Review

Nutrition during childhood cancer treatment: current

understanding and a path for future research
Lenat Joffe, Elena J Ladas

Proper nutritional status during cancer therapy has been recognised as being integral to a variety of health Lancet Child Adolesc Health 2020
outcome measures, including overall survival, treatment tolerance, and quality of life. The prevalence of Published Online
malnutrition, defined by WHO as either undernutrition or overnutrition, among children and adolescents with February 13, 2020
https://doi.org/10.1016/
cancer is reported to be as high as 75%. Yet, over the past two decades there have been limited advances in S2352-4642(19)30407-9
elucidating the underlying pathophysiological drivers of malnutrition in this population. This effect has resulted
Department of Pediatrics,
in a paucity of research aimed at improving nutritional assessment and intervention among this group. This Division of Pediatric
Review presents an in-depth discussion of the role of nutritional status in paediatric cancer care, as well as evolving Hematology, Oncology,
avenues of investigation that might propel personalised nutrition into a viable reality. Thus, nutritional science and Stem Cell Transplant,
Columbia University Irving
might facilitate individualised intervention strategies, and thereby help to optimise clinical outcomes for patients
Medical Center, New York, NY,
and survivors of childhood cancer. USA (L Joffe MD, E J Ladas PhD)
Correspondence to:
Introduction important issue underappreciated and unaddressed at Dr Elena J Ladas, Department of
The past several decades have witnessed a considerable many centres.3,4,11 Pediatrics, Division of Pediatric
Hematology, Oncology, and
improvement in childhood cancer outcomes, with the US The incidence of malnutrition during cancer care varies
Stem Cell Transplant, Columbia
National Cancer Institute’s Surveillance, Epidemiology, greatly between disease type and mode of inter­vention, University Irving Medical Center,
and End Results programme reporting a 5-year survival with undernutrition reported to be between 0% and 70% New York, NY 10032, USA
of 83% in those diagnosed before age 20 years.1 However, and overnutrition between 25% and 75%.12–14 Given the [email protected]
the long-term complications associated with multimodal burgeoning interest in personalised medicine and the
cancer therapy, which includes chemotherapy, surgery, increasing integration of advanced technology into clinical
and radiation, leave a considerable proportion of child­ practice, it is imperative to understand current research
hood cancer survivors with severe or life-threatening, of nutrition and care in order to best advance the
chronic medical conditions. Many of these debili­ science. This Review presents a timely and comprehensive
tating conditions—such as cardiovascular disease, type 2 description of the current state of nutrition science in the
diabetes, metabolic syndrome, and even predisposition to care of paediatric oncology patients, and aims to shed light
secondary malignancies—might be further promoted by on potential avenues for future research encompassing
nutrition-related problems that first manifest during this multifaceted aspect of supportive care.
therapy.2,3
Proper nutritional status during cancer therapy is Key messages
integral to numerous outcomes, such as overall survival, • As a consequence of the underlying malignancy,
tolerance to treatment, susceptibility to infection, and physiological demands, and effects of multimodal therapy,
quality of life.4,5 Given the evolving global epidemic of children with cancer are at high risk of developing
childhood obesity over the last four decades, malnutrition short-term and long-term nutritional deficiencies
is now defined by WHO as both undernutrition (body • Both undernutrition and overnutrition during childhood
mass index [BMI] <5th percentile) and overnutrition cancer care are important contributors to patient
(BMI ≥85th percentile).6 With increased opportunities for morbidity, mortality, and quality of life
multi-national research collaborations in paediatric • Nutritional status might affect health outcomes via
oncology,7 WHO growth values are of imperative body composition changes, modify the tumour
importance. Because of a complex interaction between microenvironment, and potentially alter chemotherapy
their underlying cancer, physiological requirements for pharmacokinetics
growth and development, effects of multimodal therapy, • Evaluation of nutritional status is an essential component
and treatment-related toxicities, children with cancer are of cancer care throughout therapy, with the goal of
at high risk of developing nutritional deficiencies intervention being to ensure continued normal patient
(figure 1).8,9 Yet, despite pervasiveness of nutritional growth and development
deficiencies and their extensive short-term and long-term • Research directed at understanding the underlying
implications in paediatric cancer care, profound gaps pathophysiological drivers of malnutrition among
remain in the manner by which the health-care and paediatric oncology patients is scarce; further
scientific community approach and study malnutrition in investigations using new technologies in conjunction
this population.10 Moreover, the tremendous effort needed with traditional epidemiology-driven methodology are
for treating the underlying malignancy, compounded by needed to advance understanding in this area, and to
the absence of a universal consensus for identifying those promote individualised intervention strategies
children who are at risk for malnutrition, renders this

