Brain and Spinal Tumors of Childhood

David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack

• Publisher: CRC Press
• Year: 2020
• eBook ISBN: 9781000177947
• Topic: Medicine
• Subtopic: Neurology

This second edition comes at a time of a paradigm shift in understanding of the molecular pathology and neuroscience of brain and spinal tumors of childhood and their mechanisms of growth within the developing brain. Excellent collaborative translational networks of researchers are starting to drive change in clinical practise through the need to test many ideas in trials and scientific initiatives. This text reflects the growing concern to understand the impact of the tumour and its treatment upon the full functioning of the child's developing brain and to integrate the judgments of the risks of acquiring brain damage with the risk of death and the consequences for the quality of life for those who survive. Information on the principles of treatment has been thoroughly updated. A chapter also records the extraordinary work done by advocates. All medical and allied professionals involved in any aspect of the clinical care of these patients will find this book an invaluable resource.

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Introduction

DAVID A. WALKER, GIORGIO PERILONGO, ROGER E. TAYLOR, and IAN F. POLLACK

1.1Why a Second Edition of This Book?

The first edition was the first European book to be published that focused upon the clinical management of childhood brain tumors and the associated translational scientific evidence in a single volume. As editors, we were aware of breaking this new ground and made our introductory chapter focus upon the timeline of scientific and clinical discoveries that had led up to the level of knowledge of science and practice that existed at that time. For this second edition we considered extending the timeline to cover the developments that have occurred in the interim, particularly the understanding of biological parameters and their impact on outcomes and clinical management. We concluded, however, that the explosion of knowledge was too extensive to summarize and the true impact of each development was too early to fully evaluate in a historical sense. We have lived and practiced through the past years during a paradigm shift. It is exciting but we are not entirely sure where it will take us. The greater understanding of tumor biology has also resulted in questions regarding how this should impact on treatment decisions.

The second edition of this book has therefore undergone an extensive revision to take into account the new evidence from science and practice, supporting modern approaches to the clinical presentations of childhood brain tumors. The processes needed for their timely, molecular-based diagnosis as well as neurosurgical and radiotherapy techniques are described. The pediatric medical management aimed at eradicating the tumor and the design of trials to test and evaluate new approaches are discussed. Equally important is the need to measure and understand the impact of the tumor and its treatment upon the full functioning of the developing brain of the child. This has implications acutely in the time leading up to diagnosis and during subsequent treatment. It also contributes to judgments of the risks of acquiring dysfunction or disability, with the risk of death and the inevitable consequences on quality of life for those who survive. Finally, the advances we have seen have been strongly supported and guided by a wide range of advocates across the world, who have been touched by the experience of children with brain tumors and shared their experience in the chapter on advocacy.

1.2What Can the Reader Expect in This Book?

This is not a textbook covering every aspect of the science and practice of pediatric neuro-oncology as that would need to encompass the whole of developmental neuroscience, cancer biology, and the application of multidisciplinary clinical care for children in hospital, in the community, in their education, and ultimately, in their adult life. Rather, this book is a series of authoritative statements written by international experts working as multidisciplinary collaborative groups, who have first-hand experience with how treatments have been influenced by science and delivered to children and how the scientific processes will influence the approaches in the future. The aim of the editors has been to establish an appropriate balance of authors from North America and Europe.

1.3The Scope of Challenge: Survival Versus Disability

In industrialized countries with comprehensive health systems, the majority (~65%) of children presenting with brain tumors can be offered a chance of prolonged survival. Sadly, however, about the same proportion (~60%) can be expected to have moderate or severe lifelong disability. The diverse scope of childhood brain tumors is illustrated by the image of the ten typical brain tumors of childhood (Figure 1.1).

