Pediatr Blood Cancer 2011;57:594598
Vitamin D Status in Paediatric Patients With Cancer
Akash Sinha, MBBS,1 Peter Avery, PhD,2 Steve Turner, BSc,3 Simon Bailey, PhD,4 and Tim Cheetham, MD1,5*
Background. Children with malignant disease are at increased
risk of bone disorders and cardiovascular disease. Vitamin D status
may inuence this risk and so we assessed vitamin D levels in
children with malignant disease undergoing active treatment or
surveillance post-therapy. Procedure. This was an outpatient-based
cross-sectional study of 61 children with a history of malignancy
(median age 11.1 years; range 1.524.4 years) and 60 control sub-
jects (median age 8.4 years; range 0.218.0 years) attending hospi-
tal for the management of non-malignant disorders. Serum vitamin
D (25-OH-D), parathormone levels and bone biochemistry were
determined. Vitamin D status and its relationship to age, sex, eth-
nicity, time of sampling and presence of malignant disease was
Key words: oncology; paediatrics; survivors of childhood cancer; Vitamin D
INTRODUCTION
Numerous observational studies point towards an increase
in the number of young people with vitamin D deciency and
associated disorders including hypocalcaemia and rickets [1,2].
The rising incidence of these conditions in North America and
Western Europe has been linked to an increase in the number of
mothers, children and adolescents with pigmented skin and an
increase in the amount of time spent indoors [3,4]. Sunlight has a
key role in the endogenous production of vitamin D and pig-
mented skin generates a fraction of the amount produced by fair
skin [5,6]. Nevertheless, low Ultraviolet-B exposure in the
Northern hemisphere in the winter months means that most
young people living at these latitudes will be dependent on dietary
sources, irrespective of skin colour [7]. Few foods contain signi-
cant amounts of vitamin D and hence fair-skinned children may
also have low vitamin D levels [8].
Children with chronic disease may be susceptible to low
circulating vitamin D levels and this has been highlighted by
recent studies in children with kidney disease [9,10]. One might
predict that survivors of childhood cancer will also be at increased
risk of vitamin D insufciency or deciency because of the poten-
tial impact of the disease and its treatment; these children could
spend more time indoors than their peers and the tumour and
treatment regimens may compromise the quantity and quality of
food consumed. Treatments such as chemotherapy, radiotherapy
and glucocorticoids can also have adverse effects on bone health
[11].
Of interest to researchers and clinicians is the association
between low vitamin D levels and the prevalence of extra-skeletal
diseases including multiple sclerosis, type 1 diabetes, rheumatoid
arthritis, hypertension, cardiovascular disease and a number of
different types of cancer [12]. Patients treated for malignant
disease are at risk of additional malignancies [1315] in
addition to skeletal pathology [11]. They are also at increased
risk of cardiovascular disease [16] and so optimising the vitamin
D status of this group of individuals could be particularly
advantageous.
Mindful of this background we set out to establish the vitamin
D status of young patients with malignant disease. We wanted to
compare vitamin D levels with published standards and with local
children who did not have a history of malignancy.
2011 Wiley-Liss, Inc.
DOI 10.1002/pbc.22963
Published online 3 February 2011 in Wiley Online Library
(wileyonlinelibrary.com).
determined. Results. Vitamin D status was suboptimal in 62% of
cases (25-OH-D < 50 nmol/L [20 ng/ml]). Vitamin D deciency
(25-OH-D < 25 nmol/L [10 ng/ml]) was more common in children
with malignant disease than controls (21.3% vs. 3.3%; P 0.013).
Month of sampling (P < 0.001), ethnicity (P < 0.001), older age
(P 0.011), and history of malignancy (P 0.012) were associated
with a poorer vitamin D status. Conclusions. Vitamin D levels
[25-OH-D] are lower in survivors of childhood cancer in compari-
son to control children with the majority either insufcient or
decient. Assessment and adequate replacement of vitamin D status
may be of particular value in this group of children. Pediatr Blood
Cancer 2011;57:594598. 2011 Wiley-Liss, Inc.
METHODS
The primary objective of the study was to assess the vitamin D
status of patients with malignant disease or a past history of
malignant disease attending the outpatient department of a regional
referral unit in Newcastle-upon-Tyne in Northern England. The
tertiary centre in Newcastle-upon-Tyne has a catchment area
that includes the North-East of England and North Cumbria.
