Cancer Treatment and Research Communications

Scoping Review and Expert Interview: Nutrition Therapy Recommendations for

Children with Malignancies
--Manuscript Draft--

Manuscript Number:

Article Type: Review article

Keywords: pediatric malignancy, pediatric cancer, malnutrition, nutrition

Corresponding Author: Mikhael Yosia, MD, MKK, BMedSci, PGCert, DTM&H

University of Indonesia Faculty of Medicine
INDONESIA

First Author: Pustika Amalia Wahidiyat, MD, PhD

Order of Authors: Pustika Amalia Wahidiyat, MD, PhD

Aryono Hendarto

Cut Nurul Hafifah

Ludi Dhyani Rahmartani

Ganda Ilmana

Shuffa Chilla Mayhana

Raden Muhammad Kevin Baswara

Mikhael Yosia, MD, MKK, BMedSci, PGCert, DTM&H

Abstract: Background: A significant number of children with malignancy suffer from malnutrition;
however, succinct, and practical recommendations for medical practitioners regarding
this matter are still scarce at best. By assessing available scientific evidence, current
best practices, and expert clinical experience.
Objective: This paper aims to provide a point of reference for the nutritional
management of pediatric malignancy patients] in Indonesia.
Method: This study integrates a review of scientific evidence and recommendations
from experts with direct clinical experience in the management of pediatric malignancy
through the formation of a multidisciplinary discussion group consisting of pediatric
haemato-oncology and pediatric nutritionists. Knowledge gathered to review articles,
and expert discussion was grouped into themes, which include [1] Epidemiology of
Pediatric Malignancy in Indonesia, [2] Nutritional Status of Pediatric Patients with
Malignancy, [3] Role of Nutrition for Pediatric Patients with Malignancy, [4] Nutrition
Therapy in Children with Malignancies, [5] Expert’s note.
Conclusion: Malnutrition (over and under-nutrition) in pediatric malignancy is a complex
condition that requires proper continuous monthly screening through the utilization of
anthropometric assessment and questionnaires followed by a precise nutritional
intervention that includes physical activity, adjustment of diet, feeding support, and
food supplements (including ONS) which requires a multi-disciplined approach.

Suggested Reviewers: Federico Bozzetti

University of Milan
federicobozzetti@gmail.com
Expert on Childhood Malignancies

Carmen Sapienza
Temple University
Sapienza@temple.edu
Expert in Cancer Research and Molecular Biology

Jean-Pierre Issa
Temple University
jpissa@temple.edu
Expert in pediatric oncology

Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
Cover Letter

Dear Editor of Cancer Treatment and Research Communication,

I am pleased to submit my manuscript titled "Scoping Review and Expert Interview: Nutrition
Therapy Recommendations for Children with Malignancies" for consideration for publication in
your esteemed journal, Cancer Treatment and Research Communication

The study was conducted in Indonesia and aimed to identify evidence-based recommendations for
nutrition therapy in children with malignancies. A scoping review of the literature was conducted,
followed by expert interviews with healthcare professionals experienced in providing nutrition
therapy to children with malignancies. The data were analyzed to develop a set of
recommendations to improve the nutritional status of these children during their treatment.

We certify that all the authors have agreed to the submission of this manuscript and that it has not
been submitted to another journal for consideration. Furthermore, we believe that the findings of
this study will be of significant interest to your readership as it addresses an important gap in the
literature on pediatric oncology. We confirm that this manuscript has not been published elsewhere
and is not under consideration by another journal. All authors have approved the manuscript and
agree with its submission to Cancer Treatment and Research Communication.

We have carefully followed the guidelines for manuscript preparation and submission to ensure
that the study was conducted with rigor and attention to detail. We are confident that the results of
our research are supported by sound methodology and analysis, and we believe that our manuscript
meets the high standards required for publication in your journal.

Thank you for considering our submission. We look forward to hearing from you soon.

Please address all correspondence to: Pustika Amalia Wahidiyat (pa.wahidiyat@gmail.com)

Sincerely,
Pustika Amalia Wahidiyat
Highlights

Highlight

 Children with malignancy are prone to malnutrition.

 Proper guidelines for managing malnutrition are scarce.
 This study provides recommendations for managing malnutrition in pediatric
malignancy.
 Recommendations include screening, precise nutritional intervention, and a multi-
disciplinary approach.
 The study highlights the complexity of malnutrition in pediatric malignancy.
Manuscript File Click here to view linked References

