Neuroblastoma

PEDIATRIC ONCOLOGY

Nai-Kong V. Cheung Susan L. Cohn (Eds.)

Neuroblastoma With 51 Figures and 48 Tables

123

Library of Congress Control Number 2004113134 ISBN-10 3-540-40841-X Springer Berlin Heidelberg NewYork ISBN-13 978-3-540-40841-3 Springer Berlin Heidelberg NewYork ISSN 1613-5318

Nai-Kong V. Cheung, MD, PhD

(e-mail: [email protected]) Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Susan L. Cohn, MD (e-mail: [email protected]) Department of Pediatrics and the Comprehensive Robert H. Lurie Cancer Center, Northwestern University, Feinberg School of Medicine, Children’s Memorial Hospital 2300 Children’s Plaza, Chicago, IL 60614, USA

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springeronline.com © Springer-Verlag Berlin Heidelberg 2005 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Medical Editor: Dr. Julia Heidelmann, Heidelberg, Germany Desk Editor: Meike Stoeck, Heidelberg, Germany Cover design: Erich Kirchner, Heidelberg, Germany Layout: Bernd Wieland, Heidelberg, Germany Production: Pro Edit GmbH, Heidelberg, Germany Reproduction and typesetting: AM-productions GmbH, Wiesloch, Germany 21/3151 – 5 4 3 2 1 0 Printed on acid-free paper

V

Preface

The rapid advances in our understanding of the biology and treatment of neuroblastoma make it difficult to keep up to date. The clinical facets of neuroblastoma are endlessly fascinating. Its “natural history” overtly displays the difference between cancer and a truly extraordinary non-malignant proliferative disease. An interesting and potentially promising research emphasis is to unravel the difference between the “good” and “bad” forms of the disease. Our interest in neuroblastoma was kindled by clinical observations going back many decades. For example, is it likely that neuroblastoma “metastasizes” from one adrenal to the other and to the posterior mediastinum, or that malignant secondary deposits in these three unlikely sites will disappear spontaneously? Our early observations of this phenomenon were made in the days when there were no effective treatments for neuroblastoma so it was easier willy-nilly to observe the natural history. We have seen disease wax and wane over time, such as skin lesions which became increasingly mature with each new “crop”; thus, the last one seen at 36 months was diagnosed as a neurofibroma. The results coming from the screening programs underline these concepts. They have shown that many more infants actually harbor occult neuroblastoma than are diagnosed clinically (in the nonscreened cohort population). This establishes that most such foci would have regressed spontaneously had they not been de-

tected through screening. Observations such as these suggest that 4S neuroblastoma could teach us more about what clonal growth implies than clonal growth teaches us about neuroblastoma. Obviously neuroblastoma can be a relentless, malignant disease, and these children need far better therapies than we now can muster. But the future may not lie so much in new classes of compounds or even drug adjuvants. It lies, instead, in the final understanding of what makes neuroblastoma mature into ganglioneuroma or, even more importantly, what prompts it to disappear spontaneously. Success will be measured when widespread disease in children with high-risk neuroblastoma is made to vanish through molecular genetic manipulations. Then cure will have achieved its true and very special meaning: disappearance of a life-threatening malignant disease without incurring the side effects of currently available avenues of treatment. Audrey E. Evans Professor of Pediatrics, Emeritus at the University of Pennsylvania, Senior Physician, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Giulio J. D’Angio Professor of Radiation Oncology, Radiology and Pediatrics, Emeritus at the University of Pennsylvania, Philadelphia, Pennsylvania

VII

Contents

1

Epidemiology

3

Andrew F. Olshan 1.1 1.2

Descriptive Epidemiology . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . . 1.2.1 Pregnancy and Childhood Factors 1.2.2 Medication Use . . . . . . . . . . . 1.2.3 Lifestyle Exposures . . . . . . . . . 1.2.4 Parental Occupation and Environmental Exposures . . . 1.3 Conclusions . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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1 2 2 3 3

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4 4 5

3.1 Introduction . . . . . . . . . . . . . . . . . . . 3.2 Associated Genetic Conditions . . . . . . . . 3.3 Constitutional Chromosomal Abnormalities . 3.4 Hereditary Neuroblastoma . . . . . . . . . . . 3.5 Genetic Studies of Familial Neuroblastoma . 3.6 Conclusions . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

4 2 2.1 2.2 2.3

Genetics John M. Maris, Garrett M. Brodeur . . . . . . .

21 21 22 23 25 25 26

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27 27 28

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29 29

Molecular Cytogenetics Manfred Schwab

Screening for Neuroblastoma William G. Woods

Introduction . . . . . . . . . . . . . . . . . . . . The Rationale for Neuroblastoma Screening . Early Pioneering Studies Investigating Neuroblastoma Screening in Japan . . . . . . . 2.4 Initial North American and European Neuroblastoma Screening Trials 2.5 Follow-up Studies from Japan and Europe . . . 2.6 Definitive Controlled Trials from Quebec and Germany . . . . . . . . . . . . . . . . . . . 2.6.1 Studies, Designs, and Logistics . . . . . . . 2.6.2 Studies’ Results . . . . . . . . . . . . . . . 2.7 Biologic, Psychologic, Economic, and Clinical Aspects of Neuroblastoma Screening . . . . . . . . . . 2.7.1 Biologic Aspects . . . . . . . . . . . . . . 2.7.2 Psychologic Aspects . . . . . . . . . . . . 2.7.3 Economic Aspects . . . . . . . . . . . . . 2.7.4 Clinical Implications . . . . . . . . . . . . 2.8 Conclusions . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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17 17 17 17 18 18 18

4.1 4.2 4.3 4.4

Introduction . . . . . . . . . . . . . . Classical Cytogenetics . . . . . . . . Oncogene Expression Profiling . . . “Neuroblastoma Suppressor Genes” and Loss of Heterozygosity . . . . . 4.4.1 Chromosome 1p Deletion . .

4.4.1.1 One or More “Tumor Suppressor Gene” Loci in 1p . . . . . . . . . . . . . . . .

4.4.2

Deletion of 11q . . . . . . . . . . . . . . . 4.4.2.1 Chromosome 11 Deletion and 17q Gain . . . 4.4.3 LOH of Additional Chromosomes . . . . . 4.4.4 LOH and Tumor Suppressor Genes: an Evasive Connection or Flawed Hypothesis? 4.5 Comparative Genomic Hybridization . . . . . . . 4.6 Tumor Cell Ploidy . . . . . . . . . . . . . . . . . . 4.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

31 31 32 32 32 34 34 35 35

VIII

Contents 7.3

5

Molecular and Developmental Biology of Neuroblastoma Akira Nakagawara

5.1

Neural Crest Development and Neuroblastoma 5.1.1 Genes of Neural Development and Molecular Targets of Neuroblastoma . . . . . . . . . . . . . . 5.1.1.1 Bone Morphogenetic Proteins . . . . . . . . 5.1.1.2 MASH1/hASH1 . . . . . . . . . . . . . . . . . 5.1.1.3 Phox2a and Phox2b . . . . . . . . . . . . . . 5.1.1.4 Id . . . . . . . . . . . . . . . . . . . . . . . 5.1.1.5 MYCN . . . . . . . . . . . . . . . . . . . . . Molecular Bases of Differentiation and Programmed Cell Death . . . . . . . . . . . . 5.2.1 Molecular Aspect of Spontaneous Regression . . . . . . . . . 5.2.2 Neurotrophic Factors and Their Receptors

5.2

5.2.2.1 Neurotrophins and Their Receptors in Neuroblastoma . . . . . . . . . . 5.2.2.2 Neurotrophin Signaling in Neuroblastoma . . . . . . . . . . 5.2.2.3 GDNF Family Receptors . . . . . . . 5.2.2.4 Other Factors and Receptors . . . .