Subjects
The study was approved by County Durham & Tees Valley
Research Ethics Committee and the children and/or their parents
gave informed written consent and verbal assent for their
participation in the study and the collection of the additional
blood samples during routine venepuncture.
Children from the case cohort were recruited from patients
attending the paediatric oncology out patient clinic in
Newcastle-upon-Tyne. Patients were either under active treatment
for malignant disease (n 49) or were under review post-treat-
ment (n 12). In these individuals the median time to sampling
post-treatment was 3 years (range: 0.49 years). Patients were
further subdivided into those with leukaemia/lymphoma and those
with solid tumours (body and central nervous system). We wanted
to compare the vitamin D status of the oncology group (cases)
with a group of children without malignant disease (controls). We
1
Department of Paediatric Endocrinology, Great North Childrens
Hospital, Newcastle upon Tyne, UK; 2School of Mathematics and
Statistics, Newcastle University, Newcastle upon Tyne, UK;
3
Department of Clinical Biochemistry, Great North Childrens
Hospital, Newcastle upon Tyne, UK; 4Department of Paediatric
Oncology, Great North Childrens Hospital, Newcastle upon Tyne,
UK; 5Institute of Human Genetics, Newcastle University, Central
Parkway, Newcastle upon Tyne, UK
Conict of Interest Statement: We have had no nancial interest in any
matters relating to this subject. We are also not afliated to any organ-
isation that, to our knowledge, has a direct interest in this subject matter.
*Correspondence to: Tim Cheetham, MD, Department of Paediatric
Endocrinology, Great North Childrens Hospital, Newcastle upon
Tyne NE1 4LP, UK. E-mail: tim.cheetham@nuth.nhs.uk
Received 16 August 2010; Accepted 12 November 2010

wanted this investigation to be representative of the general paedi-
atric population in North-East England and elected not to exclude
patients on the basis of ethnicity or body mass index (BMI) even
though factors such as increased skin pigmentation and high BMI
are associated with a relatively low vitamin D status [1]. Control
children were recruited from general endocrine out-patient clinics
or were attending hospital to undergo routine DMSA (technetium
dimercaptosuccinic acid) renal imaging because of a history of
urinary tract infection.
Patient age, sex, ethnicity, underlying diagnosis, history of
travel abroad and treatment were recorded and blood taken (at
the time of routine venepuncture) for the measurement of 25-
hydroxyvitamin D (25-OH-D). We felt that 25-OH-D was the
most useful and widely available reection of overall vitamin D
status although we also measured parathormone (PTH), calcium,
phosphate, and alkaline phosphatase (ALP). A questionnaire was
also completed which included information such as travel abroad
and supplementation with vitamins.
Samples were obtained between the end of June and the begin-
ning of November 2009 to capture the seasonal peak in 25-OH-D
levels [17,18] in the Northern Hemisphere. The hospital and its
catchment area is located at latitude 548N and we also obtained
data from the meteorological ofce [http://www.metofce.gov.uk/
climate/uk/2009] regarding the amount of sunlight during the
period of study.
Details of the cases and controls including their underlying
diagnoses are detailed in Tables I and II respectively. Sixty-one
cases (35 males) were recruited with a median age (range) of
11.1 years (1.524.4 years). There were three South Asian
children with pigmented skin and the remainder were fair-
skinned. Twenty-three children had an underlying diagnosis of
Leukaemia or Lymphoma whereas 38 children were classied
as having solid tumours. Eight of the nine subjects with low grade
glioma underwent chemotherapy and/or radiotherapy. Sixty con-
trols (26 males) were recruited with a median age (range) of 8.4
years (0.218.0 years). Seven children from the control cohort had
pigmented skin (4 of South Asian origin, 1 of Afro-Caribbean and
2 children being of Middle-Eastern origin). Median body mass
indices in the two groups were comparable (18.7 kg/m2 in the
cases, 18.3 kg/m2 in the controls).
