Lung Cancer:

Prevention, Management, and Emerging Therapies
1. Auflage 2010
ISBN: 978-1-60761-524-8
Verlag: Humana Press
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 538 Seiten

Defining the Lung Cancer Problem 1 Lung cancer is the leading cause of cancer death in the world. It kills almost as many Americans as cancers of the breast, prostate, colon, rectum, pancreas, and 2 kidney combined, and accounts for 28.6% of all US cancer deaths. With an increase in the 5-year relative survival rate from 13% to only 16% in the more than 2 30 years from 1974 to the present, it will take us another 840 years to eradicate lung cancer deaths if we do not improve the current rate of progress. As discussed in this text, lung cancer prevention has received substantial att- tion. The decrease in smoking in recent decades has helped, but smoking is not the only problem. Lung cancer in people who have never smoked is currently the 5th 3 leading cause of cancer death in the United States. Several factors contribute to the lethality of lung cancer, including the rapidity of tumor growth, advanced stage at diagnosis (due to nonspecificity of early sy- toms and the uncertain efficacy of screening), early development of metastases, and resistance to therapy. Several chapters in this book discuss new molecular targets that may be potentially exploitable in the future, as well as discussing our track record to date in exploiting them.

Autoren/Hrsg.

Inhaltsverzeichnis

1;Preface;7
2;Contents;10
3;Contributors;12
4;Molecular Pathology of Lung Cancer;16
4.1;Introduction;17
4.2;Molecular Pathology of Lung Cancer;17
4.2.1;Non-small Cell Lung Carcinoma;18
4.2.1.1;Pathology;18
4.2.1.2;Genetic Abnormalities;19
4.2.1.3;Angiogenesis;23
4.2.1.4;Epithelial-to-Mesenchymal Transition;24
4.2.1.5;Markers Associated with Response to Chemotherapy;24
4.2.2;Small Cell Lung Carcinoma;25
4.2.2.1;Pathology;25
4.2.2.2;Molecular Abnormalities;25
4.3;Molecular Profiling Studies in Lung Cancer;25
4.3.1;RNA Signatures;26
4.3.2;MicroRNA Profiles;27
4.3.3;DNA Copy Number Profiles;28
4.3.4;Epigenetic Methylation Profiling;28
4.3.5;Proteomic Signatures;29
4.3.6;Integrative Approaches to Profiling Data;29
4.4;Pathogenesis of Lung Cancer;30
4.4.1;Squamous Cell Carcinoma Preneoplastic Lesions;30
4.4.2;Adenocarcinoma Precursor Lesions;32
4.4.3;Precursors of Nonsmoking-Related Adenocarcinoma;32
4.5;Conclusion;33
4.6;References;34
5;Tumor Microenvironment;41
5.1;Introduction;42
5.2;Macrophages and Mast Cells;44
5.3;Dendritic Cells and Ectopic Lymph Nodes;47
5.4;T Regulatory Cells;51
5.5;Matrix Metalloproteinases;54
5.6;Cyclooxygenase-2 and Prostaglandin E2;58
5.7;Peroxisome Proliferator-Activated Receptor-Gamma and 15-Prostaglandin Dehydrogenase;61
5.8;Inflammation and Epithelial–Mesenchymal Transition;63
5.9;NF-kB;66
5.10;HGF and c-Met;67
5.11;Angiogenesis;68
5.12;Conclusion;71
5.13;References;72
6;Racial and Ethnic Diversity in Lung Cancer;84
6.1;Introduction;84
6.2;Racial Differences in Lung Cancer Incidence and Mortality;85
6.2.1;Incidence;85
6.2.2;Mortality;86