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. . . . . . 5.2.3 Functional Role of p53 Family Genes . 5.2.4 Apoptotic Signals in Neuroblastoma . 5.3 Conclusions . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

6

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46 48 48 48 50 50 51

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55 55 56 56 57 58 59 60 60

Cellular Heterogeneity Robert A. Ross

6.1 Introduction . . . . . . . . . . . . . . . . 6.2 Neural Crest Differentiation . . . . . . . 6.3 Neuroblastoma Cellular Heterogeneity 6.4 N-type Neuroblastic Cells . . . . . . . . 6.5 S-type Non-Neural Cells . . . . . . . . . 6.6 I-type Stem Cells . . . . . . . . . . . . . . 6.7 Transdifferentiation . . . . . . . . . . . . 6.8 Conclusions . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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7

Clinical Presentation Frank Berthold, Thorsten Simon

7.1 7.2

Introduction . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 7.2.1 Diagnostic Tumor Tissue . . . . . . . . . .

63 64 64

Clinical Presentation . . . . . . . . . . . . . . 7.3.1 Symptoms . . . . . . . . . . . . . . . . 7.3.1.1 Frequent Symptoms . . . . . . . . . . . 7.3.1.2 Rare but Characteristic Symptoms . . . . 7.3.2 Tumor Markers . . . . . . . . . . . . . . 7.3.2.1 Catecholamine Metabolites . . . . . . . 7.3.2.2 Neuron-Specific Enolase . . . . . . . . . 7.3.2.3 Ferritin . . . . . . . . . . . . . . . . . . . 7.3.2.4 Lactate Dehydrogenase . . . . . . . . . 7.3.2.5 Other Tumor Markers . . . . . . . . . . . 7.3.3 Primary Tumors . . . . . . . . . . . . . 7.3.3.1 Sites of the Primary Tumor . . . . . . . . 7.3.4 Metastases . . . . . . . . . . . . . . . . 7.3.4.1 Metastatic Sites . . . . . . . . . . . . . . 7.3.4.2 Bone Marrow Assessment . . . . . . . . 7.3.4.3 Definition of Cortical Bone Metastases . . 7.4 Differential Diagnosis . . . . . . . . . . . . . . 7.4.1 Small Blue Round Cell Tumors . . . . . 7.4.2 Adrenal Hemorrhage in the Newborn . 7.4.3 Nephroblastoma . . . . . . . . . . . . . 7.4.4 Esthesioneuroblastoma (Olfactory Neuroblastoma) . . . . . . . 7.4.5 Ganglioneuroma, Pheochromocytoma, Paraganglioma, Chemodectoma . . . . 7.5 Clinical and Laboratory Evaluation . . . . . . 7.5.1 Staging . . . . . . . . . . . . . . . . . . 7.5.2 Biological Types of Neuroblastoma . . 7.5.2.1 Maturative Subtype . . . . . . . . . . . . 7.5.2.2 Regressive Subtype . . . . . . . . . . . . 7.5.2.3 Progressive Subtype . . . . . . . . . . . 7.5.3 Prognostic Risk Groups . . . . . . . . . 7.5.4 Response Criteria . . . . . . . . . . . . 7.6 Conclusions . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

8

Pathology of Peripheral Neuroblastic Tumors Hiroyuki Shimada, Inge M. Ambros

8.1 8.2 8.3

Introduction . . . . . . . . . . . . . . . . . . Historical Overview . . . . . . . . . . . . . . Basic Morphology . . . . . . . . . . . . . . . 8.3.1 Neuroblastoma (Schwannian Stroma-poor) . . . . . . 8.3.2 Ganglioneuroblastoma, Intermixed (Schwannian Stroma-rich) . . . . . . 8.3.3 Ganglioneuroma (Schwannian Stroma-dominant) . . . 8.3.4 Ganglioneuroblastoma, Nodular (Composite, Schwannian Stroma-rich/ Stroma-dominant and Stroma-poor) .

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65 65 65 66 67 68 68 68 68 68 69 69 69 69 70 72 72 72 72 73

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87 88 88

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91

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91

Contents 8.4 8.5

Prognostic Classification . . . . . . . Biological Relevance . . . . . . . . . 8.5.1 Schwannian Development in Neuroblastic Tumors . . . . 8.5.2 Correlation of Histopathology with MYCN Amplification and trkA Expression . . . . . . 8.5.3 Composite Tumor . . . . . . . 8.6 Conclusion . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

9

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92 92

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93 93 94 94

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Molecular Pathology of Neuroblastic Tumors Based on Genome-wide Expression Analysis William L. Gerald

10.3 Disease Evaluation . . . . 10.3.1 Primary Site . . . . 10.3.2 Local Invasion . . . 10.3.3 Distant Metastases 10.3.3.1 Bone Metastases . .

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116 116 116 116 116

10.3.3.2 Bone-Based, Dural-Based, Leptomeningeal, and Brain Metastases . . . . . . . . . . . . 116 10.3.3.3 Marrow Metastasis . . . . . . . . . . . . . . 117

10.4 Prenatally Diagnosed Neuroblastoma 10.5 Stage-4S Neuroblastoma . . . . . . . . 10.6 Evaluation of Disease Response . . . . 10.7 Conclusion . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

11

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118 118 120 120 120

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124 124 125 125 125 126

Treatment of Neuroblastoma

11.1 Low-Risk Neuroblastoma 9.1 9.2 9.3

Introduction . . . . . . . . . . . . . . . . . . . . . Clinical Issues . . . . . . . . . . . . . . . . . . . . Technical Aspects of Gene Expression Analysis . 9.3.1 Transcript Profiling Methods . . . . . . . . 9.3.2 Data Analysis . . . . . . . . . . . . . . . . . 9.3.3 The Impact of Tissue Heterogeneity on Gene Expression Analysis . . . . . . . . 9.4 Gene Expression Analysis of NB . . . . . . . . . . 9.4.1 The NB Transcriptome and Its Relationship to Neural Crest Development . . . . . . . . 9.4.2 Gene Expression Associated with Clinically Relevant Subtypes of NB . . 9.4.3 Molecular Pathology of MYCN Amplification . . . . . . . . . . . 9.4.4 Distinct Molecular Features of NB Discovered Through Gene Expression Analysis . . . . . . . . . . . . . 9.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

10

97 98 98 98 100 100 100 100 103 103

11.1.1 11.1.2 11.1.3 11.1.4 11.1.5

Introduction . . . . . . . . . Clinical Presentation . . . . Clinical Staging . . . . . . . Biologic Prognostic Markers Treatment . . . . . . . . . .

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11.1.5.1 Localized Tumors with No Regional Spread 11.1.5.2 Regionally Invasive Unilateral Localized Tumors . . . . . . . . . . . . . . . 127 11.1.5.3 Stage 4S . . . . . . . . . . . . . . . . . . . 128

11.1.6 Future Directions . . . . . . . . . . . . . . 129 11.1.7 Conclusion . . . . . . . . . . . . . . . . . 129 References . . . . . . . . . . . . . . . . . . . . . . . . . . 129 11.2 Intermediate-Risk Neuroblastoma

Brian H. Kushner, Susan L. Cohn 105 106 106

Anatomic and Functional Imaging Sara J. Abramson, Barry L. Shulkin

10.1 Introduction . . . . . . . . . . . . . . . . . . . . 10.2 Imaging Modalities . . . . . . . . . . . . . . . . 10.2.1 Ultrasonography . . . . . . . . . . . . . . 10.2.2 Computerized Axial Tomography . . . . 10.2.3 Magnetic Resonance Imaging . . . . . . 10.2.4 Bone Scan . . . . . . . . . . . . . . . . . 10.2.5 MIBG Scintigraphy . . . . . . . . . . . . . 10.2.6 Octreotide Scanning . . . . . . . . . . . 10.2.7 Positron Emission Tomography Scanning 10.2.8 Other Tracers . . . . . . . . . . . . . . . .

Brian H. Kushner, Susan L. Cohn

11.2.1 11.2.2 11.2.3 11.2.4 11.2.5

Introduction . . . . . . . . . Clinical Presentation . . . . Clinical Staging . . . . . . . Biologic Prognostic Markers Treatment . . . . . . . . . .

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11.2.5.3 Treatment of Infant Stage-4 Neuroblastoma

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109 109 109 110 112 113 113 115 115 115

11.2.6 Future Directions . . . . . . . . . . . . . . 11.2.7 Conclusion . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3 High-Risk Neuroblastoma

131 131 133 133 133 134 134 135 136 136 137

Katherine K. Matthay, Nai-Kong V. Cheung 11.3.1 11.3.2 11.3.3 11.3.4 11.3.5 11.3.6 References .

