Pediatric Hematology and Oncology E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1471

Veröffentlichungsjahr: 2011

Beschreibung

This new textbook has an international authorship and is a practical, up-to-date resource for clinicians responsible for the care of children with oncologic and malignant hematologic disease. It is specifically designed for practicing oncologists and hematologists, pediatricians with an interest in childhood cancer and trainees seeking a systematic approach to these disorders. This new textbook has an emphasis on the visual presentation and ease of reading of contemporary and comprehensive information for children's cancers and contains detailed tables, fact boxes and illustrations. The textbook begins with an introduction to the general principles of the scientific foundation and treatment of childhood cancers and hematological malignancies. Separate sections are then devoted to descriptions of central nervous system tumors, hematological malignancies and solid tumors of childhood which encompass epidemiology, cellular and molecular biology, cancer genetics, immunology, pharmacology and the findings of clinical trials. For each area of science covered, key original references and reviews are highlighted to direct further reading. Diagnostic, biological, and therapeutic issues are integrated into each tumor-specific chapter, with evidence supporting the current rationales for risk stratification and the development of novel therapies. A final section then explores supportive care, palliative care, late effects considerations and psychosocial issues as relate to children's cancer.

Leseprobe

Contents

Contributors

1 IntroductionEdward J. Estlin, Richard J. Gilbertson and Robert F. Wynn

Scope and aims

The epidemiology of childhood cancer

Genetics in relation to children’s cancers

Cellular and molecular biology in relation to children’s cancers (Box 1.2)

Cancer immunology

The general principles of pharmacology in relation to childhood cancer

The conduct of clinical studies in children with cancer (Box 1.3)

Summary

Part I Central Nervous System Tumors of Childhood

2 Low- and High-Grade GliomaIan F. Pollack

Introduction

Epidemiology

Histopathology classification (Box 2.1)

Molecular biology

Clinical presentation

Diagnostic investigation and staging

Treatment and outcome (Box 2.2)

Strategies for follow-up and late effects

Novel therapeutic approaches

Summary and future directions for management

Acknowledgment

3 EpendymomaThomas E. Merchant and Richard J. Gilbertson

Introduction

Epidemiology

Histology

Genetics and tumor biology

Clinical presentation

Investigation and staging

Treatment of ependymoma

4 Embryonal TumorsAmar Gajjar and Steven C. Clifford

Introduction

Medulloblastoma

Treatment of other forms of embryonal tumors

Treatment strategies for relapsed disease

Complications of treatment and important late-effects

Novel therapeutic approaches

Summary and future directions for management

5 Pediatric Spinal Cord TumorsAnnie Huang, Ute Bartels and Eric Bouffet

General overview

Disease specific issues

Strategies for follow up and important late effects

Conclusions

6 Pediatric Craniopharyngioma, Mixed Glioneuronal Tumors, and Atypical Teratoid/Rhabdoid TumorAdrienne Weeks and Michael D. Taylor

Introduction

Craniopharyngioma

Mixed glioneuronal tumors

Atypical teratoid rhabdoid tumors

Part II Hematological Disorders

7 Acute Lymphoblastic LeukemiaRobert F. Wynn

Introduction

Epidemiology of acute lymphoblastic leukemia

Pathology of acute lymphoblastic leukemia

Clinical presentation of acute lymphoblastic leukemia

Treatment of acute lymphoblastic leukemia

Summary and future directions

8 Acute Myeloid Leukemia and Myelodysplastic DisordersDavid K.H. Webb/

Introduction

Acute myeloid leukemia

Acute promyelocytic leukemia (APL) [16–19]

Myelodysplastic syndromes

Down’s syndrome and myeloid malignancy

Strategy for follow-up and important late effects

Summary and future directions for management

9 Non-Hodgkin’s LymphomaAngelo Rosolen and Lara Mussolin

Introduction

Epidemiology

Classification

Clinical presentation

Investigation and staging

Treatment

Novel therapeutic approaches

Summary and future directions for management

10 Hodgkin’s LymphomaWolfgang Dörffel and Dieter Körholz

Introduction

Epidemiology and pathogenesis

Clinical presentation

Investigation and staging

Treatment

Strategies for follow up and overview of important late effects

Novel therapeutic approaches

Nodular lymphocyte predominant Hodgkin’s lymphoma

Summary and future directions for management

11 Histiocytic DisordersSheila Weitzman and R. Maarten Egeler

Introduction

Langerhans cell histiocytosis (LCH)

Hemophagocytic lymphohistiocytosis (HLH)

Conclusion

Part III Solid Tumors of Childhood

12 NeuroblastomaSucheta J. Vaidya and Andrew D. J. Pearson

Introduction

Epidemiology

Clinical features

Investigations

Ultrasonography

Computerized tomography (CT) [5]

Tumor markers (Box 12.2)

Neuroblastoma staging

Pathology

Risk stratification

Screening and neuroblastoma (Box 12.7)

Treatment of neuroblastoma

Role of chemotherapy in neuroblastoma (Box 12.9)

Differentiating therapy and neuroblastoma

Neuroblastoma in infants

Neuroblastoma in adolescents

Opsoclonus-myoclonus syndrome (OMS)/dancing eye syndrome

Late effects of treatment of neuroblastoma

Summary

13 Renal TumorsEdward J. Estlin and Norbert Graf

Introduction

Wilms’tumor (nephroblastoma)

