Sarcomas of Bone and Soft Tissues in Children and Adolescents (Pediatric Oncology)

This book is a comprehensive and up-to-date compendium on all aspects of sarcomas of bone and soft tissues in childhood and adolescence. After introductory chapters on the history, epidemiology, and biology of pediatric sarcomas, treatment considerations are extensively reviewed, with emphasis on the use of risk-adjusted treatment approaches. The pathology and biology of this diverse group of tumors are extensively reviewed. Promising new treatment approaches are discussed, and strategies for the development of new agents are appraised. The major common pediatric sarcomas, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma, are covered in detail. The authors are internationally recognized experts who offer a largely evidence-based consensus on etiology, biology, and treatment. This handbook has far-reaching applicability to the clinical diagnosis and management of childhood and adolescent sarcomas and will prove invaluable to specialists, generalists, and trainees alike. Contents 5 1: Epidemiology of Bone and Soft Tissue Sarcomas 6 1.1 Introduction 6 1.2 Descriptive Epidemiology 7 1.2.1 Osteosarcoma 7 1.2.2 Ewing Sarcoma 7 1.2.3 Rhabdomyosarcoma (RMS) 8 1.2.4 Non-rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) 9 1.3 Environmental (Non-genetic) Risk Factors 10 1.3.1 Osteosarcoma 10 1.3.1.1 Growth and Development 10 1.3.1.2 Exogenous Exposures 11 1.3.2 Ewing Sarcoma 12 1.3.3 RMS 12 1.3.4 NRSTS 13 1.4 Germline Genetic Risk Factors 13 1.4.1 Osteosarcoma 13 1.4.2 Ewing Sarcoma 14 1.4.3 RMS 14 1.4.4 NRSTS 15 1.5 Conclusion 16 References 16 2: Sarcoma Pathology and Biology 22 2.1 Rhabdomyosarcoma 22 2.1.1 Pathology 22 2.1.1.1 Alveolar Rhabdomyosarcoma 22 2.1.1.2 Embryonal Rhabdomyosarcoma 22 2.1.1.3 Spindle Cell/Sclerosing Rhabdomyosarcoma 23 2.1.2 Biology 23 2.1.2.1 Fusion-Positive Rhabdomyosarcoma 23 2.1.2.2 Fusion-Negative Rhabdomyosarcoma 24 2.1.2.3 Spindle Cell/Sclerosing Rhabdomyosarcoma 26 2.2 Ewing Sarcoma 26 2.2.1 Pathology 26 2.2.2 Biology 26 2.2.3 Ewing-Like Sarcomas 28 2.2.3.1 CIC-Rearranged Sarcomas 28 2.2.3.2 Ewing-Like Sarcoma with BCOR Rearrangements 29 2.3 Osteosarcoma 29 2.3.1 Pathology 29 2.3.2 Biology 29 2.4 Non-rhabdomyosarcoma Soft Tissue Sarcomas 31 2.4.1 Alveolar Soft Part Sarcoma 31 2.4.1.1 Pathology 31 2.4.1.2 Biology 31 2.4.2 Clear Cell Sarcoma of Soft Tissue 32 2.4.2.1 Pathology 32 2.4.2.2 Biology 32 2.4.3 Desmoid Tumor 32 2.4.3.1 Pathology 32 2.4.3.2 Biology 33 2.4.4 Desmoplastic Small Round Cell Tumor 33 2.4.4.1 Pathology 33 2.4.4.2 Biology 33 2.4.5 Malignant Peripheral Nerve Sheath Tumor 33 2.4.5.1 Pathology 33 2.4.5.2 Biology 34 2.4.6 Synovial Sarcoma 34 2.4.6.1 Pathology 34 2.4.6.2 Biology 34 2.4.7 Malignant Rhabdoid Tumor 35 2.4.7.1 Pathology 35 2.4.7.2 Biology 35 2.4.8 NTRK-Fusion Sarcomas 35 2.4.8.1 Pathology 35 2.4.8.2 Biology 35 References 36 3: Staging and Imaging of Sarcoma 42 3.1 Staging of RMS and NRSTS 42 3.2 Staging of Nonrhabdomyosarcomatous Soft Tissue Tumors (NRSTS) 45 3.3 Staging of Bone Sarcomas 46 3.4 Imaging and Staging Procedures 46 References 49 4: Multi-institutional Trials for Patients with Rhabdomyosarcoma: Lessons from