1 Scoping Review and Expert Interview:

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2 Nutrition Therapy Recommendations for Children with Malignancies
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7 4 Pustika Amalia Wahidiyat1, Aryono Hendarto2, Cut Nurul Hafifah2, Ludi Dhyani
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10 5 Rahmartani1, Ganda Ilmana1, Shuffa Chilla Mayhana3, Raden Muhammad Kevin Baswara3,
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12 6 Mikhael Yosia3
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17 8 Division of Hematology and Oncology, Department of Child Health, Cipto Mangunkusumo
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9 Hospital, Faculty of Medicine Universitas Indonesia
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22 10 Division of Nutrition and Metabolic Disease, Department of Child Health, Cipto
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24 11 Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia
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27 12 Faculty of Medicine Universitas Indonesia
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32 14 Funding: This research was funded by Danone Specialized Nutrition. Sponsor had no
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34 15 involvement or restriction regarding publication.
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16 Conflicts of Interest: All authors declare no conflict of interest.
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41 18 Corresponding Author : Mikhael Yosia
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43 19 Telephone number : +62 813-787-787-84
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45 20 Address : Jalan Salemba Raya No.6, 10430, Jakarta Pusat, Indonesia
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47 21 E-mail : mikhael.yosia@gmail.com
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60 27 Simple Summary
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 28 Children with malignancy are prone to malnutrition; however, proper guidelines on treating
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2 29 this condition are scarce. This study aims to compile available evidence followed by expert
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5 30 opinions to create a practical recommendation on managing malnutrition in children with
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7 31 malignancy.
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12 33 Abstract
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15 34 Background: A significant number of children with malignancy suffer from malnutrition;
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17 35 however, succinct, and practical recommendations for medical practitioners regarding this
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36 matter are still scarce at best. By assessing available scientific evidence, current best
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22 37 practices, and expert clinical experience.
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24 38 Objective: This paper aims to provide a point of reference for the nutritional management of
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27 39 pediatric malignancy patients] in Indonesia.
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29 40 Method: This study integrates a review of scientific evidence and recommendations from
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32 41 experts with direct clinical experience in the management of pediatric malignancy through
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34 42 the formation of a multidisciplinary discussion group consisting of pediatric haemato-
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43 oncology and pediatric nutritionists. Knowledge gathered to review articles, and expert
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39 44 discussion was grouped into themes, which include [1] Epidemiology of Pediatric
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41 45 Malignancy in Indonesia, [2] Nutritional Status of Pediatric Patients with Malignancy, [3]
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44 46 Role of Nutrition for Pediatric Patients with Malignancy, [4] Nutrition Therapy in Children
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46 47 with Malignancies, [5] Expert’s note.
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49 48 Conclusion: Malnutrition (over and under-nutrition) in pediatric malignancy is a complex
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51 49 condition that requires proper continuous monthly screening through the utilization of
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54 50 anthropometric assessment and questionnaires followed by a precise nutritional intervention
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56 51 that includes physical activity, adjustment of diet, feeding support, and food supplements
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52 (including ONS) which requires a multi-disciplined approach.
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54 Keywords: pediatric malignancy, pediatric cancer, malnutrition, nutrition
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 55 1. Introduction
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2 56
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5 57 Malnutrition in pediatric malignancies is inevitable; it may be a consequence of the
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7 58 malignancy itself or its treatment regimens. In pediatric malignancies, malnutrition can be
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10 59 defined as overnutrition or undernutrition. It is irrefutable that nutrition is crucial for a child’s
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12 60 growth and development. Unfortunately, most children with malignancies are undernourished
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15 61 at the time of diagnosis.1-3
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63 Without adequate nourishment for these children, their condition may lead to significant
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22 64 adverse effects, including increased mortality rate and infection risk, longer length of hospital
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24 65 stay, reduced chemotherapy tolerance, lowered recovery rate, and their overall prognosis.
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27 66 This is supported by previous studies in which undernourished pediatric patients
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29 67 consequently lead to a two to three times higher risk of death than well-nourished patients.
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32 68 Furthermore, nutrition-related problems also affect their quality of life. Undernourished
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34 69 pediatric malignancy patients encounter limitations in physical activity due to muscle mass
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70 deficit. Meanwhile, over nourished patients encounter cognitive and emotional control
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39 71 challenges in which they are more vulnerable to anger, fright, and misery. Consequently, they
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41 72 are unable to involve themselves in standard social settings. Therefore, evaluating the
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44 73 nutritional status and giving an appropriate nutritional intervention on both ends of the
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46 74 spectrum is critical in managing pediatric malignancies to achieve normal growth and
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49 75 development in these children.4-8
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54 77 Indonesia still faces challenges in providing sufficient care for pediatric malignancy patients.
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56 78 Unfortunately, 85% of children with malignancies receive delayed diagnosis and treatment
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79 due to inaccessibility to healthcare services. Besides that, another study had showed that the
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 80 burden of pediatric malignancy treatment is exacerbated by high treatment abandonment
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2 81 (41.7%) which eventually leads to low cure rates (9.5%). This raises the importance of
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5 82 evaluating the nutritional status of children with malignancies as well as giving an
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7 83 appropriate nutritional intervention to achieve normal growth and development; thus,
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10 84 improving their overall condition. However, studies that provide recommendations on
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12 85 nutritional intervention, specifically for pediatric malignancies, are still scarce in Indonesia.
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15 86 Therefore, by cooperating available scientific evidence, current best practices, and clinical
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17 87 experience from experts, this paper aims to provide a point of reference for the nutritional
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88 management of pediatric malignancy patients in Indonesia.9,10
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 89 2. Methods
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5 91 This study integrates scientific evidence and recommendation from experts with direct
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7 92 clinical experience in the management of pediatric malignancy. A multidisciplinary group
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10 93 was formed consisting of pediatric hemato-oncology specialists and nutritionists. On 14th
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12 94 April 2022, the coordinating committee selected and proposed the first list of topics to be
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15 95 discussed further in this study. Topics included in this study are: (1) epidemiology of
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17 96 pediatric cancer in Indonesia; (2) nutritional status in pediatric patients with malignancy; and
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97 (3) nutritional therapy for pediatric patients with malignancy. Comments and necessary
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22 98 modifications were made after a thorough evaluation from all experts during a virtual
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24 99 meeting held in June 2022.
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29 101 The authors thoroughly conducted a PubMed literature search for English, French and
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32 102 Spanish language articles published to date using the terms ‘‘malnutrition’’ OR
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34 103 ‘‘malnourishment’’ OR ‘‘parenteral nutrition,’’ OR ‘‘home parenteral nutrition,’’ OR
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104 “nutritional intervention” AND “cancer,” OR “pediatric malignancy,” to provide scientific
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39 105 evidence that substantiates this study.
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44 107 References cited in selected articles were also reviewed to identify additional relevant
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46 108 reports. Additionally, published national and international guidelines describing nutrition
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49 109 recommendations for pediatric malignancy patients were also scrutinized. An initial
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51 110 document was drafted by the Coordinating Committee, where it was reviewed again by the
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54 111 panel of experts. The Coordinating Committee evaluated the panel’s comments and modified
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56 112 the draft as what was deemed necessary. Subsequent revisions were based on feedback from
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113 the other authors until a consensus was achieved, and the final text was then validated.
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 114 3. Result
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5 116 3.1. Epidemiology of Pediatric Malignancy in Indonesia