Figure 1.1The anatomical features of ten common brain tumors in children, highlighting the predominance of low-grade glioma (green box) and range of malignant tumor types (red box). Benign tumors are slower growing with low risk of metastasis. Malignant tumors are faster growing and have a higher risk of metastasis. Symbols illustrate typical late consequences of the tumor and its treatment for survivors; cerebellar / cognitive refers to consequences of cerebellar mutism / posterior fossa syndrome and prolonged hydrocephalus upon late cognitive function. Focal injury identifies the risk of focal brain injury related to tumor or surgery. Blindness is as a consequence of tumor damage to optic tracts or prolonged raised intracranial pressure. Endocrinopathy is due to hydrocephalic / pituitary damage from tumor or surgery or radiation therapy. The figure illustrates typical population-based 5-year survival rates. ATRT, atypical teratoid rhabdoid tumor; Ca, carcinoma; EPEN, ependymoma; GCT, germ cell tumor; HGG, high-grade glioma; LG, low-grade; NF1 OPG, neurofibromatosis type 1 optic pathway glioma; PNET, primitive neuroectodermal tumor.

The benign or low-grade brain tumors identified above threaten local brain injury due to tumor progression or surgery for their removal. Where such tumors are not amenable for surgical removal, the risk of progressive focal brain injury may be modified by non-surgical treatments directed at reducing tumor bulk or preventing tumor progression, thereby arresting progression of the brain damage with which they presented. These tumors often stop growing as the child ages, although there are exceptions. The malignant or high-grade brain tumors present the additional threat of leptomeningeal metastatic dissemination and therefore the need for effective therapy to be delivered to the whole of the brain and spine to offer cure.

In this collection of tumors there are good players (Figure 1.1), where survival can be expected, often after a single operation. At the other end of the scale, there are very poor players where survival is exceptional because treatment is currently impotent. For those in the middle the various approaches to treatment are described. Progress is being made. However, the predominance of the more optimistic survival figures highlights the importance of giving equal consideration to the risks of disability and survival. For those who survive, the disability is lifelong and life altering. However the ability of the healthcare system to support patients with disabilities will also be taken into account, as will the attitude of parents and carers. For children with poor prognosis, this burden of disability and its progressive nature is the focus of palliative strategies. These differ from other cancers in childhood, as the symptoms requiring palliation are due to raised intracranial pressure or progressive brain damage, rather than metastatic disease. Management of these patients continues to pose very difficult ethical issues regarding the balance of survival vs. the quality of that survival.

1.4Bio-information Explosion

If there is a single factor that has supported the transformation of scientific understanding in this field over the past decade, it has been linked to the collaborative development of large clinical datasets associated with biosample banks arising from extraordinary collaborations on a global scale. Translational clinical scientists have worked tirelessly to explain the clinical phenomena we observe in practice by studying detailed biological processes involving these tumors of the developing brain. They have openly shared the resources from their laboratories and their clinical trials datasets and adopted sophisticated international consensus techniques to make the best of the information that is available to them. This work has identified an increasing number of inherited predisposition states for brain tumor development and a lengthening list of genetic and epigenetic mutations that characterize sporadically occurring tumor types, which are the majority. The language describing these tumor phenomena is fluid, creating new diagnostic and clinical entities with the consequence of significant uncertainty for the clinician in knowing exactly what treatment to offer, based upon the complex scientific description of the tumor in the child’s brain. The work is progressing in parallel with the study of neuro-embryology as the genetic and epigenetic mutations identified in the tumors are increasingly being mapped to specific anatomical regions and associated with specific age of tumor presentation or recurrence. Identifying the mutations, which are functional for tumor cell behavior, is the challenge. To date, there has been only one drug launched with specific molecular targeting, which has been licensed for clinical practice in brain tumors. Everolimus, an mTOR inhibitor, is licensed in the USA and Europe for the treatment of subependymal giant cell astrocytoma (SEGA) complicating the genetic condition, tuberous sclerosis complex. We await results of trials of other targeted agents. The most hopeful at the time of writing in 2020 are the mitogen activated protein (MAP) kinase-targeted drugs in low-grade glioma and plexiform neurofibroma associated with neurofibromatosis type 1.