6.3;Racial and Ethnic Differences in Risk Factors for Lung Cancer;87
6.3.1;Smoking and Tobacco Consumption;87
6.3.2;Family History of Lung Cancer;89
6.3.3;Race, Diet, and Lung cancer;89
6.3.4;Occupational and Environmental Exposures;89
6.3.5;Genetic Variations and Variations in Role of Metabolic Pathways;90
6.4;Histology and Stage at Presentation;90
6.5;Racial/Ethnic Differences in Lung Cancer Treatment;92
6.6;Survival;92
6.7;Immigration and Acculturation;95
6.8;Conclusion;95
6.9;References;96
7;Pharmacogenetics of Lung Cancer;99
7.1;Introduction;100
7.2;Genetic Predisposing Factors for Lung Cancer;100
7.2.1;Carcinogen Metabolism Genes;101
7.2.2;DNA Repair Genes;102
7.2.3;Genes Involved in Nicotine Addiction;103
7.2.4;Other Pathway Genes;103
7.3;Genetic Predictors of Clinical Outcome of Lung Cancer;104
7.3.1;Pharmacogenetics of Platinum Drug Therapy;104
7.3.1.1;Pharmacokinetics of Platinum Drug Therapy in Lung Cancer;107
7.3.1.2;Pharmacodynamics of Platinum Drug Therapy in Lung Cancer;108
7.3.1.3;Cumulative Effect of Multiple Variants;109
7.4;Radiogenetics;111
7.5;Pharmacogenetics of EGFR-Target Therapy;112
7.6;Conclusions and Perspectives;113
7.7;References;113
8;Lung Cancer Prevention;119
8.1;Introduction;119
8.2;Principles of Chemoprevention;121
8.2.1;Definition of High-Risk Groups;122
8.2.2;Biomarkers and High-Risk Groups;123
8.3;Smoking Cessation;124
8.4;Intraepithelial Neoplasia and Atypical Alveolar Hyperplasia;126
8.5;Randomized Clinical Trials;126
8.5.1;Retinoid RCTs;126
8.5.2;ATBC Study;129
8.5.3;Selenium RCTs;130
8.5.4;Anethole Dithiolethione and Budesonide RCTs;130
8.6;Molecular Targeting of Lung Carcinogenesis;131
8.6.1;Polyunsaturated Fatty Acid Metabolic Pathways;131
8.6.1.1;Arachidonic Acid Metabolism;131
8.6.1.2;COX-2, PGE2, and PGI2;132
8.6.1.3;PGI2;133
8.6.1.4;15-PGDH;134
8.6.1.5;5-LOX and Leukotriene Modifiers;134
8.6.1.6;12-LOX;135
8.6.1.7;15-LOXs;135
8.6.2;EGFR;136
8.6.3;Retinoic Acid Signaling;137
8.6.4;Insulin-Like Growth Factor Axis;138
8.6.5;PI3K/Akt;138
8.6.6;PPARg;139
8.6.7;Epigenetic Targets;139
8.7;Combinatorial Agents;140
8.8;Conclusion;141
8.9;References;142
9;Adjuvant and Neoadjuvant Therapy of NSCLC;151
9.1;Introduction;152
9.2;Adjuvant Radiation;152
9.2.1;Clinical Trials;152
9.2.2;Current Standard of Practice;153
9.3;Adjuvant Chemotherapy;154
9.3.1;Clinical Trials;154
9.3.2;Adjuvant Meta-analyses;158
9.3.3;UFT-Based Adjuvant Trials;159
9.3.4;Current Standard of Practice;160
9.4;Molecular Markers in NSCLC;161
9.5;Induction Chemotherapy;161
9.5.1;Clinical Trials;161
9.5.2;Induction Chemotherapy Meta-analyses;165
9.5.3;Surgical Morbidity and Mortality After Induction Therapy;166
9.5.4;Current Standard of Practice;167
9.6;Conclusion;167
9.7;References;167
10;Chemoradiotherapy for Inoperable Non-small Cell Lung Cancer;172
10.1;Introduction;172
10.2;Biological Basis for Radiation Treatment;173
10.3;Impact of Chemotherapy with Radiation Therapy;174
10.4;Mechanisms by Which Systemic Therapy May Potentiate Radiation;174
10.4.1;Platinum-Based Agents Plus Radiotherapy;175
10.4.2;Anti-tubulin Agents Plus Radiotherapy;176