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7 117 The estimated number of pediatric malignancies (0 to 19 years old) in the world has reached
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10 118 400,000 cases annually. In the current status quo, children from high-income countries have
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12 119 one advantage: a greater chance of survival (80%) than those from low-middle-income
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15 120 countries (20-30%). Based on the data provided by Global Center Observatory, Indonesia
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17 121 encountered 396,914 malignancies along with 234,511 deaths in 2020. It is found to be more
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122 prevalent in females than males, with 182,368 and 213,546 cases respectively. The most
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22 123 common malignancies in Indonesia are those affecting the breast, cervix, as well as the
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24 124 lungs.11,12
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29 126 In 2018, Indonesia’s Basic Health Research or Riset Kesehatan Dasar discovered that the
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32 127 number of pediatric malignancy cases is as high as 18,255 in children aged <1 year old,
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34 128 73,188 in children aged 1-4 years old, and 182,338 in children aged 5-14 years old.
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129 Unfortunately, there is still paucity of nationwide epidemiologic data regarding each type of
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39 130 malignancy in this report.12,13
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44 132 According to a study conducted at Dr. Soetomo General Hospital Surabaya, the most
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46 133 common type of pediatric malignancy is leukaemia (51.91%). Similarly, pediatric malignancy
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49 134 data from 2000-2016 at Dr. Sardjito Hospital Yogyakarta demonstrated that among 2.441
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51 135 pediatric cancer cases found in children (0 to 18 years old), the most common malignancy is
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54 136 leukemia alongside myeloproliferative and myelodysplastic diseases (58.5%). Records from
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56 137 Dr. Hasan Sadikin Hospital Bandung further supported the fact that leukemia is one of the
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138 most frequent malignancies to be found. Among 773 pediatric patients with malignancies
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 139 evaluated between January 2014 and December 2016, 44.5% among them suffered from
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2 140 acute lymphoblastic leukemia. Corresponding to previous studies, 35% of all malignancy
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5 141 cases at Dr. Cipto Mangunkusumo Jakarta (Indonesia’s national referral hospital) between
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7 142 2008-2012 involved the hematopoietic and reticuloendothelial systems. 14-17
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12 144 3.2. Nutritional Status of Pediatric Patients with Malignancy
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15 145 Nutritional problems arise in pediatric malignancies due to two main reasons: Firstly,
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17 146 malignancies tend to accelerate one's metabolic rate and decrease the body’s nutrient storage.
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147 Secondly, treatment side effects may cause patients to experience nausea, vomiting, trouble
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22 148 swallowing, and mouth sores that eventually lead to a decreased appetite and changes in the
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24 149 patient’s dietary patterns.
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29 151 Among studies included in this review, the prevalence of malnutrition in pediatric
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32 152 malignancy patients at the time of diagnosis is between 2-66%. Meanwhile, the prevalence of
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34 153 malnutrition during malignancy treatment is between 3.2%-57%. Frequency of malnutrition
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154 diagnosed after treatment is lower, ranging from 1.38%-47%. Reports of overweight and
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39 155 obesity vary between 4%-28.2% at the time of diagnosis, 5% to 31.2% during treatment, and
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41 156 10%-57.9% at the end of treatment. Three studies also reported stunting with an incidence of
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44 157 2.47%-32.4%. It was also reported that patients with advanced stage malignancies have a
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46 158 higher risk of significant weight loss.18-29
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51 160 A study by Brinksma et al. showed significant losses in z-scores of HFA, WFH, and WFA in
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54 161 solid and hematological malignancies. In hematological malignancies such as ALL, a change
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56 162 in nutritional status tend to occur in the induction and maintenance phase of the disease.
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163 Based on MUAC, the rates of malnutrition at the time of diagnosis were higher in abdominal
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 164 malignancies. Other than biological factors, extrinsic factors such as the patients’
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2 165 socioeconomic status is also a determinant factor for the patient’s nutritional status. Another
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5 166 study stated that a lower mean HFA z-score was found in patients with low SES compared to
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7 167 high SES (-0.17 vs 0.51).19,22,24
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12 169 To assess the risk of malnutrition, Hulst et al. developed STRONGKids. The questionnaire
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15 170 classified children into three different categories which are: low risk of malnutrition,
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17 171 moderate risk of malnutrition, and high risk of malnutrition. Questions include subjective
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172 clinical assessment, history of high-risk disease, history of weight gain as well as weight loss,
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22 173 and nutrition intake of patient. STRONGKids is considered to have a good sensitivity to
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24 174 detect malnutrition in pediatric patients. Although still showing high sensitivity values,
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27 175 STRONGKids was reported to be more sensitive in detecting acute malnutrition (94.1%) than
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29 176 chronic malnutrition (89.4%). Another study has also proven STRONGKids’ sensitivity to
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32 177 detect acute and chronic malnutrition, which was 71.9% and 69%, respectively.30-32
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179 In conclusion, it has been challenging to find a red line between these findings due to the
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39 180 heterogeneity of nutritional status classification and methodologies. Additionally, there is still
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41 181 no guideline on when and which anthropometric measurement can be used to assess
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44 182 nutritional status in pediatric malignancies. Nevertheless, malnourishment, both over
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46 183 nourished and undernourished, is a real problem widely found in pediatric malignancies.
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51 185 3.3. Role of Nutrition for Pediatric Patients with Malignancy
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54 186 Adequate nutrition is crucial as they do not only affect the child’s growth and development,
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188 Figure 1 demonstrates the role of bioactive food components toward the human body.
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 189 Adequate levels lead to positive effects represented by the blue arrow, while the blue lines
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32 195 Pediatric patients with malignancy require a high-protein and high-calorie diet to maintain the
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34 196 patient’s weight at an ideal level. As the main energy source of the body, both protein and
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37 197 calorie requirements are essential to give the child strength to fight against the disease. After
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39 198 undergoing treatment such as chemotherapy, radiotherapy, or surgery, these patients need
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199 higher levels of protein to heal and fight infections. The Indonesian Pediatric Association
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44 200 recommended that pediatric patients with malnutrition be given 50-75% of the recommended
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46 201 daily allowance every day in the stabilization phase and 100% of the total RDA in the
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49 202 rehabilitation phase. In terms of calorie intake, WHO recommended patients to reach 110
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51 203 kcal/kg daily in the stabilization phase (Day 1-3 of inpatient treatment) and 150-220 kcal/kg
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54 204 daily in the rehabilitation phase (Week 2-6 of inpatient treatment). As for protein intake,
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56 205 WHO recommends 1-1.5g/day in the stabilization phase, whereas it should reach 4-6 g/day in
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 207 Another essential macronutrient is fiber. Fiber facilitates the gut by reducing its exposure to
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2 208 endogenously formed carcinogens during digestion. Consequently, a low-fiber diet may harm
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5 209 the gut and eventually compromise nutrient absorption. Furthermore, multiple studies state
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7 210 that a low-fiber diet is associated with an increased incidence of colon cancer.37,38
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12 212 Micronutrients such as vitamins (A, C, E) and PUFAs are also critical for the health of
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15 213 pediatric patients with malignancy. Low β-carotene (Vitamin A) levels are associated with
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17 214 chemotherapy-associated toxicity and infection. Meanwhile, vitamin C deficiency is
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215 correlated with nausea and vomiting. Multiple studies state that adequate vitamin C intake
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22 216 improves length of hospital stay, therapy delay, and toxicity. Higher vitamin E intakes are
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24 217 also relegated with a lower incidence of infection.39,40
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29 219 PUFAs play an essential role in cell signaling processes. N-3 and n-6 affect eicosanoid
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32 220 biosynthesis, which actively controls cell growth and differentiation, immunity,
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34 221 inflammation, and angiogenesis. However, n-3 and n-6 possess opposing mechanisms (anti-
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222 inflammatory and pro-inflammatory). Given their reciprocal roles, an equilibrium of each
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39 223 component is required. In relation to malignancies, a higher n-6 to n-3 ratio may increase the
