From Local Invasion to Metastatic Cancer (eBook)

FROM LOCAL INVASION TO METASTATIC CANCER 1
Acknowledgements 5
Foreword 6
Preface 7
Contents 8
Contributors 12
Color Plates 18
I INNOVATION AND EXPERIENCE 26
Frontiers of Cancer Research: The Metastasis Challenge 27
1.1. Predicting Metastasis 28
1.2. Origins of Metastatic Potential 29
1.2.1. Cancer Stem Cell Theory of Metastasis 31
1.2.2. Germline Metastatic Potential 31
1.3. Target Genes 32
1.4. Future Directions 33
References 34
Vascular Endothelial Growth Factor: Basic Biology and Clinical Applications 35
1. Introduction 35
2. History of VEGF 36
3. Biological Effects of VEGF-A 36
4. VEGF-A Isoforms 37
5. VEGF Receptors 37
6. Role of VEGF-A in Tumor Angiogenesis 38
6.1. Clinical Trials in Cancer Patients with VEGF Inhibitors 38
7. Role of VEGF-A in Intraocular Neovascular Syndromes 39
7.1. Clinical Studies of Anti-VEGF Therapy for Neovascular AMD: Pegaptanib and Ranibizumab 40
8. Perspectives 41
References 41
Proliferation and Cancer Metastasis from the Clinical Point of View 46
References 50
Gastrointestinal Cancer and the Lymphatic System: Patterns of Micrometastasis and Lymphatic Mapping with Clinical Outcome 51
4.1. Introduction 52
4.2. Current Status of SN Navigation Surgery in GI Cancer 53
4.2.1. Esophageal Cancer 53
4.2.2. Gastric Cancer 54
4.2.3. Colon Cancer 55
4.3. Identification of Micrometastases in SN 56
4.3.1. Esophageal Cancer 56
4.3.2. Gastric Cancer 56
4.3.3. Colon Cancer 58
4.4. Prognostic Impact of Micrometastases 59
4.4.1. Esophageal Cancer 59
4.4.2. Gastric Cancer 59
4.4.3. Colon Cancer 61
4.5. Clinical Significance of Circulating Tumor Cells and Bone Marrow 62
4.5.1. New Paradigm of Microscopic Disease 62
4.5.2. CTC in GI Cancer 63
4.5.2.1. Esophageal Cancer 63
4.6. Conclusion 63
References 64
Redefined Lymphatic Anatomy of the Breast with Clinical Implications 66
5.1. Introduction 67
5.2. Historical Review of the Breast Lymphatics 68
5.3. Materials and Methods 70
5.4. Superficial Lymphatic System 72
5.5. Perforating Lymphatic System 74
5.6. Clinical Implications for Sentinel Node Biopsy 75
5.7. Conclusions 75
References 76
Should Axillary Lymph Node Dissection be Done for Breast Cancer? 77
1. Introduction 77
2. Axillary Node Dissection in Patients with Invasive Breast Cancer: Pro by Douglas Reintgen 78
3. Axillary Node Dissection in Patients with Invasive Breast Cancer: By Dr. Blake Cody 81
References 84
II TUMOR MICROENVIRONMENT AND PROLIFERATION 87
Overview of Tumor Cells and the Microenvironment 88
1. Targeting Molecular Signals in the Tumor Cell Microenvironment 88
2. Convergence of Embryonic and Tumorigenic Pathways: Role in Tumor Progression 90
References 92
III LYMPHANGIOGENESIS AND ANGIOGENESIS 93
Heme/Lymphvasculogenesis, Hem/Lymphangiogenesis, Hem/Lymphangiotumorigenesis, and Tumor Hem/Lymphangiogenesis: Need for a Terminology Adjustment 94
1. Lymphologic Perspectives 95
2. Premolecular Era of (Hem)Angiogenesis and (Blood) Vascular Cell Biology 95
3. Premolecular Era of Lymphangiogenesis and Lymphatic Cell Biology 96
4. Proposal for Terminology Adjustment 98
5. Resurgence of Interest in Lymphangiogenesis in the Molecular Era of (Hem)Angiogenesis 99
6. Angiodysplasias, Hem/Lymphangiotumorigenesis, and Tumor Angiogenesis 103
7. Angiomodulation and Angioprotection 105