Assessment of Vitamin D Status
As well as comparing cases and control groups we wanted to
compare vitamin D status with published norms and used the
following criteria: Subject category and associated vitamin D
TABLE I. Diagnosis in Cases With History of Malignant Disease
Cases Numbers (%)
Acute lymphoblastic leukaemia (ALL) 17 (27.8%)
Acute myeloid leukaemia (AML) 2 (3.2%)
Lymphoma 4 (6.5%)
Post-transplant lymphoproliferative disorder 1 (1.6%)
Medulloblastoma 8 (13.1%)
Craniopharyngioma 4 (6.5%)
Low grade glioma 9 (14.8%)
Primitive tumours 8 (13.1%)
Others (e.g., LCH, astrocytomas) 8 (13.1%)
Total 61
LCH, langerhans cell histiocytosis.
Pediatr Blood Cancer DOI 10.1002/pbc
Vitamin D Deficiency in Pediatric Oncology 595
TABLE II. Diagnosis in Control Subjects
Control subjects Numbers (%)
Congenital hypothyroidism or autoimmune 19 (31.6%)
thyroid disease
Routine DMSA renal scans (normal imaging) 13 (21.6%)
Short stature 10 (16.6%)
Pubertal disorders (thelarche, CDGP, small phalllus) 9 (15%)
Obesity 5 (8.3%)
Adrenal disorders (CAH) 3 (5%)
History of hypoglycemia 1 (1.6%)
Total 60
DMSA, dimercaptosuccinic acid; CDGP, constitutional delay of
growth and puberty; CAH, congenital adrenal hyperplasia.
(25-OH-D) level: Deciency: <25 nmol/L [19], Insufciency:
2550 nmol/L [20], Adequate: 5075 nmol/L [21], Optimal:
>75 nmol/L [21,22]. To convert to mg/L divide by 2.5.
It has been suggested that the denition of vitamin D
deciency in adults be revised with deciency being dened as
a level of 25-OH-D <50 nmol/L and vitamin D insufciency as a
level of 25-OH-D between 5080 nmol/L [23]. However, consen-
sus has not been attained as to what constitutes as vitamin D
insufciency in children. Therefore, for the sake of clarity we
have opted to use the ranges above which have been widely used
in many recent publications.
Assay Details
Serum concentration of 25-OH-D was measured using the
DiaSorin 25Hydroxyvitamin D radio-immunoassay (RIA) (Cat #
68100E Stillwater, Minnesota). The DiaSorin RIA assay involves
a two-step procedure. The rst is a rapid extraction step using
acetonitrile to isolate 25 Hydroxy vitamin D (25-OH-D) and other
hydroxylated metabolites of vitamin D. Equilibrium RIA is then
performed with 25 ml (in duplicate) extracted sample, antibody to
25-OH-D and iodinated tracer to 25-OH-D. Phase separation is
achieved by the addition of a second antibody and polyethylene
glycol. Radioactive counts in the centrifuged pellet are then inver-
sely proportional to the 25-OH-D concentration in the original
sample. Serum samples used in this study were stored at
208C
prior to analysis. Two quality controls are routinely used in the
assay with mean values of 39 and 134 nmol/L and inter assay
coefcient of variations (CVs) of 8.4% and 12.6% respectively.
The intra assay CV for this method is less than 8% with a func-
tional sensitivity of 6 nmol/L. Serum intact PTH was measured
using the Centaur chemiluminometric immunoassay. The two
quality controls used in the assay have mean values of 17.3
and 122.9 pmol/L with inter assay CVs of 16.7% and 7.4%
respectively.
Power Calculation
Power calculation was based on vitamin D data from the
North-West UK [24]. We wanted to detect a difference in square
root of vitamin D levels between case and control groups of
1 (nmol/L)0.5, approximately 25% of the difference in median
values between groups with pigmented and non-pigmented skin.
The vitamin D data were normalised by taking square roots of the
median and range. The derived square root of the SD (0.7)
together with the square root of the difference (0.2) was then
596 Sinha et al.
entered into the power calculation. Two groups of 50 could detect
this difference with 80% power (a 0.05). We therefore set out
to collect data on two groups of 60 children (cases and controls),
which would allow for issues such as missing data.
Statistical Analysis
Minitab version 14 was used to analyse the data. Comparison
between groups was undertaken using t tests and Chi-squared
tests as appropriate. The square roots of vitamin D levels were
used to normalise the data. Multiple regression was used to assess
the variables inuencing vitamin D status. Linear correlation was
used to assess the relationship between vitamin D and PTH.
