Sheffield STEPP Course Oncology and Malignant Haematology October 2016

Aims and Objectives Pre course reading Common childhood malignancy Provide overview of childhood malignancy Outline treatment principles and modalities Common childhood malignancy Consider four emergency presentations Febrile neutropenia Tumour lysis syndrome Spinal cord compression Mediastinal Mass

Overview of Childhood Malignancy 1600 cases/year in under 16’s By comparison Incidence 1 in 12 admitted to hospital 1 in 8000 develops cancer Prevalence 1 in 10 under 16’s have asthma 1 in 600 under 16’s get cancer 2nd commonest cause of death after accidents Less than 1% of all cases of malignancy Under 16 yrs = approx 1600/yr in UK (600 aged 15 – 25yrs) Average GP list – will see 1 case in 15 years Average DGH – will see 5 cases a year 3

Overall Survival Survival of children with cancer has steadily improved over the last 30 years. Slide shows survival for children registered with the UK Children’s Cancer Study Group who were diagnosed between 1977 – and 2005. Overall incidence has gradually increased, but more children are registered each year. In the 10 years between 1977 and 1985 6739 children were registered and 5 year survival was about 54% with 20 year survival just over 50% In the five years between 1986 – 1990 5293 children were registered, 5 year survival had improved to around 65% Between 1991 and 1995 6447 children were registered, 5 year survival was 72% with 10 year survival around 70% Since 1996 – 2000 7091 children were registered, and 5 and 10 year survival is about 77% From 2001 – 2005 there have been 7567 children registered and 5 year survival is around 77% 4

Implications of improving survival Ever increasing group of survivors 1 in 900 adults had cancer as child Late effects from treatment Longer follow up - new problems identified Life long follow up essential

Children vs. Adults Carcinomas very rare in children Embryonal tumours very rare in adults Leukaemia occurs at all ages More common in younger children Bone tumours and lymphomas Peak incidence: early adolescence, early adulthood The types of cancer seen in children differs markedly than those seen in adults. Even when similar disease types occur, the presentation and biological behaviour can differ. For example lymphomas occur in both children and adults but the biological behaviour is different – with indolent “low grade” lymphomas being much more common in adults and extremely rare in childhood where “high grade” types predominate. Leukaemia occurs in both children and adults – but in children the predominant type is acute lymphoblastic leukaemia, which is much less common in adults. Chronic leukaemia is extremely rare in childhood, in particular chronic lymphoid leukaemia is not seen. 6

Relative frequency in UK Acute leukaemia is the commonest malignancy seen in childhood – accounting for around 30-33% with the majority of these (80-85%) being acute lymphoblastic leukaemia. The peak incidence of acute leukaemia in “resource rich” countries is 2-6 years. This is not seen in less privileged countries. Acute myeloblastic leukaemia does not have such variation in incidence. Environmental factors are responsible for the very high incidence of B cell lymphomas in equatorial Africa. The incidence of some tumours appears to be increasing. For example there has been an average 0.7% annual increase in ALL of precursor B cell origin and Hodgkins lymphoma (1.2% per year) in the North West of England since the mid 1950s. Other studies have shown small increases in incidence of other solid tumour types. The reasons for these increases are not clear 7

Aetiology Most cases – cause is unknown Mutations in cellular genes < 5% due to identifiable genetic abnormality Interaction between environment and genes? Mutations in cellular genes Oncogenes, tumour suppressor genes Inherited (e.g. retinoblastoma) or sporadic Some children at increased risk of cancer Downs, immune-compromised, NF1 Compared with adults where environmental factors are definitely involved in the development of much malignant disease, relatively little is understood regarding the cause of most childhood cancer. Almost 50 years ago the link between exposure to irradiation in pregnancy and subsequent cancer in the child was identified. In addition the use of X rays in e past to treat benign conditions such as “enlarged thymus” and tinea capitis caused subsequent malignant neoplasms – although most of these cancers developed in adult life For many diagnostic groups in childhood, the occurrence of highest incidence at an early age, and the cell type of origin suggest that causative factors operate before birth, and possibly even before conception. A number of genetic predisposition syndromes have been identified but these currently account for less than 5% of paediatric cancers. Increasingly genetic susceptibility or variation leading to poor or abnormal handling of environmental factors or failure to repair genetic damage leading to a malignant phenotype in target cells is thought to play a crucial role in the development of childhood malignancy. Some children have an increased risk of developing malignancy such as those with Downs syndrome (increased risk of ALL and AML), children with NF1 (astrocytoma, sarcomas) and children with congenital or acquired immunodeficiency syndromes such as ataxia telangiectasia or AIDS (lymphomas) Studies of children with the WAGR syndrome (Wilms tumour, aniridia, genital abnormalities and mental retardation) led to greater understanding of genetics and cancer. A number of children with the syndrome were found to have a deletion of 11p13, and subsequently the WT1 gene was located to this region. Mutations of this gene are found in the tumour cells of many (but not all) children with Wilms who do not have the WAGR or similar syndromes Concept of Inherited vs Genetic predisposition e.g. very few cancers truly inherited secondary to single gene defect (retinoblastoma is one) whereas in many cancers there may be an as yet unidentified predisposition which requires a second hit. 8