Clear cell sarcoma of the kidney

References

14 Soft Tissue SarcomaGianni Bisogno and John Anderson

Introduction

Rhabdomyosarcoma

Non-rhabdomyosarcoma soft tissue sarcomas

15 Bone TumorsRichard Gorlick, Martha Perisoglou and Jeremy Whelan

Introduction

Benign bone tumors

Osteosarcoma

Ewing’s sarcoma family tumors (ESFT)

16 Hepatic TumorsPenelope Brock, Derek J. Roebuck and Jack Plaschkes

Introduction

Historical perspective

Epidemiology

Clinical presentation

Investigations and staging

Histopathology and cytogenetics

Principles for the treatment of hepatic tumors

Determinants of prognosis

Strategies for follow up and overview of important late effects

Novel therapeutic approaches

Summary and future directions for management

Acknowledgement

17 Germ Cell TumorsJames Nicholson and Roger Palmer

Introduction

Epidemiology and biology

Clinical presentation

Management of extracranial germ cell tumors

Management of intracranial germ cell tumors

Novel therapeutic approaches

Summary and future directions

Related tumors (included in the differential diagnosis of gonadal germ cell tumors)

18 RetinoblastomaEdward J. Estlin, Frangois Doz and Michael Dyer

Introduction and historical perspective

Epidemiology (Box 18.1)

Clinical presentation and investigation (Box 18.2)

Classification, histopathological variants, and molecular oncology

General principles of treatment for retinoblastoma (Box 18.3)

Treatment of bilateral retinoblastoma

Factors that relate to prognosis

Strategies for follow up and overview of important late effects

Genetic counseling and screening

Novel therapeutic approaches

Summary and future directions (Box 18.4)

Acknowledgment

19 Rare TumorsBernadette Brennan and Charles Stiller

Introduction

Nasopharyngeal carcinoma (Box 19.1)

Pleuropulmonary blastoma

Pancreatoblastoma (Box 19.3)

Exracranial rhabdoid tumors (Box 19.4)

Adrenocortical carcinoma

Acknowledgments

Part IV Supportive Care, Long-Term Issues, and Palliative Care

20 Supportive Care: Physical Consequences of Cancer and its TherapiesBob Phillips and Roderick Skinner

Introduction

Oncological emergencies

Central venous access devices

Symptom care

Immunity and infections

Anemia

Thrombocytopenia

Venous thromboembolism

Multidisciplinary team working and supportive care

21 Psychosocial Needs of Children with Cancer and TheirGed Lalor and Louise Talbot

Introduction

Practical adjustments

Family competence – strengths and needs

Changing relationships

Education

Family finances

Support and information sources: international resources for families and health professionals

Summary

Acknowledgements

22 Late Effects in Relation to Childhood CancerLouise Talbot and Helen Spoudeas

Introduction

Neurocognitive late effects of irradiation

Late effects of CNS chemotherapy

Late effects of non CNS-directed radiotherapy and chemotherapy

Conclusion and summary

23 Palliative CareLynda Brook

Introduction

Principles of palliative care

Pain (Box 23.5)

Pain rating scales

Gastrointestinal symptoms

Other symptoms

Neurological symptoms

Communication and psychological symptoms

The last few hours and days

Conclusion and future directions

24 Clinical Trials Involving Children with Cancer – Organizational and Ethical IssuesAblett and Edward J. Estlin

National models for the conduct of clinical trials for children with cancer

International collaborations

Legislation involving data storage, protection and transfer

Ethical considerations

Index

Colour plate appears facing page

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Library of Congress Cataloging-in-Publication Data

Pediatric hematology and oncology: scientific principles and clinical practice /edited by Edward J. Estlin, Richard J. Gilbertson, Robert F. Wynn.

p.; cm.

Includes bibliographical references.

ISBN 978–1-4051-5350-8

1. Pediatric hematology. 2. Tumors in children. I. Estlin, Edward J. II. Gilbertson, Richard J. III. Wynn, Robert F.

[DNLM: 1. Hematologic Diseases. 2. Child. 3. Neoplasms. WS 300 P3702 2010]

RJ411.P37 2010

618.92′15–dc22

2009018585

ISBN: 978-14051-5350-8

This book is dedicated to all past, present and future children with cancer and the people who care for them.

Contributors

John Anderson BA MRCP PhDSenior Lecturer in Paediatric OncologyHonorary Consultant Paediatric OncologistInstitute of Child Health and Great Ormond Street HospitalLondon, UK

Sue Ablett BA, PhD, MRCPCHExecutive DirectorChildren’s Cancer and Leukaemia Group (CCLG)Leicester, UK

Ute Bartels MDPediatric Brain Tumor ProgramThe Hospital for Sick ChildrenToronto, Ontario, Canada

Gianni Bisogno MD, PhDConsultant Paediatric OncologistDivision of Hematology and OncologyDepartment of PaediatricsUniversity Hospital of PaduaPadua, Italy

Eric Bouffet MD, FRCP(C)Director of the Paediatric Brain Tumour ProgramProfessor of PaediatricsDivision of Haematology and OncologyThe Hospital for Sick ChildrenToronto, Ontario, Canada

