Child Nutrition and Health

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CHILDREN'S ISSUES, LAWS AND PROGRAMS CHILD NUTRITION AND HEALTH No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. www.ebook3000.com

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CHILDREN'S ISSUES, LAWS AND PROGRAMS CHILD NUTRITION AND HEALTH GREGOR CVERCKO AND LUKA PREDOVNIK EDITORS New York www.ebook3000.com

Copyright © 2013 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Child nutrition and health / [edited by] Gregor Cvercko and Luka Predovnik. pages cm Includes bibliographical references and index. ISBN:  (eBook) 1. Children--Nutrition. 2. Children--Health and hygiene. I. Cvercko, Gregor. II. Predovnik, Luka. RJ206.C513 2013 618.92--dc23 2012035888 Published by Nova Science Publishers, Inc.  New York www.ebook3000.com

Contents Preface Nutrition in Children and Adolescents with Cancer vii Chapter I Terezie Tolar Mosby and Ronald D. Barr 1 Chapter II Chapter III Calcium Supplementation in Young Children 43 in Asia: Prevalence, Benefits and Risks 67 Chapter IV Shu Che, Colin Binns and Bruce Maycock Chapter V 89 Chapter VI Exposure of Slovenian Preschool Children to Preservatives 107 and Polyphosphates 121 Index Elizabeta Mičović, Mario Gorenjak, 137 Gorazd Meško and Avrelija Cencič The Breakfast Experience in Low Socioeconomic Families with Overweight Children Simone Pettigrew and Melanie Pescud Early Vitamin D Supplementation, Immune Modulation and Allergy Gian Vincenzo Zuccotti and Valeria Manfredini Factors Associated with Overweight and Obesity among Kuwaiti Young Children A. N. Al-Isa, Nadeeja Wijesekara, Ediriweera Desapriya and Yamesha Ranatunga www.ebook3000.com



Preface In this book, the authors have gathered and present current research in the study of child nutrition and health from across the globe. Topics discussed include the exposure of Slovenian preschool children to preservatives and polyphosphates; the breakfast experience in low socioeconomic families with overweight children; nutrition in children and adolescents with cancer; calcium supplementation in young children in Asia; early vitamin D supplementation, immune modulation and allergy; and the factors associated with overweight and obesity among Kuwaiti young children. Chapter I - Cancer is the most common cause of disease-related death in children and adolescents in the United States, and it is becoming a proportionately more common cause of death among young people in developing countries as well. However, cancer is highly curable in young people. In high income countries, the survival rate of children and adolescents with cancer is 80% or higher. However, more than 80% of children live in low and middle income countries where the survival rate may be as low as 5%. Nutrition plays an important role in many aspects of cancer development, treatment and long term survival. Nutritional status at diagnosis has prognostic implications. Well-nourished children have a better tolerance of intensive cancer therapy, improved chances of survival, and lower relapse rates. Children and adolescents with cancer are at higher risk for the development of malnutrition than adults during treatment due to the relatively higher nutritional needs demanded by their continuous growth and organ development. Nutritional assessment is important for the prevention, recognition, and early treatment of malnutrition. Proper assessment of the nutritional status of a patient is necessary for the determination of appropriate nutritional therapy. The goals of nutritional therapy for patients undergoing anticancer treatment are to maintain weight and to achieve age-appropriate growth and weight gain after treatment. These goals can be achieved by dietary modifications, use of dietary supplements, appetite stimulants, or nutritional support. Patients undergoing chemotherapy, radiation and hematopoietic stem cell transplantation can experience any or all of the following side effects: nausea, vomiting, mouth sores, constipation, diarrhea, altered taste, loss of appetite. Any of these side effects could result in undesirable weight loss, protein energy malnutrition or cancer cachexia. Food poisoning can occur if a person eats or drinks something that contains harmful germs. Food consumed by immunocompromised patients should be prepared in a manner to minimize bacterial growth. www.ebook3000.com

viii Gregor Cvercko and Luka Predovnik Survivors of cancer in childhood and adolescence are at risk for many long-term adverse effects of therapy. Lifestyle changes, including dietary modification, may help with the management of some of those sequelae. The three nutrition-related key areas to reduce cancer risk are weight, diet, and physical activity. There are numerous gaps in our knowledge concerning the interaction of nutrition with cancer in children and adolescents. These include the effects of nutritional interventions on cancer outcomes and the influence of such interventions on co-morbidities; all providing rich opportunities for good clinical research. Chapter II - Calcium is essential for maintaining bone health in infants and young children. The calcium intakes of weaning infants and children in Asia are relatively low in comparison to their Western counterparts. This is an increasing concern for Asian parents and is one reason the Asia Pacific region is becoming a large market for vitamins and dietary supplements. However, there is a lack of data on the long-term benefits to early calcium supplementation of healthy infants and young children. The objective of this chapter is to discuss the appropriate calcium intakes for infants and young children, the risks and benefits of calcium supplementation and to review the proportion of children in Asia who are taking calcium supplements. To achieve our objective a literature review was undertaken of the English language databases PubMed and Web of Knowledge. Studies were selected that reported outcomes of calcium intake in infants and young children, as well as systematic reviews of such studies. Studies were undertaken of children in China and a comparison group of Chinese children living in Australia to document the use of calcium supplements. The prevalence of dietary supplementation among children under five years old in China (30.0%) was higher than in Australia (21.6%). In supplement users in China, 60.3% of them took calcium supplementation while only a small number in Australia (8%) took calcium supplements. Age and feeding method of the child (ever breastfed or not) were associated with nutritional supplementation in Australia, while household income and mother’s educational status were significantly related to the use of dietary supplements including calcium supplements in China. More than half of the children took supplemental calcium in the form of calcium gluconate (51.8%) and the average intake from supplements was 131 mg per day. There is little evidence to support the general use of calcium supplements in infants who were exclusively breastfed or formula fed. Evidence from recent studies does not support the use of calcium supplementation in healthy children as a public health intervention. However, for weaning infants and children with low calcium intakes, increased intake of calcium-rich foods should be encouraged. If adequate calcium cannot be achieved through food sources, supplementation may be an effective alternative. More studies are required in infants and young children with low calcium intakes, particularly those living in Asian countries or children of Asian ethnic origin. Chapter III - The purpose of this chapter is to present exposure of preschool children to daily consumed food preservatives and polyphosphates: sorbic acid, benzoic acid, nitrate, nitrite, sulphur dioxide and polyphosphates. For exact exposure of chemicals in food, data of consumed food intake and concentration of observed chemicals in food are needed. Methodology: Among the randomly selected regions in Slovenia, we randomly selected kindergartens and children aged from 2-6 years. The study included 190 children, 98 boys and 92 girls. Anthropometric measurements of children were conducted, so data on the sex, age, measured weight and height of the children were available. The dietary intake was based on

Preface ix the 3-day-weighed record method. The data from databases obtained from the official control and monitoring of food additive content in consumed food were used to calculate estimated daily intake (EDI). Such estimated exposure of each preservative and polyphosphates EDI was compared with acceptable daily intake (ADI) and expressed as % of ADI. Results: average exposure to each preservative and polyphosphates EDI was not exceeding ADI. It is evident that average exposure to nitrites and sulphur dioxide is relatively high, while intake of benzoic acid, sorbic acid, nitrates and polyphosphates is not so high. The mean daily exposure of children to nitrites ranged from 12.8 % to 28.3 % ADI, to sulphur dioxide from 14.3 % to 21.4 % ADI, while to sorbic acid from 3.8 % to 4.5 % ADI and polyphosphates from 1.8 % to 3.9 % ADI. It is apparent that such exposure does not present any harm or threat to observed children although we should consider the fact that ADI for sum of preservatives and polyphosphates have not been set yet. Chapter IV - Dietitians emphasise the importance of a healthy breakfast as part of a balanced diet. As well as providing energy to fuel physical and mental activity, there is increasing evidence that eating breakfast assists individuals manage their food intake to prevent excessive weight gain. Parents play a critical role in determining if their children eat breakfast and, if so, the kinds of foods that are consumed at this meal. Limited previous research has specifically examined parents’ beliefs and behaviours in relation to this aspect of their children’s diets. Such information is especially important in the context of low socioeconomic families given that disadvantaged children have significantly higher rates of overweight and obesity and poorer academic performance relative to their more advantaged peers. In the present study, parents’ attitudes to breakfast and its role in children’s health were explored. A range of qualitative data collection methods was employed over an extended period (12 months) with low socioeconomic status parents of overweight children. Insights were generated into the barriers, motivators, and facilitators influencing whether parents provide their children with healthy breakfasts. Numerous factors were listed as making it difficult to ensure children eat a healthy breakfast. These included time constraints, children’s taste preferences, a lack of appetite upon waking, and a reluctance among some parents to model recommended breakfast consumption behaviours. The findings indicate that future efforts to improve children’s nutrition could (i) build on parents’ existing belief that breakfast is important and (ii) suggest coping strategies for parents to overcome the identified barriers to selecting and serving healthy breakfast foods. Chapter V - A daily Vitamin D (VitD) intake of at least 400 IU/day is recommended nowadays by most updated guidelines during the first year of life. However, it is not known whether such an intake is enough to provide all the health benefits associated with VitD and a consensus is still missing stating the serum vitD levels appropriate for global health and the cutoffs for deficiency in younger individuals. Potent immune-modulating effects of VitD have been reported in vitro and, in particular, its potential ability to influence both innate and adaptive immunity, reducing the inflammatory response associated with Th1 and Th17 cells and skewing the T cell balance towards a Th2-phenotype. VitD immune-modulation activities could thus play a role in controlling infections and reducing inflammatory responses toward viral pathogens in both children and adults. However, the evidence in relation to vitD and allergic diseases is controversial.

x Gregor Cvercko and Luka Predovnik Most evidence report a protective effect of vitD against allergy. Some studies, however, suggest that VitD supplementation can be a risk factor for asthma and atopic disorders, assuming that VitD could induce sensitization against allergens during infancy. In this chapter, published data on the relationship between vitamin D and asthma and allergy will be discussed, emphasizing the need for controlled, prospective studies on vitamin D supplementation to clarify whether it has a role in the prevention of and treatment for asthma and allergic conditions. Chapter VI - Background. Childhood obesity is becoming a global epidemic which may result in increased morbidity and mortality during young adulthood. Objectives. To identify common factors associated with overweight and obesity among Kuwaiti intermediate school children aged 10-14 years to support Kuwaiti obesity prevention policy making. Methods. Weights and heights of 343 female and 340 male students were collected to obtain body mass index (BMI). Results. The prevalence of overweight and obesity were 21.9 and 6.4% among females and 22.9 and 7.6% among males, respectively. Risk factors for obesity in males and females vary considerably and also differ between age groups. Conclusion. Health education programs focused on reducing obesity in Kuwait must be multifactorial in nature and should be defined by gender and age group.

