Leukaemias

Leukaemia is the most common malignant disease in infancy and childhood and accounts for one-third of all childhood cancers. Acute lymphoblastic leukaemia (ALL) is the most common form of the disease in childhood with its incidence highest at 3–7 years of age, falling off by 10 years [15]. Boys are affected more than girls. Approximately 80% of ALL in children is of precursor B-cell origin, about 15% is T-cell and 5% is more mature B-cell derived. Acute myeloid leukaemia (AML) is the second most common leukaemia in childhood accounting for 10%–15% of leukaemias, with 15%–20% of the cases occurring in patients with predisposing conditions that include certain congenital syndromes such as Down’s syndrome, Li –Fraumeni syndrome or DNA instability syndromes such as Fanconi anaemia [16]. Although rare, accounting for 15% of leukaemias, chronic myeloid leukaemia (CML) can occur in older children.

Five year survival rates are around 87% in children with ALL and 65% for those with AML [17]. It should be noted, however, that prognosis in infants with ALL is poor.

The leukaemias are fatal unless treated and clinical features at presentation include bone marrow failure, anaemia (pallor, lethargy), neutropenia (fever, malaise), thrombocytopenia (bruising, purpura, bleeding gums, nose bleeds) and organ infiltration; tender bones; lymphadenopathy; splenomegaly; hepatomegaly.

Diagnosis is by blood test usually showing the total white cell count to be decreased, normal or increased to 200 × 10⁹/L. Blood film examination typically shows a variable number of blast cells. A hypercellular bone marrow aspirate with >20% leukaemic blasts confirms diagnosis. A lumbar puncture is performed to confirm any leukaemia cells in the spinal fluid. Biochemical tests may show raised serum uric acid and serum lactate dehydrogenase (LDH) levels [15].

Current treatment for ALL includes initial induction chemotherapy aimed at achieving remission. The protocol is graded as regimen A for those children with standard risk disease; regimen B for those children with intermediate risk disease; and regimen C for those children with high risk disease who have not responded to initial treatment, or those with poor cytogenetics: Philadelphia chromosome t (9;22); near haploidy (<44 chromosomes); iAMP21 t (17;19); and MLL gene arrangement. All of these are rare.

Following induction the next phase of treatment is consolidation (intensification) and central nervous system (CNS) treatment aimed to completely reduce or eliminate the tumour burden and to prevent or treat CNS disease. There are one to two intensification treatment blocks in children depending on the presence of any minimal residual disease (MRD) detected after induction chemotherapy.

Maintenance chemotherapy is then given for up to 2 years in girls and up to 3 years in boys. Children with CNS disease at diagnosis may need to have cranial radiotherapy.

Intensive chemotherapy is primarily the treatment for AML, generally given as four blocks of chemotherapy 3 weeks apart, but may be delayed if the patient has not recovered their neutrophil and platelet counts to an acceptable level before commencing the next course of chemotherapy. Bone marrow transplant (BMT) is used for children with ALL or AML which is likely to recur, or for those who have relapsed disease.

Lymphomas

Lymphomas account for approximately 10% of all childhood cancers and can be divided into two main groups:

• non Hodgkin’s lymphomas (NHL) account for 60% of lymphomas and are a large group of lymphoid tumours. Those most commonly seen in children include B-cell NHL and T-cell NHL. The majority of patients present with asymmetric enlargement of lymph nodes in one or more peripheral lymph node regions. Those with diffuse bone marrow disease present with anaemia, neutropenia or thrombocytopenia. Diagnosis is made by a variety of investigations including biopsy of a swollen gland, x-rays, ultrasound scans (USS), computerised tomography (CT) scans and biochemical tests. Serum LDH levels are raised in more rapidly proliferating and extensive disease. Five year survival rates are around 85% [17]. Chemotherapy is the most important treatment for children with NHL. High dose chemotherapy and autologous stem cell transplant is sometimes used in relapsed disease.
  
• Hodgkin’s lymphoma accounts for 40% of lymphomas. Presenting symptoms are usually painless cervical and/or mediastinal adenopathy. Symptoms also generally include fever, night sweats, weight loss, fatigue and anorexia. Hodgkin’s disease is more common in adolescents than younger children. Diagnosis is made by biopsy of a swollen lymph gland, x-rays, CT scan, magnetic resonance imaging (MRI) and in some cases positron emission tomography (PET) scans. Biochemical tests include erythrocyte sedimentation rate (ESR) and C-reative protein (CRP) which are usually raised and are useful in monitoring disease progression. Serum LDH levels are increased in 30%–40% of cases. Five year survival rates are around 95% [17]. Treatment is by chemotherapy, with radiotherapy restricted to those with extended disease or lack of response to chemotherapy. Some relapsed patients may require high dose chemotherapy and autologous stem cell transplant.

Solid tumours

Solid tumours account for approximately 45% of all malignant disease in children. Diagnostic tests for most solid tumours include tumour biopsy, x-rays, USS, CT and MRI scans and in some cases PET scans and bone scans. The most common solid tumours seen in children are as follows.

• Brain tumours. Brain and spinal CNS tumours are the most common solid tumours. Medulloblastoma is the most common CNS tumour in children. Signs and symptoms of CNS tumours are generally caused by increased intracranial pressure and include headaches, vomiting, drowsiness, irritability, fits and diplopia. Other symptoms may include weakness or unsteadiness on walking. Treatment varies depending on the underlying tumour but surgery, radiotherapy or chemotherapy may be used alone or in combination. Steroids may be given to reduce swelling around the brain and a ventriculoperitoneal shunt may need to be inserted. Five year survival rate for medulloblastoma is around 80% for children with standard risk disease and between 40% and 60% in those with high risk disease, i.e. those with disseminated disease or who have undergone a subtotal resection [18].
  