Statistical signicance was set at the 5% level.
RESULTS
A total of 121 children, 118 years of age were enrolled in the
study (Tables I and II). All provided blood samples. No patient
was on regular vitamin D supplementation. Ten children had been
on holiday abroad (5 in each group) within the 28-day period
prior to sampling. The median interval between diagnosis and
time of sampling was 1.9 years (range 2.4 months to 11.9 years).
Vitamin D Levels Compared to Published Norms
The median vitamin D levels were signicantly lower in cases
compared to controls (44 nmol/L [range 9131 nmol/L] com-
pared to 52 nmol/L [range 13155 nmol/L]; P 0.02). The
distribution of vitamin D levels are shown in Table III. The
proportion of children with 25-OH-D deciency (vitamin D
<25 nmol/L) was greater in the case group than in controls (13
decient, 21.3% vs. 2 decient, 3.3%; P 0.013). All three
pigmented children in the case group were severely vitamin D
decient (<25 nmol/L) compared to one out of seven pigmented
children in the control group. Two of the seven pigmented chil-
dren in the control group had vitamin D insufciency.
Vitamin D Levels and Month of Sampling
There was a signicant fall in Vitamin D levels (P < 0.001)
from June till November, coinciding with data from the United
Kingdom meteorological ofce showing that sunlight duration in
the North of England fell as winter approached. The average
hours of sunshine during the months of the study (2009) were
similar to previous years. The average hours of sunshine during
the period from June till November were 133.6 hr/month [http://
www.metofce.gov.uk/climate/uk/2009].
TABLE III. Proportion of Cases and Control Patients With
Vitamin D Levels in the Various Reference Bands (See Methods
Section)
Vitamin D status Cases Controls
Deficiency 13 (21.3%) 2 (3.3%)a
Insufficiency 25 (40.9%) 26 (43.3%)
Adequate 14 (22.9%) 24 (40%)
Optimal 9 (14.7%) 8 (13.3%)
Total 61 60
a
Signicant difference at the 1% level.
Pediatr Blood Cancer DOI 10.1002/pbc
Factors Affecting Vitamin D Status
There was no signicant difference in month of sampling
between the two groups but the median age was signicantly
lower in the cases. This was a potential confounder because of
the increased vitamin D levels observed in younger children [25].
Multiple regression analysis showed that month of sampling,
ethnicity, age and diagnosis (case vs. control), but not sex, were
signicant determinants of vitamin D status. 28.6% of the varia-
bility in vitamin D levels was explained by these variables of
which 13.9% was explained by month (earlier date of sampling
associated with higher levels than later date of sampling;
P < 0.001), 5.9% by ethnicity (lower values in those with dark
skin; P < 0.001), 4.8% by age (greater values in younger chil-
dren; P 0.011) and 4.0% by diagnosis (higher levels in con-
trols; P 0.012). There was no evidence of an interaction
between age, ethnicity, month and diagnostic group.
Subgroup Assessment of Vitamin D Levels
Children with Leukaemia and Lymphomas tended to have
lower median vitamin D levels than children with solid tumours
but the difference was not statistically signicant (39.0 nmol/L
vs. 48.5 nmol/L, P 0.08). 56% of the Leukaemia/Lymphoma
group were insufcient whereas only 28% of the Solid tumour
group were insufcient. Both groups had similar percentages of
vitamin D deciency (20% vs. 22%). There was no statistically
signicant difference in vitamin D levels between those on treat-
ment (median 44.6 nmol/L) compared to those off treatment
(median 44.9 nmol/L).
Bone Biochemistry
Higher PTH levels were associated with signicantly lower
vitamin D status in controls (r
0.42; P <0.01) but not in
cases (r
0.07; P 0.65). There was no signicant correlation
between 25(OH)D levels and other bone parameters (calcium,
phosphate and alkaline phosphate levels) or differences in bone
parameters between the groups.
