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 ejd14@cumc.columbia.edu
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
Cancer and cancer therapy
Inflammation
Decreased Decreased Decreased
physical growth nutrition
hormone
activity intake
Poor Increased Decreased
dietary patient patient fat-
intake fat mass free mass
Overnutrition Undernutrition
Energy
balance
Figure 1: Energy balance in paediatric cancer8,9
Malnutrition in paediatric cancer stems from a multifactorial process involving the disease itself, effects of therapy,
and host inflammatory response. Resultant alterations in quantity and quality of dietary intake, physical activity
levels, fluctuations in fat and fat-free mass, and host hormonal and metabolic changes, all contribute to a loss of
energy balance in this population.
Nutrition in paediatric oncology
Epidemiology and outcomes
Among paediatric malignancies, the role of nutritional
status has been best studied in patients with leukaemia.
The literature suggests that regardless of treatment or
weight at diagnosis, patients with paediatric leukaemia
are at risk of becoming overweight or obese early in
the treatment process, and remain as such well into
survivorship.15 Two independent meta-analyses5,16 found
an adverse association between overweight or obesity
and survival outcomes in patients with acute lympho­
blastic leukaemia or acute myeloid leukaemia . In the
first study, a high BMI (≥85th percentile) conferred
poorer event-free survival in patients with acute lympho­
blastic leukaemia (relative risk [RR] 1∙35, 95% CI
1·20–1·51) and those with acute myeloid leukaemia
(1·36, 1·16–1·60), significantly increased mortality in
acute myeloid leukaemia (1·31, 1·09–1·58), and poorer
overall survival in acute myeloid leukaemia (1·56,
1·32–1·86), compared with patients with lower BMI
(<85th percentile).5 The subsequent report supported
these findings, and also showed a significant association
between high BMI at diagnosis and poorer overall
survival (hazard ratio [HR] 1·30, 95% CI 1·16–1·46) and
event-free survival (1·46, 1·29–1·64) among children
with acute leukaemia. Findings were consistent between
these investigations, despite heterogeneity in clinical
regimens and study settings among patients with diverse
ages, socioeconomic, and racial or ethnic back­grounds.16
In modern-day treatment of acute lymphoblastic
leukaemia, initial response to therapy, measured by end-
induction minimal residual disease in the bone marrow,
2 www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9
is considered to be of great prognostic value. Orgel and
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
Increased during induction (odds ratio [OR] 2·57, 95% CI
metabolic
1·19–5·54, p=0·016). Moreover, obesity and overweight
demand
were associated with poorer event-free survival irres­
pective of minimal residual disease (p=0∙012). Yet, in a
Growth
demands
similar study, Eissa and colleagues18 did not find the
same association between BMI and minimal residual
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
lymphoblastic leukaemia outcomes remains to be
determined, and current research represents the first
steps in elucidating the relationship between body
habitus and the pathophysiology of childhood acute
lymphoblastic leukaemia.