Bernadette Brennan MBChB, FRCPCH, MDConsultant Paediatric OncologistRoyal Manchester Children’s HospitalManchester, UK

Penelope Brock MD, PhD, FRCPCHConsultant Paediatric Oncologist and Honorary Senior LecturerGreat Ormond Street Hospital for Children NHS Trustand Institute of Child Health London, UK

Lynda Brook MBChB, MRCP, MScMacmillan Consultant in Paediatric Palliative CareAlder Hey Children’s Hospital Specialist PalliativeCare TeamDepartment of Pediatric OncologyAlder Hey Children’s HospitalLiverpool, UK

Steven C. Clifford PhDProfessor of Molecular Paediatric OncologyNorthern Institute for Cancer ResearchNewcastle UniversityThe Medical SchoolNewcastle-upon-Tyne, UK

Wolfgang Dörffel MDHospital for Children and AdolescentsHELIOS-Klinikum Berlin-BuchBerlin, Germany

François Doz MDDepartment of Pediatric OncologyInstitute Curie;University René DescartesParis, France

Michael Dyer PhDDepartment of Developmental NeurobiologySt Jude Children’s Research Hospital;Department of OphthalmologyHoward Hughes Medical InstituteUniversity of Tennessee Health Science CenterMemphis, TN, USA

R. Maarten Egeler MD, PhDProfessor of Pediatrics Head, Division of Immunology, Hematology, Oncology, Bone Marrow Transplantation and Auto-immune DiseasesDepartment of PediatricsLeiden University Medical CenterLeiden, The Netherlands

Edward J. Estlin BSc(Hons), PhD, MRCP, FRCPCHMacmilllan Consultant in Paediatric OncologyDepartment of Pediatric OncologyRoyal Manchester Children’s HospitalManchester, UK

Amar Gajjar MDDirector, Division of Neuro OncologyCo-Leader, Neurobiology and Brain Tumor ProgramCo-Chair, Department of OncologySt Jude Children’s Research HospitalMemphis, TN, USA

Richard J. Gilbertson MD, PhDCo-LeaderNeurobiology and Brain Tumor ProgramDirectorMolecular Clinical Trials CoreDepartments of Developmental Neurobiology and OncologySt Jude Children’s Research HospitalMemphis, TN, USA

Richard Gorlick MDAssociate Professor of Pediatrics and Molecular PharmacologyAlbert Einstein College of Medicine;Vice ChairmanDivision Chief of Pediatric Hematology and OncologyDepartment of PediatricsThe Children’s Hospital at MontefioreBronx, New York, USA

Norbert Graf MDDepartment of Paediatric Haematology and OncologyUniversity Hospital of SaarlandHomburg, Germany

Annie Huang MD, PhD, FRCP(C)Pediatric Brain Tumor ProgramThe Hospital for Sick ChildrenToronto, Ontario, Canada

Dieter Körholz MDChairman, Department of PediatricsMartin Luther University Halle/WittenbergHalle/Saale, Germany

Ged Lalor BA (Hons), CQSWSocial WorkerDepartment of Paediatric Oncology and HaematologyRoyal Manchester Children’s HospitalManchester, UK

Thomas E. Merchant DO, PhDMember and ChiefDivision of Radiation OncologySt Jude Children’s Research HospitalMemphis, TN, USA

Lara Mussolin, PhDClinica di Oncoematologia PediatricaAzienda Ospedaliera-Universita di PadovaPadova, Italy

James Nicholson DM, MA, MB, BChir, MRCP, FRCPCHConsultant Paediatric OncologistAddenbrooke’s HospitalCambridge, UK

Roger Palmer BSc (Hons), PhD MB, BChir, MRCP(UK), MRCPCHMRC Career Development FellowMRC Cancer Cell UnitCambridge, UK

Andrew D. J. Pearson MD, FRCP, FRCPCH, DCHChairman of Paediatric OncologyThe Institute of Cancer Research & Royal Marsden HospitalSutton, Surrey, UK

Martha Perisoglou MDRichard Scowcroft Research FellowDepartment of OncologyUniversity College HospitalLondon, UK

Bob Phillips MA, BM BCh, MMedSci, MRCPCHConsultant in Paediatric Oncology,Leeds Teaching Hospitals Trust, LeedsUK;MRC Research Fellow,Centre for Reviews and Dissemination,University of York,York, UK

Jack Plaschkes MD, FRCSSenior Pediatric Surgeon and Consultant forPediatric Surgical Oncology (Ret.)University Children’s HospitalBern, Switzerland

Ian F. Pollack, MD, FACS, FAAPChief, Pediatric Neurosurgery Children’s Hospital of Pittsburgh Walter Dandy Professor of NeurosurgeryVice Chairman for Academic AffairsDepartment of Neurological SurgeryDirector, UPCI Brain Tumor ProgramUniversity of Pittsburgh School of MedicinePittsburgh, PA, USA

Derek J. Roebuck MRCPCH FRCR FRANZCRConsultant Interventional RadiologistDepartment of RadiologyGreat Ormond Street Hospital for ChildrenNHS TrustLondon, UK

Angelo Rosolen MDClinica di Oncoematologia PediatricaAzienda Ospedaliera-Universita di PadovaPadova, Italy

