Cancer Immunotherapy in Children

This chapter discusses the principle of cancer immunotherapy in children and adolescents, starting with the most common form of cellular immunotherapy: allogeneic haematopoietic stem-cell transplantation (HSCT). It then discusses specific immunotherapy strategies based on the administration of classic monoclonal antibodies (mAbs) targeting tumour-associated antigens, novel bispecific antibodies that simultaneously target tumour-associated antigens and activate CD3+ T lymphocytes, and mAbs that block key inhibitory molecules of the immune system (checkpoint blockade). Finally, the chapter describes specific cellular immunotherapy approaches, such as tumour vaccine and adoptive transfer of immune cells. Although only a few immunotherapies have so far been incorporated into the standard practice for paediatric cancers, their role is enjoying a new revival, after the promising results obtained in recent clinical trials.

Myelodysplastic Syndrome, Myeloid Leukaemia of Down Syndrome, and Juvenile Myelomonocytic Leukaemia

Myeloid malignancies in children are divided into acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), juvenile myelomonocytic leukaemia (JMML), and the myeloid leukaemia of Down syndrome (ML-DS). Predisposing genetic conditions are common in MDS. Differentiating MDS from inherited bone marrow failure or AML may be challenging. Therapy consists of observation, immunosuppression, or stem-cell transplantation (SCT). Germline and somatic mutations deregulating the Ras/MAPK signal pathways are key initiating events in JMML. Genetics in JMML defines clinically relevant subgroups and indications for SCT. ML-DS presents with unique clinical characteristics and responds favourably to reduced doses of AML chemotherapy; however, relapse is often refractory to therapy.

Retinoblastoma

Retinoblastoma is the most common paediatric ocular malignancy. Its disease-free survival rate in developed countries is higher than 95%, but in the developing world this tumour presents with advanced disease leading to poorer outcome. Late diagnosis and problems with compliance for treatment affect the outcome in that setting. Retinoblastoma may occur in children with germline mutations of the RB1 gene, who usually present with bilateral heritable disease. In those with somatic mutations, it always presents as unilateral and non-hereditable disease. The former have a higher susceptibility for secondary malignancies occurring later in life. Enucleation of the affected eyeball is often curative when the disease presents intraocularly, but conservative therapies have evolved from conventional external photon-beam radiotherapy, which was associated with severe long-term toxicity, to chemotherapy plus local treatments. Recently, local intra-arterial and intravitreal chemotherapy has been more intensively used, leading to higher preservation rates.

Childhood Histiocytoses

This chapter summarizes the clinical spectrum of the histiocytic disorders—Langerhans cell histiocytosis (LCH), haemophagocytic lymphohistiocytosis (HLH), and some uncommon histiocytic disorders, including juvenile xanthogranuloma (JXG) and Rosai–Dorfman disease—as well as the current diagnostic and therapeutic approaches in these diseases. Multiple activating mutations in the RAS–RAF–MEK–ERK pathway have recently been described in LCH. Their role in the pathophysiology of the disorder and in targeted therapy is reviewed. This chapter explains the differences between primary and secondary HLH, and reviews the genetic abnormalities playing a role in both forms of HLH.

Embryonal Tumours

Paediatric embryonal tumours are highly heterogeneous entities which account for 15–20% of all childhood tumours of the central nervous system (CNS). Although historically considered one entity, integrated genomic analysis has unveiled this is no longer the case, and in fact CNS-PNET (primitive neuroectodermal tumour) has been removed from the World Health Organization (WHO) classification of CNS tumours. Patients are risk-stratified based on residual disease after surgery, metastatic dissemination, and, with the medulloblastoma subgroup, specific molecular features. In patients with medulloblastoma, 60–70% of patients over three years old are classified as standard-risk cases, while high-risk patients include those with disseminated and/or residual disease, large-cell and/or anaplastic histotypes, and MYC gene amplification in some protocols. Atypical teratoid rhabdoid tumours (ATRTs) are risk-stratified in a similar manner; however, recently integrated genomics has revealed the presence of three distinct molecular variants which seem to have distinct clinical features and outcomes. Clinical trials already underway or currently being planned will (1) examine the feasibility of reducing the dose of craniospinal irradiation and the volume of posterior fossa radiotherapy (RT) for patients generally considered at low biological risk (i.e. those with the WNT subgroup of medulloblastomas; (2) ascertain whether intensifying chemotherapy or RT can improve outcomes in high-risk patients; and (3) seek therapeutic targets that will enable tailored therapies, especially for relapsing patients and those at higher biological risk.