Although it has been less extensively studied in
paediatric solid tumours, the effect of nutritional status
on outcomes has been shown to extend to this patient
population as well. A systematic review found that BMI
outside of the normal range (between the 5th and
84th percentiles is associated with impaired overall
survival in Ewing sarcoma (HR 3·46, p=0·022) and osteo­
sarcoma (1·6, p<0∙005), with weak evidence of poorer
overall survival in rhabdomyosarcoma (1·70, p=0·0596).12
In fact, in a diverse population of patients, who were
representative of haematological malignancies, as well as
intracranial and extracranial solid tumours, those who
were under­ nourished at diagnosis had worse overall
survival than those who were not undernourished
(HR 3·63, 95% CI 1·52–8·70, p=0·004).10 Undernourish­
ment 3 months after diagnosis was also associated with
worse survival (6·34, 2·42–16·65, p<0·001), and weight
loss of more than 5% in that same period was associated
with increased episodes of febrile neutropenia with
bacteraemia in the first year after diagnosis (OR 3∙05,
95% CI 1·27–7·30, p=0·012).10
The association of malnutrition, in particular obesity,
with treatment-related complications has been high­
lighted across childhood malignancies. This finding is
exemplified by increased thrombohaemorrhagic early
death in patients with acute promyelocytic leukaemia,19
increased urinary tract infections20 and premature central
line removal21 in patients with acute lymphoblastic
leukaemia, and increased nephrotoxicity and post­
operative complications in patients with osteosarcoma.12
Additionally, malnutrition strongly influences patients’
quality of life. This has been recognised among patients
on either end of the weight spectrum. Although under­
nutrition and weight loss are associated with worse
physical functioning, overnutrition and weight gain are

Brief description
Non-imaging techniques
Anthropometric measures Body-mass index, skin fold thickness,
mid-upper-arm circumference, and waist
circumference
Bioelectrical impedance Uses impedance of electrical current to
analysis estimate fat and lean tissue mass
Air-displacement Uses a test chamber to measure pressure–
plethysmography volume relationship and derive body
volume and density
Imaging techniques
Dual-energy x-ray Measures the relative attenuation of two
absorptiometry different energy x-rays by the body
CT Series of x-ray images are used to create
detailed cross-sectional anatomical images
MRI Magnetic field and radio waves are used to
create detailed anatomical images
Table: Summary of body composition techniques23–26
reported to affect the emotional and cognitive aspects of
daily living, and social function is impaired in both
groups.22 Taken together, this evidence suggests that the
effect of nutritional status on children with cancer, both
during therapy and thereafter, is expansive in scope, and
underscores the need to better understand the underlying
mechanisms driving its development and downstream
effects.
Metabolic effects of cancer and cancer therapy
Body composition changes
The mechanisms by which nutritional status might
influence cancer outcomes are hypothesised to be the
differential metabolic effects based on body composition.23
Several factors that contribute to body composition
development during childhood and adolescence include
age, sex, pubertal status, genetic factors, dietary intake,
medical conditions, and physical activity. Body com­
position assessment centres on the quantification of lean
body mass, residual lean tissue mass, and body fat mass
or distribution between visceral and subcutaneous
compartments.4 Anthropometric measures—such as
BMI, skin fold thickness, mid-upper-arm circumference,
and waist circumference—have traditionally been used
to assess body store depletion in the clinical setting.
However, these modalities have been well recognised as
being inadequate indicators of nutritional deficiencies
in children with cancer.23 Advances in imaging tech­
niques over the past decade, including dual-energy x-ray
absorptiometry, CT, and MRI, have enabled practitioners
to more accurately discern and quantify lean and adipose
tissue compartments, and to further investigate their role
in cancer care (table).24
www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9 3
Review
Advantages Disadvantages
Easily obtained in the clinical setting and in large Prone to measurement error and variability
population-based surveys
Inexpensive, portable, can be done at the bedside, rapid Absence of precision with oscillating hydration status
application, no radiation exposure, and immediate results and in chronically ill patients, and must be done in a
rigorous, standardised manner
Validated for use in children, might be used in healthy or Limited usefulness in patients weighing less than 35 kg,
ill individuals, and no excess radiation exposure more expensive than other non-imaging techniques,
not portable, and not widely available
Paediatric-specific equations have been established, low Not portable, two-dimensional data, low precision
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
High accuracy and reproducible results, lean body mass, Radiation exposure and more expensive compared
subcutaneous fat, and visceral fat can be directly assessed with non-imaging techniques and dual-energy x-ray
absorptiometry
Best spatial resolution and body mass composition More expensive than non-imaging techniques and
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
Cachexia, a profound, progressive wasting of lean tissue
and body fat, is an effect long attributed to cancer therapy.
In contrast to the term underweight, which largely refers
to a weight category defined strictly by BMI, cancer-related
cachexia is marked by early satiety, weight loss, and severe
weakness, which is thought to be driven by inflammatory
cytokine activity. Tumour necrosis factor, IL6, interferon γ,
leukaemia inhibiting factor, and ciliary neurotrophic factor
are among the most com­ monly implicated cytokines.