Roderick Skinner BSc (Hons), MB ChB (Hons), PhD, FRCPCH, DCH, MRCP(UK)Consultant and Honorary Clinical Senior Lecturerin Paediatric and Adolescent Oncology /BMTChildren’s BMT UnitNewcastle General Hospital Newcastle upon Tyne,UK; Department of Paediatric and Adolescent OncologyRoyal Victoria InfirmaryNewcastle upon Tyne, UK

Helen Spoudeas DRCOG, FRCPCH, FRCP, MDConsultant in Neuro-Endocrine and Late Effects of Childhood Malignancy Honorary Senior Lecturer in Paediatric EndocrinologyLondon Centre for Paediatric and AdolescentEndocrinology Neuroendocrine DivisionUniversity College London & Great Ormond StreetHospital for Children NHS TrustLondon, UK

Charles Stiller MScSenior Research FellowChildhood Cancer Research GroupUniversity of OxfordOxford, UK

Louise Talbot D.Clin.Psy., BSc (Hons)Macmillan Clinical PsychologistPaediatric Psychosocial DepartmentRoyal Manchester Children’s HospitalManchester, UK

Michael D. Taylor MD, PhD, FRCSAssistant ProfessorDepartment of NeurosurgeryThe Hospital for Sick ChildrenToronto, Ontario, Canada

Sucheta J. Vaidya MBBS, DCH, MB, MDConsultant in Paediatric OncologyRoyal Marsden HospitalSutton, Surrey, UK

David K.H. Webb MD, FRCP, MRCPath, MRCPCHConsultant HaematologistDepartment of Haematology and OncologyGreat Ormond Street Hospital for ChildrenNHS TrustLondon, UK

Adrienne Weeks MDDepartment of NeurosurgeryThe Hospital for Sick ChildrenToronto, Ontario, Canada

Sheila Weitzman MB BCh, FCP (SA), FRCP (C)Senior Staff OncologistAssociate Director Clinical AffairsThe Division of Haematology and OncologyThe Hospital for Sick Children Professor, Department of PediatricsUniversity of TorontoToronto, Ontario, Canada

Jeremy Whelan MD, FRCPConsultant Medical OncologistDepartment of OncologyUniversity College HospitalLondon, UK

Robert F. Wynn BA, MD, MRCP, FRCPathConsultant Paediatric Haematologist and Programme DirectorBlood and Marrow Transplant UnitRoyal Manchester Children’s HospitalManchester, UK

1

Introduction

Edward J. Estlin1, Richard J. Gilbertson2 and Robert F. Wynn3

1Department of Pediatric Oncology, Royal Manchester Children’s Hospital, Manchester, UK,

2Departments of Developmental Neurobiology and Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA and 3 Blood and Marrow Transplant Unit, Royal Manchester Children’s Hospital, Manchester, UK

Scope and aims

The aim of this textbook is to provide the reader with a focused but comprehensive overview of the clinical and scientific principles that guide current treatments for childhood cancer. For this purpose, the book is divided into four sections, namely central nervous system tumors, hematological malignancies, non-central nervous system (CNS) solid tumors of childhood, and a final section which covers psycho-social support, palliative care and survivorship issues.

For each of the disease specific chapters, our aim is to present the reader with information that is visually distinctive and should allow easy access to key factual information that relates to the epidemiology, presentation, diagnosis, treatment, and prognosis for individual categories of childhood malignancy, along with a brief overview given of the history of therapeutic developments for any given disease type. To facilitate this, the paragraphs will contain regular bullet points to highlight the presentation of key factual information, tables and fact boxes which we hope will enable any reader to quickly pick out important information in relation to the disease type they are interested in.

Progress for the treatment of children’s cancers has traditionally involved advances at the scientific interface such as the recognition of the importance of chromosomal abnormalities, oncogene amplification and aberrations of tumor suppressor gene functions. In more recent times, advances in our understanding of the cellular biological characteristics of cancers is leading towards new insights that can enable a more rational treatment stratification and is also leading towards the development of specific and targeted therapies. Therefore, each of the disease-specific chapters will focus on an integration of the scientific and clinical principles that guide the treatment for these individual cancer types, and introduce the reader to advances in the field that are at the level of the clinical interface. Therefore, in order to help orientate the reader with the scientific information that is incorporated into individual chapters in the rest of the text book, the aim of this introduction is to help define those key scientific principles that pertain to the contemporary management of children with cancer, and which are currently informing novel therapies that are now close to or actually at the clinical interface.

For the descriptions that will be presented below, our aim is not to provide an exhaustive text and reference resource for the reader, but really to highlight the key terms and scientific principles that will serve as a glossary for the main body of the text book to follow, and which will involve referencing against contemporary textbooks and review articles that act as a starting point for further reading.

The epidemiology of childhood cancer

When compared with the adult population, cancer in children is rare and comprises less than 1% of the national cancer burdens of industrialized countries [1]. Moreover, whereas most adult cancers are carcinomas, the cancers that occur in childhood are histologically very diverse and comprise [2]:

Leukemia, myeloproliferative diseases and myelodysplastic diseases.Lymphomas and reticuloendothelial neoplasms.CNS tumors.Neuroblastoma and other peripheral nervous cell tumors.Retinoblastoma.Renal tumors.Hepatic tumors.Malignant bone tumors.Soft tissue and other extra osseous sarcomas.Germ cell tumors, trophoblastic tumors, and neoplasms of the gonads.Other malignant epithelial neoplasms and malignant melanoma.Other unspecified malignant neoplasms.