Neuroblastoma

Neuroblastoma, a malignant neoplasm of the sympathetic nervous system, is the most common extracranial solid tumour in childhood. Since its first description in the nineteenth century, its highly heterogeneous clinical presentation has challenged clinicians and fascinated basic researchers. Neuroblastoma serves as a paradigm for the prognostic utility of biological and clinical data and the potential to tailor therapy for patient cohorts at low, intermediate, and high risk for recurrence. This chapter presents an overview of the key genetic, molecular, histological, and clinical features of neuroblastoma, as well as current risk-stratification strategies and therapeutic approaches. It also highlights how our understanding of tumour pathogenesis, coupled with molecular analyses, has illuminated critical signal transduction pathways and key molecules involved in neuroblastoma tumourigenesis, pointing to novel therapeutic targets for clinical development. Future treatment avenues for relapsed neuroblastoma are discussed, including new drugs targeting ALK, MYC/MYCN, histone deacetylases, or MDM2/TP53.

Glial Central Nervous System Tumours of Childhood

Gliomas are the largest group of paediatric central nervous system (CNS) tumours and can affect any age and location. Currently, they are divided into low and high grade using the World Health Organization (WHO) classification but, increasingly, biology is being used to classify and stratify therapy, and this division may be challenged in the future. Outcomes vary greatly with some low-grade tumours being very indolent, requiring nothing more than careful observation, compared to aggressive high-grade gliomas of the brainstem that have a dismal prognosis. Current therapies are based on surgery, radiotherapy, and cytotoxic chemotherapy but, increasingly, biologically targeted therapies are being explored in an attempt to increase survival and decrease late effects and the burden of treatment.

Soft-Tissue Sarcomas

This chapter discusses soft-tissue sarcomas (STS) in children and adolescents, which comprise approximately 8% of all paediatric malignancies. It highlights the clinical, pathological, and biological characteristics of this heterogeneous group of tumors derived from mesenchymal cells, and it describes the current management and the treatment results. The first part of the chapter is dedicated to the most frequent paediatric STS, rhabdomyosarcomas (RMS), while the second part covers the diagnosis and treatment strategies for non-rhabdomyosarcoma STS (NRSTS) including synovial sarcomas (SS), adult-type NRSTS, and other histotypes (infantile fibrosarcoma (IFS), desmoplastic small round-cell tumour (DSRCT), and malignant rhabdoid tumour (MRT)).

The Epidemiology of Cancer in Children and Adolescents

Under 2% of all cancers in industrialized countries occur in childhood and adolescence, but they account for a much larger proportion of total population life years potentially lost to cancer. Total incidence is about 160 per million in children and 200 per million in adolescents. In children, leukaemias account for one third of all malignancies and CNS tumours for one quarter. In adolescents, lymphomas account for one quarter of cases and leukaemias, CNS tumours, and carcinomas each for about 15%. Five-year survival exceeds 80% for many childhood and some adolescent cancers. Although survival of adolescents is high overall, survival for several types of cancer is markedly lower than in children. Infants under a year of age also tend to have lower survival. Excess mortality continues beyond 25 years from diagnosis of childhood cancer. The risk of developing a second primary cancer is about six times that in the general population. The causes of most childhood cancers remain unknown. The principal established exogenous causes are ionizing radiation, ultraviolet radiation from sunlight, and certain viruses. Up to 10% of children and adolescents with cancer may have germline mutations in cancer predisposition genes. If one child in a family has cancer, then that child’s siblings have approximately double the risk of the general population for developing childhood cancer, but this could well be entirely accounted for by familial syndromes. Significantly raised or reduced risks of childhood cancers have been linked to polymorphic variants of certain genes, though many of these associations remain to be replicated.

Evidence-Based Paediatric Oncology

The practice of evidence-based medicine (EBM) is very important in delivering optimal patient care and the terms evidence-based medicine, or evidence-based practice, are used all around the world. This chapter discusses evidence-based paediatric oncology, including its history, an outline of what EBM is, EBM in paediatric oncology, steps in evidence-based paediatric oncology for a user of EBM, steps in guideline development as an implementer of EBM, common criticisms of EBM, and the future of EBM. The chapter gives an overview how EBM can be used in a non-exhaustive but still comprehensive way in daily practice of care for children with cancer, and which tools are available for paediatric oncologists. The majority of the chapter focuses on how to learn to become a skilled user of EBM.