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41 224 likelihood of carcinogenesis. In contrast, n-3 can target different stages of cancer
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44 225 development such as mitosis, epigenetic modification, as well as cell survival. In addition to
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46 226 that, its anti-inflammatory nature enables it to hinder NF-kB activity and accelerates the
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49 227 production of anti-inflammatory proteins such as resolvins and protectins. During malignancy
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51 228 treatment, n-3 is beneficial because it improves patient’s treatment-response, protects the
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54 229 body from treatment-related toxicity, and fights against secondary complications. To increase
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56 230 the efficacy of one’s treatment, n-3 is found to be suitable for tumor-targeting lipophilic
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231 drugs. Moreover, n-3 is critically needed to combat oxidative stress and metabolic
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 232 disturbances. Therefore, its supplementation as an adjuvant therapy for pediatric malignancy
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7 235 To conclude, a healthy diet demands a balanced amount of macro- and micronutrients. A
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10 236 balanced diet will allow the patient’s body to grow and develop normally, replace damaged
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12 237 tissues faster, lower infection rates, and give the child strength to withstand the side effects of
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15 238 cancer treatment. A balanced diet alters the risk of disease development in terms of its onset,
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17 239 progression, and severity.
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22 241 3.4. Nutrition Therapy in Children with Malignancies
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24 242 Eleven studies that analyzed the correlation between nutritional intervention and the growth
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27 243 and development of pediatric patients with malignancies were included in this review (Table
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29 244 1). These pediatric patients have been diagnosed with various malignancies, ranging from
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32 245 solid and non-solid tumors. Most patients included in the study are malnourished patients at
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34 246 the time of diagnosis. The efficacy of nutrition intervention is shown by an improvement in
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247 various anthropometric parameters including weight gain, WFH, BMI MUAC, TSFT, SSFT,
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39 248 and SISFT.
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44 250 Multiple studies analyzed the correlation between nutritional intervention and an
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46 251 improvement in a patient's appetite. TG in all studies received nutrition therapy during
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49 252 chemotherapy in the form of hypercaloric products, protein-and-energy dense isocaloric
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51 253 products, fish oil capsules, short-peptide EN, glutamine, and locally produced RUTF
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54 254 administered orally, enterally, parenterally, or intravenously.
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 256 ONS in the form of hypercaloric products or protein-energy-dense isocaloric products yielded
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2 257 promising results in increasing the patient’s nutritional status. A significant correlation
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5 258 between ONS and improvement in weight, height, BMI, TSFT, SSFT, and SISFT were found
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7 259 in TG. Widjaja et al. and Zaid et al. studied the effect of fish oil supplementation on the
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10 260 patient’s growth and development. Both studies reflected a positive correlation to the
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12 261 patient’s body weight after supplementation. Aside from weight gain, fish oil
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15 262 supplementation also increased the patient’s MUAC and appetite, which in turn increases the
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17 263 patient’s energy and protein intake.40-50
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22 265 One study examined the effects of RUTF. Patients in TG experience an exponential increase
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24 266 of weight from baseline measurements. At the end of the study, there were more patients in
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27 267 TG that achieved normal nutritional status than in the CG.45 In addition, most studies found
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29 268 no statistical significance in glutamine supplementation. According to Ward et al, there is no
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32 269 weight/height and MUAC difference between the trial and control groups. Han Y et al. also
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34 270 found similar results after four weeks of glutamine and short-peptide EN
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271 supplementation.44,46
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41 273 The mode of administration of nutritional therapy varies depending on the patient’s
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44 274 condition. If the patient does not face any eating difficulties, it is best for the patient to adhere
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46 275 to the initial eating habits. Oral nutritional supplements or high-calorie and high-protein
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49 276 meals or drinks are advised when the child is prone to malnutrition. If the patient struggles
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51 277 with eating, liquid nutrition products should be considered. The administration of nutrition
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54 278 therapy via feeding tube (nasogastric tube, gastrostomy tube, jejunostomy tube, nasoduodenal
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56 279 tubes) is given to young patients, patients that experiences nausea and vomiting, or children
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 281 and nutrients. For children with gastrointestinal complications PN should be considered.
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2 282 However, after these issues go away, it is best that the patient switches back to oral or tube
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5 283 feeding as parenteral feeding exhibits various side effects.51
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7 284
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10 285 Each patient requires different nutritional needs, determined by type of malignancy, treatment
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12 286 regimens, age, activity level, and more. Thus, the American Cancer Society recommends
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15 287 each pediatric cancer patient to consult with a RDN or registered dietitian before they begin
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17 288 treatment, specifically discussing nutrition therapy. Furthermore, RDNs can create the most
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289 suitable meal plan, mode of administration, and make suggestions on other methods to meet
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22 290 the patient’s nutritional needs.51
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27 292 Children with malignancies require specific nutritional care due to their increased risk of
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29 293 malnutrition from the cancer itself and the treatments such as chemotherapy and radiation
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32 294 therapy. Reiterating our points before, the International Society of Pediatric Oncology (SIOP)
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34 295 Nutrition Network for LMIC provides guidelines for optimizing nutrition for children with
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296 malignancies. The network recommends early screening and assessment of nutritional status,
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39 297 with individualized nutrition therapy for each child based on their needs. This may include
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41 298 addressing any deficiencies, ensuring adequate energy and protein intake, and monitoring
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44 299 weight and growth regularly. Adequate nutrition therapy can help to improve outcomes such
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46 300 as reduced toxicity and improved tolerance to chemotherapy and improve the quality of life
47
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49 301 of the child and their family. 52
50
51 302
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54 303 The SIOP Nutrition Network also recommends the use of specific nutritional interventions
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56 304 during treatment, such as the use of enteral feeding and parenteral nutrition when necessary.
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305 For example, enteral feeding may be necessary when a child is unable to eat due to
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 306 gastrointestinal side effects from chemotherapy or radiation therapy. In such cases, tube
1
2 307 feeding may be used to provide adequate nutrition to the child while allowing the
3
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5 308 gastrointestinal system to heal. The network also emphasizes the importance of involving
6
7 309 multidisciplinary teams in the care of children with malignancies, including nutritionists,
8
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10 310 physicians, nurses, and psychosocial support teams, to address any barriers to adequate
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12 311 nutrition and provide emotional support to the child and family. 52
13
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15 312
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17 313 In LMICs, the availability of nutritional interventions may be limited due to lack of resources
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19
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314 and access to medical supplies. The SIOP Nutrition Network addresses this by providing
21
22 315 training and education for healthcare providers and families, as well as advocating for
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24 316 increased access to essential medical supplies and interventions. For example, the network
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27 317 recommends the use of locally available, low-cost foods to meet the nutritional needs of
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29 318 children with malignancies, and the use of creative strategies to encourage children to eat and
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32 319 prevent food waste. 52
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22 320
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24 321 Table 1. Summary of studies assessing the effect of nutrition intervention on the growth and development of pediatric malignancies.
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26
27 Study Location Design Total Age Study Type of Malignancy Intervention Intervention Details Anthropometric Results
Sample Range Period in TG
28
29 Gokcebay Turkey RCT 45 8.7 ± 4.9 2012- Solid Tumor (Lymphoma, ONS after Patients randomized to receive two types of ONS (hypercaloric and protein and - Decrease in number of patients with malnutrition after 6 months
37
30 et al. M:40%
F:60%
y.o. 2013 neuroblastoma, Ewing
sarcoma, Wilms’ tumor,
diagnosis energy dense isocaloric product). (from 31% to 24%)*

