Lung Cancer: (eBook)

Preface 7
Contents 10
Contributors 12
Molecular Pathology of Lung Cancer 16
Introduction 17
Molecular Pathology of Lung Cancer 17
Non-small Cell Lung Carcinoma 18
Pathology 18
Genetic Abnormalities 19
Angiogenesis 23
Epithelial-to-Mesenchymal Transition 24
Markers Associated with Response to Chemotherapy 24
Small Cell Lung Carcinoma 25
Pathology 25
Molecular Abnormalities 25
Molecular Profiling Studies in Lung Cancer 25
RNA Signatures 26
MicroRNA Profiles 27
DNA Copy Number Profiles 28
Epigenetic Methylation Profiling 28
Proteomic Signatures 29
Integrative Approaches to Profiling Data 29
Pathogenesis of Lung Cancer 30
Squamous Cell Carcinoma Preneoplastic Lesions 30
Adenocarcinoma Precursor Lesions 32
Precursors of Nonsmoking-Related Adenocarcinoma 32
Conclusion 33
References 34
Tumor Microenvironment 41
Introduction 42
Macrophages and Mast Cells 44
Dendritic Cells and Ectopic Lymph Nodes 47
T Regulatory Cells 51
Matrix Metalloproteinases 54
Cyclooxygenase-2 and Prostaglandin E2 58
Peroxisome Proliferator-Activated Receptor-Gamma and 15-Prostaglandin Dehydrogenase 61
Inflammation and Epithelial–Mesenchymal Transition 63
NF-kB 66
HGF and c-Met 67
Angiogenesis 68
Conclusion 71
References 72
Racial and Ethnic Diversity in Lung Cancer 84
Introduction 84
Racial Differences in Lung Cancer Incidence and Mortality 85
Incidence 85
Mortality 86
Racial and Ethnic Differences in Risk Factors for Lung Cancer 87
Smoking and Tobacco Consumption 87
Family History of Lung Cancer 89
Race, Diet, and Lung cancer 89
Occupational and Environmental Exposures 89
Genetic Variations and Variations in Role of Metabolic Pathways 90
Histology and Stage at Presentation 90
Racial/Ethnic Differences in Lung Cancer Treatment 92
Survival 92
Immigration and Acculturation 95
Conclusion 95
References 96
Pharmacogenetics of Lung Cancer 99
Introduction 100
Genetic Predisposing Factors for Lung Cancer 100
Carcinogen Metabolism Genes 101
DNA Repair Genes 102
Genes Involved in Nicotine Addiction 103
Other Pathway Genes 103
Genetic Predictors of Clinical Outcome of Lung Cancer 104
Pharmacogenetics of Platinum Drug Therapy 104
Pharmacokinetics of Platinum Drug Therapy in Lung Cancer 107
Pharmacodynamics of Platinum Drug Therapy in Lung Cancer 108
Cumulative Effect of Multiple Variants 109
Radiogenetics 111
Pharmacogenetics of EGFR-Target Therapy 112
Conclusions and Perspectives 113
References 113
Lung Cancer Prevention 119
Introduction 119
Principles of Chemoprevention 121
Definition of High-Risk Groups 122
Biomarkers and High-Risk Groups 123
Smoking Cessation 124
Intraepithelial Neoplasia and Atypical Alveolar Hyperplasia 126
Randomized Clinical Trials 126
Retinoid RCTs 126
ATBC Study 129
Selenium RCTs 130
Anethole Dithiolethione and Budesonide RCTs 130
Molecular Targeting of Lung Carcinogenesis 131
Polyunsaturated Fatty Acid Metabolic Pathways 131
Arachidonic Acid Metabolism 131
COX-2, PGE2, and PGI2 132
PGI2 133
15-PGDH 134
5-LOX and Leukotriene Modifiers 134
12-LOX 135
15-LOXs 135
EGFR 136
Retinoic Acid Signaling 137
Insulin-Like Growth Factor Axis 138
PI3K/Akt 138
PPARg 139
Epigenetic Targets 139
Combinatorial Agents 140
Conclusion 141
References 142
Adjuvant and Neoadjuvant Therapy of NSCLC 151
Introduction 152
Adjuvant Radiation 152
Clinical Trials 152
Current Standard of Practice 153
Adjuvant Chemotherapy 154
Clinical Trials 154
Adjuvant Meta-analyses 158
UFT-Based Adjuvant Trials 159
Current Standard of Practice 160
Molecular Markers in NSCLC 161
Induction Chemotherapy 161
Clinical Trials 161