These biological markers are released by the tumour or its
surrounding cells, or both and, along with other mediators,
affect dietary intake and energy expenditure leading to a
clinical wasting syndrome.4,14
Conditions such as sarcopenia (a severe depletion
of skeletal muscle) and sarcopenic obesity (muscle
depletion in the setting of excess fat) have been increasingly
identified to more accurately characterise fluctuations in
body composition and their association with treatment-
related complications and survival in adults with cancer.23
The pathogenesis of the skeletal muscle wasting process is
possibly multifactorial, resulting in an imbalance between
synthetic and degrad­ ative protein pathways, increased
myocyte apoptosis, and decreased muscle regeneration.27
Few body composition studies among children with cancer
have been done. However, existing literature reporting on
the use of imaging for body composition assessment
has con­sistently shown that children with acute lympho­
blastic leukaemia have a notable decrease in skeletal
muscle mass,28,29 with a concomitant increase in fat
mass,17,30 following the initiation of therapy. Similarly, in
studies using non-imaging techniques to evaluate body
composition in children with various malignancies,
including intracranial and extracranial solid tumours, the
 Review
Panel 1: Components of nutritional assessment in
paediatric cancer
Dietary history
• Macronutrients and micronutrients
• Food aversion
• Allergies
• Food intolerance
Anthropometrics
• Height
• Weight
• Body-mass index
• Mid-upper-arm circumference
• Body composition assessment*
Laboratory assessment
• Micronutrient evaluation*
• Glucose monitoring
• Liver function panel
• Pre-albumin*
• Renal function panel
• Lipid panel
*Might be considered when clinically indicated.
group as a whole had a decrease in fat-free mass with a
concurrent increase in fat mass.22,31,32 The described
findings strongly support the idea that body composition
variables might be key nutritionally related prognostic
indicators among paediatric oncology patients, and
highlight the need for further investigation in this
understudied area.
Pharmacokinetic implications
Variations in lean tissue and fat mass are thought to affect
chemotherapy volume of distribution, metabolism, and
thereby modify clearance of hydrophilic or lipophilic
drugs, or both, from systemic circulation.3,33–36 A poor
correlation between body surface area and fat-free mass,
which might account for an up to three-times differ­ence
in effective volume of distribution of chemo­ therapy
administered per body surface area unit, has been shown
in adults with cancer.37 Furthermore, sarcopenia has an
adverse relationship with tolerance to treatment and
prevalence of dose-limiting toxicities in this popu­
lation24,38—such as with 5-fluorouracil in colorectal cancer39
and taxane-based chemotherapy in breast cancer.40 In
paediatrics, clinical studies evaluating body composition
and chemotherapy metabolism have largely focused on
the effect of obesity, primarily in acute lymphoblastic
leukaemia. Results have been mixed; several investigations
did not show a significant relation­ship between BMI and
daunorubicin, etoposide, or methotrexate clearance.33,41
Conversely, some studies involving doxorubicin and
mercaptopurine continue to support the role of adiposity
in cytotoxic drug activity among children with cancer.33
4 www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9
The implications of these findings might also be applicable
to novel targeted therapies. Among adults, the relationship
between body composition and drug adverse events has
been described with use of tyrosine kinase inhibitors35 as
well as various immunotherapy agents (pembrolizumab,34
nivolumab,34 and ipilimumab38). Given the intensifying
interest in studying and using these targeted agents
among a variety of paediatric malignancies, a deeper
understanding of the role of body composition is
important.
Tumour microenvironment
The influence of body tissue compartment changes is
widely thought to extend to the host and tumour
microenvironment, thereby contributing to the poor
outcomes seen in oncology patients who are obese.5
Studies have suggested that cancer-associated adipocytes
secrete growth, inflammatory, fibrotic, and angiogenic
factors, which promote tumour growth, alter the efficacy
of cytotoxic drugs, and support cancer cell resistance.16,42
In fact, several preclinical studies focusing on acute
lymphoblastic leukaemia have shown that adipocytes
confer a protective effect on leukaemia cells, allowing
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
sition to influence cancer and cancer therapy outcomes
are possibly multifactorial, combining elements from the
various implicated pathways.5 Although traditional
methods of dosing chemotherapy by weight and body
surface area might not accurately predict pharma­ co­
kinetics, the understanding of the underlying variations
between individuals and disease groups is poor.23 This is
especially true of the paediatric oncology population,
and additional research is necessary to promote under­
standing of this important factor in their care.