www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9 1

 Review

is considered to be of great prognostic value. Orgel and

Cancer and cancer therapy colleagues’ study17 of 50 children with B-precursor acute
lymphoblastic leukaemia found that those who were
obese during the induction phase of therapy had a
significantly increased risk for persistent minimal
residual disease compared with those who are not obese
Inflammation
Decreased Decreased Decreased Increased during induction (odds ratio [OR] 2·57, 95% CI
physical growth nutrition metabolic
hormone
1·19–5·54, p=0·016). Moreover, obesity and overweight
activity intake demand
were associated with poorer event-free survival irres­
pective of minimal residual disease (p=0∙012). Yet, in a
Poor Increased Decreased Growth
dietary patient patient fat- demands
similar study, Eissa and colleagues18 did not find the
intake fat mass free mass same association between BMI and minimal residual
Overnutrition Undernutrition disease or event-free survival among 373 patients with
acute lymphoblastic leukaemia. This investigation did,
however, show that patients who were obese had worse
overall survival than those who were not obese (p=0∙031).
Thus, the precise mechanism linking BMI to acute
Energy lymphoblastic leukaemia outcomes remains to be
balance
determined, and current research represents the first
Figure 1: Energy balance in paediatric cancer8,9
steps in elucidating the relationship between body
Malnutrition in paediatric cancer stems from a multifactorial process involving the disease itself, effects of therapy, habitus and the pathophysiology of childhood acute
and host inflammatory response. Resultant alterations in quantity and quality of dietary intake, physical activity lymphoblastic leukaemia.
levels, fluctuations in fat and fat-free mass, and host hormonal and metabolic changes, all contribute to a loss of Although it has been less extensively studied in
energy balance in this population.
paediatric solid tumours, the effect of nutritional status
on outcomes has been shown to extend to this patient
Nutrition in paediatric oncology population as well. A systematic review found that BMI
Epidemiology and outcomes outside of the normal range (between the 5th and
Among paediatric malignancies, the role of nutritional 84th percentiles is associated with impaired overall
status has been best studied in patients with leukaemia. survival in Ewing sarcoma (HR 3·46, p=0·022) and osteo­
The literature suggests that regardless of treatment or sarcoma (1·6, p<0∙005), with weak evidence of poorer
weight at diagnosis, patients with paediatric leukaemia overall survival in rhabdomyosarcoma (1·70, p=0·0596).12
are at risk of becoming overweight or obese early in In fact, in a diverse population of patients, who were
the treatment process, and remain as such well into representative of haematological malignancies, as well as
survivorship.15 Two independent meta-analyses5,16 found intracranial and extracranial solid tumours, those who
an adverse association between overweight or obesity were under­ nourished at diagnosis had worse overall
and survival outcomes in patients with acute lympho­ survival than those who were not undernourished
blastic leukaemia or acute myeloid leukaemia . In the (HR 3·63, 95% CI 1·52–8·70, p=0·004).10 Undernourish­
first study, a high BMI (≥85th percentile) conferred ment 3 months after diagnosis was also associated with
poorer event-free survival in patients with acute lympho­ worse survival (6·34, 2·42–16·65, p<0·001), and weight
blastic leukaemia (relative risk [RR] 1∙35, 95% CI loss of more than 5% in that same period was associated
1·20–1·51) and those with acute myeloid leukaemia with increased episodes of febrile neutropenia with
(1·36, 1·16–1·60), significantly increased mortality in bacteraemia in the first year after diagnosis (OR 3∙05,
acute myeloid leukaemia (1·31, 1·09–1·58), and poorer 95% CI 1·27–7·30, p=0·012).10
overall survival in acute myeloid leukaemia (1·56, The association of malnutrition, in particular obesity,
1·32–1·86), compared with patients with lower BMI with treatment-related complications has been high­
(<85th percentile).5 The subsequent report supported lighted across childhood malignancies. This finding is
these findings, and also showed a significant association exemplified by increased thrombohaemorrhagic early
between high BMI at diagnosis and poorer overall death in patients with acute promyelocytic leukaemia,19
survival (hazard ratio [HR] 1·30, 95% CI 1·16–1·46) and increased urinary tract infections20 and premature central
event-free survival (1·46, 1·29–1·64) among children line removal21 in patients with acute lymphoblastic
with acute leukaemia. Findings were consistent between leukaemia, and increased nephrotoxicity and post­
these investigations, despite heterogeneity in clinical operative complications in patients with osteosarcoma.12
regimens and study settings among patients with diverse Additionally, malnutrition strongly influences patients’
ages, socioeconomic, and racial or ethnic back­grounds.16 quality of life. This has been recognised among patients
In modern-day treatment of acute lymphoblastic on either end of the weight spectrum. Although under­
leukaemia, initial response to therapy, measured by end- nutrition and weight loss are associated with worse
induction minimal residual disease in the bone marrow, physical functioning, overnutrition and weight gain are