31 osteosarcoma, nasopharynx Hypercaloric product: Brand A (302 kcal/1265kJ energy, 8.4g protein, 14.9g fat for - No significant difference between isocaloric/ hypercaloric
cancer, hepatoblastoma, every 200mL container) or Brand B (300 kcal/1262kJ energy, 6g protein, 12.4g fat supplement in terms of changes in BMI, WFH, MUAC, and TSFT.
32 langerhans cell histiocytosis) for every 200ml container).
33 Isocaloric product: Brand C (201 kcal/843kJ energy, 8.4g protein, 10g fat for every
34 200mL container).
35
36 Widjaja
al. 38
et Indonesia RCT 32
M:56.2%
1-10 y.o. 2015-
2016
ALL Fish oil
supplements
Fish oil capsules given every day during chemotherapy (induction and consolidation
phase). No information on dose.
- Increase of body weight after 12 weeks*

37 F:43.8%
38
39 Zaid et al. 42
Malaysia RCT 51 4-12 y.o. 2012 Leukemia Fish oil 1 fish oil capsule (360mg EPA, 240mg DHA) given every day. - Increase of body weight, MUAC, and appetite
40 M:62.7% supplements
F:37.3%
41
42
43 Acipayam
et al. 43
Turkey RCT 41
M:57.5%
1-16 y.o. 2009-
2010
ALL and miscellaneous solid
tumor
EN for 3 months TG given two different EN formulas. - Increase of subcapsular thickness and suprailiac skinfold thickness
in TG after 3 months*
44 F:48.7% EN Products: Brand D (310 kcal energy, 18g protein, 35.8g carbohydrate, 10.6g fat, - Increase of weight, height, BMI, and TSFT in TG
1g EPA per 200ml) and Brand E (305 kcal energy, 6.75g protein, 42.5g
45 carbohydrate, 11.75g fat per 250ml)
46
47
48 Han et al. 44
China RCT 48 1-11 y.o. 2013- ALL Short-peptide TG given short-peptide enteral nutrition formulation and glutamine supplementation - Higher increase of TSFT in TG compared to CG*
M: 58.3% 2014 enteral nutrition during chemotherapy.
49 F: 41.7% and glutamine
50 supplements for 4 Short-peptide enteral nutrition formulation: (466 kcal energy, 13.7g protein, 17.5g
weeks fat, 62.8g carbohydrate per 100 gram). Glutamine: 0.4g/kg/day dissolved in 100ml
51 warm water or porridge.
52
53 45
54 Prasad et al. India RCT 260
M: 71.5%
5-15 y.o. 2015-
2018
Non-solid tumor (ALL, AML,
lymphoma) and solid tumor
SNT + RUTF for 6
weeks
RUTF is locally made and energy-dense. No information on nutritional content. - Higher increase of weight from baseline in TG*
- Normal nutritional status based on BMI-for-Age and MUAC in
55 F: 28.5% (bone tumor, germ cell tumor, TG*
Wilms’ tumor, others)
56
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18
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20
21
Ward et al.46 United Quasi-RCT 50 2-21 y.o. 2009 AML, non-Hodgkin’s One dose of TG given glutamine supplementation (0.65g/kg/day) during chemotherapy. - No significant difference between weight/height and MUAC
22 Kingdom lymphoma, Ewing sarcoma, glutamine Supplements were mixed with water at a maximum concentration of 10g/100ml increase between both groups.
23 osteosarcoma, (oral/EFT) for 7 water and a maximum total volume of 300ml) or via enteral feeding tube.
rhabdomyosarcoma days
24
25
26 Uderzo et al.47 Italy Prospective 120 0-19 y.o. 2011 ALL, AML, CML, non- Glutamine-enriched TG given intravenous glutamine-enriched solution (0.4g/kg/day) containing L- - Similar mean reduction of body weight at the end of nutrition
27 -RCT M: 69%, Hodgkin lymphoma, total parenteral alanine-glutamine dipeptide. therapy in both TG and CG.
F: 31% myelodys- nutrition
28 plastic syndrome, malignant
29 lymph histiocytosis,
rhabdomyosarcoma, juvenile
30 myelomonocytic leukemia.
31
32
33 Peccatori Nicaragua RCT 104 0-17 y.o. 2016- Non-solid tumors (ALL, ALL) ONS (oral TG given a polymeric hyper-caloric formula (balanced mix of proteins, fats, and - Decrease in number of patients with severely depleted nutritional
34 et al.48 M: 57.7% 2017 and solid tumors (brain tumors, polymeric hyper- carbohydrates) status in leukemia/ lymphoma groups after nutritional intervention
F:42.3% bone and soft-tissue sarcoma, caloric formulas) (from 63.2% to 36.8%) and in solid tumor group (from 73.1% to
35 Wilms’ Tumor, others) daily 57.7%)*
- Increase of adequately nourished patients in Leukemia/ Lymphoma
36 group (from 28.9% to 47.7%)*.
37
38
Liang et al.49 China Quasi-RCT 127 1-14 y.o. 2013- ALL ONS and short- Contents of ONS were not specified in the study. - Increase of weight in TG after chemotherapy*
39 2015 peptide enteral - Decrease of weight in CG after chemotherapy*
40 nutrition

