Pediatric and Adolescent Osteosarcoma (eBook)

Dedication 5
Preface 6
Contents 8
Contributors 12
The Epidemiology of Osteosarcoma 21
Primary Osteosarcoma 22
Incidence 22
Age 24
Gender 24
Ethnicity 25
Site 25
Mortality 26
Survival 26
Osteosarcomas Following Treatment 28
Conclusions 29
References 29
The Etiology of Osteosarcoma 32
Introduction 33
Host Factors 36
Age 36
Gender 36
Ethnicity 36
Growth 36
Height 37
Genetic and Familial Factors 37
Preexisting Bone Abnormalities 41
Environmental Factors 42
Ionizing Radiation 42
Alkylating Agents 43
Perinatal Factors 44
Viruses 44
Trauma 45
Conclusions 45
References 45
Imaging Assessment of Osteosarcoma in Childhood and Adolescence: Diagnosis, Staging, and Evaluating Response to Chemotherapy 50
Introduction 50
Classification 51
Fundamental Principles of Imaging 51
Conventional Radiography 52
Primary Osteosarcomas 52
Secondary Osteosarcomas 55
Extended Diagnostic and Therapeutic Imaging Modalities 59
Radionuclide Bone Scan 59
Angiography 59
Computed Tomography 59
Ultrasound 60
Standard Magnetic Resonance Imaging 60
Dynamic Contrast-Enhanced MRI 66
18F-FDG PET/CT 67
Monitoring Response to Chemotherapy 69
Post-Therapy Complications 73
Local Recurrence of Osteosarcoma 74
Conclusion 77
References 78
Osteosarcoma Multidisciplinary Approach to the Management from the Pathologist’s Perspective 80
Introduction 81
Classification 82
Conventional Osteosarcoma 82
Osteosarcoma Variants 86
Diagnostic Biopsy 90
Specimen Therapy Evaluation 90
Preparation of Gross Specimen 92
Histologic Analysis 93
References 100
Conditions that Mimic Osteosarcoma 102
Introduction 102
Traditional Differential Diagnosis 104
Chondrosarcoma 104
Chondroblastoma (Codman’s Tumor) 106
Fibrous Dysplasia and Osteofibrous Dysplasia (Ossifying Fibroma) 108
Aneurysmal Bone Cyst 118
Telangiectatic Osteosarcoma 122
Nontraditional Osteoid-Producing Entities 122
Dedifferentiated Chondrosarcoma 122
Clear Cell Chondrosarcoma 123
Mesenchymal Chondrosarcoma 126
Synovial Sarcoma 126
Miscellaneous Tumors and Conditions 128
Ewing Sarcoma 128
Giant Cell Tumor of Bone 130
Osteoid Osteoma and Osteoblastoma 131
Fracture 132
Osteomyelitis 132
Inflammatory Metachronous Hyperostosis 134
Myositis Ossificans 135
Bone Cysts 136
Summary 136
References 137
Surgical Management of PrimaryOsteosarcoma 140
Introduction 140
Preoperative Assessment 141
Radiologic Imaging 141
Biopsy 141
Surgical Planning 142
Surgery 144
Limb-Sparing Tumor Resection 144
Skeletal Reconstruction of the Extremity 146
Prosthetic Arthroplasty 146
Biological Constructs 149
Other Considerations 153
Soft Tissue Management 155
Rotationplasty and Amputation 156
Surveillance 157
Local Recurrence Management 157
Summary 157
References 158
The Role of Radiotherapy in Oseosarcoma 161
Introduction 162
Material/Methods 163
Radiotherapy 163
Chemotherapy 164
Assessment of Response 165
Statistical Analysis 166
Results 166
Survival 166
Local Control 169
Prognostic Factors 169
Discussion 171
Conclusions 176
References 176
Osteosarcoma Lung Metastases Detection and Principles of Multimodal Therapy 179
Introduction 179
Postal Survey 180
Location and Frequency of Metastases 182
Role of Imaging in Pulmonary Metastases 184
CT-Scanning: Possibilities and Limitations 184
Nuclear Imaging of Pulmonary Metastases 185
Implications of Imaging on Therapy 186
Manual Exploration Mandatory 186
No Role for Thoracoscopy 187
Approach to Unilateral Disease 187
Approach to Lesions “Disappearing” During Chemotherapy 188
Treatment and Outcome of Primary Pulmonary Metastases 189