2 www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9

 Review

Brief description Advantages Disadvantages

Non-imaging techniques
Anthropometric measures Body-mass index, skin fold thickness, Easily obtained in the clinical setting and in large Prone to measurement error and variability
mid-upper-arm circumference, and waist population-based surveys
circumference
Bioelectrical impedance Uses impedance of electrical current to Inexpensive, portable, can be done at the bedside, rapid Absence of precision with oscillating hydration status
analysis estimate fat and lean tissue mass application, no radiation exposure, and immediate results and in chronically ill patients, and must be done in a
rigorous, standardised manner
Air-displacement Uses a test chamber to measure pressure– Validated for use in children, might be used in healthy or Limited usefulness in patients weighing less than 35 kg,
plethysmography volume relationship and derive body ill individuals, and no excess radiation exposure more expensive than other non-imaging techniques,
volume and density not portable, and not widely available
Imaging techniques
Dual-energy x-ray Measures the relative attenuation of two Paediatric-specific equations have been established, low Not portable, two-dimensional data, low precision
absorptiometry different energy x-rays by the body radiation exposure relative to CT, more sensitive than compared with CT and MRI, and distinction between
non-imaging techniques, short measurement time, and subcutaneous and visceral adipose tissue cannot be made
less expensive than CT and MRI
CT Series of x-ray images are used to create High accuracy and reproducible results, lean body mass, Radiation exposure and more expensive compared
detailed cross-sectional anatomical images subcutaneous fat, and visceral fat can be directly assessed with non-imaging techniques and dual-energy x-ray
absorptiometry
MRI Magnetic field and radio waves are used to Best spatial resolution and body mass composition More expensive than non-imaging techniques and
create detailed anatomical images differentiation, no radiation exposure, lean body mass, dual-energy x-ray absorptiometry, longer image
subcutaneous fat, and visceral fat can be directly assessed acquisition time than CT, and contraindications to MRI
might preclude some patients

Table: Summary of body composition techniques23–26

reported to affect the emotional and cognitive aspects of Cachexia, a profound, progressive wasting of lean tissue
daily living, and social function is impaired in both and body fat, is an effect long attributed to cancer therapy.
groups.22 Taken together, this evidence suggests that the In contrast to the term underweight, which largely refers
effect of nutritional status on children with cancer, both to a weight category defined strictly by BMI, cancer-related
during therapy and thereafter, is expansive in scope, and cachexia is marked by early satiety, weight loss, and severe
underscores the need to better understand the underlying weakness, which is thought to be driven by inflammatory
mechanisms driving its development and downstream cytokine activity. Tumour necrosis factor, IL6, interferon γ,
effects. leukaemia inhibiting factor, and ciliary neurotrophic factor
are among the most com­ monly implicated cytokines.
Metabolic effects of cancer and cancer therapy These biological markers are released by the tumour or its
Body composition changes surrounding cells, or both and, along with other mediators,
The mechanisms by which nutritional status might affect dietary intake and energy expenditure leading to a
influence cancer outcomes are hypothesised to be the clinical wasting syndrome.4,14
differential metabolic effects based on body composition.23 Conditions such as sarcopenia (a severe depletion
Several factors that contribute to body composition of skeletal muscle) and sarcopenic obesity (muscle
development during childhood and adolescence include depletion in the setting of excess fat) have been increasingly
age, sex, pubertal status, genetic factors, dietary intake, identified to more accurately characterise fluctuations in
medical conditions, and physical activity. Body com­ body composition and their association with treatment-
position assessment centres on the quantification of lean related complications and survival in adults with cancer.23
body mass, residual lean tissue mass, and body fat mass The pathogenesis of the skeletal muscle wasting process is
or distribution between visceral and subcutaneous possibly multifactorial, resulting in an imbalance between
compartments.4 Anthropometric measures—such as synthetic and degrad­ ative protein pathways, increased
BMI, skin fold thickness, mid-upper-arm circumference, myocyte apoptosis, and decreased muscle regeneration.27
and waist circumference—have traditionally been used Few body composition studies among children with cancer
to assess body store depletion in the clinical setting. have been done. However, existing literature reporting on
However, these modalities have been well recognised as the use of imaging for body composition assessment
being inadequate indicators of nutritional deficiencies has con­sistently shown that children with acute lympho­
in children with cancer.23 Advances in imaging tech­ blastic leukaemia have a notable decrease in skeletal
niques over the past decade, including dual-energy x-ray muscle mass,28,29 with a concomitant increase in fat
absorptiometry, CT, and MRI, have enabled practitioners mass,17,30 following the initiation of therapy. Similarly, in
to more accurately discern and quantify lean and adipose studies using non-imaging techniques to evaluate body
tissue compartments, and to further investigate their role composition in children with various malignancies,
in cancer care (table).24 including intracranial and extracranial solid tumours, the

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The implications of these findings might also be applicable