• Neuroblastoma is the most common tumour before the age of 5 years and accounts for 8% of all childhood cancers. It arises from the neural crest tissue in the adrenal medulla and elsewhere in the sympathetic nervous system; therefore it most frequently occurs in one of the adrenal glands but can also occur alongside the spinal cord in the neck, chest, abdomen or pelvis. Most children present with an abdominal mass, loss of appetite, lethargy and bone pain. At presentation the tumour mass can often be large and complex. A variety of tests and investigations are undertaken to confirm diagnosis including meta-iodo-benzyl guanidine (mIBG) scan. Urinary catecholamine levels are raised in neuroblastoma. Chromosomes and biological markers are also examined following tumour biopsy and the presence of one of the markers, MYCN, in a certain amount in the cells (known as MYCN amplification) suggests more aggressive disease and treatment is more intensive. Treatment and survival depends on the stage of the disease. In those with high risk disease treatment involves chemotherapy, surgery, radiotherapy and in some cases high dose chemotherapy and autologous stem cell transplant. 1-cis-retinoic acid is being used as a differentiating agent to reduce the risk of relapse in high risk patients. The use of the monoclonal antibody anti-GD2, with or without interleukin-2 alongside, is currently being investigated for high risk disease. Five year survival rate is currently around 64% [17].
  
• Wilms’ tumour is a congenital malignant kidney tumour, which can be bilateral. It is most commonly seen in children under the age of 5 years with the majority presenting with a large abdominal mass. Other symptoms may include poor weight gain and loss of appetite, blood in the urine and high blood pressure. Children with the WT1 gene or WT1 syndromes have an increased risk of developing a Wilms’ tumour. Treatment depends on histology and stage of the tumour but usually involves surgery, chemotherapy and occasionally radiotherapy. Prognosis for Wilms’ tumour is good with 5 year survival rates around 90% [17].
  
• Rhabdomyosarcoma is the most common type of soft tissue sarcoma in children which develops from muscle or fibrous tissue. It can develop at any age but is more common in children under 10 years. There are two main subgroups: embryonal (80%) and alveolar (20%). Rhabdomyosarcoma occurs at a wide variety of primary sites but is most common around head and neck sites. Other sites include genito-urinary and occasionally limb, chest or abdominal wall. Treatment depends on tumour size, position and whether or not metastatic disease is present but involves chemotherapy, surgical resection and sometimes radiotherapy. Five year survival rate is around 65% [17].
  
• Ewing’s sarcoma and peripheral primitive neuroectodermal tumour (pPNET). Ewing’s sarcoma is a type of bone tumour. Any bone can be affected but it is more common in the pelvis, femur or shin bone. It can occur in the teenage years but is also seen in younger children. Persistent localised bone pain is a characteristic symptom that usually precedes the detection of a mass. Treatment involves chemotherapy followed by surgery, usually limb sparing but sometimes amputation is unavoidable followed by further chemotherapy and radiotherapy especially if surgical resection is impossible or incomplete. Poor responders may receive high dose chemotherapy and autologous stem cell transplant. Five year survival rates are around 65% [17]. pPNET is a soft tissue sarcoma of neuroepithelial origin which can be thought of as being similar to a Ewing’s sarcoma.
  
• Osteosarcoma is a high grade bone tumour which is more commonly seen in older children and teenagers and is more common in boys. It often occurs at the end of bones where new bone tissue is forming, predominantly in the arms or legs, particularly around the knee. Pain and swelling around the affected bone are the most common symptoms. Treatment depends on factors including size, position and stage of the tumour and initially involves chemotherapy. Surgery may be amputation or limb sparing surgery. Further chemotherapy is then given and treatment lasts for about a year. Radiotherapy may occasionally be given. Five year survival rates are around 50%–60% [17].
  
• Retinoblastoma is the commonest malignant eye tumour in children, accounting for around 3% of childhood cancers with most occurring under the age of 5 years. All bilateral tumours are thought to be hereditary due to the RB1 gene in 40% of cases, as are 15% of unilateral cases. Children of affected families are screened from birth. Diagnostic tests include an eye examination under anaesthetic and a blood test to look for the RB gene. Treatment options include local treatment with cryotherapy, laser therapy, external beam therapy, chemotherapy and plaque brachytherapy and in some cases enucleation is necessary. Five year survival rates are over 90% [17].
  
• Additional information on rarer tumours, e.g. hepatoblastoma and germ cell tumours, can be obtained from the Children’s Cancer and Leukaemia Group (CCLG) website [3].

Metabolic factors

Cancer cachexia is complex and multifactorial marked by early satiety, weight loss, organ dysfunction and tissue wasting. Changes in the metabolism of fat, carbohydrate and protein have been demonstrated in the cancer bearing host [26, 27]. In children with cancer the result is a cascade of metabolic events, which are typically characteristic of the acute metabolic response. In addition to glycogenolysis and lipolysis this response includes a marked increase in energy expenditure, proteolysis and gluconeogenesis. This response results in an accelerated depletion of endogenous energy and substrate stores in the face of decreased exogenous fuel substrate provision [6].

Cachexia is more common in children with solid tumours at diagnosis (33%) and during treatment (57%) compared with children with leukaemia (12% and 38%) respectively [28]. Severe weight loss in children with leukaemia appears to be associated with more intensive treatment regimens such as those for AML and children treated on regimen C.

With the ever increasing intensity of treatment regimens and treatment of relapsed patients there is a greater number of children at risk of the metabolic demands of their disease and treatment.