8. Unanswered Questions and Unquestioned Answers (Continued) (Fig. 8) 106
9. Continuing Saga and Controversy About the Lymphatic System 107
References 107
Tumor Lymphangiogenesis: What We Know and Don’t Know 110
9.1. Introduction 111
9.2. Cancer Diagnosis and Prognosis: How Important is the Role of the Lymphatics? 111
9.3. Prolymphangiogenic Factors: What is their relevance in Tumor-Induced Lymphangiogenesis? 112
9.4. Signal Transduction Pathways that Mediate Lymphangiogenesis: Common Motifs? 114
9.5. Other Mechanisms that Actively Promote Tumor Entry into the Lymphatics: What is the Relative Importance of Tumor-Induced Lymphangiogenesis? 115
9.5.1. Chemokines 115
9.5.2. Vascular Mimicry 115
9.5.3. Lymph Node Lymphangiogenesis 116
9.6. Manipulation of Tumor-Associated Lymphatics: Therapeutic Applications? 117
9.7. Conclusions 118
References 118
IV DIAGNOSTIC IMAGING OF CANCER 122
Molecular Imaging of Cancer: Receptors, Angiogenesis, and Gene Expression 123
1. Angiogenesis 124
2. Receptor Expression in Prostate and Breast Cancer 125
3. Gene Expression Imaging 127
References 129
MRI and Ultrasound Imaging of Lymph Nodes 131
1. Introduction 131
2. Mechanism of Lymph Node Enhancement 132
3. Sentinel Node Detection 133
4. Recognition of Benign From Malignant Nodes 135
5. Conclusion 137
References 137
Molecular Imaging of the Sentinel Lymph Node via Lymphoseek 139
1. Introduction 140
2. Background 140
3. Optimal tracer 141
4. Lymphoseek 141
5. Preclinical Studies 142
6. Biodistribution and Toxicity 143
7. Phase I and Phase II Clinical Trials 146
8. Conclusion 148
References 148
Lymphatic Disorders in Patients with Cancer 150
13.1. Defining Lymphedema 151
13.2. Pathogenesis of Edema including Lymphedema 152
13.3. Broad Classification of Appendicular Lymphedema 153
13.4. Primary Lymphedema 153
13.5. Secondary Lymphedema 155
13.6. Lymphedema and Breast Cancer 157
13.7. Lymphedema after Sentinel Node Surgery for Breast Cancer 159
13.8. Lymphedema after Inguinal Node Surgery 160
13.9. Lymphedema and Genitourinary Cancer 161
13.10. Lymphedema and Sarcomas 163
13.11. Other Causes of Secondary Lymphedema 164
13.12. Diagnostic Imaging in Lymphedema 164
13.13. Lymphoscintigraphy 165
13.14. Summary and Conclusions 169
References 169
3D-CT Lymphography for Mapping Metastatic Breast Sentinel Node and Axillary Nodes 173
14.1. Introduction 174
14.1. Patients 175
14.1. 3D-CT LG 175
14.1. Surgical Methods 175
14.2. Lymph Flow from Tumor to SN (13) 176
14.3. Lymph Flow from SN to Axillary Angle in Axilla (14) 178
14.4. Metastatic Evaluation by 3D-CT LG 180
14.5. Endoscopic SNB Guided by 3D-CT LG 181
14.6. Conclusion 181
References 181
Molecular Imaging of Neuroendocrine Cancer by Fusion SPET/CT 183
15.1. Introduction 184
15.2. Material and Method 184
15.2.1. Patients 184
15.2.2. Imaging Protocol 184
15.2.3. Data Analysis 185
15.2.4. Statistical Analysis 185
15.3. Results 185
15.3.1. Image Quality 185
15.3.2. Equivocal Exams 186
15.3.3. Comparison Between SPET and SPET/CT 187
15.4. Discussion 187
15.5. Conclusion 188
References 188
Functional Molecular Imaging of Prostate Cancer Lymph Node Metastases: Adenovirus-Mediated Lymph Node Detection 190
16.1. Introduction 191
16.2. Debates on Lymph Node Sampling in Prostate Cancer 191
16.3. Noninvasive Imaging Approaches for Nodal Staging 192
16.4. Adenoviral Vector-Mediated Lymphangiography 193