1.5Delivering Therapies to the Brain

Neurosurgery and radiotherapy are the mainstay of effective brain tumor therapy because they are applied directly to the brain. Neuroimaging is extremely sophisticated and can specify the anatomical location of the tumor precisely. In the last decade in many countries the delivery of radiotherapy has been radically transformed by the application of proton therapy with its ability to minimize or avoid radiation dose to non-target tissues, and is described in this book. Furthermore continued advances in the delivery technology for proton therapy have not reached a plateau. Much of the evidence for benefit is still based on dosimetric comparisons and modeling predictions of toxicity reduction. There are increasing numbers of case series, but developing randomized trials comparing proton with photon therapy with respect to long-term toxicity reduction, many years or even decades later, is problematic. Data collection, including “real-world” data, will remain an important priority.

Drug therapy is confounded by the protective nature of the blood–brain barrier when drugs are administered systemically via the blood stream. The science behind techniques to modify drugs to assist with their penetration of the blood–brain barrier is in development. Techniques to disrupt the blood–brain barrier to facilitate drug passage are in trial. Techniques to bypass the blood–brain barrier and deliver to the cerebrospinal fluid are in widespread use in childhood leukemia but are only slowly being adopted in brain tumors. Delivery of drugs to tumor cavities and directly to the tumor tissues is now feasible with surgical techniques. Transmucosal drug delivery has been explored with cannabinoid drugs in adult brain tumor. In adult practice, electric field therapy has been studied in a single randomized clinical trial, with a favorable result, there is supporting biological literature, and technical modifications of the electric field systems are in process. Immune therapy is being adopted for childhood leukemia and tested in adult cancers, although early reports are not promising for the treatment of brain tumors. There is therefore no shortage of new ideas for therapy in this group of diseases. The mistake would be to continue to disregard the mechanisms for ensuring that any treatment is delivered to the correct part of the brain and in effective quantities in future trials. There remains the challenge of ensuring the introduction of new brain-directed therapies includes the requirement for monitoring for long-term sequelae in survivors (Figure 1.2).

Figure 1.2Anatomical drug-targeting research considerations. BBB, blood–brain barrier; CNS, central nervous system; ICSF, intracerebrospinal fluid; IV, intravenously.

1.6Global...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• List of Contributors
• 1 Introduction
• 2 Epidemiology of Childhood Brain Tumors
• 3 Clinical Presentation and Associated Syndromes of Brain Tumor
• 4 Pediatric Central Nervous System Tumors as Phenotypic Manifestation of Cancer Predisposition Syndromes
• 5 Anatomical and Biological Imaging of Pediatric Brain Tumor
• 6 Neurosurgical Techniques and Strategies
• 7 Radiotherapy for Pediatric Central Nervous System Tumors – Techniques and Strategies
• 8 Physical and Cognitive Rehabilitation for Children with Brain and Spinal Tumors
• 9 Drug Delivery
• 10 Low-grade Glioma Presenting in the Optic Pathways and Hypothalamus: (NF1 and Sporadic)
• 11 Low-grade Glioma: Principles of Diagnosis and Drug Treatment
• 12 High-grade Glioma
• 13 Diffuse Intrinsic Pontine Glioma
• 14 Embryonal Tumors
• 15 Ependymoma in Childhood and Adolescence
• 16 Germ Cell Tumors of the Central Nervous System
• 17 Atypical Teratoid / Rhabdoid Tumors – AT/RT
• 18 Craniopharyngioma
• 19 Choroid Plexus Tumors and Meningiomas
• 20 Pediatric Spinal Tumors
• 21 Late Effects of Treatment for Childhood Brain and Spinal Tumors
• 22 The Power of Patient Advocacy in Pediatric Neuro-Oncology
• Index