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Nutritional status and nutritional management in children with cancer Edward P T Gaynor, Peter B Sullivan Department of Paediatric Gastroenterology, Children’s Hospital, Oxford University Hospitals NHS Trust, Oxford, UK Correspondence to Dr Edward PT Gaynor, Department of Paediatric Gastroenterology, Children’s Hospital, Oxford University Hospitals NHS Trust, Headley Way, Oxford OX3 9DU, UK; [email protected] Received 23 March 2015 Revised 25 May 2015 Accepted 2 June 2015

ABSTRACT Malnutrition is often seen at the point of diagnosis in childhood malignancy or may develop during the course of treatment. Strategies for optimal diagnosis and management of nutritional problems in children with cancer are limited in the published literature. Identification of children who may be malnourished or at nutritional risk can be achieved through improved approaches for risk stratification and classification. Once recognised, various strategies have been demonstrated to reduce malnutrition, minimise side effects of treatment and improve survival. Novel approaches in vivo and adult oncology populations provide future avenues for investigation.

INTRODUCTION Cancer is still a leading cause of death in childhood, but there has been a dramatic increase in survival rates in children. These improved rates reflect earlier diagnosis and subsequent multimodal treatment with more intensive chemotherapy, radiotherapy and surgery. Additionally there is a growing interest in the role of supportive care, especially nutrition, with an aim to improve prognoses further. Paediatric cancer is different from cancer in adults; many cancers are of embryonic origin, there is a different biology of disease with tumours often responding better to chemotherapy. Moreover many children are usually otherwise healthy at the time of diagnosis. However an impaired nutritional status at diagnoses is not uncommon. In the early years oncologists hesitated to provide aggressive nutritional support for fear that tumour growth would be enhanced. There is currently no evidence to support this.

EPIDEMIOLOGY

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An impaired nutritional state at diagnosis or during subsequent management is often seen. At the time of cancer diagnosis, malnutrition is found in 8% of children. However this masks the variation found between different types of cancer, with malnutrition being more commonly seen at diagnosis in solid tumours such as neuroblastoma, sarcomas and Wilms’ tumour. Thus the prevalence of malnutrition in children with cancer at diagnosis ranges from up to 7% in those with leukaemia to 50% in those with neuroblastoma at diagnosis. The incidence of malnutrition is often higher in children with metastatic disease.1–3 In spite of the reported prevalence of malnutrition with paediatric cancer, it has proven hard to standardise its definition, assessment and therefore to identify children at risk. This is a particular problem as until nutritional end points or outcomes

can be agreed, it will be impossible to undertake rigorous international comparisons. There are diverse definitions of malnutrition between different studies—some use weight for height less than the 50th centile, others weight for height or a BMI z-score of less than −2. These can be poor indicators of nutritional state in paediatric populations—for example weight changes can be distorted by large solid tumours (such as Wilms’, neuroblastoma or hepatoblastoma) and thereby not meet malnutrition criteria. BMI is not recommended as a sole indicator for nutritional status in paediatric oncology, as it does not correlate well to changes in free-fat mass (FFM) seen in malnutrition—given the overall contribution of FFM and extracellular fluid volume to BMI in paediatric populations. Furthermore alternative measures, such as anthropometry, are neither commonly used nor standardised as part of nutritional assessments in paediatric cancer assessment—only 5% of centres use triceps skin fold thicknesses and only 84% routinely measure dietary intake.4 With these variations in mind, agreed methods of assessment are needed at part of Standards of Care for these children. Studies have shown that FFM is significantly reduced in malnutrition, and could provide a standardised method to assess nutritional status. Body cell mass (BCM) is the most metabolically active component of FFM, and can be reliably measured by total body potassium concentration. It has been proposed that this may be the best measurement because it is independent of extracellular fluid changes. In paediatric populations, BCM z-score has been demonstrated to be significantly reduced in up to 45% of patients with cancer considered to be malnourished when compared with healthy controls.5 Nonetheless it is important to appreciate that there are no simple measures that accurately identify poor nutritional status in children treated for cancer and that whichever method is used, the risk or presence of malnutrition should be reassessed throughout the child’s subsequent treatment.