In: Child Nutrition and Health ISBN: 978-1-62257-981-5 Editors: G. Cvercko and L. Predovnik © 2013 Nova Science Publishers, Inc. Chapter I Nutrition in Children and Adolescents with Cancer Terezie Tolar Mosby1 and Ronald D. Barr2, 1St Jude Children’s Research Hospital, Memphis, TN, US 2Departments of Pediatrics, Pathology and Medicine, McMaster University, Hamilton, Ontario, Canada Abstract Cancer is the most common cause of disease-related death in children and adolescents in the United States, and it is becoming a proportionately more common cause of death among young people in developing countries as well. However, cancer is highly curable in young people. In high income countries, the survival rate of children and adolescents with cancer is 80% or higher. However, more than 80% of children live in low and middle income countries where the survival rate may be as low as 5%. Nutrition plays an important role in many aspects of cancer development, treatment and long term survival. Nutritional status at diagnosis has prognostic implications. Well- nourished children have a better tolerance of intensive cancer therapy, improved chances of survival, and lower relapse rates. Children and adolescents with cancer are at higher risk for the development of malnutrition than adults during treatment due to the relatively higher nutritional needs demanded by their continuous growth and organ development. Nutritional assessment is important for the prevention, recognition, and early treatment of malnutrition. Proper assessment of the nutritional status of a patient is necessary for the determination of appropriate nutritional therapy. The goals of nutritional therapy for patients undergoing anticancer treatment are to maintain weight and to achieve age-appropriate growth and weight gain after treatment. These goals can be achieved by dietary modifications, use of dietary supplements, appetite stimulants, or nutritional support. Patients undergoing chemotherapy, radiation and hematopoietic stem cell transplantation can experience any or all of the following side effects: nausea, vomiting, mouth sores, constipation, diarrhea, altered taste, loss of appetite. Any of these side effects could result in undesirable weight loss, protein energy malnutrition or cancer Room 3N27, Health Sciences Centre. McMaster University, 1200 Main Street West, Hamilton, Ontario, L8S 4J9, Canada, Tel: 1-905-521-2100 X 73428, Fax: 1-905-521-1703, E-mail: [email protected].

2 Terezie Tolar Mosby and Ronald D. Barr cachexia. Food poisoning can occur if a person eats or drinks something that contains harmful germs. Food consumed by immunocompromised patients should be prepared in a manner to minimize bacterial growth. Survivors of cancer in childhood and adolescence are at risk for many long-term adverse effects of therapy. Lifestyle changes, including dietary modification, may help with the management of some of those sequelae. The three nutrition-related key areas to reduce cancer risk are weight, diet, and physical activity. There are numerous gaps in our knowledge concerning the interaction of nutrition with cancer in children and adolescents. These include the effects of nutritional interventions on cancer outcomes and the influence of such interventions on co- morbidities; all providing rich opportunities for good clinical research. A. Introduction Prevalence of Cancer and Access to Care in High Income and Low Income Countries Cancer is the most common cause of disease-related death in children and adolescents in the United States [1] [2] and it is becoming a proportionately more common cause of death among young people in developing countries. In the U.S. every year more than 12,000 children (less than 15 years of age) are diagnosed with cancer, with an incidence of 155 new cases per million [3] In all high income countries combined, 50,000 children are diagnosed with cancer each year [4]. In low and middle income countries, more than 200,000 children are diagnosed with cancer annually [4]. Therefore, the great majority of children with cancer live in the developing world [5]. The most common types of cancers in children in the US are acute leukemia and brain tumors, which together account for half of all cases [6]. There are some regional and ethnic differences in cancer incidence which are not well understood but may suggest genetic predisposition or infectious etiologies [7]. Some examples are the high incidence of Burkitt lymphoma and retinoblastoma in some African regions [5], the low incidence of neuroblastoma in Blacks and of Ewing sarcoma in Chinese, and the high incidence of Kaposi sarcoma in eastern and southern Africa [7]. Malnutrition is the condition that results from an unbalanced diet in which certain nutrients are lacking - undernutrition, in excess (too high an intake) - overnutrition, or in the wrong proportions [8], although the term malnutrition is interchanged with undernutrition in common usage. Undernutrition (malnutrition) is one of the most common causes of death in children in the developing world. However, it is uncommon in the general population of children in the United States. Complications of undernutrition before a diagnosis of cancer are frequent in low-income countries, whereas childhood overnutrition is the more frequent problem among young people in high-income countries. Both undernutrition and obesity can affect treatment outcome. Treatment Outcome Cancer is highly curable in children and adolescents. In high income countries, their survival rate is 80% or higher [5]. However, more than 80% of children live in low and middle income countries where the survival rate may be as low as 5% [5]. Unfortunately, the

Nutrition in Children and Adolescents with Cancer 3 difference in survival for children diagnosed with cancer between high income and low income countries continues to widen as more advanced therapies are developed in the former but not implemented in the latter [9]. The low survival rate in low income countries is multi- factorial in origin and includes limited availability and access to care, abandonment of treatment, malnutrition and advanced disease at the time of diagnosis. In high income countries, treatment outcome depends on such factors as the type and extent of disease, and the method of treatment used. 1. Nutritional Status at Diagnosis Impact of Over and Undernutrition Nutritional status at diagnosis has prognostic implications. Well-nourished children have a better tolerance of intensive cancer treatment, improved chances of survival, and lower relapse rates [10]. Both undernutrition and overnutrition at the time of diagnosis are associated with poorer treatment outcome [11] [12]. Malnourished children are at an increased risk for treatment-related complications, reduced tolerance of therapy, altered drug metabolism, increased susceptibility to infection, and poorer treatment outcome. They are also at higher risk for improper physical and psychological development [13] [14]. As they age, malnourished children may have permanent mental and physical disabilities [15]. The younger the child, the more severe the effects of malnutrition may be. I. Undernutrition (Underweight) It is estimated that the prevalence of malnutrition in children in the general population in low income countries can range up to 32% in some parts of Africa and up to 43% in India [16]. The prevalence of malnutrition in low income countries at the time of diagnosis of cancer depends on the geographical region, type of cancer and method used to diagnose undernutrition. For example, in Central America, more than 70% of children had some type of nutritional depletion at the time of diagnosis [17]. Undernutrition was associated with higher rates of death due to abandonment of therapy and treatment failure [12]. II. Overnutrition (Overweight and Obesity) Obesity is an increasing problem among children, not just in high income countries but also in low income countries. It is estimated that, in the US, 20% of children are obese. Overweight children are taller than their peers, have earlier onset of puberty and are presumed to be more mature [18]. Childhood obesity is associated with hyperlipidemia, hypertension, diabetes and insulin resistance, hepatic steatosis, cholelithiasis, pseudotumor cerebri, sleep apnea, and orthopedic abnormalities [18]. All of those problems can affect treatment outcome. With only a small number of pharmacological investigations regarding the half-life, volume of distribution, and clearance of drugs in obese patients, there is the risk of under dosing and/or over-dosing patients considered to be obese [11].These risks can result in poorer treatment outcome and/or greater toxicities in these patients [11].

4 Terezie Tolar Mosby and Ronald D. Barr 2. Nutritional Status during Treatment Children and adolescents are at higher risk for the development of malnutrition than adults during cancer treatment due to the relatively higher nutritional needs demanded by their continuous growth and organ development. Anti-cancer treatment itself affects the nutritional status of patients and contributes to malnutrition. It is difficult to estimate the prevalence of malnutrition during treatment due to the lack of uniform criteria and adequate studies [19] but rates are estimated to be 0-10% for leukemia, 20-50% for neuroblastoma and 0-30% for other malignancies [19]. Suspected contributing factors are energy deficit, including low energy intake and increased metabolic rate, inflammation related to cachexia and malabsorption related to intestinal and other organ damage. The severity and variety of side effects depends on the nature of the disease and the treatment used. Common side effects interfering with nutrition are nausea, vomiting, loss of appetite, alteration of taste, mucositis, pancreatitis, pneumatosis intestinalis, and colitis. In those who have undergone hematopoietic stem cell transplantation (HSCT), graft versus host disease (GVHD) may result in an additional nutritional challenge. On the other hand, prolonged steroid use, physical inactivity and certain changes in metabolism predispose children with cancer to obesity. Malnutrition precludes optimal healing and recovery from therapy; therefore maximal effort should be focused on its prevention and treatment. B. Nutritional Assessment Nutritional assessment is important for the prevention, recognition, and early treatment of malnutrition. Proper assessment of the nutritional status of a patient is necessary for the determination of appropriate nutritional therapy. Special attention should be paid to metabolic derangements of macronutrients, leading to protein energy malnutrition (PEM), and micronutrients such as deficiencies of vitamin D, vitamin K, zinc, copper and selenium. There are many techniques that can be used to evaluate the nutritional status of adolescents and children. The choice of technique will depend on hospital resources, diagnosis, type of treatment, and other factors. In any case, both objective and subjective data should be used to complete the nutritional assessment. One measure alone should not be used to evaluate nutrition; therefore, healthcare providers should use critical thinking skills to assess nutritional status. 1. Screening Screening should be performed within 24-72 hours of admission for every patient and repeated regularly depending on the patient’s age, diagnosis, treatment, and other risk factors. Nutritional screening should include weight history, usual body weight, and a subjective history of current symptoms that includes, but is not limited to, nausea, vomiting, diarrhea, and appetite. Questions about food availability and who is responsible for food preparation should be asked as well. Such screening can identify children who are at risk of malnutrition

Nutrition in Children and Adolescents with Cancer 5 and need a more comprehensive nutritional assessment. See Table 1. for an example of a screening form used in St Jude Children’s Research Hospital. Table 1. Nutritional screening for nurses: inpatients done at admission; outpatients done at diagnosis and every 6 months at St Jude Children's Research Hospital Are you currently being seen by the clinical nutrition service? YES/NO Nutritional Screen Allergies to food Weight loss > 5% over 1 month Weight loss > 2 % over 1 month for infants Recent unexpected weight gain (please comment) Nausea/vomiting > 3 days Nil by mouth or poor oral intake > 3 days Total parenteral nutrition/tube feedings Problems or pain with chewing, swallowing, sucking Modified diet/dietary restrictions (please comment) Currently being breastfed Currently taking complementary/alternative medications (please comment) Other Nutritional Consult No nutritional concerns identified at this time Nutritional consult requested Comments 2. Data Collection, Evaluation and Interpretation In depth nutritional assessment should be provided anytime patients are at risk of malnutrition. Patients can be identified as at risk by medical personnel, other caregivers, or by periodic screenings. Unlike nutritional screening, nutritional assessment should be performed by a professional trained in nutritional assessment, such as a dietitian, trained nurse or a medical doctor. Nutritional assessment consists of 3 parts: data collection, data evaluation, and interpretation of findings [20]. Data collection should include diagnosis, historical data, nutrition-focused physical examination, anthropometry and measures of body composition, biochemical and hematological indices, and diet [21]. Nutritional assessment is a dynamic process performed to measure body size and composition for comparison with standards, to estimate nutritional needs, and to evaluate nutritional status and intake adequacy [22]. Diagnosis Oncologic diagnoses predispose patients to increased risks for malnutrition. Patients with cancers of the digestive tract (e.g., esophageal, gastric, pancreatic, liver, gallbladder, bile duct, and small and large intestine) especially may have severe weight loss due to changes in