16.5. Conclusions and Future Directions 197
References 199
V THERAPEUTIC TARGETING OF THE LYMPHOVASCULAR SYSTEM 202
Therapeutic Targeting of the Lymphovascular System in Cancer: Promise and Challenge 203
1. Introduction 204
2. Therapeutic Targetability of the Overall Metastatic Process 205
3. Clinical Significance of Lymph Node Metastasis 205
4. Impact of the ‘‘Marker’’ versus ‘‘Incubator’’ Controversy on Clinical Practice 206
5. Targeting Lymphangiogenesis as AntiMetastatic Cancer Therapy 207
6. Possible Clinical Utility of Antagonists of VEGFR-3 Signaling 208
References 210
Comparison of Liposomal and Aqueous Blue Dye in Visualization of Lymph Nodes Prior to Lymphadenectomy 212
1. Introduction 213
2. Material and Method 213
3. Results 214
4. Discussion 217
References 218
VI MOLECULAR MECHANISMS OF METASTASIS 220
The Role of Lymphangiogenesis in Regional Lymph Node Metastasis: Animal Models 221
1. Introduction 222
2. Animal Models of Lymphangiogenesis 223
2.1. Embryos 223
2.2. Skin Injury Models 223
2.3. Avian Chorioallantoic Membrane 223
2.4. Mouse Cornea 224
2.5. Mouse Tail 224
2.6. Regenerating Lizard Tail 224
2.7. Tadpoles 224
2.8. Zebrafish 225
2.9. Postnodal Lymphatic Vessels in Sheep 225
2.10. Transgenic Mouse Models 226
2.11. Peri- and/or Intratumoral Lymphangiogenesis 227
3. Animal Models that Demonstrated the Relationship Between Lymphangiogenesis and Lymph Node Metastasis 229
3.1. Lymphangiogenesis Associated with the Primary Tumor 229
3.2. Lymphangiogenesis Associated with the Sentinel Lymph Node 230
4. Summary 231
References 232
Sentinel Lymph Node Chemokine Microenvironment Modulated by Melanoma Metastasis 237
1. Introduction 238
2. Results 239
2.1. CXCL12 mRNA Expression in SLN 239
2.2. CCL21 mRNA Expression in SLN 241
2.3. CXCL12 and CCL21 mRNA Expression in Metastasis-Free SLN 241
2.4. IHC Analysis of Chemokine Expression in SLN 241
3. Discussion 242
References 244
Circulating and Disseminated Tumor Cells from Solid Tumors-Research and Clinical Aspects 246
1. Introduction 247
2. Bone Marrow as Common Homing Organ for Disseminating Tumor Cells 247
3. Clinical Studies on Disseminating Tumor Cells 247
4. Biological Characteristics of Disseminated and Circulating Tumor Cells 248
5. Conclusions 249
References 249
Head and Neck Cancer: An Example for the Role of Chemokine Receptors in Tumor Progression and Metastasis 251
1. Introduction 251
2. Chemokine Receptors 252
3. Chemokine Receptor Expression in Head and Neck Cancer 253
4. Chemokine Receptors Mediate Tumor Cell Migration, Invasion, and Survival 255
5. CCR7 Downstream Activation of Nuclear Factor-kappaB Completes the Autocrine Loop 257
6. Conclusion 258
References 258
Tumor and Lymph Node Lymphangiogenesis 263
1. Introduction 263
2. Tumor Lymphangiogenesis Promotes Lymph Node Metastasis 264
3. A New Concept of Tumor Metastasis: Lymph Node Lymphangiogenesis 265
4. Tumor Lymphangiogenesis and Metastasis in Human Cancers 265
5. Outlook 267
References 268
Treg, Chemokines, and Other Small Molecules: Role in Metastasis and Its Prevention 270
1. Introduction 271
2. Evolution of the Tumor-Infiltrating Lymphocyte Concept 271
3. Immunophenotyping and Subtyping TIL 272
4. Strategies to Augment Antimelanoma Immunity 274
5. Anti-CTLA-4 mAb Use in Melanoma Immunotherapy 275
6. Treg Depletion Strategies in the Immunotherapy of Melanoma 279