AETIOLOGY Malnutrition in paediatric patients with cancer is dynamic, and development of impaired nutritional status in otherwise healthy children is commonly seen during subsequent treatment. The causes of this are multifactorial, but likely involve an interplay between iatrogenic consequences of treatment, complex interactions between energy and substrate metabolism, and hormonal and inflammatory disturbances. There is a clear link between medical therapy and its complications and malnutrition—with the

Gaynor EPT, et al. Arch Dis Child 2015;0:1–4. doi:10.1136/archdischild-2014-306941

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Review greater the tumour burden, the more intense the therapy and the higher the risk of nutritional morbidity. Once established, malnutrition can lead to poor tolerance of treatment and an impaired prognosis, with around a third of those dying in the 1st year due to associated complications. Combination chemotherapy and radiotherapy, used commonly in paediatric cancer therapy, can lead to major secondary problems, most of which affect nutritional status. These include stomatitis, diarrhoea, nausea, vomiting, malabsorption, blood loss (anaemia), ileus (especially secondary to vincristine or opiates) and xerostomia. Furthermore the presence of cancer and its treatment have a profound impact on normal function of the metabolic and endocrine systems in children. Cancer is a catabolic state and leads to changes in metabolism with increased lipolysis, increased protein turnover, increased energy expenditure and anorexia. The curious thing about energy expenditure in these populations is that the normal response to anorexia, which is a prominent feature of cancer cachexia, is a decrease in energy expenditure; paradoxically in cancer, however, tumour induced cytokine release (such as tumour necrosis factor, interleukin (IL) 1, IL-6) leads to a significant increase in energy expenditure, proteolysis, gluconeogenesis and an increase in tumour related protein synthesis at the expense of muscle protein stores. Corticosteroids, frequently used in therapy, exacerbate cachexia due to their counter-regulatory effects on protein metabolism, promoting endogenous muscle protein catabolism. This leads to a loss of lean body mass and consequently weight loss, with losses greater than 5% being common after the 1st month of treatment.6 Energy levels and quality of life are further impacted by endocrine disturbances seen in these children suffering from cancer cachexia. There is an increase in catecholamines, glucagon, cortisol and growth hormone, and a decrease in insulin with relative insulin resistance and decrease in thyroid hormones, especially after cranial spinal irradiation.7–9 The consequent reduction in energy expenditure, however, does contribute to the preservation of scarce metabolic substrates. Around a third of survivors have long-term sequelae including developmental and physiological toxicity and secondary malignancies. However there is little data on the long-term consequences of malnutrition and, in contrast to cancer in adults, one needs to plan for the next 70 years rather than the next 5 years.

Nutritional support aims to reverse malnutrition seen at diagnosis, prevent malnutrition associated with treatment and promote weight and growth. There is no doubt that nutritional state has a prognostic effect on the outcome of children with cancer.

STRATIFYING NUTRITIONAL RISK AND CONSEQUENCES OF MALNUTRITION Malnutrition in cancer should not be accepted at any stage of the disease or tolerated as an inevitable process. Nutritional risk can be stratified into ‘High’ or ‘Low’, but it is also important to identify those children who may be at risk for obesity and increase in fat mass induced by cancer therapy. Children with an established nutritional deficit at diagnosis, often those with solid tumours or other advanced staged cancers, as well as children with unfavourable histology and localisation of tumour are at high risk of worsening malnutrition.11 12 Undernourishment occurs less frequently in children diagnosed with non-metastatic tumours or those with a favourable prognosis. (See table 1) Consequences of the diminished nutritional state may include decreased immune function, delayed wound healing, decrease in bone mineral content, disturbed drug metabolism, increased hospital admission and prolonged stay in hospital.13 In spite of the difficulty assessing the precise impact of malnutrition on associated cancer morbidities, a poor nutritional state is a clear prognostic factor for treatment response, quality of life and cost of care. In particular, unfavourable weight loss has been associated with reduced survival rates in children with newly diagnosed stage IV neuroblastoma,14 acute lymphoblastic leukaemia,15 and acute myeloid leukaemia.16 Furthermore, there are longer-term risks seen in survivors of common paediatric malignancies. They are at risk of obesity and cardiovascular and endocrine diseases. At diagnosis 55% of children in USA have obesity. ALL survivors, especially those who have had intracranial radiotherapy, are at risk of adult-onset obesity and often have a BMI of ≥25. Adolescent and young adult survivors of CNS tumours and lymphoma are ‘at risk’ for poor dietary practices, sedentary behaviour and poor quality of life.17–19 The development of dietary interventions and exercise is therefore very important in these groups. Modest benefits have been demonstrated with internet, phone and text delivered weight management strategies.20 With the use of robust