6 Terezie Tolar Mosby and Ronald D. Barr normal digestion and absorption [23]. Cancers posing high nutritional risks in children are advanced/metastatic solid tumors (e.g. neuroblastoma), non-Hodgkin lymphoma (stages III, IV and relapsed disease), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) with poor prognosis (high risk categories and relapsed disease), medulloblastoma and other brain tumors. All patients undergoing allogeneic HSCT are also at high risk for the development of malnutrition. Historical Data Historical data may include a medical history (acute and chronic illnesses, surgical and diagnostic procedures and medication use), diet history (use of dietary supplements), oral intake history, use of alternative or complementary medicine and weight history. Questions about the psychological status of patients should be asked with special attention to stress and depression. Patients should be asked about the use of over-the-counter medication, vitamins, and dietary and herbal supplements. Nutrition-Focused Physical Examination The nutrition-focused physical examination of an adolescent and child with cancer is an integral part of nutritional assessment and should never be omitted. It should include the general appearance and activity level of the patient. The clinician should focus on the presence of edema, ascites, cachexia, obesity, skin changes, dry mucous membranes, petechiae or ecchymoses, healing of wounds, glossitis, stomatitis, and cheilosis [24]. The physical examination should include an evaluation of body composition, including fat and muscle stores. Places to assess fat stores are overlying the lower ribs, orbital fat pads, groins, and armpits. Places to assess muscle stores are temples, clavicles, calves, and quadriceps (thighs) [25][26]. Other physical signs of malnutrition are liver enlargement and changes in skin, hair, eyes, face, lymph glands, mouth, teeth, and psychological status [27][28][29]. Nutritional skin disorders are also common as part of vitamin or mineral deficiencies [30]. Anthropometry and Measures of Body Composition These measures can be divided by level of resources needed for accomplishment and by the need for accuracy and precision as routine, midlevel and advanced. Routine measures include weight, height/length, head circumference (in children <3 years), weight for height/length, and body mass index (BMI). Midlevel measures include triceps skin fold thickness (TSFT), mid-upper arm muscle circumference (MUAMC), and waist-to-hip ratio. Advanced measures include bioelectrical methods, dual-energy X ray absorptiometry (DXA), air-displacement plethysmography (ADP), total body potassium (TBK) counting and isotope dilution methods (deuterium oxide dilution). Previous studies have shown that anthropometric measurements such as height, weight and BMI and their indexes will not accurately identify malnourished patients and should be used only as a first line of assessment for nutritional problems [31]. It has been shown that, while patients with cancer may have normal weight compared to healthy controls, they have higher fat mass and lower body cell mass (BCM - the metabolically active component of fat-free mass), which is an indicator of nutritional status

Nutrition in Children and Adolescents with Cancer 7 [31]. Anthropometry can provide a considerable amount of nutritional information about the patient. However, it is important to have trained individuals performing the anthropometry to ensure that the measurements are taken accurately and precisely. Inappropriate measurements by untrained professionals can provide misleading information on nutritional status. I. Routine Measures Weight. Weight should be measured daily while the patient is in the hospital and during each outpatient visit. Weight can be influenced by the patient’s body composition, fluid status, medication use, organ enlargement, or tumor mass. Weight should be measured at the same time of day and similar clothing should be worn for consistency. Weight is not a good indicator of nutritional status. Height/Length. Height should be re-assessed in children and adolescents periodically. In children, height should be reassessed more often during rapid growth and can be affected by chronic malnutrition (stunting), marginal deficiency of several micronutrients [32] or impaired growth due to anticancer therapy and steroid use [33]. Head circumference. In children less than 3 years of age, head circumference should be measured periodically. It is the distance from above the eyebrows and ears and around the back of the head. It should be compared to past measurements of a child's head circumference and to normal ranges for a child's sex and age (weeks, months). Weight for height/length. Weight for height or weight for length is sometimes used in children, especially in children under 3 years of age, and compared to standards using the Centers for Disease Control (CDC) growth charts or the World Health Organisation (WHO) growth charts. Weight for height (W/H) is an indicator of acute malnutrition when a child is too thin for a given height (wasting) [34]. Height for age (H/A) can be an indicator of chronic malnutrition. When a child is exposed to inadequate nutrition for a long period of time, growth is reduced, resulting in stunting [35]. Body mass index (BMI) and BMI z-score. BMI is considered to be a good indicator of fat mass in adults [36] as well as in children [37] but not a good indicator of BCM [31]. For calculation of BMI see Table 2. Table 2. Calculation of body mass index (BMI) BMI is calculated by dividing the subject's mass (weight) by the square of his or her height, typically expressed either in metric or U.S. \"customary\" units: Metric: BMI = kilograms/meters2 U.S. customary and imperial units: BMI = lb x 703/in2 where lb is the subject's weight in pounds and in is the subject's height in inches In children, BMI is calculated and compared to z-scores. BMI z-score requires the use of LMS values (The LMS parameters are the median (M), the generalized coefficient of variation (S), and the power in the Box-Cox transformation (L)) and a calculation, or it can be compared to BMI z-score charts. BMI z-score charts can be obtained from the CDC website.

8 Terezie Tolar Mosby and Ronald D. Barr II. Midlevel Measures Triceps skinfold thickness (TSFT). Arm anthropometry may be useful in assessing fat stores, especially in children and adolescents with a tumor mass [38][39][40]. In one study, patients’ skin folds were found to be a poor predictor of fat mass when compared to DXA [41]. However, in other studies, skinfolds, especially biceps skinfolds, were found to correlate strongly with the percentage of body fat [37]. They were also found to be easier to obtain in children than TSFT [37]. Nonetheless, fat stores are not a reliable indicator of malnutrition – see above. Fat folds can be used to assess body fat reserves objectively and directly, and should be re-examined for accuracy. A strict technique should be followed to obtain reproducible measurements. Calipers are used. TSFT is taken by measuring a fold of skin running parallel to the length of the arm over the triceps muscle midway between the acromion and olecranon [8]. Measured values are then compared to reference tables [42][43]. Anthropometric measures are an inexpensive option for assessing nutritional status, but they can be affected by fluid retention, dehydration, or steroid therapy [44][45]. Arm circumference. Mid Upper Arm Muscle Circumference (MUAMC) provides a measure of muscle mass [46]. It is the circumference of the upper arm, measured at the mid- point between the tip of the shoulder (acromion) and the tip of the elbow (olecranon process). In children, MUAMC is helpful for the assessment of nutritional status [47] [48]. It is good at predicting mortality and, in some studies, MUAMC alone [49] or MUAMC for age [50] predicted death in children better than any other anthropometric indicator. It also correlates well with lean body mass, as measured by DXA [41]. Calculation of Ideal Body Weight (IBW) and percentage of Ideal Body Weight (%IBW). For calculation of IBW in children and in adolescents, see Table 3. Patient’s actual weight should be compared with IBW. Percentage of IBW is typically recorded (see Table 3). The calculation of weight as a percentage of ideal weight for age, height and gender in children is shown in Table 3. Percentage of IBW may both under- and over-estimate the severity of malnutrition in children with a chronic disease [51]. Calculation of weight change. Weight change should be calculated in 1 week, 1 month, and 6 month intervals. Table 3. Calculation of ideal body weight (IBW) and percentage of IBW (%IBW) A. Estimated IBW in children and adolescents - Option # 1 Used for children under 100cm. in length. Plot weight at the 50th % ile on the weight for length/height growth curve. - Option # 2 Plot BMI at 50% ile for age on the BMI for age and gender- specific growth chart. Multiply by BMI at 50% ile by height in m2 B. Weight as a percentage of ideal body weight: Express actual weight as percentage of IBW Option # 1 (actual weight/ideal weight-for-height) x 100 Option # 2 (actual weight/ideal body weight calculated using BMI) x 100

Nutrition in Children and Adolescents with Cancer 9 III. Advanced Measures Bioelectrical Methods. Bioelectrical impedance analysis (BIA) is a method used commonly for estimating body composition. BIA provides a reliable estimate of total body water, fat mass (FM) and fat free mass (FFM) under most conditions. It can be a useful technique for analysis of body composition in healthy individuals and in those with a number of chronic conditions [52]. The “Tanita” body composition scale has been approved for use in children. It has been suggested that nutritional assessment of patients with cancer should not be limited to anthropometric methods, but that body composition analysis should be used as well [53]. Body composition scales are the most feasible, non-invasive and affordable way to estimate body composition. The cost is not as high as with other methods for assessing body composition – see below. However, one disadvantage of BIA is that it usually cannot be used in children under 5 years of age and requires the patient to be able to stand and hold handles with both hands. Dual Energy X-Ray Absorptiometry (DXA). DXA is a non-invasive technique for measuring bone mineral content (BMC) and bone mineral density (BMD) with minimal exposure to ionizing radiation [54]. It is also becoming accepted as a standard in clinical practice for assessing body composition in children [55]. The combination of whole body BMC, fat mass (FM) and fat-free mass (FFM, very similar to lean body mass) total together to equal whole body weight. Deficits in bone mineralization are common sequelae of the treatment of cancer in children and adolescents [56]. Total Body Potassium (TBK) – reference method. Total body potassium (TBK) concentration is correlated linearly with the size of the BCM. It measures BCM and FFM and is independent of extra-cellular fluid changes. BCM is the metabolically active component of FFM and it is the component of FFM that is reduced in malnutrition [57]. The measurement of BCM has been proposed as the best measurement of nutritional status in populations with cancer [31], but the technology has not been commercialized (and so is not widely available) and its interpretation in children with cancer has been criticized [58]. TBK is used mainly as a reference method due to its cost and time commitment. BCM is calculated from TBK analysis. Air-displacement Plethysmography (ADP). ADP is an advanced technique for assessing body volume, which can then be used to calculate body density and estimate FM and FFM. The principle is similar to hydrostatic (or \"underwater\") weighing. The principles of ADP include densitometry, mass measurement, volume measurement, thoracic gas volume, and surface area artifact. ADP was found to be the only method that could estimate fat mass without bias in children [59]. Isotope Dilution Methods (deuterium oxide dilution). Deuterium dilution is used for measurement of total body water. Deuterium is given orally as deuterium oxide, and after mixing with body water it is eliminated from the body in urine, saliva, sweat and human milk. The enrichment of deuterium can be measured by isotope ratio mass spectrometry or Fournier Transform InfraRed (FTIR) spectrometry. Biochemical and Hematological Indices Biochemical data include measures of visceral proteins (albumin, prealbumin, retinol binding protein and transferrin), blood glucose levels and lipid profiles. Hematological measures include hemoglobin, hematocrit, and total lymphocyte count. Collected laboratory values should be compared with reference values.

