agent-Steroid Conjugates 82
4.3.9 Alkylating Agent Resistance and Modulation 83
4.4 Toxicity 86
4.4.1 Hematopoietic Suppression 86
4.4.2 Gastrointestinal Toxicity 86
4.4.3 Pulmonary Toxicity 87
4.4.4 Renal Toxicity 87
4.4.5 Alopecia 87
4.4.6 Reproductive Toxicity 87
4.4.7 Teratogenecity 87
4.4.8 Carcinogenesis 88
4.4.9 Immunosuppression 88
4.4.10 Hypersensitivity Reactions 88
4.5 Conclusion 88
References 88
5 Anthracyclines and Anthracenediones 96
5.1 Introduction 96
5.2 Chemistry 96
5.3 Mechanism of Action 97
5.4 Pharmacokinetics 99
5.5 Clinical Uses 100
5.6 Mechanism of Resistance 102
5.7 Toxicity 103
5.8 Drug Interactions 105
References 106
6 Topoisomerase I Inhibitors -- The Camptothecins 112
6.1 Introduction 112
6.2 Chemistry 112
6.3 Mechanisms of Action 114
6.4 Clinical Use 114
6.4.1 Irinotecan 114
6.4.2 Topotecan 116
6.5 Mechanisms of Resistance 117
6.6 Pharmacokinetics 118
6.6.1 Irinotecan 118
6.6.1.1 Topotecan 121
6.7 Doses and Schedules 122
6.8 Dose Adjustments 123
6.8.1 Topotecan 123
6.8.2 Irinotecan 123
6.9 Toxicity 124
6.9.1 Topotecan 124
6.9.2 Irinotecan 126
6.10 Drug Interactions 126
6.10.1 Topotecan 126
6.10.2 Irinotecan 127
References 127
7 Folate Antagonists 133
7.1 Introduction 133
7.2 Historical Background 133
7.3 Folate Metabolism 133
7.4 Mechanism of Action of Folate Antagonists 134
7.4.1 Pharmacokinetics 135
7.4.1.1 Absorption 135
7.4.2 Distribution 135
7.4.3 Metabolism 135
7.4.4 Excretion 136
7.4.5 Drug Interactions 136
7.4.6 Neoplastic Treatments 136
7.4.6.1 Acute Leukemia 136
7.4.6.2 Lymphoma 136
7.4.6.3 Breast Cancer 137
7.4.6.4 Choriocarcinoma 137
7.4.6.5 Osteogenic Sarcoma 137
7.4.6.6 Neoplastic Meningitis 138
7.4.6.7 Head and Neck Cancer 138
7.4.6.8 Genitourinary Cancer 138
7.4.6.9 Gastrointestinal Cancer 138
7.4.6.10 Lung Cancer 138
7.4.7 MTX Toxicities 138
7.4.7.1 Hematologic 138
7.4.7.2 Renal Toxicity 138
7.4.7.3 CNS Toxicity 139
7.4.7.4 Hepatotoxicity 139
7.4.7.5 Gastrointestinal 139
7.4.7.6 Pulmonary 139
7.4.7.7 Skin 140
7.4.7.8 Teratogenic and Mutagenic 140
7.4.7.9 Bone 140
7.4.8 Antifolate Resistance 140
7.5 Intrinsic Resistance 140
7.6 Acquired Resistance 140
7.6.1 Description of Other Folate-Related Agents 141
7.6.1.1 5-Fluorouracil (5-FU, Efudex) 141
7.6.1.2 Capecitabine (Xeloda) 141
7.6.1.3 Aminopterin (4-Aminopteroic Acid, AMT) 142
7.6.1.4 Leucovorin 142
7.6.2 New Folate Antagonists 142
7.6.2.1 Edatrexate (10-Ethyldeazaaminopterin) 142
7.6.2.2 Trimetrexate (TMTX) 142
7.6.2.3 Raltitrexed (Tomudex) 142
7.6.2.4 ZD9331 143
7.6.2.5 Lometrexol (5--10-Dideazatetrahydrofolate, DDTHF, LMTX) 143
7.6.2.6 Pemetrexed (LY231514) 143
7.6.2.7 Nolatrexed (Thymitaq, AG337) 144
7.7 Conclusions and Future Directions 144
7.8 Graphics 145
7.8.1 Folate Metabolism 145
7.8.2 Folate-Related Agents 146
7.8.3 Chemical Structure Comparison of Folate and MTX 146