Panel 1: Components of nutritional assessment in to novel targeted therapies. Among adults, the relationship
paediatric cancer between body composition and drug adverse events has
Dietary history been described with use of tyrosine kinase inhibitors35 as
• Macronutrients and micronutrients well as various immunotherapy agents (pembrolizumab,34
• Food aversion nivolumab,34 and ipilimumab38). Given the intensifying
• Allergies interest in studying and using these targeted agents
• Food intolerance among a variety of paediatric malignancies, a deeper
understanding of the role of body composition is
Anthropometrics important.
• Height
• Weight Tumour microenvironment
• Body-mass index The influence of body tissue compartment changes is
• Mid-upper-arm circumference widely thought to extend to the host and tumour
• Body composition assessment* microenvironment, thereby contributing to the poor
Laboratory assessment outcomes seen in oncology patients who are obese.5
• Micronutrient evaluation* Studies have suggested that cancer-associated adipocytes
• Glucose monitoring secrete growth, inflammatory, fibrotic, and angiogenic
• Liver function panel factors, which promote tumour growth, alter the efficacy
• Pre-albumin* of cytotoxic drugs, and support cancer cell resistance.16,42
• Renal function panel In fact, several preclinical studies focusing on acute
• Lipid panel lymphoblastic leukaemia have shown that adipocytes
confer a protective effect on leukaemia cells, allowing
*Might be considered when clinically indicated. them to evade the cytotoxic effects of key treatment agents
such as vincristine, daunorubicin, and asparaginase.36,43,44
The pathophysiological processes leading body compo­
group as a whole had a decrease in fat-free mass with a sition to influence cancer and cancer therapy outcomes
concurrent increase in fat mass.22,31,32 The described are possibly multifactorial, combining elements from the
findings strongly support the idea that body composition various implicated pathways.5 Although traditional
variables might be key nutritionally related prognostic methods of dosing chemotherapy by weight and body
indicators among paediatric oncology patients, and surface area might not accurately predict pharma­ co­
highlight the need for further investigation in this kinetics, the understanding of the underlying variations
understudied area. between individuals and disease groups is poor.23 This is
especially true of the paediatric oncology population,
Pharmacokinetic implications and additional research is necessary to promote under­
Variations in lean tissue and fat mass are thought to affect standing of this important factor in their care.
chemotherapy volume of distribution, metabolism, and
thereby modify clearance of hydrophilic or lipophilic Current practice: assessment and intervention
drugs, or both, from systemic circulation.3,33–36 A poor Nutritional assessment
correlation between body surface area and fat-free mass, Evaluation of nutritional status is necessary throughout
which might account for an up to three-times differ­ence the continuum of cancer care to ensure normal growth
in effective volume of distribution of chemo­ therapy and development, and to optimise clinical outcomes
administered per body surface area unit, has been shown (panel 1). Such assessment should commence at
in adults with cancer.37 Furthermore, sarcopenia has an diagnosis and be done longitudinally during treatment
adverse relationship with tolerance to treatment and as well as into survivorship. As in most aspects of clinical
prevalence of dose-limiting toxicities in this popu­ medicine, the importance of history and physical assess­
lation24,38—such as with 5-fluorouracil in colorectal cancer39 ment cannot be under­ estimated. Baseline evaluation
and taxane-based chemotherapy in breast cancer.40 In should include dietary history to ascertain intake of
paediatrics, clinical studies evaluating body composition macronutrients and micro­nutrients, and identify known
and chemotherapy metabolism have largely focused on food aversions, allergies, or intolerances.
the effect of obesity, primarily in acute lymphoblastic Weight and height are the measurements most
leukaemia. Results have been mixed; several investigations frequently documented as they are used to ascertain
did not show a significant relation­ship between BMI and body surface area to determine chemotherapy doses;
daunorubicin, etoposide, or methotrexate clearance.33,41 however, nutritional assessments based on weight alone
Conversely, some studies involving doxorubicin and can be misleading, especially in the acutely ill patient
mercaptopurine continue to support the role of adiposity with cancer when fluid balance might be disturbed,
in cytotoxic drug activity among children with cancer.33 particularly in the presence of oedema, disease mass, or