10 Terezie Tolar Mosby and Ronald D. Barr Visceral proteins. Many factors can affect the level of visceral proteins. C- reactive protein (CRP) is a measure of systemic inflammatory response. Systemic inflammation is common in patients with cancer; it disturbs many biochemical indices and has been correlated adversely with survival [60]. If CRP levels are elevated, visceral protein levels may need to be adjusted. Albumin. The normal serum albumin level is 3.5-5 g/dL, and albumin has a half-life of approximately 20 days. Even though many factors can influence albumin levels, the pre- operative level of albumin has been found to be an excellent predictor of surgical outcome [61][62]. A reverse relationship has been found between serum albumin levels and post-operative morbidity and mortality [63]. When albumin levels are markedly low, it is a common medical practice to provide albumin infusions. Albumin concentrations can be increased by the use of corticosteroids, insulin or thyroid hormone and by dehydration (as can other markers). Albumin concentrations decrease in acutely or chronically ill patients due to the effects of inflammatory mediators on hepatic protein synthesis [64][65]. Severe liver and renal disease, malabsorption, intravascular volume overload, and zinc deficiency decrease serum albumin levels. Prealbumin and retinol-binding protein. Prealbumin (transthyrretin) and retinol binding protein, with their short half lives, reflect more recent protein intake rather than an integration of protein nutritional status. The normal level of prealbumin is 16-40 mg/dL, and prealbumin has a short half-life of just 2-3 days. It is a favorable marker for acute changes of nutritional status. Both prealbumin and albumin are acute-phase reactants. A study to determine the usefulness of visceral proteins in assessing patients after HSCT found that prealbumin, retinol-binding protein and transferrin all were sensitive markers [66]. Prealbumin, retinol- binding protein and transferrin have also been shown to be useful for nutritional assessment of patients in intensive care units [67]. However, prealbumin is influenced by some of the same factors that affect albumin [67]. Therefore, if prealbumin is used as an indicator of nutritional status, it must be recognized that its concentration can be affected by the inflammatory response and not just by the nutritional status of the patient [67]. Another factor that affects levels of prealbumin is kidney failure. In this context, prealbumin levels will be high due to a lack of degradation by the renal tubules [68]. However, serial prealbumin analysis is also a good predictor of subsequent albumin levels and adverse outcomes [69]. These tests may be expensive and require drawing blood. A variety of factors can affect laboratory values, including chemotherapy and other medications, infection, and meals. Therefore, visceral proteins may not be adequate for assessing nutritional status [70]. Blood glucose levels and lipid profile. In most people, a state of malnutrition indicates that not enough calories are being consumed to maintain metabolic demands. In malnourished patients with cancer, increased glucose production occurs in the fasting state, and there are abnormalities with insulin secretion and action [71]. Malnutrition can cause glucose intolerance and impairment of insulin secretion [72] [73]. Insulin resistance due to disease or medication used during treatment, including glucocorticoids and L-asparaginase, is common [74]. When hyperglycemia occurs, synthesis of very low-density lipoprotein (VLDL) is driven up, and both serum triglycerides and cholesterol rise. A lipid profile is a group of tests to measure total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. In cases of PEM, patients

Nutrition in Children and Adolescents with Cancer 11 experience an increase in plasma total triacylglycerol concentration (a measure of fat stored in the body) and decreased HDL concentration. This is caused by a reduction in the activity of lipoprotein lipase. Adult patients with cancer have been found to have similar lipid profiles [75]. One study involving children with cancer showed that those who had undergone HSCT and those with solid tumors had significantly higher triacylglycerol levels due to increased VLDL and LDL particles in the blood and significantly lower HDL than healthy children [76]. L-asparaginase induces prominent changes in the lipid profile, especially hypertriglyceridemia [77]. Hemoglobin/hematocrit. In a state of malnutrition, hemoglobin and hematocrit levels tend to decrease due to inadequate amounts of protein consumption and possible iron deficiency. Other causes of decreased hemoglobin and hematocrit in children with cancer include chemotherapy, penetration of malignant cells into the bone marrow, radiotherapy, inflammation, and blood loss [78]. However, hemoglobin and hematocrit levels can be falsely high if the person is dehydrated. Iron status should be considered when evaluating hemoglobin and hematocrit, and the best single marker is serum ferritin. However, ferritin is also an acute phase reactant and hence may be falsely elevated. In this case, measurement of the transferrin receptor may help establish whether the patient is truly iron deficient [79]. Many children with cancer experience iatrogenic myelosuppression and anemia of sufficient severity that repeated red blood cell transfusion is required, resulting in some degree of iron overload rather than iron deficiency. Lymphocyte count. Malnutrition can be indicated also by a trend of low total lymphocyte counts, but this may be due to chemotherapy or the impact of the disease [80][81]. Other Studies Additional studies may be performed to better evaluate a patient’s risk of malnutrition, including nitrogen balance studies and delayed hypersensitivity testing. Other tests that may be used to evaluate patients’ nutritional status are the prognostic nutritional index and the creatinine height index, that is a measurement of the 24-hour urinary excretion of creatinine, which is related to the patient’s muscle mass and can be used as an indicator of malnutrition [58]. Tests for maldigestion and malabsorption may be required in some instances. Following the screening assessment, the choice of tests and the timing of their performance will be dictated by the particular clinical circumstances. I. Nitrogen Balance Nitrogen balance studies provide assessments of protein metabolism in the body, but these are not used commonly as a clinical tool due to the necessity of urine collection. Nitrogen balance occurs when nitrogen output equals nitrogen input. Negative nitrogen balance indicates inadequate protein intake, and positive nitrogen balance indicates nitrogen retention [82]. In patients with cancer, negative nitrogen balance is a result of inadequate intake of protein and/or increased protein catabolism. Continued negative nitrogen balance can lead to protein malnutrition, which is a cause for concern in patients undergoing anticancer treatment [83]. Patients’ nitrogen balance can improve with the use of high- nitrogen total parenteral nutrition [84][83][85]. It is important to monitor nitrogen balance to prevent deterioration of lean body mass and to ensure quicker recovery. Measurement of total nitrogen is not usually available, but a reasonable surrogate is to monitor 24h urinary urea excretion and to determine how it responds to an increase in protein intake. Nitrogen intake is

12 Terezie Tolar Mosby and Ronald D. Barr measured by dividing grams of protein consumed by 6.25, as it is estimated that 6.25 grams of protein contain 1 gram of nitrogen. Urine collected for 24 hours over 3 consecutive days is the ideal way to estimate nitrogen output [86]. Such collections are challenging in small children, especially those wearing diapers, due to difficulty in achieving complete samples. II. Delayed Hypersensitivity Testing Delayed cutaneous hypersensitivity (DCH) is a test to determine whether the body reacts to foreign substances such as antigens or allergens that are injected into the skin. A reaction should occur 24-48 hours after exposure to the foreign substance. This type of test measures cell-mediated immunity. It was developed for use in adult patients and requires prior exposure to an antigen; therefore it is less useful in infants and young children. Malnutrition can affect the levels of circulating antibodies that respond to the stimuli or prevent the cells that regulate immunity from recognizing foreign stimuli, giving a person a false negative response in DCH [87]. As a result, an improvement in nutritional status should increase DCH. In one study involving 160 patients with cancer who were undergoing surgery, chemotherapy, radiation, or supportive care, nutritional repletion through intravenous hyperalimentation (IVH) was provided, and skin tests before and after IVH were examined [88]. The study showed that patients with nutritional repletion either remained positive or converted from negative to positive. This test is not commonly administered in pediatric clinical settings. III. Prognostic Nutritional Nutritional Index Prognostic nutritional index (PNI) is a method to determine nutritional status and risk of complications. PNI involves using a formula that can include variables such as albumin, prealbumin, delayed hypersensitivity, transferrin, and TSFT. This test has not been validated for infants and children. A similar test, the simple pediatric nutritional risk score, was found to be suitable for routine use to identify patients at risk of malnutrition during hospitalization. The test includes assessment of dietary intake, diarrhea and vomiting, pain, and the ability of the patient to eat [89]. The simple pediatric nutrition risk score has not been tested for children undergoing anti-cancer treatment. IV. Creatinine Height Index The creatinine height index (CHI) is a method to assess relative muscle mass. Creatinine is excreted in the urine and is a derivative of creatine, a storage form of protein in muscle. When an increased breakdown of muscle occurs in the body, the loss of creatinine is seen in the urine. The CHI can be used to assess children’s muscle mass and determine whether they are protein malnourished and need protein repletion in the diet. The CHI is defined for children as the ratio of 24-hour creatinine excretion by the patient to the amount of excretion of a healthy child of similar height. Age is not considered. If the CHI is close to 1.0, the child is within the normal range. If it is closer to zero, the child may be protein-malnourished and need nutritional supplementation [90]. One study used CHI as a way to identify a patient population as malnourished or well-nourished before surgery and to determine whether there was a difference in post-operative complications [91].

Nutrition in Children and Adolescents with Cancer 13 V. Maldigestion and Malabsorption Maldigestion or malabsorption may be assessed by a 3-day fecal fat test and calculation of the percentage of dietary fat absorbed (3-day stool collection combined with 3-day dietary record). Coefficient of fat absorption values are < 85% for infants and < 93% for older subjects, and can be used to define steatorrhea [92]. Maldigestion can be due to loss of regulated gastric emptying, insufficient pancreatic exocrine function, bile salt deficiency, or intestinal mucosal disease. Malabsorption can be caused by loss of intestinal surface area, impaired circulation or lymphatic damage in the gut, mucosal infiltration with abnormal cells, genetic mutations of transport proteins, or impaired gut motility. Diet Evaluation of a patient’s diet is an important part of nutritional assessment and consists of 3 parts: evaluation of a dietary history, assessment of current dietary intake and comparison of dietary intake to estimated calorie needs. I. Dietary History Dietary history consists of information about current dietary orders, prior history (current home feeding regimen, food consumption patterns, quality and quantity of food, food preferences, feeding environment, and food allergies and intolerances), social issues (socioeconomic status, caregivers’ perception of the patient’s nutritional status, and religious or cultural factors that affect food intake), and clinical factors (vitamin and supplement use, stool habits and characteristics, activity level, developmental status, and sleep patterns) [93]. II. Dietary Intake Oral intake can be assessed using different methods. Some common methods are 24-hour dietary recall (asking about all oral intakes from the previous day), a 3-day calorie count, or a food frequency questionnaire [94].. Obtaining a patient’s food history is an inexpensive way to determine his or her current eating habits. However, it requires the patient or caregiver to be able to recall what the child eats and estimate portion sizes. III. Comparison of Dietary Intake to Estimated Calorie Needs Current dietary intake will be compared with estimated caloric needs. A patient is considered at nutritional risk if he or she consumes less than 50% of estimated caloric needs for up to 3 days [95] or less than 80% for more than 3 days [96] . 3. Nutritional Risk Weight and height or length and BMI, or weight for height in children younger than 3 years, should be compared with values on age- and sex-specific growth charts. For children living in the United States, CDC growth charts should be used [97][98]. CDC charts have a higher percentage of children under the age of 2 being at risk for malnutrition. The CDC charts were formulated using a broader, more diversified sample of children than the NCHS and Tanner-Whitehouse charts [99]. For children from other countries, WHO charts should be used for children up to age five, since these charts only extend to this age, beyond which the

14 Terezie Tolar Mosby and Ronald D. Barr CDC charts should be used [100]. The WHO created a growth chart using children from ethnicities and cultures from various parts of the world [101]. Studies have shown that infants who are breast-fed exclusively grow at a different rate than formula-fed infants; therefore, WHO charts specific to breastfed children should be used for those infants [102]. Fenton charts are used for pre-term infants. These charts plot pre-term infants from 24 to 50 weeks of gestation and are not sex-specific. Specialized growth charts are also available for children with Down syndrome, cerebral palsy, Turner syndrome, Prader-Willi syndrome, and achondroplasia. Nutritional intervention is indicated for children at risk [96]. Determination of nutritional risk is illustrated in Table 4. Table 4. Nutritional risk Screening – periodically Assessment – at diagnosis and depending on the screening values ESTIMATION of RISK Anthropometric Measurements Weight loss  More than the 5% weight loss in 1 month  Current percentile weight or height fallen by 2 channels or more Weight for Age  Less than the 5th or >85th percentile Length or Height for Age  Less than the 5th percentile height-for-age (may indicate chronic malnutrition) Weight for Length or Height  Less than the 5th percentile or >95th percentile weight-for-length (under 3 years)  Less than the 5th percentile - underweight (indicator of inadequate weight gain)  More than the 95th percentile - indicator of obesity Body Mass Index (BMI)  More than the 95th percentile - obese  More than the 85th percentile - overweight  Less than the 15th percentile - undernourished  Less than the 5th percentile - severely undernourished

Nutrition in Children and Adolescents with Cancer 15 Ideal Body Weight (IBW) calculated from weight for length/height  More than110% - overweight  85-89% - mild undernutrition  More than 75-84% - moderate undernutrition  Less than 75% - severe undernutrition Ideal Body Weight (IBW) calculated from BMI  More than120% - overweight  80-89% - mild undernutrition  70-79% - moderate undernutrition  Less than 70% - severe undernutrition Head circumference-for-age  More than the 95th percentile (may indicate macrocephaly)  Less than 5th percentile (may indicate microcephaly or chronic malnutrition during fetal life or early childhood) Arm anthropometry Assessment of subcutaneous fat and muscle mass for signs of under/overweight  Triceps skin fold estimation of energy stores - compare to reference values  Mid-upper arm muscle circumference (MUAMC), indicator of lean body mass – compare to reference values Nutrient intake Less than 50% of estimated energy needs for up to 3 days Less than 80% of estimated energy needs for a longer period of time C. Common Complications of Treatment Affecting Nutrition Patients undergoing chemotherapy, radiation and HSCT can experience any or all of the following side effects: nausea, vomiting, mucositis, constipation, diarrhea, altered taste, loss of appetite, pancreatitis, colitis and pneumatosis intestinalis. Any of these side effects could result in undesirable weight loss, PEM or cancer cachexia. In addition, HSCT patients are at risk for GVHD and veno-occlusive disease (VOD).