7.8.4 Chemical Structures of Folate Antagonists 147
References 147
8 Platinum Complexes for the Treatment of Cancer 152
8.1 Introduction 152
8.2 Cisplatin Discovery 152
8.3 Cisplatin Analogs 153
8.3.1 Carboplatin 153
8.3.2 Oxaliplatin and DACH Complexes 153
8.3.3 Other Platinum Complexes 154
8.3.3.1 Satraplatin (JM216) 154
8.3.3.2 AMD473 155
8.3.3.3 BBR3464 155
8.3.4 Identification of New Platinum Analogs 156
8.4 Pharmacology 156
8.4.1 Pharmacokinetics 156
8.4.2 Toxicity 157
8.5 Platinum-Induced Cell Death 157
8.5.1 DNA Adducts 157
8.5.2 Damage Recognition 158
8.5.3 Damage Recognition, Signaling and Apoptosis 158
8.5.4 Decision/Commitment Phase 159
8.5.5 Apoptosis/Terminal Phase 160
8.6 Mechanisms of Resistance 160
8.6.1 Reduced Accumulation 161
8.6.2 Inactivation 162
8.6.3 Increased DNA Repair 162
8.6.4 Increased DNA Damage Tolerance 163
References 165
9 Hormonal Therapy in Cancer 172
9.1 Introduction 172
9.2 Hormonal Therapy in Breast Cancer 172
9.2.1 Selective Estrogen Receptor Modulators (SERMs) 173
9.2.1.1 Tamoxifen 173
9.2.1.2 Raloxifene 173
9.2.1.3 Toremifene 174
9.2.2 Estrogen Receptor Down-Regulators 174
9.2.3 Aromatase Inhibitors 174
9.2.3.1 Aromatase Inhibitors for Advanced Breast Cancer 174
9.2.3.2 Aromatase Inhibitors for Early Stage Breast Cancer 178
9.2.4 Ovarian Function Suppression (OFS) With or Without SERMs in Premenopausal Women 180
9.2.5 Progestational Agents 181
9.2.6 Progesterone Receptor Antagonists 181
9.2.7 Androgens 182
9.2.8 Estrogens 182
9.3 Hormonal Therapy in Ovarian Cancer 183
9.4 Hormonal Therapy in Endometrial Cancer 183
9.5 Hormonal Therapy in Uterine Sarcomas 184
9.6 Hormonal Therapy in Meningioma 185
9.7 Hormonal Therapy for Ectopic ACTH Syndrome 185
9.8 Hormonal Therapy in Neuroendocrine Tumors 185
9.9 Hormonal Therapy in Pituitary Adenoma 186
9.10 Hormonal Therapy in Cancer Anorexia, Cachexia and for Hematopoietic Recovery 186
9.11 Hormonal Therapy in Prostate Cancer 187
9.11.1 Androgen-Deprivation Therapy 187
9.11.2 The Estrogen Agonists 188
9.11.3 The LHRH Agonists 188
9.11.4 The LHRH Antagonists 189
9.11.5 Anti-Androgens 189
9.11.6 Secondary Hormonal Manipulations 189
9.12 Summary 190
References 191
10 Effects of Cancer Chemotherapy on Gonadal Function 198
10.1 Introdution 198
10.2 Effects of Cancer Chemotherapy on Gonadal Function 198
10.2.1 Chemotherapy Effects in Men 198
10.2.2 Animal Models 199
10.2.3 Clinical Assessment 199
10.2.4 Drug Effects on Spermatogenesis 200
10.2.4.1 Drugs Highly Toxic to the Germinal Epithelium 200
10.2.4.2 Drugs with Low Toxicity to Male Germ Cells 201
10.2.5 Combination Chemotherapy and Disease-Specific Considerations 201
10.2.5.1 Lymphoma 201
10.2.5.2 Testicular Cancer 202
10.2.5.3 High-Dose Chemotherapy and Bone Marrow Transplantation 203
10.2.5.4 Leukemia 203