10.4.3;Topoisomerase Inhibitors Plus Radiotherapy;177
10.4.4;Gemcitabine Plus Radiotherapy;177
10.4.5;EGFR Inhibitors Plus Radiotherapy;178
10.5;Clinical Impact of Adding Chemotherapy to Radiotherapy in NSCLC;178
10.6;Advanced Techniques for Radiation Therapy of NSCLC;180
10.7;Conclusion;182
10.8;References;182
11;Management of Advanced Non-small Cell Lung Cancer: Front Line Treatment;187
11.1;Introduction;187
11.2;Effects of Chemotherapy on Survival and Quality of Life;188
11.3;Number of Cytotoxic Agents;189
11.4;Selection of Platinum-Based Doublets;190
11.5;Carboplatin Versus Cisplatin;193
11.6;Non-platinum Combinations;194
11.7;Length of Therapy;195
11.8;Anti-VEGF Therapy;196
11.9;Anti-EGFR Therapy;197
11.10;Treatment of Elderly Patients;200
11.11;Treatment of Poor Performance Status Patients;200
11.12;References;201
12;Chemotherapy in Previously Treated Patients with Non-small Cell Lung Cancer;205
12.1;Introduction;205
12.2;Docetaxel;205
12.2.1;Phase III Trial of Docetaxel vs. Best Supportive Care: TAX 317;206
12.2.2;Phase III Trial of Docetaxel vs. a Comparator Chemotherapy Regimen: TAX 320;207
12.3;Pemetrexed;209
12.4;Erlotinib;211
12.5;Conclusion;213
12.6;References;213
13;Epidermal Growth Factor Receptor Inhibitors in the Treatment of Non-small Cell Lung Cancer;215
13.1;Introduction;215
13.2;Small Molecule Tyrosine Kinase Inhibitors;216
13.2.1;Erlotinib (Tarceva®, OSI-774; OSI Pharmaceuticals, Melville, NY, USA);221
13.2.2;Gefitinib (Iressa®, ZD1839; Astra-Zeneca, Macclesfield, United Kingdom);223
13.2.3;TKI Molecules in Development;225
13.3;Monoclonal Antibodies;226
13.4;Patient Selection for EGFR-Targeted Therapy;227
13.4.1;Clinical Factors;227
13.4.2;EGFR Expression, Copy Number, and Mutations;227
13.5;Markers of Resistance;229
13.6;Conclusion and Future Directions;229
13.7;References;229
14;Angiogenesis Inhibitors in Lung Cancer;237
14.1;Introduction;237
14.2;Role of Angiogenesis in Tumor Development;238
14.3;The Role of Vascular Endothelial Growth Factor (VEGF) in Angiogenesis;243
14.4;Anti-angiogenic Approaches;244
14.4.1;Anti-vascular Endothelial Growth Factor Monoclonal Antibodies;245
14.4.1.1;Bevacizumab in Patients with Non-small Cell Lung Cancer;245
14.4.1.2;Bevacizumab in Patients with Small Cell Lung Cancer;248
14.4.2;Small Molecule Receptor Tyrosine Kinase Inhibitors;249
14.4.2.1;Sorafenib in Patients with Non-small Cell Lung Cancer;249
14.4.2.2;Sorafenib in Patients with Small Cell Lung Cancer;250
14.4.2.3;Vandetanib in Patients with Non-small Cell Lung Cancer;251
14.4.2.4;Vandetanib in Patients with Small Cell Lung Cancer;252
14.4.2.5;Sunitinib;252
14.4.2.6;Thalidomide in Patients with Non-small Cell Lung Cancer;253
14.4.2.7;Thalidomide in Patients with Small Cell Lung Cancer;253
14.4.2.8;Cediranib;254
14.4.2.9;Other Agents;255
14.5;Conclusion;255
14.6;References;255
15;Other Molecular Targeted Agents in Non-small Cell Lung Cancer;263
15.1;Introduction;263
15.2;Cancer Cell Growth Pathways;265
15.2.1;Insulin-Like Growth Factor Receptor – IGF-1R;265
15.2.2;Targeting mTOR;267