41 Ward et al.50 n/a Systematic 595 0-21 y.o. 1980- Leukemia, lymphoma, solid Nutritional support Systematic review looking at Nutritional Support (administration of nutrients as a PN
42 Review 2011 tumors. (PN, EN, PPN, replacement/addition to normal eating habits via parenteral or enteral route). - Increase of weight in patients*
CPN) - Higher increase of TSFT, MUAC, arm muscle compared to CG*
43 Nutritional support: glutamine supplementation, high energy density feeds, high
44 fiber feeds, and omits vitamin/ micronutrient supplementation. PPN
- Higher increase of TSFT and subscapular skinfold than in CPN*
45
CPN
46 - Higher increase of weight than in PPN*
47
EN (Nasogastric)
48 - Increase of MUAC*
49
50
51
52 322
53 323 Abbreviations: RCT, Randomized Controlled Trials; y.o., Years-old; M, Male; F,: Female; TG, Treatment group; CG, Control group; ALL, Acute lymphocytic leukemia; AML, Acute myelocytic leukemia; CML, Chronic myeloid leukemia; ONS,
54
55 324 Oral nutritional supplements; EPA, Eicosapentaenoic acid; DHA, Docosahexaenoic acid; RUTF, Ready-to-use therapeutic food; SNT, Standard nutrition therapy; EN, Enteral nutrition; PN, Parenteral nutrition; PPN, Peripheral parenteral nutrition;