7. Additional Chemokine-Targeted Immunotherapy Strategies 279
8. Concluding Remarks 280
References 280
VII MOLECULAR TARGETED THERAPY AGAINST GROWTH FACTOR RECEPTORS,SIGNALING PATHWAYS AND ANGIOGENESIS AS THERAPEUTIC TARGETS 287
Molecular Targeting of Lymphangiogenesis and Tumor Metastasis 288
1. Introduction 289
2. Lymphangiogenic VEGF Receptors and Ligands 289
3. Angiopoietins and Tie Receptors 290
4. Chemokines, Chemokine Receptors, and other Cell-Homing Molecules 290
5. Matrix and Basement Membrane-Cell Interaction Proteins 291
6. Other Mediators of Lymphangiogenesis and Lymphatic Metastasis 291
7. Lymphangiogenesis and Tumor Metastasis 292
8. Strategies for Inhibition of Lymphangiogenesis and Tumor Metastasis 293
9. Antibodies Against VEGF Receptors and their Ligands 294
10. Soluble Receptors 294
11. Tyrosine Kinase Inhibitors 295
12. Other Therapeutic Agents Targeting VEGF-C/VEGFR-3 Signaling 295
13. Molecules Blocking Angiopoietins and Tie Receptors 295
14. Molecular Targeting of Chemokines and their Receptors 295
15. Targeting of Other Pathways 296
16. Future Prospects in Molecular Targeting of Lymphangiogenesis and Tumor Metastasis 296
References 296
Combined Targeting of EGFR and Angiogenesis in Aerodigestive Carcinomas 301
1. Introduction 301
2. EGFR and VEGF/VEGFR-Signaling Pathways 302
3. Strategies for EGFR and VEGF/VEGFR Inhibition 303
4. Clinical Experience with Dual Targeting of EGFR and VEGF/VEGFR 304
4.1. Nonsmall-Cell Lung Cancer 304
4.2. Squamous Cell Carcinoma of the Head and Neck 307
5. Conclusions and Future Perspectives 308
References 308
Targeting Signaling Pathways in Cancer Therapy 312
1. Introduction 313
2. Common Biological Targets 313
3. Monoclonal Antibodies and Small-Molecule Tkls 315
4. Small Molecules in Hepatocellular Cancer 317
4.1. Sorafenib 317
4.2. Sunitinib 318
4.3. EGFR Tyrosine Kinase Inhibitors 318
4.4. Conclusion 318
5. Small-Molecule Tkis in Nonsmall-Cell lung Cancer 319
6. Small Molecules in Breast Cancer 321
6.1. Gefitinib and Other EGFR-Specific TKIs 321
6.2. Lapatinib 321
7. Small Molecules in Colon Cancer 322
8. Conclusion 323
References 324
VIII IMPACT OF NODAL STATUS AND TUMOR BURDEN IN SENTINEL NODES ON THE CLINICAL OUTCOME 330
Micrometastasis of Melanoma to Sentinel Lymph Nodes 331
28.1. Introduction 331
28.2. Significance of Micrometastasis in Melanoma SLNs 332
28.3. Further Definition of Micrometastasis in Melanoma SLNs 333
28.4. Data from Randomized Studies to Show the Significance of Micrometastasis in Melanoma SLNs 335
28.5. Recent Data on Micrometastasis in Melanoma SLNs from UCSF 336
28.6. New Paradigm of Metastasis for Melanoma Based on the SLN Data 336
28.7. Conclusion 337
References 337
Sentinel Lymph Node Micrometastases in Breast Cancer: Prognostic Relevance and Therapeutic Implications 340
29.1. Introduction 341
29.2. Accuracy of the SLN Procedure and Axillary Recurrence Rate After SLN Biopsy Alone 341
29.3. Detection Rate of SLN Micrometastases 342
29.4. Correlation of SLN and Non-SLN Metastases 342
29.5. Type of Non-SLN Metastases in Patients with SLN Micro-Metastases 343
29.6. Prognostic Significance of SLN Micrometastases 343
29.7. Conclusion 344
References 345
Micrometastasis of Genitourinary Cancer to Sentinel Lymph Nodes 347
30.1. Introduction 347
30.2. Penile Carcinoma 348