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 Review

limb-sparing interventions. Aligned with general

paediatrics, height and weight should be plotted on a Panel 2: Key considerations for nutrition support in
growth curve to monitor growth and development over childhood cancer
the course of treatment and compared with pre- Children at high-risk for malnutrition
diagnosis nutritional status. Mid-upper-arm circum­ • Malnutrition or evidence of cachexia present at diagnosis
ference provides the best, easily obtained, estimate of • Patients expected to receive highly emetogenic regimens
lean body mass and adipose tissue and has been • Patients treated with regimens associated with severe
recommended to be an essential component of clinical gastrointestinal complications such as constipation,
care, particularly in children with a large tumour burden diarrhoea, loss of appetite, mucositis, or enterocolitis
or clinically significant oedema.45 Children with a low • Patients with relapsed disease
BMI (z score less than –1), children crossing at least two • Patients who are younger than 2 months
percentiles on the growth curve, weight loss greater • Patients who are expected to receive radiation to the
than or equal to 5%, a mid-upper-arm circumference oropharynx, oesophagus, or abdomen
z score less than –1 or below the 5th percentile, or • Chemotherapy protocols with high occurrence of
children meeting less than 80% of their needs through gastrointestinal or appetite-depressing side-effects, such as
dietary intake should be referred for nutrition protocols for Burkitt’s lymphoma, osteosarcoma, and CNS
counselling. Longitudinal assess­ ments are important tumours
for children at high risk for nutritional depletion • Post-surgical complications such as prolonged ileus or
because of the treatment itself or expected side-effects short gut syndrome
of treatment, each of which might necessitate advanced • Patients receiving a stem cell transplant
enteral nutritional interventions. • Inadequate availability of nutrients because of low
Biochemical laboratory assessments might be altered socioeconomic status
because of cancer therapy and concurrent infection. Any
condition that can alter the rate of protein synthesis, Indicators for nutrition referral
degradation, excretion, or inflammatory status might • Children at high-risk for malnutrition
change serum protein concentration. Prealbumin is a • Low body-mass index for age (<5th percentile or z score
better indicator of the acute state because of its shorter less than –1) or mid-upper-arm circumference
half-life; however, it is not without limitations.14 Clinical (<5th percentile or z score less than –1)
nutritional assessment should include the monitoring of • Overweight or obesity at diagnosis, especially for children
liver inflammation and function tests, renal function, diagnosed with acute lymphoblastic leukaemia
lipid panel, and glucose to determine if dietary mod­ • Crossing of two growth percentiles over the course of
ification might be indicated. For example, in children treatment, in either direction
with acute lymphoblastic leukaemia, a very low-fat diet • 5% weight loss or more from diagnosis
(<10 g/day) might be indicated in those with hyper­ • Unable to meet at least 80% of nutrient needs orally
triglyceridaemia due to co-administration of steroids and • Placement of nasogastric feeding tube
L-asparaginase. Blood glucose concen­trations should be • Indication for total parenteral nutrition
monitored in patients receiving high-dose steroids.
Several studies have found that up to a third of induction Reduced intake of antioxidants might also be associated
courses are associated with hyper­glycaemia, a condition with infection and increased hospital stay,51 whereas
that is further promoted by the presence of obesity and intakes of bone-related nutrients below the recommended
several increased treatment-related toxicities including values, specifically vitamin D and calcium, might
infectious complications.46 Children undergoing cancer increase the risk of bone morbidities among children
treatment are at risk for episodes of sepsis, which might with acute lymphoblastic leukaemia.52 Confir­mation of
be increased among those in a catabolic state and depleted suspected deficiencies with laboratory tests should be
of nutrients. done in children with severe deficiencies in intake,
A thorough assessment of nutritional status includes a prolonged diarrhoea, and malab­sorption con­ditions. The
full evaluation of dietary intake.47 Emerging evidence routine use of micronutrient supplements is contro­
suggests an association between decreased dietary intake versial, as some oncologists are concerned about
of several micronutrients following chemotherapy and the theoretical effect on chemotherapy cytotoxic action.
increased therapy-related toxicities.48 Ongoing cytotoxic However, supplementation of micro­nutrient deficiencies
therapy might also deplete the body of micronutrients. confirmed with blood specimens (eg, vitamin A,
For example, deficient intake of B vitamins might be vitamin D) within the recommended values set forth by
associated with the development of neuropathy,49,50 and the US National Academy of Science dietary reference
possibly cardiotoxicity among children with severely intakes is generally regarded as safe.53 Patients who are at
depleted intakes. Zinc is important to immune function, risk of malnutrition or have other indications for
mucosal integrity, and wound healing, and has been nutrition support should be referred to specialist teams
associated with increased infection and changes in taste. when appropriate (panel 2).

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Future directions: research and clinical practice