Induction Chemotherapy Meta-analyses 165
Surgical Morbidity and Mortality After Induction Therapy 166
Current Standard of Practice 167
Conclusion 167
References 167
Chemoradiotherapy for Inoperable Non-small Cell Lung Cancer 172
Introduction 172
Biological Basis for Radiation Treatment 173
Impact of Chemotherapy with Radiation Therapy 174
Mechanisms by Which Systemic Therapy May Potentiate Radiation 174
Platinum-Based Agents Plus Radiotherapy 175
Anti-tubulin Agents Plus Radiotherapy 176
Topoisomerase Inhibitors Plus Radiotherapy 177
Gemcitabine Plus Radiotherapy 177
EGFR Inhibitors Plus Radiotherapy 178
Clinical Impact of Adding Chemotherapy to Radiotherapy in NSCLC 178
Advanced Techniques for Radiation Therapy of NSCLC 180
Conclusion 182
References 182
Management of Advanced Non-small Cell Lung Cancer: Front Line Treatment 187
Introduction 187
Effects of Chemotherapy on Survival and Quality of Life 188
Number of Cytotoxic Agents 189
Selection of Platinum-Based Doublets 190
Carboplatin Versus Cisplatin 193
Non-platinum Combinations 194
Length of Therapy 195
Anti-VEGF Therapy 196
Anti-EGFR Therapy 197
Treatment of Elderly Patients 200
Treatment of Poor Performance Status Patients 200
References 201
Chemotherapy in Previously Treated Patients with Non-small Cell Lung Cancer 205
Introduction 205
Docetaxel 205
Phase III Trial of Docetaxel vs. Best Supportive Care: TAX 317 206
Phase III Trial of Docetaxel vs. a Comparator Chemotherapy Regimen: TAX 320 207
Pemetrexed 209
Erlotinib 211
Conclusion 213
References 213
Epidermal Growth Factor Receptor Inhibitors in the Treatment of Non-small Cell Lung Cancer 215
Introduction 215
Small Molecule Tyrosine Kinase Inhibitors 216
Erlotinib (Tarceva®, OSI-774 OSI Pharmaceuticals, Melville, NY, USA)
Gefitinib (Iressa®, ZD1839 Astra-Zeneca, Macclesfield, United Kingdom)
TKI Molecules in Development 225
Monoclonal Antibodies 226
Patient Selection for EGFR-Targeted Therapy 227
Clinical Factors 227
EGFR Expression, Copy Number, and Mutations 227
Markers of Resistance 229
Conclusion and Future Directions 229
References 229
Angiogenesis Inhibitors in Lung Cancer 237
Introduction 237
Role of Angiogenesis in Tumor Development 238
The Role of Vascular Endothelial Growth Factor (VEGF) in Angiogenesis 243
Anti-angiogenic Approaches 244
Anti-vascular Endothelial Growth Factor Monoclonal Antibodies 245
Bevacizumab in Patients with Non-small Cell Lung Cancer 245
Bevacizumab in Patients with Small Cell Lung Cancer 248
Small Molecule Receptor Tyrosine Kinase Inhibitors 249
Sorafenib in Patients with Non-small Cell Lung Cancer 249
Sorafenib in Patients with Small Cell Lung Cancer 250
Vandetanib in Patients with Non-small Cell Lung Cancer 251
Vandetanib in Patients with Small Cell Lung Cancer 252
Sunitinib 252
Thalidomide in Patients with Non-small Cell Lung Cancer 253
Thalidomide in Patients with Small Cell Lung Cancer 253
Cediranib 254
Other Agents 255
Conclusion 255
References 255
Other Molecular Targeted Agents in Non-small Cell Lung Cancer 263
Introduction 263
Cancer Cell Growth Pathways 265
Insulin-Like Growth Factor Receptor – IGF-1R 265
Targeting mTOR 267
Targeting Ras Pathway 269
Farnesyl Transferase Inhibitors (FTIs) 271
RAF/MAPK Pathway 272
Targeting MET 273
Antiangiogenic-Related Agents 274
Protein Kinase C (PKC) 275
Integrins 276
Apoptosis 277
Targeting Bcl-2 277
Proteasome Inhibitors 278
Death Receptors 279
Perspectives 280
Conclusion 281
References 282
Vaccine Therapy for Lung Cancer 289
Introduction 289
Non-Small Cell Lung Cancer Vaccine Development 290
Belagenpumatucel 290