SUPPORTIVE CARE Malnutrition is a little recognised aspect of the management of cancer in children and medical nutrition is yet to be incorporated as a standard component of cancer care in children. There is no national guidance in the UK to optimise nutrition in patients with cancer and no evidence based guidelines to inform the assessment of nutritional status or the most effective timing of nutritional intervention. Most cancer centres do not screen for nutritional problems and, if they do, they use basic weight and height methods and there is variability in the criteria for monitoring of nutritional intervention. This may mean that children with cancer who are malnourished may go unrecognised and their prognosis be affected by their poor nutritional state. It is also worth noting that assessment of nutritional status at diagnosis may not be the best indicator of overall nutritional status and indicates the need for ongoing nutritional assessment and intervention throughout therapy. There is a clear need to improve the nutritional state of children with cancer in order to induce remission. Undernourished children with cancer, particularly in the developing world, have a much increased risk of developing severe malnutrition.10 2

Table 1

Stratifying nutritional risk based on tumour types

High nutritional risk

Lower nutritional risk

Solid tumours Neuroblastoma Wilms’ tumour stage III and stage IV Rhabdomyosarcoma

Non-metastatic solid tumours Hodgkin’s disease ALL—regime A patients Retinoblastoma Germ cell tumours Tumours in remission Patients undergoing maintenance regimes

Metabolically active tumours/metastatic tumours Brain tumours for example, astrocytomas, gliomas Nasopharyngeal tumours Ewing’s sarcoma/Primitive neuroectodermal tumour (PNET) Medulloblastoma/CNS PNET Osteosarcoma Diencephalic tumours Acute lymphoblastic leukaemia (regime B and C patients, relapsed, children 10 years at diagnosis) Acute myeloid leukaemia Post bone marrow transplant (graft vs host disease)

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Review nutritional screening, it should be possible to identify risk factors, leading to early planned interventions and follow-up outcome of such intervention.

NUTRITIONAL MANAGEMENT OF CHILDREN WITH CANCER There is currently no agreed consensus for specific substrate requirements, timing or duration of nutritional interventions. Once malnutrition or the risk of malnutrition has been identified in children, however, a number of management strategies should be considered. The enteral route of nutrition is preferred in children with cancer. Maintaining sufficient nutrition to improve body weight and BCM can be a challenge. These children and families need support and motivation to overcome anorexia, and they also require a functional gastrointestinal tract with good intestinal absorption and minimal treatment-induced adverse effects such as mucositis. Consequently, it is important to consider early proactive nutritional intervention; although evidence is needed to demonstrate clinical benefits of this approach. Children with cancer cachexia require feeds that should aim for 120% EAR energy and 2–4 g/kg of protein. If they are unable to achieve this orally, tube feeding should be considered. This helps overcome poor feed tolerance or reduced intake due to mucositis, and also allows less palatable calorie enriched tube feeds to be used. If this is not successful then gastrostomy tube feeding is a safe, effectual and cost-effective method of reversing malnutrition in children with cancer, where this cannot be practically achieved orally.21 This approach has been shown to be supported by children, their families and their clinicians when other strategies have failed.22 23 There is limited evidence from trials to suggest that parenteral nutrition is more effective than enteral nutrition in well nourished children undergoing chemotherapy.24 Nevertheless, in those children where enteral feeding has failed or is not practical (eg, reduced intestinal absorption, severe vomiting or diarrhoea, pancreatitis, ileus, intestinal obstruction or intestinal manifestations of graft vs host disease) parental nutrition should be considered. Particularly as a delay in starting parenteral nutrition in as a little as a week may impair prognosis in children who have evidence of protein-energy depletion or/and a history of lower food intake at the time of diagnosis.25 This approach is not without its risks, with one study showing a 50% increased risk of bacteraemia in those patients randomised to receive TPN,26 and another showing a 2.4-fold increase in the risk of infection in children on TPN.27