10.3 Chemotherapy Effects in Women 203
10.3.1 Assessment of Ovarian Function 204
10.3.2 Animal Studies 204
10.3.3 Drug Effects on Ovarian Function 204
10.3.4 Drugs Highly Toxic to Germ Cells 204
10.3.5 Drugs with Moderate to Low Toxicity to Germ Cells 205
10.3.6 Combination Chemotherapy and Disease-Specific Considerations 206
10.3.6.1 Breast Cancer 206
10.3.6.2 Lymphoma 206
10.3.6.3 Ovarian Germ Cell Tumors 207
10.3.6.4 High-Dose Chemotherapy and Bone Marrow Transplantation 207
10.4 Counseling Patients 208
10.4.1 Assisted Reproductive Techniques (ART) for Men 208
10.4.1.1 Semen Cryopreservation 208
10.4.1.2 Tese 209
10.4.1.3 Testicular Germ Cell Transplantation 209
10.4.2 Assisted Reproductive Techniques (ART) for Women 210
10.4.2.1 Embryo Cryopreservation 210
10.4.2.2 Cryopreservation of Oocytes 210
10.4.2.3 Ovarian Tissue Cryopreservation and Transplantation 210
10.4.3 Hormonal Manipulation to Prevent Infertility 211
10.4.4 Hormone Replacement Therapy 212
10.4.4.1 Estrogen Deficiency 212
10.4.4.2 Leydig Cell Dysfunction 212
10.4.5 Mutagenic Potential of Cancer Chemotherapy 212
References 213
11 Targeting the Tumor Microenvironment for Enhancing Chemotherapy in Hematologic Malignancies 222
11.1 Introduction 223
11.2 Tumor Microenvironment Influences Hematologic Tumorigenesis and Tumor Cell Survival 224
11.2.1 Transforming Growth Factor-ß 225
11.2.2 Vascular Endothelial Growth Factor and Fibroblast Growth Factor 225
11.2.3 Interleukin-6 226
11.2.4 B Cell Activating-Factor of the Tumor Necrosis Factor Family 227
11.3 Tumor Microenvironment Influences Drug Sensitivity and Resistance 228
11.3.1 De novo Drug Resistance 229
11.3.2 Acquired Drug Resistance 231
11.4 Targeting Tumor-Stroma Interaction and Pathways for Therapy of Hematologic Malignancies 232
11.4.1 Chemotherapy Targeting bcl-2 233
11.4.2 Targeting Soluble Factors and Adhesion Molecules 234
11.4.3 Immunomodulatory Drugs 234
11.4.4 Bortezomib 234
11.5 Conclusions 234
References 235
Part II Biological Therapy 241
12 Cytokines in the Treatment of Cancer 242
12.1 Introduction 242
12.2 Interleukin-2 (IL-2) 244
12.3 Interferon-Alpha 246
12.4 Challenges Associated with Cytokine Therapy in Cancer 247
12.5 Conclusions 249
References 249
13 Antibody-Based Therapies for Solid Tumors 250
13.1 Introduction 250
13.2 History 250
13.3 Antibodies Targeting VEGF 251
13.4 Bevacizumab 251
13.4.1 Colorectal Carcinoma 252
13.4.2 Breast Cancer 252
13.4.3 Non-small-cell Lung Cancer 252
13.4.4 Renal Cell Carcinoma 252
13.4.5 Malignant Glioma 253
13.4.6 Ovarian Cancer 253
13.4.7 Other Tumors 253
13.4.8 Side Effects 253
13.5 Trastuzumab 253
13.5.1 Metastatic Breast Cancer 254
13.5.2 Adjuvant Therapy 254
13.5.3 Side Effect Profile/Cardiac Toxicity 255
13.6 Antibodies to the Epidermal Growth Factor Receptor (EGFR) 255
13.6.1 EGFR Biology and Expression in Cancer 255