Survival Probability with Multimodal Therapy 189
Tumor-Related Prognostic Factors in Primary Pulmonary Metastases 189
Rationale for Surgery in Primary Pulmonary Metastases 190
Role of Chemotherapy in Primary Metastases 190
Pulmonary Metastases at Recurrence 191
Survival 191
Prognostic Factors in Pulmonary Recurrence 193
Treatment and Prognosis of Metachronous Pulmonary Metastases 193
Surgery in Relapsed Osteosarcoma 193
Second Line Chemotherapy in Relapsed Osteosarcoma 193
Summary and Perspectives for the Future 195
Participants of the Survey Agreed to their Names Being Published 195
References 196
Surgical Treatment of Pulmonary Metastases from Osteosarcoma in Pediatric and Adolescent Patients 199
Historical Background 199
Presentation and Evaluation 200
Indications for Surgical Resection 202
Surgical Resection 203
Outcomes 208
Surveillance and Recurrence 211
Future Directions 213
Summary 213
References 213
Non-Surgical Treatment of Pulmonary and Extra-pulmonary Metastases 216
Introduction 216
Reduction of Recurrent or Metastatic Osteosarcoma with Drugs (Chemotherapy) 218
Reduction of Osteosarcoma with “Physical” Means: Using Physics! 218
Radiation Therapy 221
Thermal Ablation 221
Summary and Conclusion 224
References 225
Adjuvant Chemotherapy in Osteosarcoma 230
Introduction 231
The Promise of Chemotherapy 232
Comparison of Results with Historical Controls 232
Controversy: Are Historical Controls Valid? 234
The Multi-Institutional Osteosarcoma Study 241
The Ramifications of MIOS 243
Acceptance of Adjuvant Therapy for Osteosarcoma 243
Denouement 244
References 246
Osteosarcoma: Review of the Past, Impact on the Future. The American Experience 249
Introduction 250
Conpadri/Compadri Series 250
High-Dose Methotrexate with Leucovorin Rescue 252
Doxorubicin 255
Cisplatin 255
Oxazaphosphorines 261
Less Frequently Employed Chemotherapeutic Agents 263
Chemotherapy Regimens 264
Inadequacy of Chemotherapy 265
Conspectus: Impact on the Conduct of Future Investigation and Treatment 267
References 267
Osteosarcoma: The European Osteosarcoma Intergroup (EOI) Perspective 273
Introduction 273
First EOI Study (80831)10 274
The Second EOI Study (80861)11 275
Dose Intensity in 80831 and 80861 Studies12 279
Pilot Study of Interval Compression13 281
Third EOI Randomised Study: MRC B006 and EORTC 8093114 281
Conspectus 283
References 283
The Treatment of Nonmetastatic High Grade Osteosarcoma of the Extremity: Review of the Italian Rizzoli Experience. Impact on th 285
Introduction 285
Prechemotherapy Era 286
Patients Treated Only with Surgery 286
Amputation According to the Cade Method 286
Prophylactic Irradiation of Lungs 286
Immunotherapy with Autologous Vaccine 287
Chemotherapy Era 287
Adjuvant Chemotherapy 287
Neoadjuvant Chemotherapy 288
Prognostic Factors 291
Postrelapse Survival 292
Late Effects 293
Future Directions 294
Conclusions 295
References 295
Osteosarcoma: The COSS Experience 298
Introduction 298
The Cooperative Osteosarcoma Study Group COSS 298
Registration Policy 299
Aims 299
Scope of this Paper 299
25 “Neoadjuvant COSS Years”: Patients and Methods 300
Patients 300
Treatment Strategy 300
Statistical Analyses 303
25 “Neoadjuvant COSS Years”: Results 303
Patient Characteristics 303
Response to Induction Chemotherapy 303
Type of Surgery 307
Overall Outcome and Causes of Death 307
Prognostic Factors 309
Discussion 311
Local Therapy 311
Mortality 312
Prognostic Factors 313
Treatment of Recurrent Disease 315
Conclusions 315
References 316
Treatment of Osteosarcoma. The Scandinavian Sarcoma Group Experience 318
Introduction 318