15.2.3;Targeting Ras Pathway;269
15.2.3.1;Farnesyl Transferase Inhibitors (FTIs);271
15.2.3.2;RAF/MAPK Pathway;272
15.2.4;Targeting MET;273
15.3;Antiangiogenic-Related Agents;274
15.3.1;Protein Kinase C (PKC);275
15.3.2;Integrins;276
15.4;Apoptosis;277
15.4.1;Targeting Bcl-2;277
15.4.2;Proteasome Inhibitors;278
15.4.3;Death Receptors;279
15.5;Perspectives;280
15.6;Conclusion;281
15.7;References;282
16;Vaccine Therapy for Lung Cancer;289
16.1;Introduction;289
16.2;Non-Small Cell Lung Cancer Vaccine Development;290
16.2.1;Belagenpumatucel;290
16.2.2;GVAX;291
16.2.3;L-BLP-25;294
16.2.4;IDM-2101;294
16.2.5;B7.1 Vaccine;295
16.2.6;L523S Vaccine;296
16.2.7;Epidermal Growth Factor Vaccine;296
16.2.8;Melanoma-Associated Antigen E-3 Vaccine;297
16.2.9;Transcriptase Catalytic Subunit Antigen Vaccine;298
16.2.10;Dexosome Vaccine;298
16.2.11;a.(1,3)-Galactosyltransferase;299
16.2.12;Non-Small Cell Lung Cancer Dendritic Cell Vaccines;299
16.2.13;Cyclophilin B;299
16.3;Small Cell Lung Cancer Vaccine Development;300
16.3.1;Fucosyl-GM1;300
16.3.2;BEC2;300
16.3.3;PolySA;302
16.3.4;WT1;302
16.4;Conclusion;303
16.5;References;303
17;Gene-Based Therapies for Lung Cancer;314
17.1;Introduction;314
17.2;Gene Therapy to Replace Genes Including Missing/Defective Tumor Suppressor Genes;316
17.2.1;Mechanism of p53 Tumor Suppression and Rationale for p53 Gene Therapy;316
17.2.1.1;Preclinical Studies of p53 Gene Replacement;317
17.2.1.2;Clinical Trials of p53 Gene Replacement;318
17.2.1.3;Gene Replacement in Combination with Conventional DNA Damaging Agents in NSCLC;318
17.2.1.4;Clinical Trials of Tumor Suppressor Gene Replacement Combined with Chemotherapy;319
17.2.1.5;Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy;319
17.2.1.6;Systemic Gene Therapy for Metastases;320
17.2.1.7;Summary and Conclusions;321
17.3;Antisense Technology in NSCLC;322
17.3.1;Protein Kinase C-a: ISIS 3521;323
17.3.2;Clusterin: OGX-011;324
17.3.3;H-ras: ISIS 2503;325
17.3.4;C-Raf-1: ISIS 5132;325
17.3.5;Bcl-2: Oblimersen;326
17.3.6;Survivin: LY2181308;326
17.4;RNA Interference;327
17.4.1;Antitumor Effects of RNAi;328
17.4.2;RNAi Delivery;329
17.4.3;Potential Hurdles for siRNA Cancer Therapeutics;329
17.5;Concluding Remarks;330
17.6;References;331
18;Lung Cancer Resistance to Chemotherapy;340
18.1;Lung Cancer and Resistance;340
18.2;Types of Resistance;341
18.3;Importance of the Host Genotype;342
18.4;Chemotherapy as “Targeted” Therapy;343
18.5;Drug and Oxygen Delivery;343
18.6;Extracellular pH;347
18.7;Drug Uptake;349
18.8;Drug Efflux;350
18.8.1;Multidrug Resistance Protein;351
18.8.2;MDR1/p-Glycoprotein;351
18.8.3;Breast Cancer Resistance Protein;352
18.8.4;Ral-Interacting Protein (RLIP76) (RALBP1);353
18.8.5;Lung Resistance Protein;353
18.8.6;P-Type Adenosine Triphosphatase (ATP 7B);353
18.9;Drug Detoxification;353
18.9.1;Glutathione (GSH);353
18.9.2;Glutathione-S-Transferase-pi;354
18.9.3;Metallothioneins;354
18.9.4;Dihydrodiol Dehydrogenase;355
18.9.5;Cytotoxicity Bypass;355
18.9.6;Peroxiredoxin V;355
18.9.7;Deoxycytidine Deaminase;355
18.10;Drug Activation: Deoxycytidine Kinase;356