The past two decades have seen major advances in
nutritional research. Although the overarching aims
remain to foster health, prevent disease, and improve
Genetics performance, the development of omics technologies
such as genomics, metabolomics, proteomics, and
the study of the human microbiome have made the
notion of personalised nutrition an achievable reality
(figure 2).57,61 At present, most recommendations for
nutritional health and dietary interventions are drawn
from norms of population data. However, a great deal of
intrinsic variation in, and complexity of, personal
Metabolomics Disease formation Microbiome
and progression genetic makeups exists, which interacts with a multitude
of environmental stimuli and culminates in a dis­
similarity of response between individuals. The
assimilation of omics technologies into traditional
epidemiology-driven nutritional research might pave
the way for a systems-based approach to promote
the development of this emerging field of precision
nutrition.57,61,62 New technological methods facilitate
Diet and environment research on nutrient interactions with genes, proteins,
and metabolites, and the application of bioinformatics
Figure 2: Path to personalised nutrition
57–60
enables researchers to more efficiently manage, analyse,
Innovative technological methods will augment the understanding of the manner in which nutritional and
environmental factors interact with individual genes, proteins, and metabolites. and understand nutritional data. Collectively, these
research methods promote the development of large
databases dedicated to tracking and observing trends
Nutritional intervention related to nutrition. This new era of nutritional research
Nutritional interventions are challenging for children with methods will enable investigators to better understand
cancer because of the multiple factors concurrently individual variability in dietary responses, discover
affecting appetite and dietary intake. The primary goal for novel dietary biomarkers, identify high-risk populations,
nutritional intervention is to sustain and promote normal provide molecular insights on metabolic pathways, and
growth and development while the patient is receiving the tailor lifestyle and treatment recommendations to the
necessary anticancer therapy.4,14 Historically, clinicians were individual.57,61,63,
primarily concerned with maintaining optimal weight
and preventing nutritional deficiencies. However, the The genetics of obesity
increasing prevalence of obesity has required most Over the past decade, genome-wide association studies
clinicians to balance both ends of the nutritional spec­ have revolutionised the manner in which the scientific
trum—ie, undernutrition and overnutrition.54 Nutritional community understands the role of genetic predisposition
intervention should be proactive to prevent the development to obesity. This method enables a comprehensive and
of undernutrition in patients at high risk of becoming unbiased investigation of causal genetic variants in the
nutritionally depleted, rather than being reactive and population, and has been shown to be successful over
targeting reversal of undernutrition only when it becomes time. Among adults, more than 100 loci have been
apparent.55 The most appropriate intervention must be able implicated in BMI, and several of those have been
to meet the nutrition needs while also addressing symptom identified as key factors in the paediatric population as
management. Typical side-effects affecting dietary intake well.64,65 Moreover, several dedicated paediatric loci
are oral, oesophageal and bowel mucositis, severe nausea associated with extreme obesity have been discovered;
or vomiting, gastrointestinal obstruction, constipation, and however, genetic predisposition only explains a small
diarrhoea. A family-based approach is generally regarded proportion of paediatric obesity.65 Several prediction
as optimal, as parents are an essential component in models have been proposed for using genetic information
delivering nutrition throughout the course of therapy. to predict obesity risk for specific groups.66,67 Further­
Awareness of cultural differences overlaps into nutrition; more, genetic predisposition might interact with
sensitivity is required when advising patients whose the metabolome, environmental factors, and lifestyle
nutritional practices are different. Low socioeconomic behaviours affecting mechanisms that are not fully
status of the parents will affect their ability to sustain understood. Preliminary evidence suggests that genetics
adequate nutritional needs when at home.56 A dietitian’s might have a role in the development of obesity among
support and education to staff, families, and patients is a survivors of acute lymphoblastic leukaemia.68 Future
crucial component of optimal nutritional care. research might lead to the incorporation of genetics into

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childhood cancers associated with a high risk of obesity cancer, dietary components such as fibre and lipids are
development so that timely interventions might be given. suggested to directly influence carcinogenesis via effect
on the intestinal epithelium, epigenome modification,
Nutritional genomics and apoptosis regulation.70 Similarly, DNA microarray
The growing incidence of malnutrition and prevalence of analysis of breast cancer cells showed that components of
associated chronic diseases calls for further understanding pomegranate downregulate genes that are critically
of the intricate relationship between human genetics and involved in DNA double-strand break repair, thereby
the environment. Nutritional genomics is a field primarily benefiting growth inhibition and apoptosis. In prostate
composed of two research branches: nutrigenomics and cancer cells, these same extracts modulate phenotypic
nutrigenetics, which together describe the interaction expression of proteins involved in cytoskeletal function,
between diet-derived nutrients and genes.57 Nutrigeno­mics proteasome activity, and NF-κB signalling.71
studies how foods affect the expression of genetic The field of nutritional genomics is still in its infancy,
information at an individual level, and the manner in and has not yet touched on the manifold interaction
which distinctive genetic makeup affects how individuals between genes, nutrients, and the environment among
metabolise and respond to dietary nutrient components. children and adolescents. However, advanced technologies
Host and disease phenotypes might be modulated via looking at the genome, proteome, and metabolome along
influence of bioactive food constituents on the expression with bioinformatics have made the aspiration of precision
and function of DNA, RNA, protein, and metabolites. nutrition an attainable reality. This field alone has the
Thus, nutrigenomics explores dietary activity at a potential to transform the understanding of, and approach
transcriptional, translational, and metabolic level.3,57 to, nutritional assessment and intervention among
Genome-wide association studies have helped to identify patients and survivors of childhood cancer.3,57
numerous genetic variants involved in energy meta­bolism,
satiety and appetite, growth, nutrient absorption, and Metabolomics
many other nutrition-related processes. However, many of Metabolomics is the quantitative analysis of, and
these are not well understood, and there is much to comparison between, a large number of low-molecular-
uncover when it comes to the transformation of genetic weight metabolites (typically <1500 Da), which act as
variation to phenotypic expression.62 The high-throughput either substrates or products in the cellular metabolic
omics technologies are regarded as key factors in pathways of living organisms.57,58,72 Detectable molecules
contemporary systems biology, which enables investi­ are highly diverse, and include peptides, amino acids, and
gators to better understand these complex biological nucleic acids, as well as carbohydrates, organic acids, and
interactions and, ultimately, provide patients with unique inorganic species.57 Metabolomics enables investigators
dietary recommendations as a means of preventing or to assess individual-level nutritional status and to
treating chronic disease.57 understand how single nutrients influence metabolic
The many common variations in the human genome, regulation. In doing so, the aim is to ultimately use this
including those of nutrient-related genes, are known as information to formulate individualised diets that would
single-nucleotide polymorphisms (SNPs). Nutrigenetics help to prevent chronic disease.58,59 Moreover, applying
focuses on the interaction between, and integrated metabolic profiling to whole populations might promote
influence of, these SNPs on an individual’s metabolic the understanding of what predisposes specific groups to
response to particular dietary components.57,62 The certain diseases. Metabolomics provides a snapshot of
two most common methods in nutrigenetic study are genomic interaction with the host environment, including
candidate gene analysis and whole-genome linkage disease, physiological conditions as a consequence of
screening. Candidate gene analysis is mainly hypothesis drug treatment, nutrition, and lifestyle.58,67 Thus,
focused, and aims to identify and study biologically metabolites under investigation might one day become
associated genes. Genome-wide linkage screening links biomarkers for disease detection and even targets for
whole genome polymorphisms to other physiological drug development.59
variables. In doing so, this method highlights genes In the clinical setting, mass spectrometry and nuclear
associated with a particular variable of interest, such as magnetic resonance-based techniques have been most
disease-related markers.57 commonly used in the study of metabolomics. Analysis
Nutritional genomics application in oncology has shown can be done on various biological fluids (eg, blood, urine),
promise among a variety of nutrients, one of which is tissue types, and stool.57,72 Methods have been established
selenium. Selenoprotein involvement has been implicated for screening central carbon metabolism, including
in cellular maintenance, antioxidant activity, mitochondrial glycolysis and the tricarboxylic acid cycle, amino acid
function, and immune response. Variations in genes pathways, lipid pathways, and selected secondary
involved in selenium metabolism were shown to interact metabolism pathways.72 Developments in both nuclear
with selenium concentrations to modulate risk for a magnetic resonance and mass spectrometry include
variety of malignancies, including breast, prostate, and increase in sample output, sensitivity, resolution, and
colorectal cancers.69 In fact, among patients with colorectal ability to identify and quantify metabolites.57,72 Multivariate