Materials and Methods 319
Results 321
Discussion 324
Conspectus 326
References 326
Childhood Osteosarcoma: Multimodal Therapy in a Single-Institution Turkish Series 328
Introduction 329
Patients and Methods 330
Patients and Pretreatment Work-Up 330
Treatment 331
Chemotherapy 331
Surgery 332
Radiotherapy 332
Characteristics and Variables 332
Assessment of Response 333
Toxicity 333
Statistical Analysis 333
Follow-Up 334
Results 334
Demographic and Disease-Related Data 334
Treatment Results 334
Preoperative Chemotherapy and Response 334
Surgery 336
Radiotherapy 338
Postoperative Chemotherapy 338
Histologic Response 338
Treatment Complications 338
Chemotherapy Dose Intensity and Acute Toxicity 338
Acute and Late Complications of Surgery 339
Outcome, Survival, and Prognosis 339
Discussion 343
References 345
International Collaboration is Feasible in Trials for Rare Conditions: The EURAMOS Experience 348
Introduction 349
Contemporary Results 350
EURAMOS 352
Rationale for Ifosfamide and Etoposide 352
Rationale for Maintenance Therapy with Pegylated Interferon 354
Rationale for Quality of Life (QL) Evaluation 355
Regulatory Concerns 355
Accrual: Registration and Randomization 357
Conspectus and Conclusion 358
Bibliography 358
Pediatric and Adult Osteosarcoma: Comparisons and Contrasts in Presentation and Therapy 363
Introduction 364
Conspectus 370
References 370
The Role of Physical Therapy and Occupational Therapy in the Rehabilitation of Pediatric and Adolescent Patients with Osteosarc 373
Introduction 373
The Interdisciplinary Rehabilitation Team 374
The Physical Therapist 374
The Occupational Therapist 374
The Purpose of Rehabilitation in Cancer Care 375
Historical Overview of Rehabilitation Therapy 375
Current Rehabilitation Concepts 376
Goals of Physical Therapy 376
Goals of Occupational Therapy 376
Triggers for Referral 376
Complications that Can Affect Rehabilitation 377
Current Physical-Therapy Practice 378
Presurgical Phase 379
Postsurgical Phase 379
The Acute Postsurgical Phase (Postoperative Day 0–2 weeks) 380
The Subacute or Intermediate Postsurgical Phase (2–6 Weeks after Surgery) 381
The Chronic or Late Postsurgical Phase (6 Weeks and Beyond as Needed) 381
Physical Therapy After Lower-Extremity Surgery 382
Current Occupational-Therapy Practice 382
The Occupational-Therapy Assessment 382
Occupational Therapy and Upper-Extremity 384
Presurgical Phase 384
Postsurgical Phase 384
Shared Occupational-Therapy and Physical-Therapy Interventions 385
Orthotics 385
Amputations and Prosthetics 385
Equipment 387
Discharge Recommendations 387
Future Considerations 388
Conclusions 388
References 389
Caring for Children and Adolescents with Osteosarcoma: A Nursing Perspective 391
Family-Centered Care 392
Developing Patient Tools 392
One Page Summary 392
Calendars 392
Medication Schedules 393
Medication Bags (“Tackle Boxes”) 393
Flash Drive 394
Outpatient/Home Chemotherapy 394
Symptom Prevention and Management 395
Disease-related Pain 396
Post Operative Pain 396
Progressive Disease Pain 396
Oral Mucocitis 397
Nausea and Vomiting 397
Nutrition 397
Developing Local Experts 398
Maintaining Hope 398
Summary and Conclusions 399
References 399
Prosthetics for Pediatric and Adolescent Amputees 401
Introduction 401
General Principles 402
Upper Extremity 404
Construction Design for Lower Extremity 406
Foot 408
Knee 414
Socket Accommodations for Growth 415
Liners 418
Locking Liner with Pin 418
Suspensions 418
Suspension Sleeves 420
Suspension for the Transfemoral Prosthesis 420
Silesian Belt 420
Van Ness Rotationplasty 420