North American Studies from 1967 Through 1997 52 4.1 Introduction 52 4.2 The First 30 Years, 1970–2000 53 4.2.1 The IRS Era, 1972–1997 53 References 57 5: Treatment of Rhabdomyosarcoma 58 5.1 Introduction 58 5.2 Initial Evaluation 59 5.3 Treatment Assignment 60 5.4 Treatment 60 5.4.1 North American Perspective 60 5.4.2 European Perspective 62 5.5 Future Directions 65 References 66 6: Current Approaches to Therapy: Soft Tissue Sarcomas Other than Rhabdomyosarcoma in Children and Adolescents 69 6.1 Introduction 69 6.2 Local Therapy 70 6.2.1 Surgery 70 6.2.2 Radiotherapy 71 6.3 Conventional Chemotherapy 72 6.4 Specific Therapy for Diseases 74 6.4.1 Synovial Sarcoma 74 6.4.2 Other “Adult-Type” Sarcomas (Fibrosarcoma, Liposarcoma, Mesenchymal Chondrosarcoma, PECOMA, Leiomyosarcoma, Epithelioid Sarcoma, Clear Cell Sarcoma, Angiosarcoma, Undifferentiated Sarcoma) 75 6.4.3 Malignant Peripheral Nerve Sheath Tumor 77 6.4.4 Desmoid Tumor 78 6.4.5 Rhabdoid Tumor 79 6.4.6 Infantile Fibrosarcoma 81 6.4.7 Desmoplastic Small Round Cell Tumor 83 6.4.8 Dermatofibrosarcoma Protuberans 84 6.4.9 Gastrointestinal Stromal Tumor (GIST) 84 6.4.10 Inflammatory Myofibroblastic Tumor 85 6.4.11 Alveolar Soft Part Sarcoma 85 References 86 7: Osteosarcoma: History of Therapy 90 References 92 8: Osteosarcoma-Approach to Therapy 94 8.1 Introduction 94 8.2 Clinical Presentation 95 8.3 General Outline of Multidisciplinary Treatment 95 8.4 Imaging at Diagnosis and During Systemic Treatment: Essentials 95 8.5 Biopsy: Procedure 96 8.6 What Can Be Learned from the Biopsy Specimen? 96 8.7 Systemic Treatment 97 8.7.1 Choice of Drugs 97 8.7.2 High-Dose Methotrexate 97 8.7.3 Doxorubicin 98 8.7.4 Cisplatin 98 8.7.5 Ifosfamide 99 8.7.6 Other Agents 99 8.8 Local Treatment of the Primary Tumor 100 8.9 Primary Metastases 102 8.10 Prognosis After Multimodal Treatment 103 8.11 Physical Rehabilitation and Surveillance for Late Effects 103 8.12 Surveillance for Recurrence 105 8.13 Treatment Options in Case of Recurrence 105 8.14 Conclusion 106 References 106 9: Contemporary Approach to Therapy for Ewing Sarcoma 113 9.1 Introduction 113 9.2 Treatment of the Patient with Newly Diagnosed Localized EWS 113 9.2.1 Systemic Therapy for Localized EWS 113 9.2.2 Local Control Strategies for Localized EWS 117 9.3 Treatment of the Patient with Newly Diagnosed Metastatic EWS 118 9.3.1 Systemic Therapy for Metastatic EWS 118 9.3.2 Role of Surgery and Radiation in Metastatic EWS 120 9.4 Treatment of the Patient with Recurrent EWS 121 9.4.1 Systemic Therapy for Recurrent EWS 121 9.4.2 Role of Surgery and Radiation in Recurrent EWS 123 9.5 Management of Ewing-Like Sarcoma 124 9.6 Late Effects of Therapy Following EWS Therapy 125 9.7 Future Directions to Improve Outcomes for EWS 125 References 126 10: Experimental Models 131 10.1 Introduction 131 10.2 Human Cell Lines 131 10.2.1 Cell Lines Derived from Human Tumor Tissue 131 10.2.2 Genetically Defined Sarcoma Cell Lines 134 10.3 Murine-Based Preclinical Models and Their Role in Drug Development 135 10.4 Domesticated Animals 136 10.5 Lower Organisms 138 10.6 Future Directions 140 Appendix. Guidelines for Preclinical Studies 140 References 141 11: Strategies for New Agent Development in