Treatment Approach for High-Risk Disease 138 Induction Therapy . . . . . . . . . . . . . 139 Local Control . . . . . . . . . . . . . . . . 141 Consolidation Therapy . . . . . . . . . . . 142 Therapy of Minimal Residual Disease . . . 144 Conclusion . . . . . . . . . . . . . . . . . 145 . . . . . . . . . . . . . . . . . . . . . . . . . 145

X

Contents 11.4 The Role of Surgery in the Treatment of Neuroblastoma

11.6.3

Michael P. La Quaglia 11.4.1 11.4.2 11.4.3

Introduction . . . . . . . . . . . . . . History . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . 11.4.3.1 Stage 1 . . . . . . . . . . . . . . . . . 11.4.3.2 Stage 2 . . . . . . . . . . . . . . . . . 11.4.3.3 Stage 3 . . . . . . . . . . . . . . . . . 11.4.3.4 Stage 4 . . . . . . . . . . . . . . . . . 11.4.4 Risk Status and Surgical Intervention 11.4.4.1 Low-Risk Patients . . . . . . . . . . . 11.4.4.2 Intermediate Risk . . . . . . . . . . . 11.4.4.3 High Risk . . . . . . . . . . . . . . . . 11.4.4.3.1 Gross Total Resection . . . . . . . . . .

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149 149 151 151 152 152 153 155 156 156 156 156

PBSC Collection . . . . . . . . . . . . . . . . . . . 11.6.4 Conclusion . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . 11.7 Minimal Residual Disease Measurement 11.6.3.1 11.6.3.2 11.6.3.3 11.6.3.4 11.6.3.5 11.6.3.6 11.6.3.7

11.4.6.1 11.4.6.2 11.4.6.3 11.4.6.4 11.4.6.5 11.4.6.6

Surgical Complications and Mortality Surgical Technique . . . . . . . . . . . Initial Biopsy . . . . . . . . . . . . . . . Cervical Lesions . . . . . . . . . . . . . Cervico-Thoracic Lesions . . . . . . . . Mediastinal Tumors . . . . . . . . . . .

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11.7.1 11.7.2

11.7.2.1

11.7.3

157 158 158 159 159 159

Lesions in the Upper Abdomen and Retroperitoneum . . . . . . . . . . . 159 Pelvic Tumors . . . . . . . . . . . . . . . 159

11.4.7 Conclusion . . . . . . . . . . . . . . . . 160 References . . . . . . . . . . . . . . . . . . . . . . . . . . 161 11.5 Radiation Therapy

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177 177 178 178 179 180 181 182 182 182

Irene Y. Cheung, Peter F. Ambros

11.4.4.3.2 Rationale for Gross Total Resection in High-Risk Patients . . . . . . . . . . . . 156 11.4.4.3.3 Local Control . . . . . . . . . . . . . . . . 157

11.4.5 11.4.6

Vascular Access . . . . . . . . . . . Collection . . . . . . . . . . . . . . Techniques for Stem Cell Mobilization Target Dose for PBSC Infusion . . . . Processing and Storage of PBSC . . . Tumor Cell Purging . . . . . . . . . Storage . . . . . . . . . . . . . . . .

Introduction . . . . . . . . . . Techniques in the Detection of Tumor Cells in the Hematopoietic System Histology/Cytology . . . . . . Detection Methods for MRD .

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11.7.3.1

Immunocytology/ Immuno histochemistry . . . . . . . 11.7.3.2 Automatic Immunofluorescence Detection Techniques . . . . . . . . . 11.7.3.3 Reverse Transcription-Polymerase Chain Reaction . . . . . . . . . . . . . 11.7.3.3.1 Real-Time Quantitative RT-PCR . . . 11.7.3.3.2 Molecular Targets . . . . . . . . . . 11.7.3.3.3 Perspectives on Molecular Detection

. . . 186 . . . 187 . . . 188

. . . 11.7.4 Clinical Relevance of MRD . . . . . . 11.7.5 Future Directions . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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188 188 188 189 190 191

12.1 Introduction . . . . . . . . . . . . . . . . . . . . . 12.2 Treatment Strategies for Resistant Disease . . . 12.2.1 Primary Refractory Disease . . . . . . . . 12.2.2 Early Relapse . . . . . . . . . . . . . . . . 12.2.3 Late Relapse . . . . . . . . . . . . . . . . . 12.2.4 Multiply Relapsed Disease . . . . . . . . . 12.3 Cytotoxic Chemotherapeutic Agents . . . . . . . 12.3.1 Alkylating and DNA Cross-Linking Agents 12.3.1.1 Ifosfamide and Cyclophosphamide . . . . .

193 195 195 196 196 196 196 197 197

Suzanne L. Wolden, Daphne A. Haas-Kogan 11.5.1 11.5.2

Background . . . . . . . . . . . . . . . Radiation Approach According to Risk Stratification . . . . . . . . . . 11.5.2.1 Low- and Intermediate-Risk Disease . . 11.5.2.2 Intermediate-Risk Disease . . . . . . . . 11.5.2.3 Stage-4S Disease . . . . . . . . . . . . . 11.5.2.4 High-Risk Disease . . . . . . . . . . . . 11.5.3 Radiation Techniques . . . . . . . . . 11.5.3.1 General Technical Considerations . . . . 11.5.3.2 Intraoperative Radiation Therapy . . . . 11.5.4 Side Effects of Radiation . . . . . . . . 11.5.5 Conclusion . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . 11.6 Stem Cell Transplantation

. 164 . . . . . . . . . . .

164 164 164 165 165 167 167 169 170 171 171

Stephan A. Grupp 11.6.1 11.6.2 11.6.2.1 11.6.2.2

Introduction . . . . . . . . . . Autologous Transplant in Neuroblastoma . . . . . . Children’s Cancer Group 3891 . Experimental HDC/SCR . . . .

. . . . . . 173 . . . . . . 174 . . . . . . 174 . . . . . . 175

12

Treatment of Relapsed and Refractory Neuroblastoma Katherine K. Matthay, Brian H. Kushner

12.3.1.2 Melphalan Combined with Buthionine Sulfoximine . 12.3.1.3 Platinum Compounds . . . . 12.3.1.4 Temozolomide . . . . . . . . 12.3.1.5 Tirapazamine . . . . . . . . .

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197 198 198 199

Contents 12.3.2 Topoisomerase Inhibitors . . . . . 12.3.2.1 Irinotecan . . . . . . . . . . . . . . 12.3.2.2 Topotecan . . . . . . . . . . . . . . 12.3.2.3 Pyrazoloacridine . . . . . . . . . . . 12.3.2.4 Rebeccamycin . . . . . . . . . . . . 12.4 Tumor-Targeted Biologic Agents . . . . . 12.4.1 Retinoids . . . . . . . . . . . . . . . 12.4.2 Tyrosine Kinase Inhibitors . . . . . 12.4.3 Modulators of Apoptotic Pathway and Angiogenesis . . . . . . . . . . 12.4.3.1 Anti-Angiogenic Agents . . . . . . . 12.4.3.2 Arsenic Trioxide . . . . . . . . . . . 12.4.3.3 Demethylating Agents . . . . . . . . 12.4.3.4 Histone Deacetylase Inhibitors . . . 12.5 Immunologic Therapy . . . . . . . . . . . 12.5.1 Anti-GD2 . . . . . . . . . . . . . . . 12.5.2 Interleukins . . . . . . . . . . . . . 12.5.3 Vaccines . . . . . . . . . . . . . . . 12.6 131I-Metaiodobenzylguanidine . . . . . . 12.7 Conclusion . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

13

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199 199 200 200 201 201 201 201

14.4 Humoral Immunotherapy . . . . . . 14.4.1 Effector Mechanisms of MAb 14.4.2 Clinical Application of MAb . 14.4.2.1 Naked MAb . . . . . . . . . . .

. . . . . . . . . . . .