30.3. Prostate Gland 349
30.4. Bladder Carcinoma 350
30.5. Testicular Carcinoma 351
30.6. Renal Carcinoma 355
30.7. Conclusion 355
References 355
Sentinel Lymph Node Mapping in Colorectal Cancer 360
31.1. Introduction 361
31.2. Lymph Node Micrometastasis in Colon Cancer 361
31.3. Sentinel Lymph Node Mapping in Colorectal Cancer 363
31.3.1. Historical Review 363
31.3.2. Definition of a Sentinel Lymph Node 364
31.3.3. Technique of Sentinel Lymph Node Mapping in Colon Cancer 364
31.3.4. Technique of Sentinel Lymph Node Mapping in Rectal Cancer 366
31.3.5. Dyes Used in Sentinel Lymph Node Mapping in Colorectal Cancer 366
31.3.6. Ex Vivo Mapping 368
31.3.7. Laparoscopic Experience 368
31.3.8. Pathological Examination of SLNs 368
31.3.9. The Swiss Trial: The Amount of Dye is Related to the Size of the Tumor 369
31.3.10. Skip Metastasis 369
31.4. Multicenter Trials Evaluating Sentinel Lymph Node Mapping in Colorectal Cancer 370
31.5. Our Multicenter Trial Results 371
31.6. Colon Cancer 371
31.7. Rectal Cancer 372
31.8. Conclusion 374
References 375
Application of Cancer Biology in Cancer Staging and Predicting Clinical Outcome 379
References 385
IX IMMUNE RESPONSES IN THE DRAINING LYMPH NODES AGAINST CANCER:IMPLICATION FOR IMMUNOTHERAPY 387
Role of Lymph Nodes in Immunotherapy of Malignant Tumors 388
1. Introduction 388
2. Structure and Anatomy 389
3. Generation of Effector Cells for Adoptive Immunotherapy 389
4. Key Role of Antigen-Presenting Cells 391
5. Process of Dc -Tumor Cell Fusion 392
6. Sensitization by Fusion Cells 393
7. Future Directions 395
References 396
Tumor-Related Immune Modulation of the Regional Lymph Nodes 398
References 401
Reversal of Immune Suppression in Sentinel Lymph Nodes 404
35.1. Introduction 405
35.1. Historical Prospective 405
35.2. Role of the Immune System in SN 406
35.3. The Argument for Focused Analysis of SN 408
35.4. Immunohistochemistry Analysis of Sentinel and Non-Sentinel Lymph Nodes for Dendritic Cell Markers 409
35.5. Gene Expression of Dendritic Cell Markers of Activation from Sentinel and Non-Sentinel Lymph Nodes 410
35.6. Evaluate Gene Expression of TH-1- and TH-2-Related Cytokines from Sentinel and Nonsentinel Lymph Node Matches 412
35.7. Development of Real-Time Quantitative RT-PCR Analysis for Evaluation of Sentinel and Nonsentinel Lymph Node Matches 413
35.8. Evaluation of GM-CSF to Reverse the Phenotypic Changes to Sentinel Lymph Nodes 416
35.9. Significance of GM-CSF Data 417
References 417
Vaccine-Primed Lymph Node Cells in the Adoptive Immunotherapy of Cancer: Presence of Host Immune Suppression Induced by Established Cancer 421
1. Introduction 422
2. Tumor-Draining Lymph Node Cells: Animal Studies 422
3. Vaccine-Primed Lymph Node Cells: Clinical Studies 423
4. Immune Suppression of Tumor-Draining Lymph Node Effector Cells 424
5. Possible Mechanisms of Immune Suppression 426
6. Summary 427
References 427
X THE ROLE OF STEM CELLS IN CANCER METASTASIS 429
Cancer Stem Cells in Metastatic Melanoma 430
1. Cancer Stem Cells 430
2. Melanoma Stem Cells 432
3. Cancer Stem Cells in Metastasis 432
4. Therapeutic Implications of Melanoma Stem Cells 434
References 435
Implications of Cancer Stem Cells for Tumor Metastasis 437
38.1. Stem Cells: General Principles 438
38.2. Cancer Stem Cells: Definition and Identification 438