16 Terezie Tolar Mosby and Ronald D. Barr Protein Energy Malnutrition PEM occurring in association with cancer is usually a mixture of inadequate intake combined with the stress and catabolism caused by the disease, and adverse side effects of the treatment. An inadequate energy intake is associated with loss of adipose tissue which can be measured as a reduction in skin fold thicknesses (see anthropometric measures). It is useful to think of PEM as adapted or unadapted [20]. The central concern is whether the subject’s protein homeostasis is able to adapt to an insufficient intake; if so the serum albumin will remain normal. In the unadapted state, protein homeostasis is unable to adapt; serum albumin falls and there is rapid wasting of muscle mass as occurs in cancer cachexia. Most often there are differing degrees of energy and protein insufficiency. Hence the use of the term PEM, which was first introduced to describe malnutrition occurring in children. Cancer Cachexia Cancer cachexia is a well recognized condition in which there is rapid deterioration in body composition. Wasting occurs in skeletal muscle as well as other components of lean body mass (see anthropometric measurements of muscle wasting). Furthermore, there is a disturbance of whole protein homeostasis with net catabolism, negative nitrogen balance, a decrease in blood urea nitrogen and a fall in serum albumin. If untreated, cancer cachexia results in rapid deterioration of the patient’s nutritional status, leading to a “nitrogen death”. In children and adolescents with cancer, cachexia is influenced by several factors, including type of disease, socioeconomic status, and type of treatment. Graft-versus-Host Disease GVHD is a potential complication following allogeneic HSCT. The donor's immunoregulatory cells attack the patient's organs, impairing their ability to function and increasing their susceptibility to infection. To increase the odds of engraftment and minimize the risk of GVHD, the donor and patient are matched as closely as possible based on human leukocyte antigen typing. There are two types of GVHD: acute and chronic. Traditionally, the presence of GVHD beyond 100 days after HSCT was called chronic GVHD. However, the National Institutes of Health recommends now that acute and chronic GVHD should be distinguished by clinical manifestations and not by time after transplantation. The new classification includes late-onset acute GVHD (after 100 days) and an overlap syndrome with features of both acute and chronic GVHD [103]. Acute GVHD. The signs of acute GVHD may be a skin rash appearing on the individual's hands and feet. Cramping, nausea, and watery or bloody diarrhea are other signs of GVHD in the stomach or intestines. A rising bilirubin with jaundice may be a sign that acute GVHD has affected the liver. Chronic GVHD can be multisystemic involving the skin, gastrointestinal tract, liver, musculoskeletal system, and the immune system. To date, there has been no effective means to prevent chronic GVHD. The most successful treatment of patients with chronic GVHD is a

Nutrition in Children and Adolescents with Cancer 17 systematic approach to management with a multidisciplinary team. Two means of treating GVHD that have been found effective are extracorporeal photopheresis and psoralen and ultraviolet A irradiation (PUVA) therapy. Extracorporeal photopheresis involves removing the blood from the body and then treating it with a combination of ultraviolet light and certain drugs that become active on exposure to light. Once the blood has been treated, it is then returned to the patient. PUVA therapy is a photodynamic therapy that is used to treat GVHD specifically affecting the skin. During PUVA therapy, the patient will receive the drug psoralen, which becomes activated in the presence of light, either by mouth or by applying it to the skin. The patient then undergoes ultraviolet A radiation. If an individual develops GVHD, he or she can experience any or all of the following side effects: dry mouth, decreased secretion of saliva making swallowing difficult, and difficulty eating acidic foods because of burning and discomfort. GVHD may also cause a lack of lubrication in glands in the stomach and intestines, which interferes with the ability to properly absorb nutrients from food. Other symptoms may include heartburn, stomach pain, nausea, diarrhea and vomiting. There may be malabsorption of macronutrients from food and weight loss. Patients with GVHD often require immunosuppressive medications such as cyclosporine, mycophenolate, and steroids. Dietary guidelines are to follow a low-bacteria, lactose-free, and/or GVHD low residue, bland diet. Veno-Occlusive Disease Veno-occlusive disease (VOD) is a potentially serious liver problem caused by high doses of chemotherapy or radiation given before HSCT. The blood vessels within the liver become swollen or obstructed, impairing the liver's ability to remove toxins, drugs, and waste products from the bloodstream. Fluid accumulates in the liver, causing swelling and tenderness. A patient with VOD may experience any or all of the following symptoms: jaundice, enlarged liver, pain and tenderness in the area of the liver, rapid weight gain, edema, or accumulation of fluid in the abdominal cavity (ascites) The nutritional intervention for VOD is to limit fluid intake to maintenance level or less. These patients may require aggressive fluid restriction to prevent a buildup of fluid that may cause respiratory and renal complications. This may compromise energy intake for a short time. Parenteral nutrition is usually concentrated to the limit to provide maximal energy with restricted volume. The features of VOD are encountered usually in the first 4 weeks after the conditioning/preparative regimen for HSCT. VOD is also referred to as sinusoidal obstruction syndrome (SOS) specifically for cases resulting from chemotherapy or HSCT. Renal Complications Patients may have pre-existing renal dysfunction as a result of their underlying disease and/or previous therapy. High dose chemotherapy and radiation as part of anti-cancer treatment or administered in the preparative regimen for HSCT may cause renal damage directly.

18 Terezie Tolar Mosby and Ronald D. Barr Rapid cytolysis of tumor can cause tumor lysis syndrome with renal injury resulting from hyperphosphatemia. Post-transplant infections can lead to acute renal dysfunction because these may be accompanied by hypotension and renal hypoperfusion. Antimicrobials used for prophylaxis and treatment of infections are also commonly nephrotoxic. A patient with renal dysfunction may require reduced volumes of fluid, decreased amounts of protein or amino acids, or adjustment in electrolytes. During renal dysfunction, parenteral nutrition is usually concentrated to the limit to provide maximal energy with restricted volume. Mucositis Mucositis is a common occurrence in cancer patients. It is a painful inflammation and ulceration of the mucous membranes lining the digestive tract and occurs due to chemotherapy, local radiation, and total body irradiation. It also reduces an individual’s ability to eat and drink adequately. Pain medications can help manage mucositis, but intravenous infusions may also be necessary to prevent dehydration and malnutrition. Furthermore, oral glutamine supplementation has been shown to decrease the severity of mucositis in children undergoing HSCT [104]. Infection The risk of bacterial, viral, and fungal infections is high in cancer patients, as treatment destroys the normal production of neutrophils, monocytes, and macrophages. Common side effects of infection include diarrhea, nausea and vomiting. Food safety guidelines are recommended during periods of neutropenia. Typically, a low bacteria diet may be indicated. Furthermore, if the patient is symptomatic, a low lactose diet may be needed due to a decrease of intestinal lactase from antibiotic medication. Probiotics, such as Lactobacillus, may also be administered to modify the enteric flora. However, more research is needed to confirm safety and efficacy of probiotics on the immune system in neutropenic patients [105]. Pancreatic Insufficiency Pancreatic insufficiency occurs when the pancreas does not secrete enough digestive enzymes for normal digestion to occur. It may be caused by high doses of chemotherapy or radiation. In severe cases, malabsoprtion may occur. This leads to deficiencies of essential nutrients and is associated with loose and fatty stools (steatorrhea). The coefficient of fat absorption values are < 85% for infants and < 93% for older subjects, and can be used to define steatorrhea [91]. An easier and more effective method for determining maldigestion and malabsorption resulting from pancreatic insufficiency is a fecal elastase test. This test is a much more sensitive method of determining pancreatic insufficiency and the need for pancreatic enzyme replacement therapy than a fecal fat test.

Nutrition in Children and Adolescents with Cancer 19 Hemorrhagic Cystitis Hemorrhagic cystitis is diffuse inflammation of the bladder leading to dysuria and hematuria. It occurs in patients undergoing HSCT due to the conditioning regimen of chemotherapy (especially if this includes cyclophosphamide), radiation or infection. Fluid intake and output needs to be monitored closely in patients with hemorrhagic cystitis. Fluid intake may need to be increased. D. Nutritional Requirements Different methods exist for estimation of calorie and protein needs; for example, calculation of calorie needs in children undergoing HSCT (Table 5), using indirect calorimetry, or using double labeled water, the “gold standard” of caloric and protein estimations. Resting metabolic rate should be calculated using the FAO/WHO/UNU Expert Consultation for Human Energy requirements [106] and adding the activity quotient. Table 5. Energy requirements (kcal) of pediatric HSCT patients Age Calories (kcal) 1-12 months BMR1 x 1.6-1.8 1-6 years BMR x 1.6-1.8 7-10 years BMR x 1.4-1.6 11-14 years BMR x 1.4-1.6 15-18 years BMR x 1.5-1.6 >19 years BEE2 x 1.5 1BMR equations: WHO Method [143] located under the Calculators tab. 2BEE equations: Harris-Benedict Equation [117] Indirect Calorimetry Indirect calorimetry can be useful anytime hypermetabolism or hypometabolism is suspected and precise calorie requirements need to be estimated for weight management. The energy needs of a patient can be estimated either by using the World Health Organisation(WHO) predictive equation [106] or measured directly by respiratory gas exchange using an indirect calorimeter. Indirect calorimetry by the metabolic cart test or portable resting metabolic rate analyser measures energy expenditure and determines the caloric needs of the patient. Indirect calorimetry measures oxygen consumption, carbon dioxide production, and the respiratory quotient to determine energy expenditure and caloric needs. It is useful to relate the measured resting metabolic rate (RMR) with the calculated RMR [107].