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201 201 202 202 202 203 203 203 204 204 204 205

14.5 Cellular Immunotherapy . . . . . . . . . . . . 14.5.1 Activation of NK and NKT Cells . . . . 14.5.2 Activation of MHC-Restricted T Cells . 14.5.3 Pre-clinical and Clinical Testing of T-cell Based Therapy in Neuroblastoma 233 14.5.3.1 Immunostimulants . . . . . . . . . . . . . . 233 14.5.3.2 Tumor Vaccines . . . . . . . . . . . . . . . 233

Management of Neurologic Complications Kim Kramer, Michael R. Pranzatelli

13.1 Introduction . . . . . . . . . . . . . . . . . . . . 13.2 Epidural Neuroblastoma . . . . . . . . . . . . . 13.3 Metastatic Disease to the Central Nervous System . . . . . . . . . 13.4 Opsoclonus–Myoclonus . . . . . . . . . . . . . 13.4.1 Immunology . . . . . . . . . . . . . . . 13.4.2 Pharmacology . . . . . . . . . . . . . . . 13.4.3 Laboratory Testing . . . . . . . . . . . . 13.4.4 Treatment . . . . . . . . . . . . . . . . . 13.4.4.1 Neuromodulation . . . . . . . . . . . . . 13.4.4.2 Adjunctive Therapy . . . . . . . . . . . . 13.4.4.3 Precautions . . . . . . . . . . . . . . . . . 13.5 Treatment-Related Neurologic Complications . 13.6 Conclusions . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

14

XI

. 213 . 213 . . . . . . . . . . . .

216 217 218 218 218 219 219 220 220 220 220 221

Immunology and Immunotherapy Nai-Kong V. Cheung, Paul M. Sondel

14.1 Introduction: The Case for Immunotherapy . . . 223 14.2 The Immunobiology of Neuroblastoma . . . . . 224 14.3 How Neuroblastoma Escapes the Innate and Adaptive Immune Systems . . . . . . . . . . 225

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14.4.2.2 Antibody in Combination with Cytokines 14.4.2.3 Antibody Immunoconjugates . . . . . .

14.4.3 Humoral Vaccines . . . . . . . . . . . . 14.4.3.1 Ganglioside-KLH Vaccines . . . . . . . . 14.4.3.2 Anti-Idiotype Vaccine . . . . . . . . . .

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226 226 227 227 229 229 232 232 232 232 232 233

14.5.3.3 Adoptive Therapy Using Autologous Cytotoxic Lymphocytes . . . . . . . . . . . 234 14.5.3.4 Adoptive Therapy Using Allogeneic Lymphocytes . . . . . . . . . . . . . . . . . 234

14.6 Conclusions . . . . . . . . . . . . . . . . . . . . . 235 References . . . . . . . . . . . . . . . . . . . . . . . . . . 235

15

Differentiation and Retinoids Carol J. Thiele, C. Patrick Reynolds

15.1 Introduction . . . . . . . . . . . . . . . . . . . . 15.1.1 Neural Crest Development . . . . . . . . 15.1.2 NB as a Neural Crest Derivative . . . . . . 15.1.3 NB and Adrenal Medullary Development 15.1.4 Neural Crest Gene Expression During Development . . . . . . . . . . . . . . . 15.1.5 MYCN in Neural Crest Development . . . 15.2 Neurotrophins in Neural Crest Development . 15.2.1 TrkA and NB . . . . . . . . . . . . . . . . 15.2.2 TrkB and NB . . . . . . . . . . . . . . . . 15.3 Differentiation . . . . . . . . . . . . . . . . . . . 15.3.1 Retinoids . . . . . . . . . . . . . . . . . . 15.3.2 Retinoic Acid Receptors . . . . . . . . . . 15.4 13-cis-Retinoic Acid . . . . . . . . . . . . . . . . 15.4.1 High-Dose, Pulse, 13-cis-RA . . . . . . . . 15.4.2 13-cis-RA vs All Trans-Retinoic Acid . . . 15.4.3 Post-Consolidation 13-cis-RA Therapy for High-Risk NB . . . . . . . . . . . . . . 15.5 Fenretinide . . . . . . . . . . . . . . . . . . . . . 15.6 Conclusions . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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243 243 244 244

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245 245 245 246 247 247 247 248 249 250 250

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250 253 254 254

XII

Contents

16

Angiogenesis Darrell J. Yamashiro, Susan L. Cohn

18

16.1 Introduction . . . . . . . . . . . . . . . . . . . 16.2 Vascularity in Neuroblastoma . . . . . . . . . 16.3 Expression of Proangiogenic Factors . . . . . 16.3.1 VEGF and VEGF Receptors . . . . . . . . 16.3.2 Matrix Metalloproteinases . . . . . . . 16.4 Expression of Angiogenesis Inhibitors . . . . 16.4.1 Pigment Epithelium-Derived Factor . . 16.4.2 Secreted Protein Acidic and Rich in Cysteine . . . . . . . . . . . 16.4.3 Thrombospondin-1 . . . . . . . . . . . 16.5 Regulation of Angiogenesis by MYCN . . . . 16.6 Preclinical Testing of Antiangiogenic Agents 16.6.1 VEGF Blockade . . . . . . . . . . . . . . 16.6.2 TNP-470 . . . . . . . . . . . . . . . . . 16.6.3 Endostatin . . . . . . . . . . . . . . . . 16.7 Conclusions . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

17

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257 258 258 258 259 260 260

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260 260 261 261 261 261 261 262 263

Experimental Therapeutics and Preclinical Models Jennifer K. Peterson, Peter J. Houghton

17.1 Introduction . . . . . . . . . . . . . . 17.2 Heterotransplant Models . . . . . . . 17.2.1 Cytotoxic Agents . . . . . . . . 17.2.2 Signal Transduction Inhibitors 17.2.3 Angiogenesis Inhibitors . . . . 17.2.4 Viral-Based Therapies . . . . . 17.2.5 Immunotherapy and Radioimmunotherapy . . 17.3 Transgenic Models . . . . . . . . . . 17.4 Syngeneic Models . . . . . . . . . . . 17.5 Conclusion . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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267 268 268 270 271 271

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272 272 273 273 274

Late Effects of Treatment Caroline Laverdière, James Gurney, Charles A. Sklar

18.1 Introduction . . . . . . . . . . . . . . . . . 18.2 Long-Term Complications for Low- and Intermediate-Risk Neuroblastoma Survivors . . . . . . . . . 18.2.1 Musculoskeletal . . . . . . . . . . . 18.2.2 Neurological . . . . . . . . . . . . . 18.3 Long-Term Complications for Survivors of High-Risk Neuroblastoma . . . . . . . . 18.3.1 Audiological . . . . . . . . . . . . . 18.3.2 Endocrine . . . . . . . . . . . . . . 18.3.2.1 Thyroid Function . . . . . . . . . . . 18.3.2.2 Reproductive Endocrine Function . . 18.3.2.3 Growth . . . . . . . . . . . . . . . . 18.3.3 Musculoskeletal Complications and Neurological Deficits . . . . . 18.3.4 Dental . . . . . . . . . . . . . . . . 18.3.5 Pulmonary . . . . . . . . . . . . . . 18.3.6 Cardiac . . . . . . . . . . . . . . . . 18.3.7 Renal . . . . . . . . . . . . . . . . . 18.3.8 Neurocognitive . . . . . . . . . . . 18.3.9 Subsequent Malignant Neoplasms 18.4 Health-Related Quality of Life . . . . . . . 18.5 Conclusion . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

19

. . . . 277

. . . . 278 . . . . 278 . . . . 278 . . . . . .