GVAX 291
L-BLP-25 294
IDM-2101 294
B7.1 Vaccine 295
L523S Vaccine 296
Epidermal Growth Factor Vaccine 296
Melanoma-Associated Antigen E-3 Vaccine 297
Transcriptase Catalytic Subunit Antigen Vaccine 298
Dexosome Vaccine 298
a.(1,3)-Galactosyltransferase 299
Non-Small Cell Lung Cancer Dendritic Cell Vaccines 299
Cyclophilin B 299
Small Cell Lung Cancer Vaccine Development 300
Fucosyl-GM1 300
BEC2 300
PolySA 302
WT1 302
Conclusion 303
References 303
Gene-Based Therapies for Lung Cancer 314
Introduction 314
Gene Therapy to Replace Genes Including Missing/Defective Tumor Suppressor Genes 316
Mechanism of p53 Tumor Suppression and Rationale for p53 Gene Therapy 316
Preclinical Studies of p53 Gene Replacement 317
Clinical Trials of p53 Gene Replacement 318
Gene Replacement in Combination with Conventional DNA Damaging Agents in NSCLC 318
Clinical Trials of Tumor Suppressor Gene Replacement Combined with Chemotherapy 319
Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy 319
Systemic Gene Therapy for Metastases 320
Summary and Conclusions 321
Antisense Technology in NSCLC 322
Protein Kinase C-a: ISIS 3521 323
Clusterin: OGX-011 324
H-ras: ISIS 2503 325
C-Raf-1: ISIS 5132 325
Bcl-2: Oblimersen 326
Survivin: LY2181308 326
RNA Interference 327
Antitumor Effects of RNAi 328
RNAi Delivery 329
Potential Hurdles for siRNA Cancer Therapeutics 329
Concluding Remarks 330
References 331
Lung Cancer Resistance to Chemotherapy 340
Lung Cancer and Resistance 340
Types of Resistance 341
Importance of the Host Genotype 342
Chemotherapy as “Targeted” Therapy 343
Drug and Oxygen Delivery 343
Extracellular pH 347
Drug Uptake 349
Drug Efflux 350
Multidrug Resistance Protein 351
MDR1/p-Glycoprotein 351
Breast Cancer Resistance Protein 352
Ral-Interacting Protein (RLIP76) (RALBP1) 353
Lung Resistance Protein 353
P-Type Adenosine Triphosphatase (ATP 7B) 353
Drug Detoxification 353
Glutathione (GSH) 353
Glutathione-S-Transferase-pi 354
Metallothioneins 354
Dihydrodiol Dehydrogenase 355
Cytotoxicity Bypass 355
Peroxiredoxin V 355
Deoxycytidine Deaminase 355
Drug Activation: Deoxycytidine Kinase 356
Drug Binding: Platinums 356
Increased, Decreased, or Altered Target 356
Folate Pathway 356
Stathmin (Oncoprotein 18) 356
Tubulin 357
Topoisomerase (Topo) II-a 357
DNA Repair 358
Excision Repair Cross-Complementation Group 1 Protein 358
Other NER Pathway Components 359
Ribonucleotide Reductase M1 359
Rad51 360
Breast Cancer 1 360
DNA Mismatch Repair 361
Other Potentially Relevant DNA Repair Factors 361
Damage Tolerance 361
Reduced Apoptotic Response 361
p53 361
Caspases 363
SAPK/c-Jun N-Terminal Kinase and c-Jun 363
Apoptosis Signal Transduction 364
Other Proapoptotic Factors 364
Apoptosis Inhibitors 364
Cyclooxygenase-2 364
Telomeres and Telomerase 365
Heat Shock Proteins (HSPs) 365
Caveolin-1 365
Cell Attachment to Extracellular Matrix 365
Epidermal Growth Factor Receptor 366
HER-2/neu (erbB-2, p185) 367
Extracellular Signal-Regulated Kinase (ERK1/2) and MAPK/ERK Kinase (MEK) 367
Phosphatase and Tensin Homolog (PTEN)/Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (Akt)/Mammalian Target of Rapamycin (m 368
PTEN/PI3K 368
Akt 368
P70 S6 Kinase (p70S6K) and S6 369
K-ras and the RasGTPase Regulator RasGAP 369
PKC 370
Mitogen-Activated Protein Kinase (MAPK) phosphatase-1 (MKP1) 370
Bcl-2 and Related Proteins 371
Bcl-2 371
Bcl-xL 372
Myeloid Cell Leukemia-1 Protein 372
Other Bcl-2 Family Members 372
Survivin 373
Inhibitor of Apoptosis Proteins (IAPs), X-Linked Inhibitor of Apoptosis Protein (XIAP), and Livin (ML-IAP or KIAP) 373