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 Review

and absorption of nutritional substances by breaking

Search strategy and selection criteria down proteins, lipids, and carbohydrates from the diet.58
We searched PubMed for peer-reviewed articles with the With the advent of high-throughput sequencing methods
search terms “childhood cancer”, “nutritional status”, and bioinformatics techniques, current literature
“malnutrition”, “body mass index”, “body composition”, “fat suggests that the microbiome has an important role in
mass”, “fat-free mass”, “lean tissue mass”, “overall survival”, human health and disease, including cancer.60 The
“event-free survival”, “treatment related toxicity”, “adverse microbiota has been hypothesised to be involved in the
effects”, “chemotherapy pharmacokinetics”, “metabolome”, development of several gastrointestinal cancers,75
“nutritional genomics”, “microbiome”, and “obesity genes” paediatric leukaemia,76,77 and several toxicities related to
from Jan 1, 2000, to May 31, 2019. We also selected relevant administration of chemotherapy or radiation.78–81
articles from our personal files and from reference lists of Few clinical and interventional studies of the microbiome
identified papers. We prioritised publications after 2014; have been done in paediatric oncology, with most studies
however, commonly cited and highly regarded (defined by being observational. The composition and diversity of the
high citation count and journal impact factor) older microbiome have been associated with survival of
publications were also included. Randomised controlled haematopoietic stem cell transplantation and its related
trials, observational studies, retrospective studies, meta- complications.82 For example, Biagi and colleagues83
analyses, editorials, and review articles were included, described fluctuations in microbiome among children
whereas conference abstracts and case reports were undergoing haematopoietic stem cell trans­plantation and
excluded. We only searched for articles published in English, found that the onset of acute graft-versus-host disease was
or those translated into English. associated with distinct microbial signatures between
patients who developed the disease compared with those
who did not. These results mirror several studies that have
statistical and bioinformatics techniques can then be been done in adults who received haemopoietic stem cell
used for data mining of complex metabolic profiles that transplantation.84 One small pilot study tested the safety
encompass genetic, environmental, microbiome, dietary, and feasibility of a probiotic, Lactobacillus plantarum,
and lifestyle information.72 Investigations involving among children undergoing haemopoietic stem cell
metabolomics can now be applied to better understand transplantation,80 the results of which prompted an
diet in the context of cancer and the downstream effects ongoing trial being done in the Children’s Oncology
of oncological care. Group, evaluating the role of probiotic therapy for the
Application of metabolomic technology in the oncology prevention of acute graft-versus-host disease among
setting has been most commonly reported in patients children and adolescents (NCT03057054).
with colorectal cancer.70,73 Metabolomics analyses have The role of the gut microbiome in other paediatric
revealed different metabolite signatures between stool, malignancies is also under investigation. Similar with
malignant tissue, and healthy adjoining mucosa. Studies other findings, Rajagopala and colleagues’ case-control
of the faecal metabolome show altered short-chain fatty study77 found that children with acute lymphoblastic
acid, amino acid, and unsaturated fatty acid metabolism leukaemia had different microbial composition at
in this population; another study revealed that pathways diagnosis when compared with their sibling controls.
for urea, caffeine, and galactose metabolism might be The gut microbiome has also been associated with an
linked to disease progression.70 Several investigations increased risk of infections in paediatric acute
have even suggested a positive relationship between a lymphoblastic leukaemia.85 Others have hypothesised
variety of nutrients, including pomegranate and coffee that modulation of the microbiome during and after
components, metabolic profiles, and chemoprotective therapy might affect the development of treatment-
effects in colorectal cancer.73 Thus, among patients with related late-effects among survivors of childhood cancer.86
colorectal cancer, metabolomics potentiates the On the basis of the available literature, the microbiome
identification of new cancer metabolite biomarkers. is an emerging area that might provide insight into the
Studies integrating gene and protein expression profiles development of certain paediatric cancers and might be a
with metabolic fingerprints allow for a more in-depth target of clinical trials in which the aim is to reduce
analysis of an individual’s response to nutritional treatment-related toxicities. Additional research is
interventions,71 and their application in paediatric warranted—particularly trials that explore the optimal
oncology will further the field’s understanding in the role dosing, species, and timing of probiotic therapy.
of food and patient outcomes.
Conclusion
The microbiome Poor nutritional status is linked to adverse outcomes both
The human microbiota consists of 100 trillion microbes during the treatment of childhood cancer and extending
that coexist in a symbiotic relationship; the microbiome into survivorship. In the course of therapy, both
consists of the genes encoded by these cells.74 Microbiome undernutrition and overnutrition are widely recognised
makeup begins at birth, and functions in the digestion as contributors to increased morbidity and mortality,