Current practice: assessment and intervention
Nutritional assessment
Evaluation of nutritional status is necessary throughout
the continuum of cancer care to ensure normal growth
and development, and to optimise clinical outcomes
(panel 1). Such assessment should commence at
diagnosis and be done longitudinally during treatment
as well as into survivorship. As in most aspects of clinical
medicine, the importance of history and physical assess­
ment cannot be under­ estimated. Baseline evaluation
should include dietary history to ascertain intake of
macronutrients and micro­nutrients, and identify known
food aversions, allergies, or intolerances.
Weight and height are the measurements most
frequently documented as they are used to ascertain
body surface area to determine chemotherapy doses;
however, nutritional assessments based on weight alone
can be misleading, especially in the acutely ill patient
with cancer when fluid balance might be disturbed,
particularly in the presence of oedema, disease mass, or

limb-sparing interventions. Aligned with general
paediatrics, height and weight should be plotted on a
growth curve to monitor growth and development over
the course of treatment and compared with pre-
diagnosis nutritional status. Mid-upper-arm circum­
ference provides the best, easily obtained, estimate of
lean body mass and adipose tissue and has been
recommended to be an essential component of clinical
care, particularly in children with a large tumour burden
or clinically significant oedema.45 Children with a low
BMI (z score less than –1), children crossing at least two
percentiles on the growth curve, weight loss greater
than or equal to 5%, a mid-upper-arm circumference
z score less than –1 or below the 5th percentile, or
children meeting less than 80% of their needs through
dietary intake should be referred for nutrition
counselling. Longitudinal assess­ ments are important
for children at high risk for nutritional depletion
because of the treatment itself or expected side-effects
of treatment, each of which might necessitate advanced
enteral nutritional interventions.
Biochemical laboratory assessments might be altered
because of cancer therapy and concurrent infection. Any
condition that can alter the rate of protein synthesis,
degradation, excretion, or inflammatory status might
change serum protein concentration. Prealbumin is a
better indicator of the acute state because of its shorter
half-life; however, it is not without limitations.14 Clinical
nutritional assessment should include the monitoring of
liver inflammation and function tests, renal function,
lipid panel, and glucose to determine if dietary mod­
ification might be indicated. For example, in children
with acute lymphoblastic leukaemia, a very low-fat diet
(<10 g/day) might be indicated in those with hyper­
triglyceridaemia due to co-administration of steroids and
L-asparaginase. Blood glucose concen­trations should be
monitored in patients receiving high-dose steroids.
Several studies have found that up to a third of induction
courses are associated with hyper­glycaemia, a condition
that is further promoted by the presence of obesity and
several increased treatment-related toxicities including
infectious complications.46 Children undergoing cancer
treatment are at risk for episodes of sepsis, which might
be increased among those in a catabolic state and depleted
of nutrients.
A thorough assessment of nutritional status includes a
full evaluation of dietary intake.47 Emerging evidence
suggests an association between decreased dietary intake
of several micronutrients following chemotherapy and
increased therapy-related toxicities.48 Ongoing cytotoxic
therapy might also deplete the body of micronutrients.
For example, deficient intake of B vitamins might be
associated with the development of neuropathy,49,50 and
possibly cardiotoxicity among children with severely
depleted intakes. Zinc is important to immune function,
mucosal integrity, and wound healing, and has been
associated with increased infection and changes in taste.