13.6.2 Antibody vs. Tyrosine Kinase Inhibitor 255
13.7 Cetuximab 256
13.7.1 Head and Neck Cancer 256
13.7.2 Colorectal Cancer 257
13.7.3 Other Tumor Types Under Study 257
13.8 Panitumumab 257
13.8.1 Predictors of Resistance 258
13.8.2 Management of Toxicity 258
13.9 Dual Antibody Therapy 258
13.10 Conclusion 259
References 259
14 Cancer Vaccines 262
14.1 Introduction 262
14.2 Tumor-Associated Antigens 262
14.2.1 Melanoma Antigens 263
14.2.2 Other Tumor-Associated Antigens 264
14.3 Novel Vaccine Approaches 265
14.3.1 Peptide Vaccines 265
14.3.2 Recombinant Viruses as Vaccines 269
14.3.3 DNA-Based Vaccines 272
14.3.4 Dendritic Cell-Based Vaccines 274
14.3.5 Sipuleucel-T (Provenge) 278
14.4 Prospects 278
References 279
15 Adoptive Immunotherapy of Cancer Using Autologous Lymphocytes 290
15.1 Introduction 290
15.2 History and Big Events for Developing AIT 290
15.3 Rationale of AIT 291
15.4 Progress of the Generation of Effector Lymphocytes 291
15.4.1 First Generation 291
15.4.1.1 LAK Cells 291
15.4.1.2 TILs 291
15.4.2 Second Generation: In Vitro Tumor Sensitization Technique 292
15.4.2.1 Whole Tumor Cells 292
15.4.2.2 Tumor Cell Engineering 293
15.4.3 Third Generation: Use of DCs 293
15.4.3.1 Peptide/DC System 293
15.4.3.2 Tumor Lysate and Tumor Fusion on DC System 293
15.4.3.3 Tumor RNA/DC System 294
15.4.4 Novel Effector Cells that are not Restricted by HLA Expression 294
15.4.4.1 NKT Cells 294
15.4.4.2 . dT Cells 295
15.5 Problems of AIT 295
15.5.1 How to Expand Cells and Their Persistence In Vivo 295
15.5.2 Conditioning of the Host Immune Environment 296
15.6 Future Perspective 296
15.7 Clinical Trials and Translational Research 297
15.8 Conclusion 297
References 297
16 Oncolytic Virotherapy of Cancer 300
16.1 Introduction 300
16.2 Mechenisms of Tumor Selectivity 301
16.2.1 Inherent Tumor Selectivity 301
16.2.2 Viral Gene Inactivation 303
16.2.3 Transcriptional Targeting 306
16.2.4 Regulation of mRNA Stability 306
16.2.5 mRNA Translational Control 307
16.2.6 Transductional Targeting 308
16.3 Mechanisms of Antitumoral Potency 308
16.3.1 Intrinsic Antitumoral Activity 308
16.3.2 Antitumoral Immune Responses 309
16.3.3 Expression of Therapeutic Genes 309
16.3.4 Sensitization to Chemotherapy and Radiotherapy 310
16.4 Targeting Cancer Stem Cells 310
16.5 The Host Immune Response: A Double-Edged Sword 311
16.6 Clinical Trials 312
16.7 Conclusions 313
References 313
Part III Other 322
17 Protein Kinase Inhibitors 323
17.1 Introduction 323
17.2 C-Kit and BCR-ABL Tyrosine Kinases Imatinib 324
17.3 Dasatinib 325
17.4 Nilotinib 326
17.5 EGFR and HER2 Tyrosine Kinase Inhibitors 326
17.6 Gefitinib 326
17.7 Erlotinib 327
17.8 Lapatinib 329
17.9 Canertinib 329
17.10 Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors 329
17.11 Sunitinib 329