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279 279 280 280 281 282

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282 282 282 283 283 283 284 284 285 285

Perspectives and Future Directions Nai-Kong V. Cheung, Susan L. Cohn

References . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Subject Index . . . . . . . . . . . . . . . . . . . . . . 293

XIII

Contributors

Sara J. Abramson, MD (e-mail: [email protected]) Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

Irene Y. Cheung, ScD (e-mail: [email protected]) Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

Inge M. Ambros, MD

Nai-Kong V. Cheung, MD, PhD

(e-mail: [email protected]) Children’s Cancer Research Institute, St. Anna Kinderspital, Kinderspitalgasse 6, 1090 Vienna, Austria

(e-mail: [email protected]) Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

Peter F. Ambros, PhD

Susan L. Cohn, MD (e-mail: [email protected]) Department of Pediatrics and the Comprehensive Robert H. Lurie Cancer Center, Northwestern University, Feinberg School of Medicine, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614, USA

(e-mail: [email protected]) Children’s Cancer Research Institute, St. Anna Kinderspital, Kinderspitalgasse 6, 1090 Vienna, Austria Frank Berthold, MD

(e-mail: [email protected]) Children’s Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany

William L. Gerald, MD

(e-mail: [email protected]) Department of Pathology, Memorial Sloan-Kettering Cancer Center, 275 York Avenue, New York, NY 10021, USA

Garrett M. Brodeur, MD

(e-mail: [email protected]) Division of Oncology, The Children’s Hospital of Philadelphia and the University of Pennsylvania, Abramson Pediatric Research Center 902, Philadelphia, PA 19104, USA

Stephan A. Grupp, MD, PhD

(e-mail: [email protected]) Director, Stem Cell Biology, Division of Oncology, Children’s Hospital of Philadelphia and University of Pennsylvania, 3615 Civic Center Blvd., ARC 902, Philadelphia, PA 19104, USA

XIV

Chapter 2

Pediatric Cerebellar Astrocytomas Contributors

James Gurney, MD

John M. Maris, MD

(e-mail: [email protected]) Division of Pediatric Epidemiology, University of Minnesota, Mayo Mail Code 715, 420 Delaware Street SE, Minneapolis, MN 55455, USA

(e-mail: [email protected]) Division of Oncology, The Children’s Hospital of Philadelphia and the University of Pennsylvania, Abramson Pediatric Research Center 902, Philadelphia, PA 19104, USA

Daphne A. Haas-Kogan, MD

Katherine K. Matthay, MD (e-mail: [email protected]) Department of Pediatrics, M647, University of California San Francisco School of Medicine, 505 Parnassus, San Francisco, CA 94143-0106, USA

(e-mail: [email protected]) Department of Radiation Oncology, School of Medicine, University of California at San Francisco, 2356 Sutter Street, San Francisco, CA 94115-0226, USA

Akira Nakagawara, MD Peter J. Houghton, PhD

(e-mail: [email protected]) Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, 332 Lauderdale, Memphis, TN 38105-2794, USA

(e-mail: [email protected]) Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba, 260-8717, Japan Andrew F. Olshan, MD

Kim Kramer, MD

(e-mail: [email protected]) Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Brian H. Kushner, MD

(e-mail: [email protected]) Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

(e-mail: [email protected]) Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7435, USA Jennifer K. Peterson, MD (e-mail: [email protected]) Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, 332 Lauderdale, Memphis, TN 38105-2794, USA Michael R. Pranzatelli, MD

(e-mail: [email protected]) Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

(e-mail: [email protected]) Departments of Neurology and Pediatrics, National Pediatric Myoclonus Center, Southern Illinois University School of Medicine, P.O. Box 19658, Springfield, IL 62794-9658, USA

Caroline Laverdière, MD (e-mail: [email protected]) Sainte-Justine Hospital, Recherche Clinique Hemato-Oncologie, 3175 Cote Ste-Catherine, Montreal, Quebec, Canada H3T 1C5

C. Patrick Reynolds, MD, PhD (e-mail: [email protected]) USC-CHLA Institute for Pediatric Clinical Research, Division of Hematology/Oncology MS 57, Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90054-0700, USA

Michael P. La Quaglia, MD

Contributors

Robert A. Ross, PhD

XV

(e-mail: [email protected]) Laboratory of Neurobiology, Department of Biological Sciences, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA

Paul M. Sondel, PhD (e-mail: [email protected]) Department of Pediatric Hematology/Oncology, University of Wisconsin, K4/448, 600 Highland Avenue, Madison, WI 53792, USA

Manfred Schwab, PhD

Carol J. Thiele, PhD

([email protected]) German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

(e-mail: [email protected]) Cell and Molecular Biology Section, Center for Cancer Research, NCI, NIH CRC, Room 1-3940, 10 Center Drive, MSC-1105, Bethesda, MD 20892-1105, USA

Hiroyuki Shimada, MD (e-mail: [email protected]) Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, MS 43, Los Angeles, CA 90027, USA

Suzanne L. Wolden, MD

(e-mail: [email protected]) Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA William G. Woods, MD

Barry L. Shulkin, MD

(e-mail: [email protected]) Department of Radiological Sciences, MS 752, St. Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, Tennessee, 38105-2794, USA

(e-mail: [email protected]) The Daniel P. Amos Children’s Chair for the AFLAC Cancer Center and Blood Disorders Service, Children’s Healthcare of Atlanta/Emory University, 1405 Clifton Road, Atlanta, GA 30322, USA Darrell J.Yamashiro, MD

Thorsten Simon, MD

(e-mail: [email protected]) Children’s Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany Charles A. Sklar, MD

(e-mail: [email protected]) Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

(e-mail: [email protected]) Department of Pediatric Oncology, Irving Pavilion 7, 161 Fort Washington Avenue, New York, NY 10032, USA

Chapter 1

Epidemiology Andrew F. Olshan

Contents 1.1 1.2

Descriptive Epidemiology . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . . 1.2.1 Pregnancy and Childhood Factors 1.2.2 Medication Use . . . . . . . . . . . 1.2.3 Lifestyle Exposures . . . . . . . . . 1.2.4 Parental Occupation and Environmental Exposures . . . 1.3 Conclusions . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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1 2 2 3 3

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4 4 5

This chapter reviews the epidemiology of neuroblastoma including the descriptive epidemiology and the evidence for an association with environmental exposures such as parental occupation, medication use during pregnancy, parental smoking and alcohol consumption, pregnancy history, and other exposures.

1.1 Descriptive Epidemiology In the United States neuroblastoma accounts for 7.2% of all cancers among children younger than 15 years of age (SEER 2003). It is the most common extracranial solid tumor of childhood. Approximately 650 children are diagnosed with neuroblastoma in the United States each year (Goodman et al. 1999). Based upon 1424 incident cases identified by the Surveillance, Epidemiology, and End Results Program of the U.S. National Cancer Institute (NCI) for 1975–2000, the total incidence of neuroblastoma was 10.2 per million children under age 15 years (age-adjusted to the 2000 U.S. standard million population; SEER 2003). The rates were 10.3 per million for males and 10.1 for females. Rates by race and ethnicity were 10.8 for whites, 8.4 for black children, and 7.5 for children of other racial/ethnic groups. The incidence rates by age category were 19.6 per million for ages 1–4 years, 2.9 for ages 5–9 years, and 0.7 for 10–14 years. Neuroblastoma is the most common malignancy among infants (61.3 per million). The incidence rate among infants was slightly higher among males (62.8) than females (59.8). Based upon international registry data, the incidence of neuroblastoma is highest among Caucasians

1

2

Chapter 1 Table 1.1. Neuroblastoma survival by gender, race, age, and stage 5-year relative survival rate (%)a

a

Male

64

Female

65

White

65

Black

60

90% survival is expected following moderate-dose chemotherapy and surgery. In contrast, outcome remains poor for children older than 1 year with metastatic NB, with or without MYCN amplification, and during the past decade there has been only a modest improvement in cure. This small gain is due to intensification of induction chemotherapy, megatherapy consolidation, biological/immunological therapy and improved supportive care. Several clinical trials, including the large prospective randomized CCG-3891 study which demonstrated superior outcome for patients randomized to myeloablative therapy and bone marrow transplant vs chemotherapy during consolidation (Matthay et al. 1999), support the hypothesis that dose intensification is an important component to achieve successful treatment of metastatic NB (Cheung and Heller 1991).Whether intensification is most beneficial during induction or during consolidation remains controversial. Although promising results have also been observed in recent pilot studies test-