www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9 5
Review
Panel 2: Key considerations for nutrition support in
childhood cancer
Children at high-risk for malnutrition
• Malnutrition or evidence of cachexia present at diagnosis
• Patients expected to receive highly emetogenic regimens
• Patients treated with regimens associated with severe
gastrointestinal complications such as constipation,
diarrhoea, loss of appetite, mucositis, or enterocolitis
• Patients with relapsed disease
• Patients who are younger than 2 months
• Patients who are expected to receive radiation to the
oropharynx, oesophagus, or abdomen
• Chemotherapy protocols with high occurrence of
gastrointestinal or appetite-depressing side-effects, such as
protocols for Burkitt’s lymphoma, osteosarcoma, and CNS
tumours
• Post-surgical complications such as prolonged ileus or
short gut syndrome
• Patients receiving a stem cell transplant
• Inadequate availability of nutrients because of low
socioeconomic status
Indicators for nutrition referral
• Children at high-risk for malnutrition
• Low body-mass index for age (<5th percentile or z score
less than –1) or mid-upper-arm circumference
(<5th percentile or z score less than –1)
• Overweight or obesity at diagnosis, especially for children
diagnosed with acute lymphoblastic leukaemia
• Crossing of two growth percentiles over the course of
treatment, in either direction
• 5% weight loss or more from diagnosis
• Unable to meet at least 80% of nutrient needs orally
• Placement of nasogastric feeding tube
• Indication for total parenteral nutrition
Reduced intake of antioxidants might also be associated
with infection and increased hospital stay,51 whereas
intakes of bone-related nutrients below the recommended
values, specifically vitamin D and calcium, might
increase the risk of bone morbidities among children
with acute lymphoblastic leukaemia.52 Confir­mation of
suspected deficiencies with laboratory tests should be
done in children with severe deficiencies in intake,
prolonged diarrhoea, and malab­sorption con­ditions. The
routine use of micronutrient supplements is contro­
versial, as some oncologists are concerned about
the theoretical effect on chemotherapy cytotoxic action.
However, supplementation of micro­nutrient deficiencies
confirmed with blood specimens (eg, vitamin A,
vitamin D) within the recommended values set forth by
the US National Academy of Science dietary reference
intakes is generally regarded as safe.53 Patients who are at
risk of malnutrition or have other indications for
nutrition support should be referred to specialist teams
when appropriate (panel 2).
 Review
Genetics
Metabolomics Disease formation
and progression
Diet and environment
Figure 2: Path to personalised nutrition
57–60
Innovative technological methods will augment the understanding of the manner in which nutritional and
environmental factors interact with individual genes, proteins, and metabolites.
Nutritional intervention
Nutritional interventions are challenging for children with
cancer because of the multiple factors concurrently
affecting appetite and dietary intake. The primary goal for
nutritional intervention is to sustain and promote normal
growth and development while the patient is receiving the
necessary anticancer therapy.4,14 Historically, clinicians were
primarily concerned with maintaining optimal weight
and preventing nutritional deficiencies. However, the
increasing prevalence of obesity has required most
clinicians to balance both ends of the nutritional spec­
trum—ie, undernutrition and overnutrition.54 Nutritional
intervention should be proactive to prevent the development
of undernutrition in patients at high risk of becoming
nutritionally depleted, rather than being reactive and
targeting reversal of undernutrition only when it becomes
apparent.55 The most appropriate intervention must be able
to meet the nutrition needs while also addressing symptom
management. Typical side-effects affecting dietary intake
are oral, oesophageal and bowel mucositis, severe nausea
or vomiting, gastrointestinal obstruction, constipation, and
diarrhoea. A family-based approach is generally regarded
as optimal, as parents are an essential component in
delivering nutrition throughout the course of therapy.
Awareness of cultural differences overlaps into nutrition;
sensitivity is required when advising patients whose
nutritional practices are different. Low socioeconomic
status of the parents will affect their ability to sustain
adequate nutritional needs when at home.56 A dietitian’s
support and education to staff, families, and patients is a
crucial component of optimal nutritional care.