Nrf2/Heme Oxygenase-1 373
P21WAF1/CIP1 373
Other Antiapoptotic Factors 374
Cell Cycling 374
Cell Cycle Phase 374
Mitotic Slippage/Aneuploidy 375
Cell Cycle Regulators 375
Retinoblastoma Protein 375
S-Phase Kinase-Associated Protein 2 and p27Kip1 375
E2F1 and E2F4 376
CHK2 376
Mitotic Spindle Checkpoint 376
14-3-3 376
Other Cell Cycle Regulators 377
Transcription Factors 377
Nuclear Factor-k.B 377
Other Transcription Factors 377
Summary 378
References 379
Small Cell Carcinoma of the Lung 403
Introduction 404
Epidemiology and Etiology 404
Pathology 405
Classification of SCLC 405
Histology 405
Molecular Pathology 406
Clinical Presentation 406
Paraneoplastic Syndromes 406
Staging 409
Natural History and Prognosis 411
Initial Management of SCLC 411
First-Line Chemotherapy for Extensive Stage SCLC 411
Alternating or Sequential Regimens 413
Etoposide–Platinum-Based Triplet Regimens 414
Other Platinum Doublets 415
Increased Dose Intensity or Density 415
Prolonged Administration of Chemotherapy 417
First-Line Chemotherapy for Limited Stage SCLC 418
The Role of Surgery in Limited Stage SCLC 418
Thoracic Radiation in Limited Stage SCLC 419
Thoracic Radiation Therapy Dose and Fractionation 419
Timing of Thoracic Radiation Therapy Relative to Chemotherapy 421
Prophylactic Cranial Irradiation 422
Relapsed Disease 424
New Systemic Therapies for SCLC 427
Cytotoxic Agents 427
Molecular Biology and Novel Targeted Therapies 427
Tumor Suppressor Genes 427
Nonreceptor Proto-oncogenes 428
Growth Factor and Receptor Abnormalities 428
Angiogenesis 429
Matrix Metalloproteinases 431
CD56 Antigen 431
Conclusions 431
References 432
Mesothelioma 443
Epidemiology and Etiology 444
Histologic Subtypes 447
Diagnosis and Staging 448
Therapy for Locoregional Disease 450
Surgery 450
Radiotherapy 452
Definitive Therapy 453
Prophylactic Therapy 456
Chemotherapy and Biological Therapy 457
Neoadjuvant Chemotherapy 457
Intrapleural Chemotherapy 459
Intrapleural Gene Therapy and Immunotherapy 459
Therapy for Advanced Disease 460
Radiotherapy 460
Chemotherapy 461
Biologic Therapy 462
Anti-angiogenic Agents 463
Histone Deacetylase Inhibitors 464
Ribonuclease Inhibitors 464
Proteasome Inhibitors 464
Other Targets and Agents 464
Conclusions 465
References 465
Advances in Oncology Clinical Research: Statistical and Study Design Methodologies 474
Introduction 474
Adaptive Methods for Dose Finding in Oncology 476
Outcome Adaptive Clinical Trials 480
Randomized Outcome Adaptive Clinical Trials 480
Real-Time Updating of Adaptive Clinical Trials 481
Randomized Discontinuation Trials 482
Personalized Medicine 483
Other Adaptive Methods 484
Bayesian Designs 484
Sample Size Reassessment Methods 485
Discussion 486
References 487
Palliative Care for Patients with Lung Cancer 489
Introduction 489
Role of Palliative Care in Patients with Advanced Lung Cancer 490
Patient Access to Palliative Care 490
Survival Estimation 491
Decision Making at the End of Life 492
Symptom Management 495
Dyspnea 495
Pain 496
Fatigue 498
Cough and Hemoptysis 501
Anorexia and Cachexia 502
Depression and Anxiety 503
Conclusion 504
References 504
The Future of Lung Cancer 509
Past, Present, and Beyond 509
Newer Strategies for Diagnosis and Treatment 510
Molecular Targeted Therapies 510
Towards Individualized Therapy 510
Tumor Molecular Profiling 512
Non-invasive Molecular Testing and Monitoring 514
Exploring the Tumor Microenvironment 515
Preclinical Models for Studying New Therapies 515
Targeting Cancer Stem Cells 516
Summary 518
References 518
Index 521