N.-K. V. Cheung · S. L. Cohn

ing tandem cycles of high-dose therapy plus stemcell rescue (Grupp et al. 2000; Kletzel et al. 2002) (Chap. 11), further dose escalation is likely to be unacceptable. In addition, despite achieving complete clinical remission, the majority of children with highrisk disease will relapse due to drug-resistant residual disease. Eradication of refractory microscopic disease remains the most significant challenge in the treatment of metastatic NB. The paradigm of “more is better” should be questioned and additional highrisk trials testing biological and targeted agents need to be designed (Chap. 11). Recently, the differentiation agent 13-cis retinoic acid was shown to be clinically effective when administered in the setting of minimal residual disease in the randomized CCG 3891 clinical trial (Matthay et al. 1999) (reviewed in Chap. 15). This seminal study demonstrated that a biological agent was capable of impacting outcome in high-risk NB. The COG is currently conducting a randomized prospective study comparing the efficacy of anti-GD2 ch14.18 antibody plus cytokines and 13-cis retinoic acid vs 13-cis retinoic acid alone in the setting of minimal residual disease. Clinical trials have also been developed in Europe to test immunotherapy in high-risk NB, and a single-arm study investigating the efficacy of the anti-GD2 antibody 3F8 plus GM-CSF, is ongoing at Memorial Sloan-Kettering Cancer Center. Additional phase-I and phase-II studies are testing other targeted therapies (see Chap. 12). As outlined in Chaps. 14–17, preliminary studies suggest that several immunotherapeutic molecules, new retinoids, anti-angiogenic agents, and other experimental therapeutics have activity against refractory disease. As reviewed in Chap. 18, a variety of acute and late complications from NB and its treatment may occur; these include late effects of chemotherapy, radiation therapy, and surgery. High-risk patients are at greatest risk because of the intensive multi-modality treatment strategies that are currently utilized. Reliable identification of the subset of patients currently classified as high risk who do not require intensive therapy would significantly decrease long-term morbidity and treatment-related mortality for these very young patients. For example, data from both the POG and CCG indicate that toddlers 12–18 months of age

Perspectives and Future Directions

with favorable biology stage-4 tumors may not require the current intensive high-risk treatment regimen to be cured (Schmidt et al. 2003; George et al. 2003); however, ultimate improvements in survival and reductions of late effects may require more targeted therapies. Research aimed at discovering new genes and pathways critical to NB tumorigenesis and drug resistance should be prioritized. It is hoped that these biologically based treatment approaches will prove to be more effective and less toxic than the current regimens. We have learned important lessons from NB. The clinical biology of stage-4S and local-regional NB, when combined with the findings of the screening study (Chap. 2), have challenged accepted oncological principles. If clinical progression from local regional small NB to metastatic disease does not generally occur, adjuvant cytotoxic therapy is probably not necessary for the majority of these patients. On the other hand, despite general sensitivity of NB to chemotherapy, curing minimal residual metastasis remains difficult. Research focused on its measurement, control, or eradication should be emphasized. Most important of all, with the growing list of promising therapies, efforts devoted to their timely and effective integration into an overall curative strategy should have high priority.

Chapter 19

References Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216 Cheung NK, Heller G (1991) Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol 9:1050–1058 George RE, London WB, Maris JM, Cohn SL, Diller L, Brodeur GM, Castleberry RP, Look AT. Hyperdiploidy plus Non-amplified MYCN Confers a Favorable Prognostic Group in Children 12 to 18 Month of Age with Disseminated Neuroblastoma: A Pediatric Oncology Group Study. J Clin Oncol (in press) Grupp SA, Stern JW, Bunin N, Nancarrow C, Ross AA, Mogul M, Adams R, Grier HE, Gorlin JB, Shamberger R, Marcus K, Neuberg D, Weinstein HJ, Diller L (2000) Tandem highdose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol 18:2567–2575 Kletzel M, Katzenstein HM, Haut PR,Yu AL, Morgan E, Reynolds M, Geissler G, Marymount MH, Liu D, Kalapurakal JA, Shore RM, Bardo DM, Schmoldt J, Rademaker AW, Cohn SL (2002) Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 20:2284–2292 Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB, Reynolds CP (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. N Engl J Med 341:1165–1173 Schmidt ML, Lal A, Seeger RC, Maris JM, Shimada H, O’Leary M, Gerbing RB, Matthay KK. Favorable prognosis for patients ages 12–18 month with stage 4 MYCN-nonamplified neuroblastoma. J Clin Oncol (in press)

291

Chapter 1 ■■■■■■■■

293

Subject Index

14.G2a 229 1A7 203 3F8 186, 189, 226 A ABMT (Autologous bone marrow transplantation) 142 ADCC (Antibody dependent cell-mediated cytotoxicity) 226 Adenoviral vectors 271 Adjuvant therapy efficacy 185, 186, 190 Adolescents 124 Adolescents/adults 128 Adoptive Therapy 234 Adrenal hemorrhage 72 Advanced-stage tumors 34 Age 78 Akt 48 49 Alcohol consumption 3 Allogeneic hematopoietic cell transplant 144 Alpha particles 230 Amifostine 280 Angiogenesis Inhibitors 271 Angiopoietin-2, 258 Antenatal ultrasonography 131 Anti-Angiogenic Agents 201 Antibody Immunoconjugates 229 Antibody-conjugates 272 Anti-GD2-antibody 139 Anti-idiotype vaccine 203 Anti-idiotypic antibody – Ab2 229 – Ab3 229 APC (Antigen-presenting cells) 223 Apoptosis 253 Apoptotic Pathway 201 Array CGH 34 Array technology 29

Arsenic trioxide 202 Artemin 48 ASH1 (Achaete-Scute homolog-1) 42, 43 Astatine 230 ATRA (All-trans retinoic acid) 247, 250 Average annual percentage 2 Avian paramyxovirus 271 B B7 233, 234 Bad 48 Bax 48, 49 Bcl-2 50, 194 Bcl-X1 50 Bcl-XL 194 BCNU 143 BDNF (Brain derived neurotrophin factor) 46, 47 Biopsy 64, 151 Birth – characteristics 2 – defects 3 – weight 3 Bismuth-213 230 Bispecific Antibodies 231 BM (Bone marrow) 185, 186, 188, 189, 190 – metastasis 70, 71 BMP2 (Bone morphogenetic protein) 43 BMP2/4 45 BMPs 41 Bone metastasis 72 Brain metastases 216 Breakpoint region 31 Breastfeeding 3 Buthionine sulfoximine 197

C C3b 227 c-Abl 49, 50 cAMP 45 Carboplatin 139, 143, 198 Cardiomyopathy 283 Caspase-1 50 Caspase-3 50 Caspase-8 50, 202 Catecholamine metabolites 63, 68 Catecholamines 8, 17, 18 – Assays 10, 13 – – False-positive 14, 17 – – Sensitivity 12, 14 – – Specificity 12, 17 CBF-1 44 CBHA 202 CCG 3891 study 174, 250 CCND1 (Cyclin D1) 43, 44 CD1d 225 CD28 (Costimulatory molecule) 224, 234 CD34 selection 175, 181 CD3ξ or γ chain 234 CD40 225 CD40L 225 CD44 58, 80 CD46 (Membrane cofactor protein) 226 CD55 (Decay accelerating factor) 226 CD56 224 CD59 (Homologous restriction factor) 226 CD66b 266 CD80 (B7-1/BB1) 224 CD86 (B7-2/B70) 224 CD122 225 CD154 225 CD161 225 Cdk4/cyclin D kinase 49

294

Subject Index Cellular Immunotherapy 232 CEP-701 201 Ceramide 253, 254 Cesarean birth 2 CgA (Chromogranin A) 56, 57, 58, 68, 71 CGH (Comparative genomic hybridization) 34 ch14.18 226 c-Ha-Ras 50 Chemodectoma 73, 77 Chemosensitivity 268 Chemotherapy 142, 144 Chromaffin cells 42 Chromosomal breakpoints 30 Chromosome – 1p 28, 29, 31, 32, 34 – 1p36 64, 80, 92 – 3p26 79, 80 – 9p21 32 – 11q deletion 31, 32 – 11q23 79, 80 – 12q gene amplification 106 – 14q32 32 – 17q 136 – – gain 31, 32, 34 – – translocations 32, 79, 80, 82 – 17q21 79, 81 CIR (Chimeric immune receptor) 233 Cisplatin 139 13-cis-retinoic acid 144, 249, 250, 251, 252, 253 Ck1 43 c-kit 201 CMC (Complement-mediated cytotoxicity) 226 Coagulopathies 129 COG A3973 182 COJEC 139, 141 Computerized axial tomography 110 Congenital central hypoventilation syndrome 21 Congential neuroblastoma 23 Constitutional rearrangements 32 Cord compression 213, 215 CpG 233 CR3 (CD11b/Cd18) 226 CR4 227 CREB 45 c-Ret 45 CTL (Cytotoxic T-lymphocytes) 225 Cyclophosphamide 139, 143 Cytogenetic analyses 31 Cytogenetics 27 Cytotoxic therapies 267