17.12 Vandetanib 330
17.13 Raf Kinase Inhibitors 331
17.14 Sorafenib 331
17.15 Mammalian Target of Rapamycin Kinase (mTOR) Inhibitor 331
17.16 Temsirolimus 332
17.17 Conclusion 332
References 332
18 Inhibitors of Tumor Angiogenesis 335
18.1 Introduction 335
18.2 Agents Targeting the VEGF Signaling Pathway 335
18.2.1 Bevacizumab (Avastin) 336
18.2.2 PTK787/ZK222584 (Vatalanib) 339
18.2.3 Sorafenib (Nexavar) 339
18.2.4 ZD6474 (Zactima) 340
18.2.5 VEGF-Trap 340
18.3 Metronomic Dosing of Chemotherapy 341
18.4 Conclusion 341
References 341
19 Transcatheter Management of Neoplasms 345
19.1 Introduction 345
19.2 Hepatic Neoplasms 345
19.3 Urological Malignancies 348
19.4 Head and Neck Cancers 349
19.5 Metastases 350
References 350
20 Tumor Stem Cells: Therapeutic Implications of a Paradigm Shift in Multiple Myeloma 352
20.1 Introduction 352
20.2 Support for the Tumor Stem Cell Hypothesis 353
20.3 Tumor Stem Cells Resemble Non-malignant Tissue Stem Cells 354
20.4 Multiple Myeloma Stem Cells 354
20.5 Clonal B Cells in MM 355
20.6 Differentiation Hierarchy 356
20.7 Migratory Characteristics of Early Versus Late MM Cells 357
20.8 Pathological Characteristics of Early MM Cells 357
20.9 MM Stem Cells in the Context of Other Cancer Stem Cells 359
20.10 Conclusion: Therapy of the MM Stem Cell 359
References 360
Part IV Hyperthermia 366
21 Induced Hyperthermia in the Treatment of Cancer 367
21.1 Basic Principles of Clinical Hyperthermia 367
21.1.1 Classification of Hyperthermia Techniques 367
21.1.1.1 Thermal Dose and Dose-Response Correlation 367
21.1.1.2 Clinical Application 368
21.1.2 Locoregional Approaches 368
21.1.2.1 Local Hyperthermia 368
21.1.2.2 Regional Radiofrequency Hyperthermia 369
21.1.2.3 Capacitive Methods in Locoregional Hyperthermia 371
21.1.3 Whole-Body Hyperthermia (WBH) 372
21.1.4 Hyperthermic Chemoperfusion 372
21.1.4.1 Hyperthermic Isolated Perfusion of a Limb, the Liver, and Lung 372
21.1.4.2 Hyperthermic Intraperitoneal and Vesical Perfusion 374
21.1.5 Future Developments 374
21.1.5.1 Technological Innovations in Radiofrequency Hyperthermia 374
21.1.5.2 Novel Interstitial (''Corpuscular'') Technologies 375
21.1.5.3 Immunological and Genetic Targets 375
21.1.6 Conclusion 376
References 376
Part V Supporting Measures 380
22 Hematologic Support of the Patient with Malignancy 381
22.1 Introduction 381
22.2 Blood Component Therapy in Patients with Cancer 382
22.2.1 Red Cell Transfusion in Patients with Cancer 382
22.2.1.1 Transfusion of Red Cell Components 384
22.2.2 Platelet Transfusion in Patients with Cancer 387
22.2.3 Granulocyte Transfusion in Patients with Cancer 390
22.2.4 Transfusion of Plasma and Coagulation Factor Concentrates in Patients with Cancer 392
22.3 Transfusion Risks Unique to Cancer Patients 393
22.3.1 Introduction 393
22.3.2 Cytomegalovirus Infection 395