6 www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9
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
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
Microbiome
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
research on nutrient interactions with genes, proteins,
and metabolites, and the application of bioinformatics
enables researchers to more efficiently manage, analyse,
and understand nutritional data. Collectively, these
research methods promote the development of large
databases dedicated to tracking and observing trends
related to nutrition. This new era of nutritional research
methods will enable investigators to better understand
individual variability in dietary responses, discover
novel dietary biomarkers, identify high-risk populations,
provide molecular insights on metabolic pathways, and
tailor lifestyle and treatment recommendations to the
individual.57,61,63,
The genetics of obesity
Over the past decade, genome-wide association studies
have revolutionised the manner in which the scientific
community understands the role of genetic predisposition
to obesity. This method enables a comprehensive and
unbiased investigation of causal genetic variants in the
population, and has been shown to be successful over
time. Among adults, more than 100 loci have been
implicated in BMI, and several of those have been
identified as key factors in the paediatric population as
well.64,65 Moreover, several dedicated paediatric loci
associated with extreme obesity have been discovered;
however, genetic predisposition only explains a small
proportion of paediatric obesity.65 Several prediction
models have been proposed for using genetic information
to predict obesity risk for specific groups.66,67 Further­
more, genetic predisposition might interact with
the metabolome, environmental factors, and lifestyle
behaviours affecting mechanisms that are not fully
understood. Preliminary evidence suggests that genetics
might have a role in the development of obesity among
survivors of acute lymphoblastic leukaemia.68 Future
research might lead to the incorporation of genetics into

childhood cancers associated with a high risk of obesity
development so that timely interventions might be given.
Nutritional genomics
The growing incidence of malnutrition and prevalence of
associated chronic diseases calls for further understanding
of the intricate relationship between human genetics and
the environment. Nutritional genomics is a field primarily
composed of two research branches: nutrigenomics and
nutrigenetics, which together describe the interaction
between diet-derived nutrients and genes.57 Nutrigeno­mics
studies how foods affect the expression of genetic
information at an individual level, and the manner in
which distinctive genetic makeup affects how individuals
metabolise and respond to dietary nutrient components.
Host and disease phenotypes might be modulated via
influence of bioactive food constituents on the expression
and function of DNA, RNA, protein, and metabolites.
Thus, nutrigenomics explores dietary activity at a
transcriptional, translational, and metabolic level.3,57
Genome-wide association studies have helped to identify
numerous genetic variants involved in energy meta­bolism,
satiety and appetite, growth, nutrient absorption, and
many other nutrition-related processes. However, many of
these are not well understood, and there is much to
uncover when it comes to the transformation of genetic
variation to phenotypic expression.62 The high-throughput
omics technologies are regarded as key factors in
contemporary systems biology, which enables investi­
gators to better understand these complex biological
interactions and, ultimately, provide patients with unique
dietary recommendations as a means of preventing or
treating chronic disease.57
The many common variations in the human genome,
including those of nutrient-related genes, are known as
single-nucleotide polymorphisms (SNPs). Nutrigenetics
focuses on the interaction between, and integrated
influence of, these SNPs on an individual’s metabolic
response to particular dietary components.57,62 The
two most common methods in nutrigenetic study are
candidate gene analysis and whole-genome linkage
screening. Candidate gene analysis is mainly hypothesis
focused, and aims to identify and study biologically
associated genes. Genome-wide linkage screening links
whole genome polymorphisms to other physiological
variables. In doing so, this method highlights genes
associated with a particular variable of interest, such as
disease-related markers.57
Nutritional genomics application in oncology has shown
promise among a variety of nutrients, one of which is
selenium. Selenoprotein involvement has been implicated
in cellular maintenance, antioxidant activity, mitochondrial
function, and immune response. Variations in genes
involved in selenium metabolism were shown to interact
with selenium concentrations to modulate risk for a
variety of malignancies, including breast, prostate, and
colorectal cancers.69 In fact, among patients with colorectal
www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9 7
Review
cancer, dietary components such as fibre and lipids are
suggested to directly influence carcinogenesis via effect
on the intestinal epithelium, epigenome modification,
and apoptosis regulation.70 Similarly, DNA microarray