38.3. Cancer Stem Cells: Role in Tumor Metastasis 440
38.4. Conclusions 445
References 445
Prostate Cancer Stem Cells and Their Involvement in Metastasis 448
1. Introduction 449
2. Normal Prostate Stem/Progenitor Cells 449
3. CSCs: Resemblance to Normal SCs and Seeds of Tumor Development 450
4. Human Prostate CSCs: PCa-Initiating Cells 450
4.1. Surface Markers 451
4.2. Side Population Technique 451
4.3. Sphere-Formation Assays 451
5. CSCs and Metastasis 451
6. Potential Roles of CSCs in PCa Metastasis and Therapeutic Implications 452
References 453
XI GENOMIC SIGNATURES OF CANCER:BASIS FOR SELECTIVE ADJUVANT THERAPY 455
Estrogen Receptor-Positive Breast Cancer: Traditional Prognostics, Molecular Pathology: A New Breast Cancer Taxonomy and 21st Century Personalized Prognostic and Predictive Assays 456
40.1. Introduction 457
40.1.14. The Dawn of Molecular Pathology 457
40.1.14. Breast Carcinoma 457
40.2. Traditional Prognostic and Predictive Factors 457
40.2.1. Introduction 457
40.2.2. Tumor Stage: Axillary Lymph Nodes 458
40.2.3. Isolated Tumor Cells: pN0i+ 458
40.2.4. AJCC Cancer Staging Manual 459
40.2.5. Micrometastases: pN1mi 459
40.2.6. Tumor Size 459
40.2.7. Tumor Grade 459
40.2.8. Histologic Subtypes 461
40.2.9. Hormone Receptors: An Introduction 461
40.2.9.1. The Estrogen and Progesterone Receptors 462
40.2.10. ER Negativity 462
40.2.10.1. Estrogen Receptor beta 462
40.2.10.2. Methods of Measuring Hormone Receptors 462
40.2.10.3. Methods of Measuring Hormone Receptors: the Ligand-Binding Method 463
40.2.10.4. Methods of Measuring Hormone Receptors: Immunohistochemistry 463
40.2.11. Protocol: Estrogen Receptor 463
40.2.12. Clinical Validation: Estrogen Receptor as a Continuous Variable 463
40.2.13. Clinical Validation: Progesterone Receptor 465
40.2.14. Endocrine Therapy 466
40.2.14.1. Tamoxifen-Resistance in ER+ Breast Cancer 466
40.2.14.2. Acquired Endocrine Resistance 466
40.2.14.3. Other Markers 466
40.3. Personalized Medicine: 21st Century Prognostic and Predictive Molecular Tools 467
40.3.1. Roadmap 467
40.3.2. Technology Introduction 467
40.3.2.1. Microarray Analysis: What Is It and Why Is It Valuable? 467
40.3.3. DNA Expression Microarrays: ‘‘Expression Arrays’’ 468
40.3.3.1. Functional Genomics 468
40.3.4. Gene Arrays: Technical Comments (14) 468
40.3.5. Gene Expression Arrays: Methodology 468
40.3.6. Comparative Genomic Hybridization: Methodology 469
40.3.7. Array CGH 470
40.3.8. Quantitative Real-Time Polymerase Chain Reaction 470
40.3.9. Introduction: 21st Century Prognostic and Predictive Factors 471
40.4. A New Breast Taxonomy: Molecular Subtypes Using Unsupervised Classification 471
40.4.1. Unsupervised Molecular Taxonomy of Breast: Luminal A/B, HER2, and Basal Subtypes of Breast Carcinoma 471
40.4.2. Confirmation of Taxonomy: Evaluation of Breast Cancer Data from van’t Veer et al. 472
40.4.3. Tumor Subtypes Are Associated with Significant Difference in Clinical Outcome 473
40.4.4. Breast Tumor Subtypes Represent Reproducible Distinct Biological Entities 474
40.4.5. Conclusion: New Breast Taxonomy 474
40.5. Genomic Classifiers: Prognostic and Predictive Signatures 475
40.5.1. Introduction 475
40.5.2. Classifier Development (54) 475
40.6. The Mammoprint Breast Cancer Assay 476
40.6.1. Breast Cancer Classifier: van’t Veer et al. (59) 476
40.6.2. Validation of the 70-Gene Classifier (60) 478