20 Terezie Tolar Mosby and Ronald D. Barr Double Labeled Water Double labeled water is considered the “gold standard” for measuring metabolic rate. It is a form of water in which both the natural hydrogen and oxygen moieties have been replaced partly or completely for tracing purposes (i.e., labeled) with an isotope of each element. An average metabolic rate is measured over a period of time. The minimum number of samples is two; the initial sample and the second sample taken later. This method is safe for infants, children and adolescents. However, one disadvantage is its high cost. Energy Needs The energy needs of children with cancer are not well described. On the one hand, energy requirements may be higher due to mucositis, nausea and vomiting, and diarrhea. Furthermore, GVHD may also increase energy requirements after transplantation. However, a study by Ringwald-Smith et al [95] showed that the standard estimation equations for energy expenditure overestimate the energy needs of pediatric patients undergoing HSCT significantly. Similarly, a study on children undergoing allogeneic HSCT showed significant reductions in Resting Energy Expenditure (REE) after transplantation [108]. Until more research is undertaken on estimating energy needs, the use of indirect calorimetry is the best method currently available. Energy needs may be increased because of treatment, fever, infection, GVHD, metabolic complications, and the normal growth demands of children. Protein needs are increased for tissue repair and to decrease breakdown of lean body mass. These may be increased during high-dose corticosteroid therapy and during active GVHD, and may be modified if hepatic, renal, or neurological function is altered. Fat needs are altered when lipid clearance is decreased in patients with hepatic dysfunction Carbohydrate needs may be decreased if hyperglycemia occurs. For obese cancer patients, use adjusted body weight to calculate energy needs. See Table 6 for identifying failure to thrive (FTT) and calculating the energy requirements in this circumstance. Table 6. Calculating failure to thrive (FTT) 1) Weight for height/length below 5th percentile 2) Less than 80% of IBW based on height FTT (kcal/kg) = (RDA kcal for weight for age) x IBW (weight for height at 50%)/ actual weight OR add on 10% energy factor, using the BMR. Protein Requirements Children undergoing anticancer treatment have been shown to have decreased lean body mass [108]. Therefore, protein requirements should be increased to minimize this loss.

Nutrition in Children and Adolescents with Cancer 21 Protein is often calculated per 1 g nitrogen. In patients receiving parenteral nutrition, the usual non-protein calories to nitrogen (NPC: N2) ratio is 150 to 250 NPC for every gram of nitrogen provided. When monitoring for response, assess the prealbumin levels weekly. Prealbumin is influenced by fluid disturbances as well as renal and hepatic failure; therefore, prealbumin concentrations should not be used as a measure of response in those patients who are hemodynamically unstable. A baseline prealbumin should be obtained at the beginning of enteral or parenteral therapy. Albumin has a long half-life and therefore should not be used to assess response to nutritional support over a short period of time. See Table 7. for the equation to calculate protein requirements, Table 8 for the special circumstance of HSCT and Table 9 for the equation to determine protein requirements for those with FTT. Protein restriction may be required in patients with renal failure and liver failure. Table 7. Calculating protein requirements: (The equation to determine the grams of protein/kilogram of body weight of a patient) (Total energy / NPC) x 6.25 Body weight NPC = nonprotein calories NPC for low-stress patients (1 g nitrogen / 250 kcal) NPC for medium-stress patients (1 g nitrogen / 200 kcal) NPC for a catabolic child (1 g nitrogen / 150 kcal) 1 g nitrogen = 6.25 g protein Table 8. Protein requirements (g/kg/d) of pediatric HSCT patients Age Protein (g/kg/d) 1-12 months 3 1-6 years 2.5-3 7-10 years 2.4 11-14 years 2 15-18 years 1.8 >19 years 1.5 Table 9. The equation to determine protein requirements for those with FTT Protein = [protein required for weight for age (gm/kg/d) x IBW (kg)]/3.5 For patients with a pre-renal elevation of blood urea nitrogen (BUN) not related to renal failure (eg, gastrointestinal bleed, aggressive therapy with loop diuretics), protein restriction should be considered if the BUN rises above 60 (mg/dL). Also, it should be taken into consideration if the patient is maintained on catabolic steroid therapy. For Failure to Thrive (FTT), protein should be increased to 1.5 to 2.0 times the DRI (Dietary Reference Intake) for age. Avoid exceeding 4 g/kg. In a patient receiving total parenteral nutrition, use the total

22 Terezie Tolar Mosby and Ronald D. Barr energy: nitrogen ratio of 150 to 250 NPC for every gram of nitrogen provided. Protein tolerance can be monitored with BUN, serum creatinine, nitrogen balance, visceral proteins, and ammonia levels in patients with liver failure. Fat Requirements For infants and toddlers, fat intake equivalent to 30% to 55% of total energy is appropriate. Those older than 2 years may need less than 30% without compromising growth. More than 50% is not recommended. In total parenteral nutrition, fat should supply 20% to 60% of energy needs. Upper limit in infants is 4 g/kg/d. Medium-chain triglyceride (MCT) oil does not provide essential fatty acids (EFA) nor facilitate absorption of fat soluble vitamins. Monitor the patient receiving more than 86% of total fat as MCT oil, which contains 8.3 kcal/g. Microlipid is a source of EFA, containing 4.5 kcal/mL. Fluid Requirements Monitoring for fluid tolerance and response. Fluid needs may be increased in patients with significant losses like those with gastrointestinal (GI) suctioning, GI fistulas, persistent vomiting, diarrhea, and high fever. Fluid needs may be decreased in patients with renal failure or pulmonary edema, patients at risk for VOD, or patients at risk for capillary leak syndrome, which includes those undergoing high-dose chemotherapy, total body irradiation, and interleukin therapy. Table 10. Calculating fluid needs Method 1 Body Weight (kg) Amount per Day Maintenance 1-2 120-150 mL/kg 3-10 100 mL/kg 11-20 1,000 mL + 50 mL/kg for each kg above 10 >20 - 40 1,500 mL + 25 mL/kg for each kg above 20 >40 1,500 mL/m2 body surface area Method 2 Maintenance: > 11 kg = 1,500-1,800 mL/m2/day Fluid tolerance and response can be monitored by assessing weight changes, 24-hour fluid input and output, BUN, physical examination including skin turgor, and urine output. See Table 10 for calculating fluid needs.

Nutrition in Children and Adolescents with Cancer 23 Vitamin and Mineral Needs Vitamins and minerals are essential for normal growth and development in children. While there are no specific requirements for children with cancer, the patient’s nutritional plan should meet 100% of the Dietary Reference Intake (DRI) of vitamin and minerals. Risk of vitamin deficiency is higher in patients with diarrhea, vomiting and malabsorption. If vitamin and mineral supplementation is required, iron-free supplements are generally recommended as many patients experience repeated red blood cell transfusion, resulting in some degree of iron overload rather than iron deficiency. Of particular importance in children undergoing treatment for cancer are the nutrients required for bone development and maintenance. A recent study showed that vitamin D insufficiency and deficiency are common in children after anticancer treatment [109]. Vitamin D deficiency can be caused by many things, including limited sun exposure and malabsorption. Furthermore, long-term survivors are at risk for loss of bone mineral density (BMD) and subsequent osteoporosis [110]. Therefore, vitamin D and calcium levels should be monitored. The latest recommendations for Vitamin D intake are 600 IU/d [111]. Patients undergoing treatment may also be at risk for other vitamin and mineral deficiencies, especially vitamin K, zinc, copper and selenium. More research is needed regarding vitamin and mineral supplementation during treatment. E. Nutritional Therapy The goals of nutritional therapy for patients undergoing anticancer treatment are to maintain weight, and to achieve age-appropriate growth and weight gain after treatment. These goals can be achieved by dietary modifications, use of dietary supplements, appetite stimulants, or nutritional support. Oral Intake An evaluation of dietary intake and adequacy during anticancer treatment is paramount. Understanding how well the patient is eating before and during treatment will provide invaluable information that will aid in assessing the individual’s nutritional status and developing a nutritional plan. Detailed food records can be used to determine food preferences and aversions, and assist in managing the individual’s nutritional care. A complete dietary history should include an evaluation of oral and gastrointestinal symptoms related to chewing and swallowing, dental health, taste alterations, heartburn or gastric reflux, mucositis, and bowel habits. Appetite Stimulants The use of appetite stimulants in this patient population is recommended when other attempts to increase oral intake (such as oral supplements) have failed. A variety of appetite stimulants exists (see Table 11 ).

24 Terezie Tolar Mosby and Ronald D. Barr Table 11. Appetite stimulants Agent Trade Adverse Reactions Dronabinol Name Drowsiness, dizziness, depression, Marinol detachment, anxiety, difficulty concentrating, mood change, xerostomia, orthostatic Megestrol Megace hypotension, tachycardia, ataxia, headache acetate Edema, insomnia, fever, headache, depression, breakthrough bleeding and Cyproheptadine Periactin amenorrhea, changes in menstrual flow, nausea, vomiting, stomach cramps, cholestatic jaundice, hepatotoxicity, thrombophlebitis, hyperpnea Drowsiness, headache, fatigue, thickening of bronchial secretions, pharyngitis, nausea, diarrhea, abdominal pain, xerostomia, arthralgia Nutritional Support There are two main types of nutritional support available – enteral nutrition (EN) and parenteral nutrition (PN), depending on whether the gastro-intestinal tract is used for the delivery of support. Delivery of nutrients into the gut is the preferred method of feeding when use of the gastrointestinal (GI) tract is feasible. Utilization of the GI tract may not be feasible for the following reasons: persistent vomiting, intractable diarrhea, GVHD of the gut, ileus, a prolonged period of bowel rest after surgery, and inadequate gag reflex. Parenteral nutrition should only be utilized when the GI tract is not usable for at least 7 to 10 days. Exceptions to the “7- to 10-day rule” are children younger than 4 years of age or those who are already malnourished. There are different options for administration of EN. For example, gastrostomy or jejunostomy; nasogastric, nasojejunal, orogastric and orojejunal tubes. Enteral feedings using gastric or post-pyloric tubes are a viable option for some groups of patients, including those undergoing HSCT. Nasojejunal (NJ) tubes were used successfully in one small pilot study of adult allogeneic transplant recipients [112]. Mixed success has been achieved in other studies using naso-gastric (NG) tubes in adults and children [113][114] [115]. Difficulties with successful enteral feeding are related primarily to feeding intolerance with nausea, vomiting, and diarrhea. There has also been reluctance among care providers to insert tubes into neutropenic and/or pancytopenic patients, although the risk of infection has not been proven to be greater than the risk of feeding parenterally throughout transplantation. Parenteral nutrition (PN) is not always superior to individualized enteral feeding. It is recommended that total PN (TPN) be reserved for patients who cannot take advantage of enteral feedings (EN). Studies have found that, although TPN is shown to preserve body mass in critically ill patients, it is also linked to specific complications and high costs [116]. Although EN has been found in some cases to be less effective in maintaining BCM, use of EN did not change the outcomes of hematological recovery, length of hospitalization, and