D DAN 43 Dancing eyes 66 Dancing feet 66 DBH 45 DCC (Delete in colon cancer) 48 Decitabine 202 Dendritic cell vaccines 204 Depsipeptide 202 Depudecin 202 Diploidy 31, 34, 35 Differentiation 243, 244, 245, 247, 248, 249, 254 – Induced 56, 59 – Neural crest 42, 55, 56, 243, 244, 245 Disialoganglioside GD2 186, 188 DNA ploidy 77, 78, 80 DNA vaccines 204, 273 DNRG 81 Dopamine-β-hydroxylase genes 44 Dosage effect 32 Dose intensification 290 Dose-intensity 139 Dose-intensive induction 138,144, 145 Double minutes 27 Down syndrome 23 DP1 49 DSRCT (Desmoplastic small round cell tumor) 72 DTC (Disseminated tumor cell) 187, 190 DTIC (Dacarbazine) 198 E E2F1 49 E3 ubiquitin ligase complex 43 ECEL1 48 Educational achievement 284 EGF-R (Epidural growth factor-receptor) 226 γ-emission 230 Endostatin 261 Engineered vaccines 144 Engraftment 144 Enhanced expression 29 Enteric neurons 42 Enumeration of CD34+ cells 179 Epidural involvement 215 Epigenetic – change 32 – silencing 31

Epirubicin 139 ERK 46, 49 Esthesioneuroblastoma 72 Ethnicity 1 Etoposide 143 Expression array 28 F Familial neuroblastoma 21 Fanconi’s syndrome 283 Fas 234 Fas-L 226 Favorable 34, 92, 93 FcγR (Fc gamma-receptors) – FcγRI (CD64) 226 – FcγRII (CD32) 226 – FcγRIII (CD16) 226 Femoral catheter 177 Fenretinide 144 Ferritin 67, 68 Fetal alcohol syndrome 3 βFGF (Fibroblast growth factor) 258 FGF-R (Fibroblast growth factor-receptor) 48 First hit 29 Flt-3L 233 G GAGE 224 α-galactosyl-ceramide 225 Ganglioneuroma 73 Gata3 45 G-CSF (granulocyte colony stimulating factor) 178, 179 GD2, 70, 224 – ganglioside 203 – synthase 188, 189, 190 GD3, 224, 225 GDNF (glial cell line derived neurotrophic factor) 48 Gene dosage changes 32 Gene expression analysis 98, 105, 106 Genetic 27, 35 – heterogeneity 32 – imbalance 32 Germ-cell damage 282 GFRα 48 GH (Growth hormone) deficiency 282 Gleevec 201 Gli 43

Subject Index Gli1 43 Glucan 203 Glutathione 197 GM2 224 GM-CSF (Granulocyte macrophage colony stimulating factor) 178, 226, 233, 234 GP58 224 GP95 224 graft-vs-tumor 233 Grb 46 Gross Total Resection 152 GSK3 43 H HAMA (Human anti-mouse antibody) 229 Haploinsufficiency 31, 32 hASH1 (Human achaete-scute homolog -1) 43 HAT enzymes 202 HDAC (Histone deacetylase) inhibitors 144, 202 HDC/SCR (High-dose chemotherapy with stem cell rescue) 174, 175 Hearing aids 280 HES1 42, 44 HES5 42 Heterochromia 67 Heterogeneity 64 Heterotopic (subcutaneous) tumors 270 Hh (Hedgehog) 43 HIF1α 42 HIF2α 42 High-Risk 35, 138, 141 Hirschsprung disease 21, 44 Histology 64 βHLH (Helix loop helix) 44 Homer-Wright-rosette 71 Hormones 3 Horner’s syndrome 66, 67, 124 HSR (Homogenously staining chromosomal region) 27 Hu14.18 203 Hu14.18-IL-2 231 HuD 42 Hutchinson type 63 HVA (Homovanillic Acid) 8, 9, 10, 67, 68 Hyperdiploidy 138 Hypertension 66 Hypothyroidism 204, 280

I 131

I-3F8 230 I-anti-GD2 141 iC3b 227 ICAM (Intercellular adhesion molecule) 225 Id2 42 Ifosfamide 139, 197 IFN-γ (Interferon gamma) 225 IGF2 (Insulin like growth factor-2) 43, 48 Immune-resistance 235 Immunity – Adaptive 223 – Innate 223 Immunoconjugates 227, 230, 231 Immunocytochemistry – Neurofilament 160, 56, 58, 59 – S100A6 (Calcyclin) 59 Immunocytokines 144, 231 immunocytology 139, 186, 188, 189, 190 Immunology 223 Immunomagnetic depletion 181 Immunostimulants 233 Immunotherapy 223, 224, 226, 232, 273 Immunotoxins 231 Incidence 1, 7, 11, 12, 13, 15, 16, 18 Induced abortions 2 Infertility 3 INRG (International NB Risk Group) 289 INSS (International neuroblastoma staging system) 67, 71, 73, 74,75, 77 Integrins ανβ3 and ανβ5 258 Intensive induction 138 IL (Interleukin) – IL-1 234 – IL-2 203, 225, 232, 233, 234 – IL-4 225 – IL-6 261 – IL-10 225 – IL-12 203, 225, 232, 234 – IL-15 232 – IL-18 232 International Neuroblastoma Pathology – Classification 87, 92, 93, 94 – Committee 87, 92 Interstitial deletions 31 Iproplatin 139 Irinotecan 199 Irradiation 144 Isolex 300i device 181 I-type cells 56, 58 131

295 J JNK (c-Jun NH2-terminal kinase) 48, 49 K Kinase 224 Kinsbourne syndrome 66 L L1-CAM 224 Laminectomy 278 Large-volume leuka-pheresis 178 LDH (Lactate dehydrogenase) 67, 68 Leukocyte function antigen – LFA-1 225, 226 – LFA-3 225 Leptomeningeal 216, 217 Leydig cell failure 282 Liver 124, 133 Local control 138, 142, 156, 165 Local Progression 157 LOH (Loss of heterozygosity) 29 Lung fibrosis 283 Lymph node(s) 127, 136, 151 Lymphotactin 234 M MAGE 224 Malignant potential 56, 58 Marrow ablative 138, 139 MASH1 (Mouse achaete-scute homolog-1) 41, 42, 43, 45 Maternal occupations 4 Math 43 Mdm2, 49, 50 MEK 46, 49 MEKK 49 Melanocytes 42 Melphalan 142, 143, 197 Metastases 70 MHC (Major histocompatibility complex) class 234 MIBG (Metaiodobenzylguanidine) 64, 72, 204 Microarray 100 Miltenyi Clini-MACS 181 Miscarriage 2 MKI (Mitosis-karyorrhexis index) 88, 89, 91, 92

296

Subject Index MK (midkine) 48 MMP (Matrix metalloproteinase) 259 – MMP-2 202, 259 – MMP-9 202, 259 Molecular pathology 97, 103 Molecular pathways 35 Monoclonal antibody 226, 227 Mortality 9, 11, 12, 14, 15, 16, 18 MRD (Minimal residual disease) 138, 145, 224, 230 MRI (Magnetic resonance imaging) 112 MRP (Multi-drug resistance protein) 80, 194 MS-275 202 MT-MMP-1 (Membrane type-matrix metalloproteinase-1) 259 Multiple primary tumors 23 Multistep Targeting 230 Multivitamin 3 Mutational 32 MYCN 28, 29, 42, 43, 45, 56, 58, 93, 224 – amplification 64, 76, 80, 82, 98, 103, 138, 261 – amplified 29, 31, 32, 34,143 – oncogene 224, 272 Myeloablative chemotherapy 142, 143, 144, 145 Myelodysplasia/leukemia 284 Myelopathy, transverse 66 N N1E115 48 N-6 139 N-7 139 NB-p260 224 NCAM 70, 224 Near-pentaploid 34 Negative selection 181 Neural crest cancer stem cells 58 Neurocristopathies 21 NeuroD 43 Neurofibromatosis type 1 22 Neurofilament protein 56, 58, 59 Neurogenin 43, 44 Neurologic complication 213 Neuropeptide Y 69 Newborns 126 Newcastle disease virus 271 NF160 45 NFκB pathway 226 NGF (Nerve growth factor) 46, 47 NHL 72