analysis of breast cancer cells showed that components of
pomegranate downregulate genes that are critically
involved in DNA double-strand break repair, thereby
benefiting growth inhibition and apoptosis. In prostate
cancer cells, these same extracts modulate phenotypic
expression of proteins involved in cytoskeletal function,
proteasome activity, and NF-κB signalling.71
The field of nutritional genomics is still in its infancy,
and has not yet touched on the manifold interaction
between genes, nutrients, and the environment among
children and adolescents. However, advanced technologies
looking at the genome, proteome, and metabolome along
with bioinformatics have made the aspiration of precision
nutrition an attainable reality. This field alone has the
potential to transform the understanding of, and approach
to, nutritional assessment and intervention among
patients and survivors of childhood cancer.3,57
Metabolomics
Metabolomics is the quantitative analysis of, and
comparison between, a large number of low-molecular-
weight metabolites (typically <1500 Da), which act as
either substrates or products in the cellular metabolic
pathways of living organisms.57,58,72 Detectable molecules
are highly diverse, and include peptides, amino acids, and
nucleic acids, as well as carbohydrates, organic acids, and
inorganic species.57 Metabolomics enables investigators
to assess individual-level nutritional status and to
understand how single nutrients influence metabolic
regulation. In doing so, the aim is to ultimately use this
information to formulate individualised diets that would
help to prevent chronic disease.58,59 Moreover, applying
metabolic profiling to whole populations might promote
the understanding of what predisposes specific groups to
certain diseases. Metabolomics provides a snapshot of
genomic interaction with the host environment, including
disease, physiological conditions as a consequence of
drug treatment, nutrition, and lifestyle.58,67 Thus,
metabolites under investigation might one day become
biomarkers for disease detection and even targets for
drug development.59
In the clinical setting, mass spectrometry and nuclear
magnetic resonance-based techniques have been most
commonly used in the study of metabolomics. Analysis
can be done on various biological fluids (eg, blood, urine),
tissue types, and stool.57,72 Methods have been established
for screening central carbon metabolism, including
glycolysis and the tricarboxylic acid cycle, amino acid
pathways, lipid pathways, and selected secondary
metabolism pathways.72 Developments in both nuclear
magnetic resonance and mass spectrometry include
increase in sample output, sensitivity, resolution, and
ability to identify and quantify metabolites.57,72 Multivariate
 Review
Search strategy and selection criteria
We searched PubMed for peer-reviewed articles with the
search terms “childhood cancer”, “nutritional status”,
“malnutrition”, “body mass index”, “body composition”, “fat
mass”, “fat-free mass”, “lean tissue mass”, “overall survival”,
“event-free survival”, “treatment related toxicity”, “adverse
effects”, “chemotherapy pharmacokinetics”, “metabolome”,
“nutritional genomics”, “microbiome”, and “obesity genes”
from Jan 1, 2000, to May 31, 2019. We also selected relevant
articles from our personal files and from reference lists of
identified papers. We prioritised publications after 2014;
however, commonly cited and highly regarded (defined by
high citation count and journal impact factor) older
publications were also included. Randomised controlled
trials, observational studies, retrospective studies, meta-
analyses, editorials, and review articles were included,
whereas conference abstracts and case reports were
excluded. We only searched for articles published in English,
or those translated into English.
statistical and bioinformatics techniques can then be
used for data mining of complex metabolic profiles that
encompass genetic, environmental, microbiome, dietary,
and lifestyle information.72 Investigations involving
metabolomics can now be applied to better understand
diet in the context of cancer and the downstream effects
of oncological care.
Application of metabolomic technology in the oncology
setting has been most commonly reported in patients
with colorectal cancer.70,73 Metabolomics analyses have
revealed different metabolite signatures between stool,
malignant tissue, and healthy adjoining mucosa. Studies
of the faecal metabolome show altered short-chain fatty
acid, amino acid, and unsaturated fatty acid metabolism
in this population; another study revealed that pathways
for urea, caffeine, and galactose metabolism might be
linked to disease progression.70 Several investigations
have even suggested a positive relationship between a
variety of nutrients, including pomegranate and coffee
components, metabolic profiles, and chemoprotective
effects in colorectal cancer.73 Thus, among patients with
colorectal cancer, metabolomics potentiates the
identification of new cancer metabolite biomarkers.
Studies integrating gene and protein expression profiles
with metabolic fingerprints allow for a more in-depth
analysis of an individual’s response to nutritional
interventions,71 and their application in paediatric
oncology will further the field’s understanding in the role
of food and patient outcomes.