Nutrition in Children and Adolescents with Cancer 25 survival. However, with EN, the most common toxicities and the high costs that are associated with TPN were avoided [113]. Studies have also found that an aggressive enteral feeding program, along with the help of a supportive team, can help to maintain nutritional status in the pediatric oncology population. A study by Hastings, White, and Young [117] found that EN via a NG tube was effective in providing nutrition during HSCT. Their findings were supported by a study that found that EN, when tolerated, was successful in limiting nutritional decline during HSCT [114]. A study by Stratton and colleagues [118] looked specifically at enteral and parenteral nutrition (PN) tube feeds with respect to appetite sensations and food intake. This study found that EN improved anorexia and voluntary food consumption typically in malnourished patients during recovery and that “small amounts of food taken orally during PN may relieve appetite sensations more effectively than PN alone.” The study concluded that total energy intake is amplified when PN is combined with oral food intake. PN has also been shown to delay resumption of oral intake in HSCT patients [119]. A study by Papadopoulou and colleagues [114] examined EN specifically after HSCT. Their research found that patients receiving EN had fewer episodes of fever, as well as fewer positive blood cultures. The study also observed that EN is more effective in preventing deterioration of nutritional status after HSCT than in patients not receiving EN. A significant positive correlation between duration of feeds and improvement in nutritional status was also found. EN provides an easy way to administer oral medications, with the exception of cyclosporine, given via a NG tube. A lower incidence of diarrhea was also found in patients on EN in comparison to those on TPN [115]. One study found that, during a time of extreme gut toxicity, continuous NG feeding could accelerate the healing process [120]. Other studies concerning EN and TPN found that EN maintained mucosal integrity by supporting the barrier function of the gut and therefore lowering the risk of bacterial translocation [121][122]. Glutamine The amino acid glutamine has been highlighted as a fuel source for rapidly replicating cells. Several studies have attempted to evaluate the clinical efficacy of glutamine- supplemented nutrition in patients with cancer [123]. Although one randomized, controlled study of glutamine-supplemented parenteral nutrition showed improved nitrogen balance, fewer clinical infections, and shorter length of hospital stay [124], subsequent studies have demonstrated similar but less dramatic results in allogeneic [125] and autologous [126] HSCT recipients. Another study using parenteral glutamine supplementation during autologous HSCT was associated with more relapses and death [127]. Studies using oral glutamine supplementation have found that they have no significant effects on clinical outcomes during HSCT [128][129]; therefore, the routine use of glutamine has not yet been justified. However, other studies suggest that glutamine supplements are safe and effective in reducing the severity of mucositis in children undergoing anticancer treatment and should be given consideration in the routine care of patients with cancer [104]. Patients with glutamine- supplemented diets have shown a significant decrease in the number of days they required morphine and total parenteral nutrition (TPN), both of which are objective indicators of a decrease in the severity of mucositis [130].

26 Terezie Tolar Mosby and Ronald D. Barr Refeeding Syndrome Refeeding syndrome is a problem that often occurs with the initiation of aggressive nutritional support. PN support is most commonly associated with the onset of refeeding syndrome, but this metabolic abnormality has been found to occur with both EN and PN. This syndrome is characterized by the individual becoming metabolically unstable with the development of hyperglycemia, hyperlipidemia, and hypophosphatemia. Individuals at highest risk for developing refeeding syndrome include chronically semi-starved, marasmic patients who have adapted largely to the use of free fatty acids and ketone bodies as energy sources. Some patients undergoing anti-cancer treatment may fit into this category because of treatment-induced weight loss and anorexia. Because nutritional support is commonly used with the HSCT population, a clear understanding of the causes and ways to prevent refeeding syndrome is crucial. To avoid the development of refeeding syndrome, nutritional support in patients at risk should be increased slowly [131][132]. Different Diets used in Children with Cancer Food poisoning can occur if a person eats or drinks something that contains harmful germs. Food consumed by immunocompromised patients should be prepared in a manner to minimize bacterial growth. Table 12. lists recommended dietary practices for immunocompromised patients. Some hospitals use stricter guidelines than those listed. Although there has been little convincing evidence that a low-microbial meal plan leads to a better outcome in the oncology setting, it is clear that food pathogens exist and, intuitively, fewer pathogens should reduce risk. A reasonable approach to keep recommendations current and appropriate is to consider questionable items individually with systematic analysis of food culture data. Because food culturing may be impractical for many institutions, another way to obtain food safety information is from reputable sources. Table 12. Dietary practices for immunocompromised patients  Practice good hand washing before, during, and after preparing and eating meals.  Do not share food with others.  Avoid foods from street vendors, salad bars, and shared bins of foods in grocery stores.  Wash raw foods well before eating; inspect for bruises, cuts, and mold. Do not eat food that smells bad.  Cook meats, fish, poultry, and eggs until well done.  Do not eat hot dogs, luncheon meats, or deli meats, unless these are reheated until steaming hot.  Do not eat pates or meat spreads unless canned or shelf stable.  Avoid unpasteurized selections of dairy products, fruit juices, vegetable juice, honey, and beer.

Nutrition in Children and Adolescents with Cancer 27  Do not eat soft cheeses such as feta, brie, and camembert, blue-veined cheeses, or Mexican-style cheeses such as queso blanco, queso fresco, and panela, unless these have been cooked. Pasteurized cheeses are still considered high risk.  Avoid raw eggs and smoked or pickled fish.  Keep foods at lower than 40°F or greater than 140°F to minimize growth of bacteria.  Clean all preparation items thoroughly before and after use to avoid cross- contamination.  Keep refrigerated leftovers for no more than 3 days.  Well water should come from a well that is tested yearly and it should be boiled 15 to 20 minutes before use.  Use clean utensils and food-preparation areas.  Divide leftovers into small units and store in shallow containers for quick cooking.  Refrigerate leftovers within 2 hours of cooking.  Discard leftovers that were kept at room temperature for more than 2 hours.  Reheat leftovers or heat partially cooked foods to more than 165°F throughout before serving.  Bring leftover soups, sauces, and gravies to a rolling boil before serving. F. Nutritional Monitoring and Evaluation Nutritional monitoring and frequency of reassessment will depend on the risk level and condition of the patient [95]. Patients at high risk will be assessed within 24 hours of admission and reassessed at a minimum of 2 times per week. The following factors, among others, may be true of these high-risk patients:  On nutritional support  Bone marrow transplantation (initial – see Table 13)  Weight loss of 3% to 5% in the last month  Nil by mouth status greater than 3 days Patients at moderate risk will be assessed within 72 hours of admission and reassessed, at a minimum, one time per week. These patients may present the following features, among others:  Non-chemotherapy induced nausea, vomiting and diarrhea  Mucositis and other oral problems  Modified diet Patients at low risk will be assessed within 72 hours of admission and reassessed as indicated. It is possible that these patients may be newly diagnosed and on protocols. Table 13 shows a suggested schedule for monitoring indices during early stages of HSCT.

28 Terezie Tolar Mosby and Ronald D. Barr Table 13. Suggested schedule for monitoring blood biochemical and other indices during early stages of HSCT Test Frequency Sodium, potassium, chloride, Every day until stable on total parenteral nutrition (TPN), then 3 times carbonate, BUN, creatinine, per week while on long-term TPN calcium, magnesium Phosphorus Three times per week until stable on TPN, then weekly Ionized calcium With consistent low serum calcium Liver function tests, albumin, Three times per week until Day +30, then weekly while on TPN total bilirubin Prothrombin time Weekly while on multiple antibiotics Vitamin D (25 OH D2+D3) Pre-transplant; then every 3 months until one year Zinc1 When increased losses are suspected Manganese, copper, selenium Monthly when on long-term TPN (4-6 weeks) Triglycerides Weekly while on intravenous lipid emulsion Weights Daily while an inpatient, then with every outpatient visit Input/Output Daily while an inpatient 1Clinical discretion should be used when evaluating zinc levels, keeping in mind that zinc levels in blood do not reflect tissue stores G. Follow-up Guidelines after Completion of Therapy Survivors of cancer in childhood are at risk for many long-term adverse effects of therapy. Lifestyle changes, including dietary modification, may help with the management of some of those sequelae. Dietary recommendation at discharge are listed in Table 14. Survival rates are increasing for most children with cancer. The 5-year survival rates for all cancers combined in high income countries has improved from 58.1% in 1975–77 to 83% for ages 0- 4 years; 81.2% for ages 5-9 years; 82.7% for ages 10-14 years; and 82.8% for ages 15-19 years in 2001-2007 [133]. The progress in survival rates is attributable largely to improvements in treatment and advances in research. Table 14. Discharge planning for pediatric oncology patients may include any or all of the following  Education on high-energy/high-protein diet  Education on the following diets: low bacteria or food safety, and lactose free  Graft-versus-host disease (GVHD) bland  Mucositis  Provision of oral supplement of choice and instruction on how to use  Provision of appetite stimulant and education on daily dosage  Education on how to keep dietary records  Education on parenteral nutrition (PN) or enteral nutrition (EN) Follow-up with outpatient dietitian as needed

Nutrition in Children and Adolescents with Cancer 29 The Children’s Oncology Group has developed Long-Term Follow-up Guidelines for Survivors of Childhood Adolescent and Young Adult Cancers [134]. These guidelines represent a statement of consensus from a panel of experts in the late effects of cancer treatment in young people. The current version of the COG-LTFU Guidelines (Version 3.0) is available online (www.childrensoncologygroup.org). Diet and Physical Activity for Survivors The American Institute for Cancer Research (AICR) also has guidelines for cancer survivors: Nutrition and the Cancer Survivor [135]. The three key areas to reduce cancer risk are weight, diet, and physical activity. The most recent recommendations from the World Cancer Research Fund (WCRF) / AICR second expert report (WCRF/AICR, 2007) are applicable for prevention of a secondary tumor or a recurrence. Table 15. lists the ten recommendations for cancer prevention. Table 15. Recommendations for cancer prevention 1. Be as lean as possible without becoming underweight. 2. Be physically active for at least 30 minutes every day. 3. Avoid sugary drinks. Limit consumption of energy-dense foods. 4. Eat more of a variety of vegetables, fruits, whole grains and legumes such as beans. 5. Limit consumption of red meats (such as beef, pork and lamb) and avoid processed meats. 6. If consumed at all, limit alcoholic drinks to 2 for men and 1 for women a day. 7. Limit consumption of salty foods and foods processed with salt (sodium). 8. Don't use supplements to protect against cancer. 9. *It is best for mothers to breastfeed exclusively for up to 6 months and then add other liquids and foods. 10. *After treatment, cancer survivors should follow the recommendations for cancer prevention. And always remember – do not smoke or chew tobacco *Special Population Recommendations. Anyone who has received a diagnosis of cancer should receive specialized nutritional advice from an appropriately trained professional. Additional recommendations covered in the Nutrition and the Cancer Survivor guidelines include: 1. Rethink the ratio of plant foods to animal foods (aim for two thirds or more plant- based foods) 2. Cook with care (marinate meats; don’t cook meats directly over the flame; avoid charred or burnt meat) 3. Handle food safely (keep hands, counters, dishes, cutting boards and utensils clean; wash fruits and vegetables thoroughly; use separate dishes/chopping boards/utensils for preparing raw meat, fish or poultry; thaw frozen food in microwave or refrigerator).