Care of the Prosthesis 423
Socket 423
Upper Extremity Harness 423
Control Cable 424
Cosmetic glove 424
Personal Care and Hygiene 424
Conclusion 424
Functional, Psychosocial and Professional Outcomes in Long-Term Survivors of Lower-Extremity Osteosarcomas: Amputation Versus 427
Introduction 428
Functional Outcomes 429
Amputation 430
Limb Salvage 431
Reoperation After Limb Salvage 433
Economic Considerations 435
Psychosocial and Professional Outcomes 436
Late Effects of Therapy 438
Conclusions 438
References 439
Bridging the Gap Between Experimental Animals and Humans in Osteosarcoma 444
References 450
Is There a Role for Immunotherapy in Osteosarcoma? 452
What Is Immunotherapy? 452
Historical Overview 453
Active Immunotherapy 454
Immune Stimulatory Agents 456
Adoptive Immunotherapy 458
Conclusions and Hope for the Future 459
References 460
Molecular Classification of Osteosarcoma 463
Introduction 463
Prognostic Markers of Osteosarcoma 464
Expression Profiling of Osteosarcoma 464
Use of Multigene Classifier to Predict Response to Preoperative Chemotherapy in IB 466
Conclusions 468
Acknowledgements 469
References 469
Current Concepts on the Molecular Biology of Osteosarcoma 470
Introduction 470
Genetic Alterations Involved in Osteosarcoma Pathogenesis 471
Cell of Origin 474
Redundancy 474
The Potential Clinical Relevance of Osteosarcoma Biology Studies 475
Approaches to Identify Therapeutic Targets 477
The Pediatric Preclinical Testing Program 478
Conclusion 479
References 479
How the NOTCH Pathway Contributes to the Ability of Osteosarcoma Cells to Metastasize 482
Introduction 483
Regulation of Notch Pathway Signaling 483
Notch in Normal Bone and Limb Development 484
Notch in Cancer 485
Experimental Evidence 485
Notch Pathway Expression in Osteosarcoma 485
Gamma-Secretase Inhibitors Block Osteosarcoma Invasiveness 487
Direct Manipulation of Notch Pathway Components Alters Invasiveness 487
Notch inhibition Reduces Metastasis in an Orthotopic Xenograft Model of Osteosarcoma 489
Hes-1 Expression Is Associated with Reduced Survival in OS Patients 492
Valproic Acid Induces Notch Pathway Expression and Invasion in Osteosarcoma 493
Discussion 495
Acknowledgments 497
References 497
The Role of Fas/FasL in the Metastatic Potential of Osteosarcoma and Targeting this Pathway for the Treatment of Osteosarcoma 500
Introduction 501
Role of Fas in the Metastatic Potential of OS Cells in the Lung 502
Therapeutic Effect of Aerosol Therapy on Established OS Lung Metastases 506
Summary 509
References 510
Bone Marrow Micrometastases Studied by an Immunomagnetic Isolation Procedure in Extremity Localized Non-metastatic Osteosarcoma 512
Introduction 512
Background 513
Materials and Methods 514
Results 515
Discussion and Future Perspectives 516
Summary 516
References 517
Strategies to Explore New Approaches in the Investigation and Treatment of Osteosarcoma 519
Introduction 520
Genetic Alterations in Osteosarcoma 520
Chromosomal Abnormalities 520
Genetic Abnormalities 521
Activation of Growth Factor Signaling Pathways 522
Insulin-Like Growth Factors 522
Src Kinase 522
Modulation of Cell Surface Receptors 523
Modeling the Metastatic Cascade 525
Therapeutic Implications 527
References 529
History of Orthopedic Oncology in the United States 531
History of Orthopedic Oncology in the United States 531
Chemotherapy 542
Radiographic Imaging 549
Advances in Reconstructive Surgery 549
Surgical Experience 556
Development of Sarcoma Referral Centers 559
Current History 561
References 571
Editorial Summation 574
A Final Comment 576
Index 577