Presentation Localised mass Problems from disseminated disease Lymphadenopathy Organomegaly Soft tissue or bony mass Problems from disseminated disease Bone marrow infiltration Problems from localised mass Airway obstruction from lymphadenopathy Diagnosis of malignant disease in child can be difficult – rare diseases are not usually the first thing that is thought of. So listen to the history, do careful examination – and think about the possibility Cervical lymphadenopathy is not uncommon in childhood but most children with this do not have cancer Abdominal distension may be due to tumour in organ such as kidney, or constipation Aches and pains are a frequent complaint in childhood – only very rarely due to leukaemia Breathlessness and wheeze much more likely to be due to asthma than lymphoma Headaches very unlikely to be due to CNS tumour, but frequently are present in child with brain tumour 9

Aims of Treatment Cure disease Minimise physical sequelae Minimise psychosocial sequelae Childhood cancer survivors are followed up for life. Many patients develop long term physical or psychological problems. Up to a third will exhibit symptoms compatible with PTSD if screened for them. For conditions with good long term outcomes the emphasis is now moving towards the concept of “quality of cure” with randomised trials examining whether it is possible to reduce the intensity of treatment without reducing overall survival. Examples include Wilm’s tumour, Standard risk ALL, Hodgkin’s 10

Principles of treatment Local Therapy Surgery Radiotherapy Systemic Therapy Chemotherapy Small molecules Immune modulators The treatments chosen and the way in which they are combined depend on the individual clinical situation. In general, haematological malignancy is treated with systemic therapy, particularly chemotherapy +/- small molecules or targeted antibodies Solid tumours usually require surgery, if this can be achieved without unacceptable morbidity. Exceptions would be the lymphomas, where surgery is rarely indicated. In many solid tumours chemotherapy is given upfront (neo-adjuvant) to reduce tumour bulk and facilitate surgery, followed by post operative (adjuvant) chemotherapy to mop up any microscopic disease left behind locally or elsewhere. If patients are to receive surgery and radiotherapy, surgery often comes first although there are some exceptions.

Pathway Diagnostic and staging investigations Definitive treatment plan Response assessment and toxicity monitoring End of treatment and restaging Surveillance Long term follow up Multidisciplinary approach at all stages Psychosocial support throughout Diagnostic and staging investigations take a finite amount of time, and cannot always be sped up. It is important to ensure that all of the necessary information is gathered before treatment starts to ensure correct diagnosis and risk group allocation (where appropriate) so that patients are neither under or over-treated. Acute leukaemia is often confirmed within 24 hours (Bone marrow and LP for cytology) allowing treatment to be started. Further information becomes available over the next couple of weeks (cytogenetics, MRD status) which influences further treatment, but does not change initial management. Solid tumours usually take between one to two weeks to fully stage, although in emergencies treatment may be started on a “best guess” basis, or with partial information e.g. mediastinal mass, spinal cord compression. Bone marrow trephines, needed to confirm or disprove marrow involvement take 5-7 days to process.

Complications during Treatment Alopecia N+V Immunosuppression Gram negative PCP Measles VZV Mucositis Anaemia and Thrombocytopenia Anorexia, diarrhoea, constipation Patients vary widely with regard to the severity of side effects they experience, although within individual patients the side effect profile often appears to be fairly consistent each time they are exposed to a particular course of chemotherapy. Most patients experience some toxicity. There is no correlation between the severity of side effects and the effectiveness of anticancer activity (parents often ask).