The microbiome
The human microbiota consists of 100 trillion microbes
that coexist in a symbiotic relationship; the microbiome
consists of the genes encoded by these cells.74 Microbiome
makeup begins at birth, and functions in the digestion
8 www.thelancet.com/child-adolescent Published online February 13, 2020 https://doi.org/10.1016/S2352-4642(19)30407-9
and absorption of nutritional substances by breaking
down proteins, lipids, and carbohydrates from the diet.58
With the advent of high-throughput sequencing methods
and bioinformatics techniques, current literature
suggests that the microbiome has an important role in
human health and disease, including cancer.60 The
microbiota has been hypothesised to be involved in the
development of several gastrointestinal cancers,75
paediatric leukaemia,76,77 and several toxicities related to
administration of chemotherapy or radiation.78–81
Few clinical and interventional studies of the microbiome
have been done in paediatric oncology, with most studies
being observational. The composition and diversity of the
microbiome have been associated with survival of
haematopoietic stem cell transplantation and its related
complications.82 For example, Biagi and colleagues83
described fluctuations in microbiome among children
undergoing haematopoietic stem cell trans­plantation and
found that the onset of acute graft-versus-host disease was
associated with distinct microbial signatures between
patients who developed the disease compared with those
who did not. These results mirror several studies that have
been done in adults who received haemopoietic stem cell
transplantation.84 One small pilot study tested the safety
and feasibility of a probiotic, Lactobacillus plantarum,
among children undergoing haemopoietic stem cell
transplantation,80 the results of which prompted an
ongoing trial being done in the Children’s Oncology
Group, evaluating the role of probiotic therapy for the
prevention of acute graft-versus-host disease among
children and adolescents (NCT03057054).
The role of the gut microbiome in other paediatric
malignancies is also under investigation. Similar with
other findings, Rajagopala and colleagues’ case-control
study77 found that children with acute lymphoblastic
leukaemia had different microbial composition at
diagnosis when compared with their sibling controls.
The gut microbiome has also been associated with an
increased risk of infections in paediatric acute
lymphoblastic leukaemia.85 Others have hypothesised
that modulation of the microbiome during and after
therapy might affect the development of treatment-
related late-effects among survivors of childhood cancer.86
On the basis of the available literature, the microbiome
is an emerging area that might provide insight into the
development of certain paediatric cancers and might be a
target of clinical trials in which the aim is to reduce
treatment-related toxicities. Additional research is
warranted—particularly trials that explore the optimal
dosing, species, and timing of probiotic therapy.
Conclusion
Poor nutritional status is linked to adverse outcomes both
during the treatment of childhood cancer and extending
into survivorship. In the course of therapy, both
undernutrition and overnutrition are widely recognised
as contributors to increased morbidity and mortality,

while during survivorship, overnutrition is one of the risk
factors for a myriad of debilitating chronic diseases, such
as diabetes and cardiovascular disease.22 Although great
strides have been made in the under­standing of nutrition
and its multifaceted biological and physiological effect on
health outcomes in paediatric oncology, further clinical
and translational investigations are needed to advance the
field. Further examination of the epidemiology and
aetiologies of malnutrition in this population is needed,
in conjunction with the omics technologies of today.3,8
Integration of these methods is necessary to broaden the
scientific community’s understanding of the way in
which diet interacts with the individual, and facilitate the
development of personalised nutritional interventions
and protocols.61 Customising and optimising nutritional
status during and after treatment can be used to prevent
or mitigate treatment-related complications, improve
quality of life, and long-term survival for patients and
survivors of childhood cancer.
Contributors
All authors participated in the conceptualisation and creation of the
manuscript, literature search, writing, as well as original and final
editing of the manuscript.
Declaration of interests
We declare no competing interests.
Acknowledgments
This work was supported by The Tamarind Foundation to EJL, the
American Cancer Society to EJL (grant number 127000-MRSG-14-157-01-
CCE), and the US National Institutes of Health to LJ (grant number T32
CA094061-17).
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