22.3.3 Transfusion Associated Graft vs. Host Disease (TA-GVHD) 395
22.3.4 The Physician's Role in Transfusion Safety 396
22.4 Future Directions 396
References 397
23 Current Status of Bone Marrow Transplantation for Treatment of Cancer 406
23.1 Introduction 406
23.2 Autologous Stem Cell Transplantation 406
23.3 Stem Cell Mobilization and Collection 407
23.3.1 Definition 407
23.3.2 Mechanism of HPC Mobilization 407
23.3.3 Mobilization Regimens 408
23.3.4 HPC Collection 408
23.3.5 Future Directions 409
23.4 Myeloablative and Non-myeloablative Allogeneic Stem Cell Transplantation (NST) 409
23.4.1 Clinical Experience with Ablative Allogeneic Transplant 409
23.4.2 Allogeneic Transplantation Using Unrelated Donors 410
23.4.3 Graft-Vs.-Host Disease (GVHD) 410
23.4.4 Non-Myeloablative Stem Cell Transplants (NST) 410
23.4.5 Comparison of NST with Fully Myeloablative HSCT 410
23.5 Specific Disease Indications 411
23.5.1 Hematological Malignancy 411
23.5.1.1 Acute Lymphoblastic Leukemia in Adults 411
23.5.1.2 HSCT in ALL 412
23.5.1.3 Significance of Graft Vs. Leukemia Effect in ALL 412
23.5.1.4 Different Sources of Hematopoietic Cells for Transplants in ALL 413
23.5.1.5 Conclusions 413
23.5.2 Acute Myeloid Leukemia 413
23.5.2.1 Prognostic Factors in AML 414
23.5.2.2 The Effect of Consolidation Therapy Prior to Transplant 414
23.5.2.3 Source of Hematopoietic Cells for Transplants in AML 414
23.5.2.4 The Use of Unrelated Donor Cells 415
23.5.2.5 Considering the Best Consolidation Strategy for AML Patients 415
23.5.3 Reduced Intensity Regimens for AML 416
23.5.4 Conclusions 416
23.5.5 Chronic Lymphocytic Leukemia 416
23.5.5.1 Auto-HSCT in CLL 417
23.5.5.2 Allo-HSCT in CLL 417
23.5.5.3 Auto-HSCT Vs. Allo-HSCT in CLL 418
23.5.6 Conclusions 418
23.5.7 Chronic Myeloid Leukemia 418
23.5.8 Multiple Myeloma 420
23.5.8.1 Single auto Transplant Vs. Conventional Dose Therapy Alone 420
23.5.8.2 Tandem Vs. Single Auto Transplant 420
23.5.8.3 Allogeneic Transplantation 421
23.5.9 NHL and Hodgkin Disease 422
23.5.9.1 Role of Autologous Transplantation for Indolent Lymphoma 422
23.5.9.2 Role of Allogeneic Transplantation for Indolent Lymphoma 423
23.5.9.3 Role of Autologous Transplantation for Aggressive Lymphoma 423
23.5.9.4 Role of Allogeneic Transplant for Aggressive Lymphoma 424
23.5.10 Hodgkin's Disease 424
23.5.11 Solid Tumors 425
23.5.11.1 Germ Cell Tumor 425
23.5.11.2 High-Dose Chemotherapy (HDT) for Relapsed Refractory Disease 425
23.5.11.3 HDT for Primary Therapy of High Risk Disease 425
23.5.12 Renal Cell Cancer 426
23.5.13 Breast Cancer 426
23.6 Summary and Conclusion 427
References 427
24 Pain Management in Cancer Patients 435
24.1 Cancer Pain Types 436
24.2 Pharmacological Management of Cancer Pain 437
24.3 Surgical Management of Cancer Pain 445
References 448