Pediatric Sarcomas 150 11.1 Strategies for New Agent Development 150 11.2 Small Molecule Inhibitors 150 11.2.1 PARP Inhibitors 150 11.2.2 MET Inhibitors 152 11.2.3 Mammalian Target of Rapamycin (mTOR) Inhibitors 152 11.2.4 Tropomyosin Receptor Kinase Inhibitors 153 11.2.5 Phosphatidylinositol-3-Kinase (PI3K) Inhibitors 153 11.2.6 Wee1 and CHK1 Inhibitors 154 11.2.7 Fibroblast Growth Factor Receptor (FGFR) Inhibition 154 11.2.8 Cyclin-Dependent Kinase (CDK) Inhibition 154 11.2.9 Selective Inhibitors of Nuclear Export (SINE) 155 11.3 Targeting Cell Surface Molecules 156 11.3.1 SEMA-4D Inhibition 156 11.3.2 Insulin- Like Growth Factor Receptor 1 (IGF-1R) Inhibition 157 11.3.3 Platelet-Derived Growth Factor Receptor (PDGFR) Inhibition 157 11.3.4 Targeting Tumor Antigens: CD56 157 11.3.5 Targeting Tumor Antigens: GD2 158 11.3.6 Targeting Tumor Antigens: GPNMB 158 11.4 Anti-angiogenesis 158 11.5 Bone Signaling 159 11.6 Epigenetic Targeting 161 11.6.1 Heat Shock Protein 90 161 11.6.2 Histone Deacetylase (HDAC) 161 11.6.3 Histone Lysine-Specific Demethylase 1 (LSD1) 162 11.7 Summary and Conclusions 162 References 162 12: Immunotherapy for Pediatric Sarcomas 166 12.1 Introduction 166 12.2 Amplifying Natural Immune Responses 167 12.2.1 Checkpoint Blockade 168 12.2.2 Innate Immune Activators 169 12.2.3 Cytokine-Based Immunotherapy 169 12.2.4 Oncolytic Viruses 170 12.2.5 Anti-tumor Vaccines 171 12.3 Synthetic Immunotherapies to Generate Immune Responses 171 12.3.1 Monoclonal Antibodies 172 12.3.1.1 GD2 172 12.3.1.2 HER2 172 12.3.1.3 B7-H3 173 12.3.2 T Cells Expressing Affinity Matured T Cell Receptors (TCRs) 173 12.3.3 Chimeric Antigen Receptor (CAR) 174 12.3.4 Bispecific Antibodies 175 12.4 Conclusions and Future Directions 176 References 176 Front Matter ....Pages i-v Epidemiology of Bone and Soft Tissue Sarcomas (Philip J. Lupo, Logan G. Spector, Schuyler O’Brien, Joshua D. Schiffman, Simone Hettmer)....Pages 1-16 Sarcoma Pathology and Biology (Marielle Yohe, Javed Khan, Erin Rudzinski)....Pages 17-36 Staging and Imaging of Sarcoma (Carola A. S. Arndt, Andrea Ferrari)....Pages 37-46 Multi-institutional Trials for Patients with Rhabdomyosarcoma: Lessons from North American Studies from 1967 Through 1997 (R. Beverly Raney, Carola A. S. Arndt, Harold M. Maurer)....Pages 47-52 Treatment of Rhabdomyosarcoma (Carola A. S. Arndt, Ewa Koscielniak, Gianni Bisogno)....Pages 53-63 Current Approaches to Therapy: Soft Tissue Sarcomas Other than Rhabdomyosarcoma in Children and Adolescents (Daniel Orbach, Sheri L. Spunt, Andrea Ferrari)....Pages 65-85 Osteosarcoma: History of Therapy (Paul Meyers)....Pages 87-90 Osteosarcoma-Approach to Therapy (Stefan Bielack, Matthew G. Cable, Richard Gorlick, Stefanie Hecker-Nolting, Leo Kager, Neyssa Marina et al.)....Pages 91-109 Contemporary Approach to Therapy for Ewing Sarcoma (Steven G. DuBois, Uta Dirksen)....Pages 111-128 Experimental Models (Susanne A. Gatz, Janet Shipley, Charles Keller, Corinne M. Linardic)....Pages 129-147 Strategies for New Agent Development in Pediatric Sarcomas (Emily G. Greengard, Brenda J. Weigel)....Pages 149-164 Immunotherapy for Pediatric Sarcomas (Allison Pribnow, Karin Straathof, Robbie G. Majzner)....Pages 165-180