NICD 44 NK (Natural killer) cells 223, 224, 225, 226 NKT 224 NLRRs (Neuronal leucine-rich repeat receptors) 48 N-myc see “MYCN” Non-Hodgkin’s lymphoma 72 Notch 42, 44 Notocord 42 NOXA 49 ∆Np75 48–50 NSE (Neuron specific enolase) 67, 68, 71 NT-3 (Neurotrophin) 46, 47 NT-4/5 (Neurotophin) 46, 47 N-type cells 56–58 Nuclear pRB 49 NY-Eso-1 224 O Occupation 4 OJEC 139, 140 Olfactory Neuroblastoma 73 Oncogenes 27, 28 OPEC 139, 140 OMS (Opsoclonus-myoclonus syndrome) 66, 124, 217, 218, 219, 220 Orthotopic models 270 Osteosarcomas 284 Ototoxicity 279 Ovarian failure 281 Oxaliplatin 198 Oxamflatin 202 P P13K 49 p14ARF 49, 50 p21WAF1 43, 44, 50 p27 247 p27kIP1 43 p53 42, 48, 194, 199 p73 42 p75NTR 46, 47 PACE4 44 Palliation 169 Paraganglioma 73 Parc 49 β-particles 230 PB (peripheral blood) 185, 186, 188, 189, 190

PBSC (Peripheral blood stem cell) 173, 177 PBSCH (Peripheral blood stem cell harvest) 141 PC12, 46 PDGF (Platelet derived growth factor) 258 PDGFR 43 PEDF (Pigment epithelium-derived factor) 260 Pepper type 63, 75 Pepper-and-salt-structure 71 Peripherin 45 Pesticides 4 p-glycoprotein 194 Pheochromocytoma 73 Pheresis catheter 177 Phox2a 42, 44, 45 Phox2b 22, 42, 44, 45 PI3-kinase 48 PKA 43 Ploidy 34 PNET (Peripheral neuroectodermal tumor) 72 Polymorphic markers 30 Preclinical Detection – See “Screening” Premature Menopause 281 Prenatally diagnosed neuroblastoma 118 Preterm birth 3 Prevention – See “Screening” Primary neuroblastoma 109 Primary Tumor 69 Prognostication 129, 134 Progression 35 Ptc 43 Ptch1 43 PTN (Pleiotrophin) 48 PUMA 49 Purging 142 Pyrazoloacridine 200 Q QS-21 232 R Race 1 Radiation 142 – therapy 145, 165 Radioimmunoconjugates 230 Raf 46, 49

Subject Index Ras 46, 49 RBI alleles 29 RBP-Jκ 44 Rebeccamycin 201 Reproductive history 2 Resectability 74, 125 Resection 142 Response criteria 81 Ret 42, 48 Retinoic acid receptors 248, 250 Retinoids 247, 252 Risk group 77 RIT (Radioimmunotherapy) 230 RT-PCR (Reverse transcriptionpolymerase chain reaction) 188, 189, 190 S SAGE (Serial analysis of gene expression) 100, 105 SAHA (Suberoylanilide hydroxamic acid) 202 SCG10 45 Sch 46 Scoliosis 216, 278 Screening 7–20, 126, 131 – Ascertainment 10, 13, 14, 15 – Austria 9, 10, 17 – Biologic Characteristics 7, 11, 15, 17 – Clinical implications 18 – Compliance 10, 11, 12, 13, 14 – Cost-effectiveness 17 – Economic aspects 17 – England 9 – European 9, 10, 11 – False – Positive 13, 14, 17 – False-Negative 8 – Florida 11, 13 – Germany 9, 11, 12, 13, 14, 15, 17, 16, 18 – Greater Delaware Valley 11, 13 – Halo-effect 11, 16 – Japan 8, 10, 11, 12, 15, 17, 18 – Mass screening 31 – Methodologic Limitations 9 – Minnesota 9, 10, 11, 13 – North-America 9, 10, 12, 13 – Predictive value 13 – Ontario 11, 13 – Population-Based Cohort 9, 11 – Principles 9, 11 – Psychologic aspects 17 – Quebec 9, 11, 12, 13, 14, 15, 16, 17, 18 – Sensitivity 10, 12, 14

– Specificity 10, 12, 17 – Texas 10 – Urine Collection 10, 12 Second hit 29 Secondary leukemia 204 γ-secretase 44 Sensory neurons 42 SEREX 233 SgII (Secretogranin II) 56, 58 Shh (Sonic Hedgehog) 43 Shimada histology 78 Signal Transduction Inhibitors 270 Ski 43 Skp2 43 Skin nodules 135 Slipped capital femoral epiphysis 278 Smad 43 Small blue round cell tumors 72 Smo 43 Smoking 3 Soft tissue sarcomas 284 Soluble IL-2-Rα 232 Somatic events 27 SOS 46 SPARC (Secreted protein acidic and rich in cysteine) 260 Spontaneous regression 35, 124, 126 SRO (Smallest region of overlapping deletions) 29 Stage 1 124, 133, 134 Stage 2A 124 Stage 2B 124 Stage 4 138, 145 Stage 4N 136 Stage 4S 118, 124, 125, 128, 129, 133, 134, 135, 136, 137 Staging 73,151 Stem cell mobilization 178 S-type cells 57–59 Subcutaneous nodules 124, 133 Subtype – maturative 75 – progressive 77, 80 – regressive 76 Suppressor genes 29 Surgery 139, 142, 149 – resection of primary 139, 141 Survival rates 2, 9, 11 Survivin 50 Survivors 277 SVV 42 Sympathetic neurons 42 Symptoms 65 Syngeneic models 273 Systemic exposures 270

297 T Tandem transplant 175 TAp73 50 Target Dose 179 Targeted radiotherapy 141 Taxol 139 Tc (technetium) bone scan 72 γ/δ+T cells 224 T-cell receptor 224 T-cells 224, 226, 231, 233, 234, 235 α/β+ T-cell 233 Telomerase 103 Temozolomide 198 Tetraploid 34, 35 TGF (Transforming growth factor) – TGF-α 258 – TGF-β 43 TH (Tyrosine hydroxylase) 44, 45, 71, 188, 189, 190 Thalidomide 202 T-helper cell – (TH1) 225 – (TH2) 225 Thiotepa 143 Thrombospondin-1 (TSP-1) 260 Thyroid neoplasm 284 TIMP-2 259 Tirapazamine 199 TNP-470 (AGM-1470) 261 Topotecan 200 Total body irradiation 142,144, 279 Transcript Profiling 98 Transcriptome 100 Transdifferentiation 60 Transgenic neuroblastoma model 272 Transplant 142 Triploidy 31, 34, 35 Trk receptors 201, 245, 246 – TrkA 42, 46, 47, 79, 80, 93 – TrkB 42, 46, 47 – TrkC 42, 46, 47 Tumor Cell Purging 181 Tumor heterogeneity 186, 188, 190 Tumor marker 67 Tumor suppressor – genes 27, 29, 31, 32, 35, – locus 31 Tumor tissue 64 Tumor Vaccines 233 Tumor vascularity 271 Tumor volume 157 Tumor-specific mutations 31 Turner syndrome 23

298

Subject Index Two-hit model 29, 32 Two-step genetic sequence of tumor development 28 Tyrosine kinase inhibitor 201 U Ultra-high-risk 139 Unfavorable histology 92, 93 V αVβ3 232 Vaccines 204 Vascular encasement 152

VEGF (Vascular endothelial growth factor) 232, 258 – VEGF-B 258 – VEGF-C 258 – VEGF-R (Receptor) 226 – VEGF-R2/KDR 232 Vincristine 139, 143 VIP (Vasoactive intestinal peptide) 124 Viral-Based Therapies 271 VMA (Vanillylmandelic Acid) 8, 9, 10, 67, 68 W Wilms’ tumor 73 Wnt 43

X Xenografts 268 Y 90

Y (Yttrium-90) 230 Z

Zuckerkandl organ 69