18.11;Drug Binding: Platinums;356
18.12;Increased, Decreased, or Altered Target;356
18.12.1;Folate Pathway;356
18.12.2;Stathmin (Oncoprotein 18);356
18.12.3;Tubulin;357
18.12.4;Topoisomerase (Topo) II-a;357
18.13;DNA Repair;358
18.13.1;Excision Repair Cross-Complementation Group 1 Protein;358
18.13.2;Other NER Pathway Components;359
18.13.3;Ribonucleotide Reductase M1;359
18.13.4;Rad51;360
18.13.5;Breast Cancer 1;360
18.13.6;DNA Mismatch Repair;361
18.13.7;Other Potentially Relevant DNA Repair Factors;361
18.14;Damage Tolerance;361
18.15;Reduced Apoptotic Response;361
18.15.1;p53;361
18.15.2;Caspases;363
18.15.3;SAPK/c-Jun N-Terminal Kinase and c-Jun;363
18.15.4;Apoptosis Signal Transduction;364
18.15.5;Other Proapoptotic Factors;364
18.16;Apoptosis Inhibitors;364
18.16.1;Cyclooxygenase-2;364
18.16.2;Telomeres and Telomerase;365
18.16.3;Heat Shock Proteins (HSPs);365
18.16.4;Caveolin-1;365
18.16.5;Cell Attachment to Extracellular Matrix;365
18.16.6;Epidermal Growth Factor Receptor;366
18.16.7;HER-2/neu (erbB-2, p185);367
18.16.8;Extracellular Signal-Regulated Kinase (ERK1/2) and MAPK/ERK Kinase (MEK);367
18.16.9;Phosphatase and Tensin Homolog (PTEN)/Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (Akt)/Mammalian Target of Rapamycin (m;368
18.16.9.1;PTEN/PI3K;368
18.16.9.2;Akt;368
18.16.9.3;P70 S6 Kinase (p70S6K) and S6;369
18.16.10;K-ras and the RasGTPase Regulator RasGAP;369
18.16.11;PKC;370
18.16.12;Mitogen-Activated Protein Kinase (MAPK) phosphatase-1 (MKP1);370
18.16.13;Bcl-2 and Related Proteins;371
18.16.13.1;Bcl-2;371
18.16.13.2;Bcl-xL;372
18.16.13.3;Myeloid Cell Leukemia-1 Protein;372
18.16.13.4;Other Bcl-2 Family Members;372
18.16.14;Survivin;373
18.16.15;Inhibitor of Apoptosis Proteins (IAPs), X-Linked Inhibitor of Apoptosis Protein (XIAP), and Livin (ML-IAP or KIAP);373
18.16.16;Nrf2/Heme Oxygenase-1;373
18.16.17;P21WAF1/CIP1;373
18.16.18;Other Antiapoptotic Factors;374
18.17;Cell Cycling;374
18.17.1;Cell Cycle Phase;374
18.17.2;Mitotic Slippage/Aneuploidy;375
18.17.3;Cell Cycle Regulators;375
18.17.3.1;Retinoblastoma Protein;375
18.17.3.2;S-Phase Kinase-Associated Protein 2 and p27Kip1;375
18.17.3.3;E2F1 and E2F4;376
18.17.3.4;CHK2;376
18.17.3.5;Mitotic Spindle Checkpoint;376
18.17.3.6;14-3-3;376
18.17.3.7;Other Cell Cycle Regulators;377
18.18;Transcription Factors;377
18.18.1;Nuclear Factor-k.B;377
18.18.2;Other Transcription Factors;377
18.19;Summary;378
18.20;References;379
19;Small Cell Carcinoma of the Lung;403
19.1;Introduction;404
19.2;Epidemiology and Etiology;404
19.3;Pathology;405
19.3.1;Classification of SCLC;405
19.3.2;Histology;405
19.3.3;Molecular Pathology;406
19.4;Clinical Presentation;406
19.4.1;Paraneoplastic Syndromes;406
19.5;Staging;409
19.6;Natural History and Prognosis;411
19.7;Initial Management of SCLC;411
19.7.1;First-Line Chemotherapy for Extensive Stage SCLC;411
19.7.2;Alternating or Sequential Regimens;413
19.7.3;Etoposide–Platinum-Based Triplet Regimens;414
19.7.4;Other Platinum Doublets;415
19.7.5;Increased Dose Intensity or Density;415
19.7.6;Prolonged Administration of Chemotherapy;417