Thus, for children, carcinomas are rare, and the majority of cancers present as acute leukemia, lymphoma (non-Hodgkin’s lymphoma, Hodgkin’s disease), sarcoma (osteogenic sarcoma, rhabdomyosarcoma), germ cell tumor and embryonal malignancies (neuroblastoma, nephroblastoma, medulloblastoma, hepatoblastoma). Embryonic tumors, which are thought to arise during intra-uterine or early post-natal development from an organ rudiment or immature tissue, and form structures that are characteristic of the affected part of the body, are rare in adults.

The age-standardized incidence of all cancers in children under the age of 15 years is between 70 and 160 per million children per year, corresponding to a risk of 1 in 100 to 1 in 400, and an annual worldwide incidence of approximately 160 000 new cases per year [2]. The epidemiology of childhood cancers is characterized by [1, 2]:

The incidence is highest in the first 5 years of life, reaches a nadir at 9–10 years of age and then rises thereafter.Boys are affected more than girls.While total incidence rates vary only modestly between world regions, there is more marked variation for diagnostic subgroups. For example, among children of North America and Europe, acute leukemia forms the largest diagnostic sub-group, accounting for one-third of the total number of cases, with a lower incidence seen for sub-Saharan Africa, where lymphomas predominate as the most frequent childhood cancer.Within geographical regions, there are indications that racial influences may form a part in the susceptibility of children to cancer. For example, whereas in the USA, the incidence rates for acute lymphoblastic leukemia are highest for children of Hispanic origin, and lower for those of Afro-American ethnicity, the incidence of Wilms’ tumor is lowest for this latter ethnic group.Brain and spinal cord tumors are second only to leukemia in industrialized countries, where they account for 20–25% of childhood cancer. The lower recorded incidence in developed countries may represent under diagnosis.Neuroblastoma and nephroblastoma have a fairly constant incidence rate worldwide.Environmental influences play a part in the variations of the incidence rate for individual cancers types found worldwide.Embryonal tumors and common acute lymphoblastic leukemia tend to affect younger children, osteogenic sarcoma and Hodgkin’s disease are more a diagnosis of adolescence, and rhabdomyosarcoma has bi-modal peaks with both younger children and adolescents being affected.

However, for the great majority (>95%) of cases of childhood cancer the causation is unknown, but those factors that are known to increase the risk of childhood are indicated in Box 1.1, and can be generally categorized as:

Genetic causes – The largest contributions here come from heritable retinoblastoma, neurofibromatosis type 1 (NF1), tuberous sclerosis and the Li-Fraumeni syndrome. For example, children with NF1 have a relative risk for glioma and soft tissue sarcoma of 40, and germline mutations of the tumor suppressor gene TP53 (Li-Fraumeni genetic abnormality) are present in most children with adrenocortical carcinoma and about 10% of children with rhabdomyosarcoma.Infection – associated with Epstein-Barr virus (Hodgkin’s lymphoma & nasopharyngeal carcinoma), hepatitis B (hepatocellular carcinoma) and Human Herpes Virus 8 (Kaposi sarcoma), a phenomenon that at least in part explains some of the worldwide differences for the incidence rates of these diseases.Although the subject of extensive investigation, the influence of other environmental factors such as ultraviolet light, electromagnetic fields is uncertain, although the Chernobyl nuclear disaster has seen an associated increase in thyroid cancer in children of the affected geographical region.

Box 1.1The epidemiology of childhood cancer.

Genetic causes – retinoblastoma, neurofibromatosis type 1, tuberous sclerosis, Li-Fraumeni cancer family syndromeConstitutional chromosomal disorders – Down’s syndrome, Turners syndromeInherited immunodeficiency and bone marrow failure syndromesIrradiationInfection

Genetics in relation to children’s cancers

The study and investigation of the genetics of children’s cancers has led to important advances in the understanding of the epidemiology and causation of certain malignancies such as retinoblastoma; the recognition of karyotypic abnormalities provides a vital part of the diagnosis and risk stratification for therapy of many children’s cancers. Some examples are described as follows:

Philadelphia chromosome, which represents translocation between chromosomes 9 and 22 [t(9;22)], confers an adverse prognosis when this is associated with the diagnosis of acute lymphoblastic leukemia in children [3].Other translocations such as the translocation involving chromosomes 11 and 22 [t(11;22)] can help define disease entities such as Ewing’s tumor and malignant peripheral neuroectodermal tumor from their differential diagnoses [4].Chromosome losses from 1p and 11q and gain of chromosomal material for 17q for neuroblastoma are associated with an adverse outcome for this cancer type [5].

The chromosomal translocations described for acute lymphoblastic leukemia (ALL) and Ewing’s tumor above promote the malignant phenotype of these cancers. For example, the Ewing’s tumor gene translocation results in an oncogenic transcription factor, EWS-Fli-1, and the Philadelphia translocation results in production of a constitutively active receptor kinase, bcr-abl, which has influences on proliferation, cell cycle control, and cell death. The recognition of the links between the genetics of cancer and subsequent cellular biological functions are leading to advances in therapy with mechanism-based compounds, such as imatinib in the case of bcr-abl positive leukemia [3].