40.6.3. Criticisms 479
40.7. Onco Type DXtrade 479
40.7.1. Introduction: Onco type DXtrade 479
40.7.2. Assay Design 479
40.7.3. Technical Feasibility Studies 480
40.7.4. Development Studies 480
40.7.5. Recurrence Score Calculation 480
40.7.6. Clinical Validation Studies 480
40.7.6.1. NSABP B-14: Introduction 480
40.7.7. Study Design 480
40.7.8. Methodology 481
40.7.9. Analysis 481
40.7.10. Results 481
40.7.11. Additional Validation Study: Kaiser Permanente Study 482
40.7.12. Prediction of Chemothrerapy Benefit: NSABP B-20 482
40.7.13. Results 482
40.7.14. Reclassification Versus Guidelines 483
40.8. Conclusion 483
References 484
Molecular Signatures in Melanoma Progression 487
41.1. Introduction 487
41.2. Biology Of Tumor Metastasis 488
41.3. Molecular Signatures: From Nevus To Melanoma 489
41.3.1. B-RAF Activating Mutation as a Precursor 489
41.3.2. Defining the Molecular Signatures in Melanoma Progression 489
41.3.2.1. Transition from RGP to VGP and Extending the Findings to Metastatic Melanoma 490
41.3.3. CDH3 and MMP-10 491
41.3.3.1. Distinguishing a Benign Nevus from a Primary Melanoma 493
41.3.4. Osteopontin as a Novel Molecular Prognostic Marker for Melanoma 494
41.3.4.1. Perform a Multiclass Analysis Comparing nevi, Primary, and Metastatic Lesions 495
41.3.5. Molecular Marker NCOA3 Overexpressed in Metastatic Melanoma 495
41.4. Molecular Markers And Sentinel Lymph Node Biopsy 496
41.5. Implications And Future Direction 496
References 497
XII PROMISING NEW TREATMENTS FOR SOLID TUMORS 500
Targeted Therapy for Breast Cancer: A Focus on HER2/neu and Antiangiogenic Therapy 501
1. Introduction 502
2. Targeting HER2/NEU 502
3. LAPATINIB 504
4. Novel HER2-Directed Therapy 505
5. Targeting HER2 and the Vascular Endothelial Growth Factor Receptor 506
6. Antiangiogenic Therapy 507
References 508
Advances in the Treatment of Colorectal Cancer: Targeting Receptors of Disease 510
1. Introduction 510
2. Angiogenesis 512
2.1. Bevacizumab 512
2.2. Sunitinib 513
3. Epidermal Growth Factor Receptor Pathway 513
3.1. Cetuximab 514
3.2. Panitumumab 514
3.3. Genetic Selection in Colorectal Cancer: KRAS Mutations and Efficacy of Anti-EGFR Therapy 515
4. Combined Targeting Of Angiogenesis And Egfr 516
5. Conclusion 516
References 517
Developments in the Management of Genitourinary Malignancies: Prostate Cancer and Renal Cell Carcinoma 520
1. Prostate Cancer 520
1.1. Secondary Hormonal Manipulations 520
1.2. MDV3100 522
1.3. Chemotherapy for Castration-Resistant Prostate Cancer 522
1.4. Epothilone Analogs: Ixabepilone 522
1.5. Chemotherapy Plus Angiogenesis Inhibition 523
1.6. VEGF Tyrosine Kinase Inhibition 523
1.7. Other Investigational Agents 523
1.7.1. Atrasentan 523
1.8. Immunotherapy 524
1.8.1. Sipuleucel-T 524
1.8.2. Cellular Vaccination 524
1.8.3. Anti-CTLA4 Therapy: Ipilimumab 525
1.9. Prostate Cancer: Conclusions 525
2. Renal Cell Carcinoma 525
2.1. Drug Targets in Renal Cell Carcinoma 526
2.1.1. VHL in Kidney Cancer 526
2.1.2. mTOR in Kidney Cancer 526
2.2. VEGF Pathway-Directed Angiogenesis Inhibitors 526
2.2.1. Bevacizumab 526
2.2.2. Sunitinib 527
2.2.3. Sorafenib 527
2.3. mTOR Inhibition 528
2.3.1. Temsirolimus (CCI-779) 528
2.3.2. RAD001 529
2.4. Renal Cell Carcinoma-Conclusions 529
References 529
Advances in the Treatment of Lung Cancer 532
1. Nonsmall-Cell Lung Cancer 533