8 www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9

 Review

while during survivorship, overnutrition is one of the risk 13 Hamilton EC, Curtin T, Slack RS, et al. Surgical feeding tubes in
factors for a myriad of debilitating chronic diseases, such pediatric and adolescent cancer patients: a single-institution
retrospective review. J Pediatr Hematol Oncol 2017; 39: e342–8.
as diabetes and cardiovascular disease.22 Although great 14 Ladas EJ, Sacks N, Meacham L, et al. A multidisciplinary review of
strides have been made in the under­standing of nutrition nutrition considerations in the pediatric oncology population:
and its multifaceted biological and physiological effect on a perspective from Children’s Oncology Group. Nutr Clin Pract
2005; 20: 377–93.
health outcomes in paediatric oncology, further clinical 15 Zhang FF, Liu S, Chung M, Kelly MJ. Growth patterns during and
and translational investigations are needed to advance the after treatment in patients with pediatric ALL: a meta-analysis.
field. Further examination of the epidemiology and Pediatr Blood Cancer 2015; 62: 1452–60.
16 Amankwah EK, Saenz AM, Hale GA, Brown PA. Association
aetiologies of malnutrition in this population is needed, between body mass index at diagnosis and pediatric leukemia
in conjunction with the omics technologies of today.3,8 mortality and relapse: a systematic review and meta-analysis.
Integration of these methods is necessary to broaden the Leuk Lymphoma 2016; 57: 1140–48.
scientific community’s understanding of the way in 17 Orgel E, Mueske NM, Sposto R, Gilsanz V, Freyer DR,
Mittelman SD. Limitations of body mass index to assess body
which diet interacts with the individual, and facilitate the composition due to sarcopenic obesity during leukemia therapy.
development of personalised nutritional interventions Leuk Lymphoma 2018; 59: 138–45.
and protocols.61 Customising and optimising nutritional 18 Eissa HM, Zhou Y, Panetta JC, et al. The effect of body mass index
at diagnosis on clinical outcome in children with newly diagnosed
status during and after treatment can be used to prevent acute lymphoblastic leukemia. Blood Cancer J 2017; 7: e531.
or mitigate treatment-related complications, improve 19 Abla O, Ribeiro RC, Testi AM, et al. Predictors of
quality of life, and long-term survival for patients and thrombohemorrhagic early death in children and adolescents with
t(15;17)-positive acute promyelocytic leukemia treated with ATRA
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Contributors 20 Li MJ, Chang HH, Yang YL, et al. Infectious complications in
All authors participated in the conceptualisation and creation of the children with acute lymphoblastic leukemia treated with the Taiwan
manuscript, literature search, writing, as well as original and final Pediatric Oncology Group protocol: a 16-year tertiary
editing of the manuscript. single-institution experience. Pediatr Blood Cancer 2017; 64.
21 Fu AB, Hodgman EI, Burkhalter LS, Renkes R, Slone T, Alder AC.
Declaration of interests Long-term central venous access in a pediatric leukemia population.
We declare no competing interests. J Surg Res 2016; 205: 419–25.
Acknowledgments 22 Brinksma A, Sanderman R, Roodbol PF, et al. Malnutrition is
associated with worse health-related quality of life in children with
This work was supported by The Tamarind Foundation to EJL, the
cancer. Support Care Cancer 2015; 23: 3043–52.
American Cancer Society to EJL (grant number 127000-MRSG-14-157-01-
23 Joffe L, Schadler KL, Shen W, Ladas EJ. Body composition in
CCE), and the US National Institutes of Health to LJ (grant number T32
pediatric solid tumors: state of the science and future directions.
CA094061-17). J Natl Cancer Inst Monogr 2019; 2019: 144–8.
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