Cellular and molecular biology in relation to children’s cancers (Box 1.2)

Receptor kinases and intracellular signalling

Although underlying genetic abnormalities such as loss of tumor suppressor function and gain of oncogenic gene activity may underlie the pathogenesis of individual cancers in children, science is now bringing us insights into the processes that are important as biological determinants of the malignant phenotype in cancer cells. For example, extracellular growth factor/cytokines or mitogens can bind to receptors on the cell surface that are linked to receptor kinases, or these cell surface receptors can be constitutively active [6]. Such ligand/receptor interactions can lead to:

The activation of intercellular signalling pathways such as Akt/PI3, mTOR and MAP kinases, which in turn leads to:The dysregulation of various cellular activities such as gene expression, mitosis, differentiation, cell survival/apoptosis and motility, and invasiveness.

Moreover, genetic mutations can also lead to dysregulation of intracellular signalling, as in the example of loss of the inhibitory effect of PTEN function on Akt/PI3 signalling by gene deletion [7], or the loss of tumor suppressor gene function by gene promoter methylation as in the example of Ras-association domain family 1. Proteins in the ras family are very important molecular switches for a wide variety of signal pathways that control such processes as cellular skeletal integrity, proliferation, cell adhesion, apoctosis and migration. Ras-related proteins are often deregulated in cancers, leading to increased invasion and metastases, and decreased apoctosis. Ras activates a number of pathways, but especially an important one seems to be the mitogenactivated protein kinases, which themselves transmit signals downstream to other protein kinases and gene-regulatory proteins. Inappropriate activation of the gene can occur when tumor suppressor genes are lost, such as the tumor suppressor gene NF1, and ras oncogenes can be activated by point mutations to be constitutively activated [8].

Box 1.2Cancer biology and immunology.

Loss of tumor suppressor function or amplification of oncogenic function promotes malignant phenotypeDysregulation of cellular signallingDeregulation of cell cycle controlDisordered proliferation, metastases and survivalKnowledge informing treatment stratifications and novel therapiesImmunological properties exploited in diagnosis and therapy.

The biological characteristics of cancers are also influenced by their environment. For example, tissue hypoxia is known to contribute to the pathogenesis and maintenance of the malignant phenotype, and interaction between the physicochemical properties of cancers and biological systems that control cellular proliferation, migration, and survival is now increasingly well understood. As a particular example of this, the vascular endothelial growth factor family of ligands and receptors are modulated by hypoxia, and has now been extensively studied for both children’s and adult malignancies. This in turn is bringing forward the rational introduction of novel mechanism-based therapies that aim to disrupt specific processes important for the pathogenesis of cancer [9], rather than attempting to cause cancer cell death by non-specific DNA damage as in the case of most conventional cytotoxic agents as will be discussed below.

Cell cycle control

Cell cycle progression is monitored by surveillance mechanisms, or cell cycles checkpoints, that ensure that initiation of a later event is coupled with the completion of an early cell cycles event. Dysregulation of the progression of cells through the cell cycles is also a feature of malignant cells, and defects in certain molecules such as p53, the retinoblastoma protein (pRb) and cyclin kinase inhibitors (e.g. p15, p16, p21) that control the cell cycle have been implicated in cancer formation and progression [1O]. Virtually all human tumors degregulate either the retinoblastoma (pRb/p16(INK4a)/cyclin D1) and/or p53 (p14 (ARF)/mdm2/p53) control pathways [10].

One of the most studied control systems in cancer involves p53, otherwise known as protein 53, a transcription factor that regulates the cell cycle, and hence functions as a tumor suppressor [11].

p53 has many anti-cancer mechanisms in that it can activate DNA repair proteins when DNA has sustained damage, it can hold the cell cycle at the G1/S regulation point upon DNA damage recognition, and it can initiate apoptosis if the DNA damage proves to be irreparable [11].In normal cells, p53 is usually inactive, bound to the protein MDM2, which prevents its action and promotes its degradation by acting as a ubiquitin ligase. Upon DNA damage or other stress, various pathways will lead to the association of P53 and the MDM2 complex [12].

Once activated, P53 will either induce cell cycle arrest to allow repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

If the p53 gene is damaged, then tumor suppression is severely impaired. People who inherit only one functional copy of the p53 gene, TP53, are at risk of developing tumors in early adulthood, a disease known as the Li-Fraumeni cancer family syndrome. Indeed, more than 50% of human tumors contain a mutation or deletion of the TP53 gene [2]. The occurrence of retinoblastoma serves as a paradigm for the effects of loss of the tumor suppressor function of pRb, and this will be discussed in Chapter 18 of the textbook.

Cancer biology and risk stratification

Advances in our understanding of the biology of childhood cancer are providing new insights into prognosis and will serve to underpin rational approaches to the stratification of treatments. For example, whereas an adverse prognosis for childhood medulloblastoma is found to relate to the growth factor receptor erb-b2 expression [13], nuclear accumulation of beta-catenin is associated with the activation of the Wnt/Wg signalling pathway and a more favorable prognosis [14]. This information may allow a staged reduction in the radiotherapy burden for the treatment of medulloblastoma, and also promote the development of specific mechanism-base therapies [15].