25 Management of Nausea and Vomiting in Cancer Patients 451
25.1 Introduction 451
25.2 Mechanisms of Emesis 451
25.2.1 Anatomy 451
25.2.2 Neurotransmitters and Receptors 451
25.2.3 Dopamine Receptor Antagonists 451
25.2.4 Serotonin (5-HT3) Receptor Antagonists 453
25.2.5 Dopamine-Serotonin Receptor Antagonists 453
25.2.6 Substance P Receptor Antagonists 453
25.3 Chemotherapy-Induced Nausea and Vomiting 453
25.4 Agents in Clinical Use for the Treatment of Chemotherapy-Induced Nausea and Vomiting 454
25.4.1 Serotonin (5-HT3) Receptor Antagonists 454
25.4.2 Palonosetron 455
25.4.3 Dopamine-Serotonin Receptor Antagonists 456
25.4.4 Substance P (NK-1) Receptor Antagonists Aprepitant 456
25.4.5 Fosaprepitant 457
25.4.6 Casopitant 458
25.4.7 Corticosteroids 459
25.4.8 Olanzapine 459
25.4.9 Gabapentin 460
25.4.10 Cannabinoids 460
25.5 Clinical Management of Chemotherapy-Induced Nausea and Vomting 461
25.5.1 Principles in the Management of CINV 461
25.5.2 Single Day-Chemotherapy 461
25.5.3 Multiple-Day Chemotherapy 461
25.5.4 Rescue Therapy 462
25.5.5 Refractory Therapy 462
25.6 Radiation-Induced Emesis 462
25.6.1 Prevention of Radiotherapy-Induced Nausea and Vomiting 462
25.7 Opioid-Induced Chronic Nausea and Emesis 462
25.7.1 Treatment of Opioid-Induced Chronic Nausea 462
25.8 Summary and Conclusions 463
25.9 Future Developments 464
References 465
26 Nutrition in the Management of the Cancer Patient 470
26.1 Introduction 470
26.2 Nutrition at Initial Diagnosis and Rationale for Intervention 470
26.3 Nutrition Strategies During Treatment and Recovery 471
26.4 Nutritional Factors and Risk for Recurrence and Survival 474
26.4.1 Nutritional Factors and Survival in Breast Cancer 475
26.4.2 Nutritional Factors and Survival in Prostate Cancer 479
26.4.3 Nutritional Factors and Survival in Colorectal Cancer 480
26.4.4 Nutritional Factors and Survival in Other Cancers 483
26.5 Summary and Conclusions 486
References 486
27 Predictive Value of IFN-.-Induced Indoleamine 2,3-Dioxygenase (IDO) Expression in Cancer Patients 492
27.1 Introduction 492
27.2 Basic Immunological Principles of Tumor and Host Interactions 493
27.2.1 Immunological Mechanisms Facilitating Tumor Immune Escape 493
27.3 Role of IFN-. During Innateand Adaptive Anti-tumor Immune Responses 495
27.3.1 Effects of Sustained IFN-. Production in Cancer Patients 496
27.4 IFN-. Induces IDO-Mediated Tryptophan Catabolism 496
27.5 IDO-Mediated Tryptophan Catabolism in Patients with Malignant Disease A Predictive Marker 497
27.6 Enhanced Tryptophan Depletion Due to IDO Results in Immunodefiency 499
27.7 Sustained IDO Activity Accounts for Several Symptoms Such as Cachexia, Anemia, Organ Failure and Depression of the Terminally ILL Cancer Patient 500
27.8 Nutrition and Tryptophan Availability 501
References 502
Subject Index 505