56 325 CPN, Central parenteral nutrition; WFH, Weight-for-height; BMI, Body mass index; TSFT, Triceps skinfold thickness; MUAC, Mid-upper arm circumference.
57 326 Notes: The symbol (*) indicates significant results (p value = <0.05),
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 327 3.5. Experts’ Notes
1
2 328
3
4
5 329 The nutritional status of pediatric patients with malignancy plays a vital role in determining
6
7 330 the patient’s prognosis and overall survival rate. Hence, aggressive nutritional interventions
8
9
10 331 should be administered immediately. However, an algorithm of the specific nutritional
11
12 332 intervention given to pediatric patients with malignancies that is applicable in Indonesia has
13
14
15 333 not been constructed. This raises the urgency for authors to incorporate prior knowledge
16
17 334 extracted from the scoping review with various experts’ recommendations to create a
18
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335 treatment guideline that physicians could adhere to in the management of pediatric
21
22 336 malignancy patients. According to experts consulted in this study, the algorithm provided in
23
24 337 this study may be applied by general practitioners that encounter any case of pediatric
25
26
27 338 malignancy, especially in low-resource settings. Furthermore, parents or caregivers of these
28
29 339 patients may also use this algorithm as a guide to provide the most suitable diet.
30
31
32 340
33
34 341 Pediatric patients with malignancy are at risk of undernutrition and overnutrition depending
35
36
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342 on the type of malignancy, demography (age and sex), and treatment history. Thus, risk factor
38
39 343 assessment (Figure 2) should precede quantitative assessments to classify if the patient is
40
41 344 posed to a greater risk of undernutrition or overnutrition. Afterwards, nutritional status
42
43
44 345 assessment should be conducted (Figure 3). Furthermore, MUAC should be assessed if the
45
46 346 patient shows signs of hepatosplenomegaly to provide a more precise measurement. If
47
48
49 347 screening results are found to be normal, physicians should advise the patient to have regular
50
51 348 monthly screenings for redetermination of their nutritional status. Meanwhile, patients with
52
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54 349 abnormal screening results should be assessed by quantitative assessments.
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56 350
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 351 Nutritional intervention (Figure 4) is provided depending on the patient’s nutritional status.
1
2 352 Generally, patients are prescribed 3 sessions of moderate intensity training every week.
3
4
5 353 Moreover, underweight patients are advised to increase consumption of energy and protein-
6
7 354 rich food as well as maintain adequate fluid intake. Lastly, overweight patients should be
8
9
10 355 advised to implement a healthier lifestyle. As for the root of administration, oral feeding is
11
12 356 opted for patients without any chewing disabilities whereas EN may be prescribed if it is
13
14
15 357 inadequate. Furthermore, parenteral nutrition is only prescribed if EN is deemed inadequate.
16
17 358
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19
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359 Following the principle of multimodal treatment in the management of pediatric
21
22 360 malignancies, a more specific nutritional intervention revolving around the dosage of macro
23
24 361 or micronutrients as well as the daily recommended intake should be consulted to a dietitian.
25
26
27 362 This is because each intervention should be highly suited to each patient’s condition. As the
28
29 363 treatment is administered, intensive monitoring and evaluation should be done by the dietitian
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32 364 or nutritionist assigned to the patient.
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35 365
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37 366 Figure 2. Risk factor assessment for pediatric patients with malignancy.8,33
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32 367
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34 368 Figure 3. Nutritional status examination and risk factors for malnutrition of
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36 369 pediatric patients with malignancy.
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42 370
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44 371 Figure 4. Recommendation for treatment and intervention of malnutrition in pediatric
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47 372 patients with malignancy.
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374
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42 375 Figure 5. Nutritional intervention corresponding to malignancy treatment.
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 383 Table 2. Indication for oral, nasogastric, gastronomy, and parenteral nutritional interventions
1
2
3 TREATMENT MODALITY INDICATION
4
5 - Compromised GI absorption and/or unable to tolerate enteral feeding for
6 more than 3 to 5 days
Parenteral Nutrition - Paralytic ileus
7 - Severe vomiting, diarrhea, pancreatitis
8 - Graft vs. host disease in the intestinal tract
9
10 - Energy intake reaches >90-100% of estimated requirement
11 Oral Feeding - Improvement in nutritional status post-treatment
12 - Stable nutritional status
13
14 - Weight loss
15 - Energy intakes <90% of estimated requirement for 3–5 days post
16 Nasogastric Tube (NGT) interventional intervention
17 - <3 days severe mucositis
18 - Normal emptying of gaster
19
20 - Weight loss
- Energy intakes <90% of estimated requirement for 3–5 days post NG
21 tubes intervention
22 Gastrostomy or - Emesis and/or severe mucositis
23 Jejunostomy Feeding - Undertreatment of head or neck radiotherapy
24 - Swallowing abnormality
25 - Prolonged dependence on enteral feeding
- Unwilling to accept NG tube
26 - Older patients who would prefer this route
27
28
29 384
30
31 385 4. Discussion
32
33
34 386
35
36 387 Global Cancer Observatory stated that there were 396.914 new cases of malignancy in
37
38
39 388 Indonesia during the year 2020 with 234.511 deaths.12 Devastatingly, the Basic Health
40
41 389 Research recorded that pediatric malignancy (0-14 years old) is as high as 273,781 cases in
42
43
44
390 2018.13 Malnutrition is highly prevalent among them, may it be at the time of diagnosis
45
46 391 (67%), during treatment (57%), or at the end of their treatment (57%).18-27
47
48 392
49
50
51 393 First, pediatric patients with malignancy should be evaluated for risk of malnutrition based on
52
53 394 the type of cancer, treatment, and patient's demography (Figure 2). Professionals may used a
54
55
56 395 guideline developed by the ESPEN known as The Pediatric Yorkhill Malnutrition Scoring
57
58 396 System (PYMS) to assess children who are at risk of malnutrition. Risk assessment is based
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 397 on the patient’s BMI, weight loss history, dietary patterns, and predicted effect of a recent
1
2 398 medical condition. Additionally, SCAN (Nutrition Screening Tool for Childhood Cancer)
3
4
5 399 may also be utilized. Similar to PYMS, parameters assessed include the patient’s weight loss
6
7 400 history, dietary patterns with an addition of the patient’s type and stage of malignancy as well
8
9
10 401 as history of gastrointestinal symptoms.53,54
11
12 402
13
14
15 403 Afterwards, an assessment of pediatric malignancy patients’ nutritional status is critical to
16
17 404 determine the most appropriate nutritional intervention. Patient’s nutritional status is
18
19
20
405 evaluated using screening tools (STRONGKids), anthropometric measurements (WFH, HFA,
21
22 406 WFA), as well as alloanamnesis with the patient’s parents or caregiver to obtain information
23
24 407 on the child’s eating habits, food preferences, and allergies (Figure 3). HFA calculations give
25
26
27 408 information if the patient's height is normal or stunted. Meanwhile, MUAC and/or TSFT is
28
29 409 measured to evaluate the nutritional status in patients with organomegaly or ascites and
30
31
32 410 provide a more accurate result.23
33
34 411
35
36
37
412 The ABCDE (Anthropometric, Biochemical, Clinical, Dietary, Exercise) nutritional
38
39 413 assessment approach may also be used as it is a comprehensive and systematic method for
40
41 414 evaluating the nutritional status of children with malignancies. This approach considers
42
43
44 415 multiple factors that can impact nutritional status and guides the development of
45
46 416 individualized nutrition interventions. The first step in the ABCDE approach is to assess
47
48
49 417 anthropometric measurements, such as height and weight, which can be used to calculate
50
51 418 nutritional indices such as BMI and assess for malnutrition or wasting. Biochemical
52
53
54 419 parameters are also important indicators of nutritional status. The patient’s protein status can
55
56 420 be measured by checking the serum creatinine, pre-albumin, albumin, and transferrin. Serum
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421 C-reactive protein levels can be used to assess a patient's inflammatory status. Specific
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 422 vitamin and mineral levels can be checked in cases of nutritional deficiency. Additionally, the