Cancer immunology

Knowledge of the immunology of childhood cancer is important for the diagnosis of childhood leukemias and can also be exploited for the therapy of childhood cancers. For example, the cluster of differentiation (CD nomenclature) has been developed to characterize the monoclonal antibodies that have been generated against epitopes on the surface molecules of leucocytes.

The CD system is commonly used as cell markers; this allows cells to be defined based on what molecules are present on their surface.CD molecules are utilized in cell sorting using various methods, including flow cytometry, and can be used for the recognition of stem cells (CD34+, CD31−): all leukocyte groups, (CD45+): T lymphocytes, (CD3+) and B leukocytes, (CD19+).

The immune system can also be utilized to direct therapy against the cancers themselves. For example, dendritic cell-based immunotherapy utilizes dendritic cells, which are antigen-presenting cells that are harvested from patients to activate a cytotoxic response towards an antigen. Briefly, the dendritic cells are harvested from patients, these cells are then either incubated with an antigen or infected with a viral vector, and the activated dendritic cells are then transfused back into the patient. These cells then present the tumor-associated antigens to the effector lymphocytes, namely CD4+ T-cells and CD8+ T-cells, and some classes of B lymphocyte also. A similar procedure exists for T cell-based adoptive immunotherapy, which sees T-cells that have a natural or genetically-engineered reactivity to a patient’s cancer expanded in vitro and than adoptively transferred into the cancer patient [16].

In the situation of bone marrow transplantation, in particular in the case of allogeneic bone marrow transplantation, a balance is sought between rejection of the transplanted graft, eventual immune tolerance of the graft and maintenance of a controlled degree of graft versus host disease in order to maximize anti-leukemic effect [17].

The general principles of pharmacology in relation to childhood cancer

Radiotherapy continues to form an important part of the treatment of many childhood cancers, and this will be discussed further in the subsequent disease-specific chapters of this textbook. The cornerstone for the treatment of many cancers of childhood remains conventional chemotherapy agents, and a summary of these is presented below. Although a detailed description of the properties of anticancer agents in terms of their pharmacokinetic profiles, and a description of the cellular and molecular pharmacological processes that can limit or potentiate their effectiveness in cancer cells, is beyond the scope of this chapter, the reader is referred to the excellent reference text by Chabner and Longo for further information [18]. Basically, conventional chemotherapy agents usually act to promote DNA damage in all cells of the body, and the cure for cancer thus relies on there being a therapeutic index allowing eradication of the tumor at acceptable toxicity to the patient. The conventional cytotoxic agents commonly employed in the therapy of children’s cancer include the following classes of agent:

Alkylating agents that cross-link DNA – examples include ifosfamide, cyclophosphamide, cisplatin, carboplatin, busulphan, melphalan, and temozolomide.Anti-metabolites that cause fraudulent incorporation of bases into DNA – examples include methotrexate, 6-mercaptopurine and cytarabine.Anti-tumor antibiotics that have variety of actions such as free radical formation, DNA intercalation, topoisomerase II inhibition – examples include doxorubicin, daunorubicin and actinomycin-D.Topoisomerase inhibitors that prevent normal conduct of DNA relaxation to facilitate repair and replication – examples include etoposide (topoisomerase II inhibitor) and topotecan and irinotecan (topoisomerase I inhibitor).Vinca alkyloids that promote microtubular instability and inhibit the polymerization of tubulin – examples include vincristine and vinorelbine.Miscellaneous agents – examples include prednisone, dexamethasone and L-asparaginase.

The science of pharmacology has contributed to the progress of the cure of children’s cancers over the years, and also the pharmacokinetic profiles (how the drug is handled by the body) and pharmacodynamic effects (the effect the drug has on the body) remains important for the rational selection of treatment schedules for existing and novel therapies. These concepts have been extensively studied, mainly in relation to acute lymphoblastic leukemia, and in particular in an elegant series of studies performed at St Jude Children’s Research Hospital in Memphis, USA.

When considering the pharmacological properties of anticancer agents, the plasma concentration-versus-time profile is important as this allows a measurement of peak, maximum, or steady-state drug concentrations, the half-life of decline of drug concentration, measures of system exposure, and the volume of distribution found. Pharmacological studies also define the routes of elimination and metabolism of chemotherapeutic agents [18].

When studied, pharmacological parameters have generally been shown to be important for the prognosis of childhood cancers. For example, the dose intensity (amount of chemotherapy received over a period of time) of chemotherapy agents has been shown to be important for diseases as diverse as infant ependymoma [19] and acute lymphoblastic leukemia [20]. The clinical pharmacological studies performed at St Jude’s Children’s Research Hospital with methotrexate, in the context of the treatment of acute lymphoblastic leukemia, serve as a paradigm for the investigation of the relationship between pharmacokinetics, cellular pharmacology, and the cellular determinants of chemo-sensitivity and prognosis.

Over a series of studies performed in the 1980s up to the present day, successive investigations have demonstrated the importance of high-dose methotrexate steady-state concentration and systemic exposure, and also the relationships of these to the optimal intracellular metabolism of methotrexate in leukemic blasts for children with ALL. They have led to therapeutic strategies that have improved survival for children with this disease [20].Similar findings for dose intensity and systemic exposure have been described for the metronomic/maintenance chemotherapy phase of treatment of childhood ALL, where the influence of genetic polymorphisms that related to the metabolism of this thiopurine agent have been related to factors such as toxicity and survival [21].