1.1. Early Disease 533
1.1.1. Radiation Therapy 533
1.1.2. Adjuvant Chemotherapy 533
1.2. Locally Advanced NSCLC 534
1.3. Advanced Disease 534
1.3.1. Cytotoxic Chemotherapy 534
1.4. Targeted Therapies 535
1.4.1. Epidermal Growth Factor Inhibitors 535
1.4.2. Angiogenesis Inhibitors 535
1.5. Predictive and Prognostic Molecular Markers 535
2. Small-Cell Lung Cancer 536
3. Conclusions 537
References 537
XIII RECENT ADVANCES IN THE TREATMENT OF MELANOMA 540
Pegylated Interferons in the Adjuvant Treatment of Melanoma 541
46.1. Introduction 541
46.2. Background and History of Interferons 542
46.3. Effects of Interferon-alpha 542
46.4. Pegylated Interferon-alpha Compared to Classic Interferon-alpha 542
46.5. Adjuvant Treatment with Interferon-alpha 544
46.6. Adjuvant Treatment with Pegylated Interferon-alpha 545
References 548
Sorafenib, a Multikinase Inhibitor: Results from Clinical Trials in Melanoma Patients 551
47.1. Introduction 552
47.2. Sorafenib: Mode of Action 552
47.3. Sorafenib: Clinical Trials in Various Cancers 553
47.4. Single-Agent Sorafenib: Clinical Trials in Melanoma 555
47.5. Sorafenib Plus Dacarbazine in Melanoma 555
47.6. Sorafenib Plus Temozolomide in Melanoma 555
47.7. Carboplatin, Paclitaxel with or without Sorafenib 556
47.8. Other Phase II Trials with Sorafenib 556
47.9. Sorafenib and Pegylated Interferon-alpha2b in Metastatic Melanoma 558
47.10. Conclusions 558
References 559
Targeting Immunological Synapse: New Horizons in Immunotherapy for Cancer 561
1. Immunological Synapse 562
2. Targeting Inhibitory Molecules 563
2.1. CTLA-4 (CD152) 563
2.2. Programmed Death-1 565
3. Targeting Co-Stimulatory Molecules 566
3.1. CD28 566
3.2. 4-1BB 566
3.3. OX-40 566
4. Targeting APCS 567
4.1. CD40 567
5. Autoimmunity 568
6. Where do we come from? what are we? where are we Going? 569
References 571
Cutaneous Metastases of Melanoma: New Treatment Options 577
1. Introduction 578
2. Topical Treatment with 2-4 DNCB 578
3. Intratumoral IL-2 Treatment 579
3.1. Indication for intratumoral IL-2 treatment 579
3.2. Management of intratumoral IL-2 treatment 580
3.3. Tumor responses under intralesional IL-2 therapy 580
4. Topical Treatment with Imiquimod 581
5. Discussion 582
References 582
Neoadjuvant Approaches in Melanoma 585
1. Introduction 586
2. Immunity and Immunotherapy in Melanoma and Implications for Adjuvant and Neoadjuvant Therapy 586
3. Adjuvant High-Dose IFN-alpha2b for High-Risk Resected Melanoma 587
4. Neoadjuvant Treatment of Potentially Resectable Local-Regional Metastases of Cutaneous Melanoma 588
5. Neoadjuvant Concurrent Biochemotherapy in Melanoma Patients with Local-Regional Metastases 588
6. Neoadjuvant Treatment with High-Dose IFN-alpha2b for Patients with Regional Nodal Presentation or Recurrence as Stage IIIB-C Melanoma 589
7. Conclusion 590
References 590
Implications of Chemo/Biochemotherapy in the Treatment of Metastatic Melanoma 592
1. Introduction 592
2. Cytotoxic Chemotherapy 593
3. Immunotherapy 593
4. Biochemotherapy 593
5. Summary and Conclusions 594
References 594
XIV FUTURE PERSPECTIVES 595
Future Perspectives for Cancer Metastasis: Unanswered Questions and Unquestioned Answers 596
1. Introduction 596
2. Cancer Metastasis and the Lymphovascular System 597
3. Unanswered Questions and Unquestioned Answers 597
References 599
Index 600