1
2 423 patient's bone health status can be measured by checking serum magnesium, calcium, and
3
4
5 424 vitamin D meanwhile organ function status should be evaluated by checking serum
6
7 425 creatinine, liver enzymes, and urea.55
8
9
10 426
11
12 427 The clinical component of the ABCDE approach involves evaluating for clinical signs of
13
14
15 428 malnutrition, such as muscle wasting or edema, and/or specific nutrient deficiency This can
16
17 429 also include assessing for symptoms of nutrient deficiencies or excesses, which can be
18
19
20
430 common in children with malignancies. For instance, subcutaneous fat loss, recent weight
21
22 431 change, skin change, hair change, edema, and specific signs of nutrient deficiency are all
23
24 432 indicators of nutrient deficiency that should be highlighted. Dietary assessment is carried out
25
26
27 433 by evaluating the child's food intake and identifying any barriers to adequate nutrition, such
28
29 434 as nausea or taste changes related to cancer treatments. Patients may be asked to write
30
31
32 435 ‘nutritional diaries’ that includes macronutrient and micronutrient intake, food preferences,
33
34 436 food intolerances, allergies. This method aims to ease medical professionals to evaluate the
35
36
37
437 patient’s dietary patterns and determine what specific nutrients need to be focused on.
38
39 438 Finally, the exercise component of the ABCDE approach considers the impact of physical
40
41 439 activity on nutritional status, particularly in children who may have limited mobility due to
42
43
44 440 their cancer or treatment.55
45
46 441
47
48
49 442 By using a multidimensional approach to nutritional assessment, the ABCDE approach can
50
51 443 help identify specific nutritional needs and guide the development of individualized nutrition
52
53
54 444 interventions for children with malignancies. This can include the use of enteral or parenteral
55
56 445 nutrition support, dietary modifications, and exercise interventions. The ABCDE approach
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 446 also emphasizes the importance of ongoing monitoring and adjustment of nutrition
1
2 447 interventions as the child's needs change over time.55
3
4
5 448
6
7 449 Patients who are found to be well-nourished should be advised to conduct monthly
8
9
10 450 screenings. However, if the screening shows abnormal results, physicians should continue to
11
12 451 conduct quantitative assessment (degree of physical performance, symptoms of nutritional
13
14
15 452 deficit, and nutritional intake). Quantitative assessment results should further support the
16
17 453 physician's diagnosis and group the patient into underweight, normal, or overweight.
18
19
454
20
21
22 455 After conducting a nutritional assessment, physicians may start choosing the suitable mode of
23
24 456 administration for the patient. Enteral nutrition is very advantageous considering its
25
26
27 457 feasibility, safety, invasiveness, cost, as well as similarity to physiological processes.
28
29 458 Additionally, enteral nutrition preserves the intestine’s anatomic and immunologic mucosal
30
31
32 459 barrier thus yielding promising results and reducing side effects of long-term use. Parenteral
33
34 460 nutrition is only indicated when the patient’s nutritional status could not be maintained and/or
35
36
37
461 improved via enteral route. Further explanation regarding the indication of each route of
38
39 462 administration is provided in Table 2. There are various nutrition therapy that is able to
40
41 463 support the growth and development in pediatric patients with malignancies, which comprises
42
43
44 464 of oral nutritional supplements in the form of hypercaloric as well as protein and energy-
45
46 465 dense isocaloric products (e.g. Nutrinidrink (1.5kcal/ml), Nutren Junior (1kcal/ml), Entrakid
47
48
49 466 (1kcal/ml), Nutrisure (1kcal/ml), fish oil capsules (EPA, DHA), Short-peptide enteral
50
51 467 nutrition formulation, glutamine, and ready-to-use therapeutic food (RUTF). Oral nutritional
52
53
54 468 supplements are opted as the first intervention used to improve weight as well as calorie and
55
56 469 protein intake in pediatric oncology settings. Multiple studies stated that improvement in
57
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470 quality of life, duration of hospital stay, and immune function were evident after the
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 471 administration of ONS. Furthermore, ONS has been proven to significantly improve social
1
2 472 function, cognitive function, and physical function of patients with malignancies. 56-58
3
4
5 473
6
7 474 Poor levels of physical activities are commonly reported in patients with malignancies.
8
9
10 475 Unfortunately, low physical activity along with malignancy treatment result in significant
11
12 476 unfavorable impact to one’s muscle mass. A systematic review reported that regular exercises
13
14
15 477 possess positive effects on the patient’s muscle mass. Due to this reason, physical activity is
16
17 478 recommended for pediatric patients with malignancies. Not only beneficial for preventing
18
19
20
479 loss of muscle mass, but physical activity also improves depression, fatigue, and quality of
21
22 480 life. Previous studies stated that resistance training was more beneficial than aerobic training
23
24 481 on muscle strength and mass. Hence, we recommend at least 3 sessions (10-60
25
26
27 482 minutes/session) of moderate intensity resistance and/or aerobic training every week for all
28
29 483 patients (Figure 4). These training sessions may be in the form of resistance to aerobic
30
31
32 484 exercises to strengthen their muscles. However, this may be modified according to the
33
34 485 patient’s functional status.59-63
35
36
37
486
38
39 487 Improvements in food intake and body weight were seen after nutritional therapy in
40
41 488 undernourished pediatric malignancy patients. Therefore, for patients without disability, we
42
43
44 489 recommend increasing oral intake and eating energy-rich and protein-rich food with well
45
46 490 tolerated fluids (Figure 4). If physicians encounter a case where the goal of nutrition therapy
47
48
49 491 is not achieved with increasing oral intake alone, ONS should be considered. Undernourished
50
51 492 patients should also avoid dietary supplementation that may restrict energy intake, such as
52
53
54 493 ketogenic diet, fasting, or any forms of diet that has not been proven beneficial for
55
56 494 malnourished pediatric malignancy patients to prevent further nutrition insufficiency.63,64
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 496 Aside from monthly screenings, patients with normal nutritional status should maintain
1
2 497 adequate macronutrient and micronutrient intake and avoid consumption of high-dose
3
4
5 498 micronutrients (if specific deficiencies are absent). About 50% patients with malignancies are
6
7 499 hypermetabolic. Aside from being in a hypermetabolic state, pediatric patients newly
8
9
10 500 diagnosed with malignancy had a higher REE and free-fat mass compared to normal values.
11
12 501 Meanwhile, in advanced cancer patients, TEE is lower than normal values due to lower
13
14
15 502 physical activity. Therefore, patients with normal nutritional status should be prescribed the
16
17 503 nutritional therapy with the same TEE as a healthy individual. Lastly, overnourished pediatric
18
19
20
504 malignancy patients should be prescribed exercise and be encouraged to implement a
21
22 505 healthier lifestyle, which includes excessive eating habits. Nutritional interventions may also
23
24 506 be adjusted to treatment regimens undergone by the patient (Figure 5).65-68
25
26
27 507
28
29 508 5. Conclusions
30
31
32 509 Malnutrition (over and under-nutrition) in pediatric malignancy is a complex condition that
33
34 510 requires proper continuous monthly screening through the utilization of anthropometric
35
36
37
511 assessment and questionnaires followed by a precise nutritional intervention that includes
38
39 512 physical activity, diet adjustment, feeding support, and food supplements (including ONS).
40
41 513 Ensuring malnutrition in pediatric patients with malignancy is adequately addressed requires
42
43
44 514 a multi-disciplined approach involving different subspecialists and medical personnel directly
45
46 515 involved with pediatric malignancy patients.
47
48
49 516
50
51 517 6. Acknowledgements
52
53
54 518 This study was supported by Danone Specialized Nutrition. Authors would like to thank
55
56 519 fellow colleagues in the Faculty of Medicine Universitas Indonesia for their support and input
57
58
59
520 in the writing of this article.
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 521 Authors’ Contributions: PAW, AH, CNH, LDR, GI, MY designed overall research plan
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Author Contributions Statement

Author Contribution Statement

Authors’ Contributions: PAW, AH, CNH, LDR, GI, MY designed overall research plan

and study oversight; SCM, RMKB, MY collected data; SCM, RMKB, MY had primary

responsibility for final content; All authors wrote the manuscript; All authors have read

approved the final manuscript.

Declaration of Interest Statement

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

Pustika Amalia Wahidiyat

Amilia Pustika Wahidiyat