Pharmacological studies are an essential part of the structure of Phase I studies and also, in many cases, Phase 2 studies where relationships between the pharmacokinetic profiles of new agents and pharmacodynamic effects, such as toxicity and disease response, could be identified at as early a stage as possible in order to inform rational scheduling, and even in some cases, adaptive dosing.

The conduct of clinical studies in children with cancer (Box 1.3)

At a national and increasingly international level, the various phases of clinical trials in children with cancer are conducted as multicenter or even multinational collaborations [22]. New drug development is performed through the auspices of multicenter collaborations, such as the Innovative Therapies for Children’s Cancers in Europe, or the Children’s Oncology Group Early Clinical Studies Committee or the Pediatric Brain Tumor Consortium in North America. International guidelines have been established for the prioritization of new agents and also for the methodological considerations involved in Phase I trials.

Upon completion of developmental pre-clinical studies in adults and children, which would include efficacy, toxicity, and pharmacokinetic information, a new drug can enter a Phase I assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the agent.These studies are usually dose-ranging and involve escalation of cohorts of patients, and children who have no other hope of cure or significant palliation are eligible for such studies, which are designed to describe dose limit and toxicities that prevent further dose escalation and thereby establish the maximum-tolerated dose to take forward for Phase II study.

Box 1.3Key facts – clinical trials and pharmacology in childhood cancer.

International collaborations are now the normPhase I studies define the safe dose to take forward for phase II studies of efficacyPhase III trials compare first-line treatmentsPharmacokinetic and pharmacodynamic studies now embedded in phase I/II trial processPharmacogenetics, dose intensity, pharmacokinetics and cellular pharmacology guides the rational use of chemotherapy agents study to

Once the initial safety of this new drug is confirmed in the Phase I trial, Phase II trials are performed, usually in children with relapsed disease, to assess how well the drug works at the prescribed dose and schedule. Such studies involve an initial cohort of patients to determine that some clinical activity could be expected and Phase II trials in pediatric oncology usually follow a two-stage design, which allows early termination of studies if the efficacy level is too low or is adequately high, and in general objective response rates of 20–30% are deemed as interesting enough to take a new agent forward.

Phase III trials are the staple activity of the national and international study groups in pediatric oncology. Phase III trials compare the effectiveness of an experimental therapy with that of a standard or control therapy and are only feasible in a collaborative group or multicenter setting. Phase III clinical trials usually include a randomization between treatment times and are commonly based on sequential or factorial designs, and generally require the recruitment of hundreds of children with a given disease type in order to answer questions of statistically significant differences between different treatments.

Summary

The treatment of children with cancer in the western industrialized world has been long held as a model for multicenter collaborations involving a wider multidisciplinary team. Over the past 40 years, the survival for many children’s cancers has improved markedly, and the overall survival rates are now in the area of 75–80%. However, diseases such as diffuse intrinsic pontine glioma, metastatic sarcoma in adolescence, and high-risk neuroblastoma are still associated with a poor prognosis and new therapies will be needed to improve this for the future.

The early clinical trial study groups for Europe and North America are increasingly working with the pharmaceutical industry to develop new compounds of interest. A major challenge ahead will be to prioritize their introduction into upfront treatment protocols for high risk diseases and to design study methodologies that optimize the scientific information gained for each clinical trial. In addition, our discipline has traditionally held a strong interest in the late physical and psychological effects of the treatment of children’s cancer, and this also will be important as new therapies are introduced and perhaps more children survive, but maybe in difficult circumstances following treatment with modalities such as cranial radiotherapy. Having introduced the scientific terminologies that the reader may encounter in the various disease-specific chapters of this textbook, we hope that the integration of the clinical and scientific principles that follow for the different tumor types will reflect our practice in terms of where we have come from, where we are at present, and where we might be going for the future.

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I

Central Nervous System Tumors of Childhood

2

Low- and High-Grade Glioma

Ian F. Pollack

Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Introduction

Gliomas account for more than half of childhood central nervous system neoplasms [4, 5]. On a regional basis, they comprise at least 60% of supratentorial hemispheric tumors, 50% of supratentorial midline tumors and 40% of infratentorial tumors. The majority of such lesions are World Health Organization Grade I or II (i.e. low-grade) astrocytomas [4, 5] or other low-grade glial and glioneuronal neoplasms, such as oligodendrogliomas, oligoastrocytomas, gangliogliomas, and a number of less common lesions, such as pleomorphic xanthoastrocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma [6–11]. In contrast to the situation in adults, grade III or IV (i.e. high-grade or malignant) gliomas account for a minority of glial neoplasms in children in all locations within the neuraxis, with the notable exception of the brainstem, in which so-called diffuse malignant gliomas are substantially more frequent than lower grade lesions [3]. Given the diversity in the types of gliomas that arise in children, there are a wide range of therapeutic approaches, based both on histology and tumor location, and a correspondingly diverse profile of outcomes, incorporating the prognostically most favorable (e.g. cerebral and cerebellar pilocytic astrocytoma) and least favorable (e.g. diffuse brainstem glioma) tumor subtypes in pediatric neuro-oncology.