19.7.7;First-Line Chemotherapy for Limited Stage SCLC;418
19.8;The Role of Surgery in Limited Stage SCLC;418
19.9;Thoracic Radiation in Limited Stage SCLC;419
19.9.1;Thoracic Radiation Therapy Dose and Fractionation;419
19.9.2;Timing of Thoracic Radiation Therapy Relative to Chemotherapy;421
19.10;Prophylactic Cranial Irradiation;422
19.11;Relapsed Disease;424
19.12;New Systemic Therapies for SCLC;427
19.12.1;Cytotoxic Agents;427
19.12.2;Molecular Biology and Novel Targeted Therapies;427
19.12.2.1;Tumor Suppressor Genes;427
19.12.2.2;Nonreceptor Proto-oncogenes;428
19.12.2.3;Growth Factor and Receptor Abnormalities;428
19.12.2.4;Angiogenesis;429
19.12.2.5;Matrix Metalloproteinases;431
19.12.2.6;CD56 Antigen;431
19.13;Conclusions;431
19.14;References;432
20;Mesothelioma;443
20.1;Epidemiology and Etiology;444
20.2;Histologic Subtypes;447
20.3;Diagnosis and Staging;448
20.4;Therapy for Locoregional Disease;450
20.4.1;Surgery;450
20.4.2;Radiotherapy;452
20.4.2.1;Definitive Therapy;453
20.4.2.2;Prophylactic Therapy;456
20.4.3;Chemotherapy and Biological Therapy;457
20.4.3.1;Neoadjuvant Chemotherapy;457
20.4.3.2;Intrapleural Chemotherapy;459
20.4.3.3;Intrapleural Gene Therapy and Immunotherapy;459
20.5;Therapy for Advanced Disease;460
20.5.1;Radiotherapy;460
20.5.2;Chemotherapy;461
20.5.3;Biologic Therapy;462
20.5.3.1;Anti-angiogenic Agents;463
20.5.3.2;Histone Deacetylase Inhibitors;464
20.5.3.3;Ribonuclease Inhibitors;464
20.5.3.4;Proteasome Inhibitors;464
20.5.3.5;Other Targets and Agents;464
20.6;Conclusions;465
20.7;References;465
21;Advances in Oncology Clinical Research: Statistical and Study Design Methodologies;474
21.1;Introduction;474
21.2;Adaptive Methods for Dose Finding in Oncology;476
21.3;Outcome Adaptive Clinical Trials;480
21.3.1;Randomized Outcome Adaptive Clinical Trials;480
21.3.2;Real-Time Updating of Adaptive Clinical Trials;481
21.3.3;Randomized Discontinuation Trials;482
21.3.4;Personalized Medicine;483
21.4;Other Adaptive Methods;484
21.5;Bayesian Designs;484
21.6;Sample Size Reassessment Methods;485
21.7;Discussion;486
21.8;References;487
22;Palliative Care for Patients with Lung Cancer;489
22.1;Introduction;489
22.2;Role of Palliative Care in Patients with Advanced Lung Cancer;490
22.2.1;Patient Access to Palliative Care;490
22.2.2;Survival Estimation;491
22.2.3;Decision Making at the End of Life;492
22.3;Symptom Management;495
22.3.1;Dyspnea;495
22.3.2;Pain;496
22.3.3;Fatigue;498
22.3.4;Cough and Hemoptysis;501
22.3.5;Anorexia and Cachexia;502
22.3.6;Depression and Anxiety;503
22.4;Conclusion;504
22.5;References;504
23;The Future of Lung Cancer;509
23.1;Past, Present, and Beyond;509
23.2;Newer Strategies for Diagnosis and Treatment;510
23.3;Molecular Targeted Therapies;510
23.4;Towards Individualized Therapy;510
23.5;Tumor Molecular Profiling;512
23.6;Non-invasive Molecular Testing and Monitoring;514
23.7;Exploring the Tumor Microenvironment;515
23.8;Preclinical Models for Studying New Therapies;515
23.9;Targeting Cancer Stem Cells;516
23.10;Summary;518
23.11;References;518
24;Index;521