30 Terezie Tolar Mosby and Ronald D. Barr H. Prevention Causes of cancer in childhood are largely unknown. Small numbers are associated with Down syndrome, other chromosomal and genetic abnormalities, and ionizing radiation exposure. Nutrition plays an important role in many aspects of cancer development, treatment and long term survival. Recently, maternal diet and breastfeeding have been studied in relation to the development of cancer during childhood [136][137][138]. Some studies suggest that breastfeeding and a maternal diet containing folate and antioxidants during pregnancy can prevent some cancers in children [139][140]. I. Gaps in Knowledge and Opportunities for Research There are numerous gaps in our knowledge concerning the interaction of nutrition with cancer in children and adolescents. These include the effects of nutritional interventions on cancer outcomes and the influence of such interventions on co-morbidities; all providing rich opportunities for good clinical research. Conclusion Cancer is the leading cause of disease-related death in children and adolescents in the U.S and Canada. In the U.S. every year more than 12,000 children are diagnosed with cancer; approximately 155 new cases per million in the age group less than 15 years. Cancer is highly curable in young people. In high income countries the survival rate is 80% or higher. However, more than 80% of children live in low and middle income countries where the survival rate may be as low as 5%. Nutrition plays an important role in many aspects of cancer development, treatment and long term survival. The nutritional status of children when diagnosed with cancer can affect the outcome of treatment. Malnutrition, in the form of under and overnutrition, has a negative impact on the survival rate. Malnourished children are at an increased risk for treatment- related complications, reduced tolerance to therapy, altered drug metabolism, increased susceptibility to infection, and poorer treatment outcome. Anti-cancer treatment itself affects the nutritional status of patients and contributes to malnutrition. The severity and variety of side effects will depend on the nature of the disease and the treatment protocol used. Common side effects interfering with nutrition are nausea, vomiting, loss of appetite, alteration of taste, mucositis, pneumatosis intestinalis, and colitis. In those who have undergone hemopoietic stem cell transplantation, graft versus host disease (GVHD) may result in an additional nutritional challenge. On the other hand, prolonged steroid use, physical inactivity and certain changes in metabolism predispose children to obesity. Malnutrition precludes optimal healing and recovery from therapy; therefore maximal effort should be focused on its prevention and treatment. Nutritional assessment of children diagnosed with cancer is important for targeting dietary intervention. Special attention should be paid to metabolic derangements of

Nutrition in Children and Adolescents with Cancer 31 macronutrients, leading to protein energy malnutrition, and micronutrients such as deficiencies of vitamin D, vitamin K, zinc, copper and selenium. Dietary intervention includes the use of dietary supplements, modular boosters, appetite stimulants, probiotics, enteral and parenteral nutrition. Specific diets may be used during treatment, such as in periods of neutropenia, GVHD and other circumstances. Survivors of cancer in childhood are at risk for many long term adverse effects of therapy. Lifestyle changes, including dietary modification, may help with the management of some of those sequelae. But there are numerous gaps in our knowledge concerning the interaction of nutrition with cancer in children and adolescents. These include the effects of nutritional interventions on cancer outcomes and the influence of such interventions on co-morbidities; all providing rich opportunities for good clinical research. Patient Education Resources Recommendations for Patients to Manage Treatment-Related Side Effects Alterations in Taste and Smell  Decreased taste sensation o Select appealing foods; consider smell, texture and appearance. Bright colors attract interest. o Red meat may taste different; substitute poultry, fish, eggs, or other protein-rich foods. o Avoid foods that do not look and/or smell good. Try cold foods: cold sandwiches, cheese, shakes. o Try foods at room temperature.  Dental problems o Rule out dental problems as the source of strange tastes. o Ask your dentist about good mouth care. Mouth and Throat Problems  Sore mouth or throat, difficulty swallowing, and jaw pain Try soft and/or pureed foods that are easy to chew and swallow. o Cook foods until they are tender. o Cut foods into small pieces. o Use a blender to puree food and add gravies or sauces to moisten. o Use a straw to drink liquids. o Try foods at room temperature. o Adjust swallowing technique by tilting head back or moving it forward. o Rinse your mouth with water after eating to remove residual food and bacteria. o Ask your doctor about anesthetic lozenges and sprays for the mouth and throat. o Ask yourdentist/doctor to recommend a product to coat/protect mouth and throat. o Avoid foods that are irritating, such as rough, coarse foods; spicy or salty foods; and acidic foods like chili pepper. Replace citric fruits and juices with nectars.  Dental problems

32 Terezie Tolar Mosby and Ronald D. Barr o Maintain regular dentist visits. o Use a soft toothbrush and/or toothpaste for sensitive teeth/gums. o Avoid candies or gum that contain sugar; try sugar-free gum or candy instead. o Avoid sticky foods like caramel or chewy candy bars. o Ask your dentist/doctor to recommend a product to coat/protect your mouth and throat. o Rinse your mouth with water after eating to remove residual food and bacteria. o Ask your dentist to recommend a special cleaning product if gums and mouth are sore.  Dry mouth o Use a blender to puree food and add gravies to moisten. o Use lip salves to keep lips moist. o Sip on water or ice chips every few minutes. o Sweet/tart foods produce more saliva—this is not indicated with sore mouth or throat. o Suck on sugar-free hard candy, popsicles, or sugar-free gum—produces more saliva (if mouth and throat are not sore). o Rinse your mouth with water after eating to remove residual food and bacteria. o Ask your dentist/doctor to suggest artificial saliva. Gastrointestinal Complications  Cramps, bloating and gas, heartburn, getting full quickly and easily o For heartburn, sit up or stand for about an hour after eating. o Rest after meals (sitting up); do not participate in vigorous activity. o Wear loose-fitting clothing. o Avoid eating 1 to 2 hours before cancer treatment. o Avoid gas-producing foods such as broccoli, cabbage, cauliflower, beans, lentils, and onions. o Eat small amounts often and slowly. o Ask your doctor about medications.  Diarrhea o Drink plenty of liquids to prevent dehydration. o Consume small amounts of food throughout the day vs. three large meals. o Replenish sodium and potassium. o Eat a low-fiber diet. o Avoid grease, fat, raw foods, spices. o Drink liquids at room temperature. o Limit caffeine, strong teas, soda, and chocolate. o Rule out lactose intolerance.  Constipation o Drink plenty of liquids. o Drink something hot 30 minutes before expected bowel movement. o Eat a high-fiber diet. o Ask your doctor about stool softener/laxative.

Nutrition in Children and Adolescents with Cancer 33 Anorexia/Cachexia  Nausea and vomiting o Keep track of when nausea and/or vomiting occurs and the potential cause in a food diary. o Avoid hot foods—these add to nausea. o Avoid favorite foods during periods of nausea and vomiting. o Avoid greasy, fried, or heavily spiced foods. o Eat crackers or Melba toast before getting out of bed. o Ask your doctor about antiemetics. o Eat small amounts often and slowly. o Avoid eating in rooms with strong odors. o Drink fewer liquids with meals—these can cause a bloated feeling. o Drink/sip liquids throughout the day. o Drink cool/cold beverages. o With vomiting, avoid trying to drink or eat until it is resolved. o Drink small amounts of clear liquids until vomiting is controlled; then advance to full liquids and eventually a soft and/or regular diet.  Loss of appetite o Ask your doctor about an appetite stimulant. o Keep snacks handy and munch throughout the day. o Ask your dietitian/doctor about adding nutrients to diet with supplements. o Serve small food portions on small plate. o Stay calm at mealtimes; don’t rush to finish meals. o Question depression; consult a psychiatrist. o Encourage eating with others, such as family or friends. o Eat whenever hungry; don’t restrict intake to mealtimes only. o Take advantage of good days to increase your food intake. Weight Gain  Delay dieting/losing weight until the cause of weight gain is identified.  Follow no concentrated sweets/no added salt diet if weight gain is attributed to steroids.  Use glycemic load method to plan meals if insulin resistance is suspected.  Use a hunger scale.  Exercise regularly unless it is contraindicated.  Try to identify emotional and environmental reasons for overeating and snacking. References [1] Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., Smigal, C., et al. (2006). Cancer statistics, 2006. CA: A Cancer Journal for Clinicians, 56, 106-130. [2] Ries, L. A., Smith, M.A., Gurney, J.G., Linet, M., Tamra, T. and Young, J.L., (1999). Cancer incidence and survival among children and adolescents: United States SEER

34 Terezie Tolar Mosby and Ronald D. Barr program 1975-1995. National Cancer Institute, SEER program Bethesda, MD: NIH publication no 99-4649. [3] US Cancer Statistics Working Group. (2012). United States Cancer Statistics: 1999- 2008. Incidence and Mortality Web-based Report. US Department of Health and Human Services. Centers for Disease Control and Prevention and National Cancer Institute, Atlanta. [4] Kellie, S. J., and Howard, S. C. (2008). Global child health priorities: what role for paediatric oncologists? European Journal of Cancer, 44, 2388-2396. [5] Barr R., Antillon F., Agarwal B., Mehta P., and Ribeiro R. (2011). Pediatric oncology in countries with limited resources. In: P. A. Pizzo and D. G. Poplack (Eds.), Principles and Practice of Pediatric Oncology (6th ed, 1463-1473). Philadelphia, PA: Lippincott Williams and Wilkins. [6] National Cancer Institute.(2012). A Snapshot of Pediatric Cancers. http://www.cancer.gov/aboutnci/servingpeople/cancer-statistics/snapshots. [7] Stiller, C. A., and Parkin, D. M. (1996). Geographic and ethnic variations in the incidence of childhood cancer. British Medical Bulletin, 52, 682-703. [8] Medical dictionary. (n.d.) Retrived from: http://medical-dictionary.thefree dictionary. com/Protein-Energy+Malnutrition. [9] Howard, S. C., Marinoni, M., Castillo, L., Bonilla, M., Tognoni, G., Luna-Fineman, S., et al and MISPHO Consortium Writing Committee (2007). Improving outcomes for children with cancer in low-income countries in Latin America: a report on the recent meetings of the Monza International School of Pediatric Hematology/Oncology (MISPHO)-Part 1. Pediatric Blood and Cancer, 48, 364-369. [10] Donaldson, S. S., Wesley, M. N., DeWys, W. D., Suskind, R. M., Jaffe, N., and vanEys, J. (1981) A study of the nutritional status of pediatric cancer patients. American Journal of Diseases of Children,135:1107-1112. [11] Rogers, P. C., Meacham, L. R., Oeffinger, K. C., Henry, D. W., and Lange, B. J. (2005). Obesity in pediatric oncology. Pediatric Blood and Cancer. 45,881-891. [12] Antillon F, de Maselli T, Garcia T, Rossi E, and Sala A. (2008). Nutritional status of children during treatment for acute lymphoblastic leukemia in the Central American Pediatric Hematology Oncology Association (AHOPCA): preliminary data from Guatemala. Pediatric Blood and Cancer.50(Suppl 2),502-505. [13] Grantham-McGregor, S. M. and Fernand, L. C. (1997). Commission of nutritional challenges of the 21st century. Geneva, Switzerland: United Nations ACC/SCN. [14] United Nations Children's Fund. (1996). The state of the world's children. New York, NY: UNICEF. [15] Kroll, J. L. (2007). New directions in the conceptualization of psychotic disorders. Current Opinion in Psychiatry, 20, 573-577. [16] World Health Organization. (2012). World health statistics 2012. Retrieved from http://www.who.int/gho/publications/world_health_ statistics/2012/en/index.html. [17] Sala, A., Rossi, E., Antillon, F., Molina, A. L., de Maseli, T., Hernandez, A., Ortiz, R., et al. (2012). Nutritional status at diagnosis is related to clinical outcomes in children and adolescents with cancer: a perspective from Central America. European Journal of Cancer, 48, 243-52. [18] Dietz, W. H. (1998). Health consequences of obesity in youth: childhood predictors of adult disease.Pediatrics, 101(3 Pt 2),518-525.

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