THE FUTURE Tremendous progress has been made in improving cancer cure rates through the systematic evaluation of chemotherapy, surgery and radiation therapy. Precision medical approaches to paediatric cancer care will allow for curing the currently incurable, possibly with less immediate and long-term side effects. Various future strategies have been identified that may help prevent or reduce the risk of malnutrition in these children. Glutamine is an abundant amino acid in the plasma and muscle of humans, and is used as a major fuel and nitrogen source for rapidly dividing cells such as enterocytes and lymphocytes. As such it has been proposed to play a key role in maintaining mucosal cell integrity and gut barrier function. Chemostatic drugs result in structural and functional injuries to the gastrointestinal tract resulting in mucositis. Animal models have demonstrated that exogenous glutamine supplementation Gaynor EPT, et al. Arch Dis Child 2015;0:1–4. doi:10.1136/archdischild-2014-306941

may play a role in ameliorating detrimental effects of these drugs on the gastrointestinal mucosa.28 The evidence in humans, however, is varied. In adults and children it has been demonstrated that glutamine is non-toxic and tolerated orally. In adult oncology populations a reduction in chemotherapyinduced stomatitis,29 a reduction in the severity and duration of mucositis,30 and a reduction in need for parenteral nutrition has been shown following glutamine supplementation.31 The evidence of benefit of this is more limited in paediatric populations, with only a significant reduction in the use of parenteral nutrition being demonstrated.32 Further studies investigating the optimal dose of glutamine and in a larger paediatric population are required. Other avenues for explorations may be in the use of antioxidants in children undergoing chemotherapy. In one observation study, children with a new diagnosis of ALL were given varying amounts of oral antioxidant supplements—with greater ingestion of vitamin C, vitamin E and β-carotene associated with few therapy delays and less toxicity and a lower incidence of infection.33 Furthermore, it is known that antioxidant levels are reduced in paediatric oncology patients receiving chemotherapy,34 which may impair prognosis. There is concern, however, that the formation of reactive oxygen species by antioxidants may impair the action of some chemotherapy agents, although there are no trials where this has been demonstrated. Nonetheless, the optimal intake of antioxidants during treatment and their possible role as an adjunct to current therapies require further study. There are currently no drugs approved for the prevention or treatment of cancer cachexia. New therapeutic strategies are required to help increase lean mass and reduce skeletal muscle catabolism. Following the identification of a number of mechanistic pathways several therapeutic targets have been identified. Nuclear transcription factor-kB activation appears to play a crucial role in cachexia in murine cancer models, with inhibition attenuating protein degradation in muscle and significantly reducing overall weight loss.35 Growth factors and anabolic steroids are also currently under investigation. Ghrelin and ghrelin agonists, stimulate the production of growth hormone from the anterior pituitary gland and increase appetite. These may provide interesting novel targets, with human trials of oral analogues showing some modest improvements in lean body mass.36 There is also interest in the use of anabolic steroids, such as testosterone, which has been used successfully with cachexia-associated chronic diseases, such as chronic heart failure.37 This however is likely to be limited in children who may be prepubertal or who have not completed their growth. Finally, specific dietary interventions may improve outcomes in children undergoing cancer therapy. Ketogenic diets, such as those used for many years in resistant epilepsy, may be of benefit in the management of certain cancers that are dependent on glycolysis. In spite of making up a third of childhood malignancies, advances in malignant brain tumour treatments with surgery, radiotherapy or chemotherapy are limited. Many brain tumours have lost the ability to metabolise ketones, unlike the surrounding neurons and glia, instead relying on more readily metabolised substrates for growth. In mouse models of brain tumours,38 dietary energy restriction appears to be antiangiogenic and proapoptotic, and there have been two cases published where this has been beneficial in paediatric astrocytomas.39 Its future use may be limited by tolerability and compliance, as experienced in other areas of paediatric medicine.40 3

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Review CONCLUSION The current literature offers few clinical trials that explore the consequences of nutritional support or the needs of paediatric patients with cancer. International agreement is required to standardise the definition and assessment of malnutrition to allow proper comparisons between interventions in these children. With increasingly robust standards of care in oncology, however, this should be feasibly achieved. Newer multimodal therapeutic strategies for paediatric cancer, combined with evidence based nutritional support, should allow for further improvement in prognosis in these children. Contributors PBS—contributed to the topic area and outline of the article. EPTG —authored the article content and tables, contributed to the literature search. Competing interests None declared. Provenance and peer review Commissioned; externally peer reviewed.

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Nutritional status and nutritional management in children with cancer Edward P T Gaynor and Peter B Sullivan Arch Dis Child published online June 30, 2015

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Nutritional status and nutritional management in children with cancer.

Malnutrition is often seen at the point of diagnosis in childhood malignancy or may develop during the course of treatment. Strategies for optimal dia...
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