DISCUSSION
This is the rst study to assess and compare vitamin D levels
in children with a history of malignant disease in comparison to a
group of out-patient attendees without a history of malignant
disease. Our data indicate that children with cancer or a history
of cancer who were attending the Oncology outpatient clinics are
more likely to have low vitamin D levels although the impact of
such a history was smaller than factors such as month of year and
ethnicity. The denition of what constitutes an appropriate vita-
min D status has been the subject of controversy. Differences in
assay performance and limited evidence to justify grouping vita-
min D values in a way that is not closely linked to functional
clinical outcomes are obvious limitations. Our denition was
therefore based on a pragmatic approach which has been broadly
accepted in the literature [1922]. We assessed vitamin D levels at
a time of the year when they were likely to be relatively high
because of sunlight exposure [17]. Vitamin D levels fell between
June and November which correlated with falling hours of sun-
shine and we suspect that values in these patients in the winter or
early spring would have been signicantly lower.

We did not nd it surprising that control children had a sub-
optimal vitamin D status because there have been numerous
reports to this effect in recent years [1]. Accumulating evidence
suggests that the supplementation of patients with a history of
malignant disease might be particularly advantageous but our
local cohort do not appear to have been targeted by health pro-
fessionals to date. The Department of Health (UK) recommends
that all infants and children be supplemented with vitamin D
[http://www.dh.gov.uk] and it can be argued that health pro-
fessionals need to actively target groups at particular risk of
vitamin D deciency as well as the population in general.
Children with fair skin in our study had a sub-optimal vitamin
D status despite the month of sampling and younger as well as
older children had relatively low levels.
A number of factors could explain the increased likelihood of
survivors of childhood cancer having low vitamin D levels. Poor
diet, more time spent indoors compared to their peers and the
toxic effects of chemotherapy/radiotherapy all may have a role
here. Our local practice involves advising children on therapy for
leukaemia to apply sunscreen lotion (Sun Protection Factor >30)
and to avoid direct sunlight whilst undergoing chemotherapy
because of the risk of photosensitivity. Approximately 30% of
our patients will have been given this advice although in practice
when sunscreen lotions are applied they may not completely
block the solar induced cutaneous production of previtamin D3
[26]. One could speculate that altered susceptibility to obesity
might inuence 25-OH-D status in the cases [27] but there was
no difference in BMI between the two groups.
Observational studies in humans and animal models [2834]
have indicated that vitamin D may have a benecial role in cancer
prevention and survival following cancer and this is, perhaps, an
extra motivation for targeting these patients. The mechanism of
action of vitamin D in this regard is unclear but may be related to
its role in the regulation of cell growth and differentiation.
Vitamin D may inhibit tumour angiogenesis, stimulating mutual
adherence of cells and enhancing intercellular communication
through gap junctions, thereby strengthening the inhibition of
proliferation that results from tight physical contact with adjacent
cells within a tissue (contact inhibition) [28,35]. It is very import-
ant to highlight the fact that association is not the same as cau-
sality and as such low vitamin D levels in some of the studies
conducted in human subjects could simply be an epiphenomenon;
intervention studies with vitamin D will help to address this issue.
There was no signicant difference in vitamin D levels between
those undergoing treatment and those post-treatment, which
suggests that a low vitamin D status may not be closely linked
to the effects of cytotoxic therapy.
We were surprised to nd that a relationship between vitamin
D status and PTH was not seen in survivors of childhood cancer.
This may reect the relatively small study numbers or the poten-
tial confounding impact of chemotherapeutic agents on bone
biology. It may also reect the fact that the survivors of childhood
cancer tended to be younger than controls because a more con-
sistent relationship between vitamin D and PTH develops as
children mature [36].
In summary, children with a history of malignant disease are at
a particularly high risk (21.3%) of being vitamin D decient. For
reasons relating to skeletal health, cardiovascular health and risk
of further malignancy we feel that the assessment and adequate
Pediatr Blood Cancer DOI 10.1002/pbc
Vitamin D Deficiency in Pediatric Oncology 597
replacement of vitamin D status in the short and long term should
be seen as a priority in these patients.
ACKNOWLEDGMENT
We would like to express our gratitude to Newcastle
Healthcare Charity for funding the assay costs for this study.
We would like to also thank Jackie OSullivan and Diane
Barstow, Endocrine Specialist Nurses and Louise Richardson for
their assistance in data collection. We would also like to thank the
nursing staff of the Oncology Out Patient Unit for help with
patient recruitment.
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