VOLUME 36 • NUMBER 21 • JULY 20, 2018

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Endocrine Late Effects in Childhood Cancer Survivors

Wassim Chemaitilly, Laurie E. Cohen, Sogol Mostoufi-Moab, Briana C. Patterson, Jill H. Simmons, Lillian R.
Meacham, Hanneke M. van Santen, and Charles A. Sklar

Author affiliations and support information

(if applicable) appear at the end of this A B S T R A C T
article.
Endocrine complications are highly prevalent in childhood cancer survivors. Approximately 50% of
Published at jco.org on June 6, 2018.
survivors will experience at least one hormonal disorder over the course of their lives. Endocrine
Corresponding author: Wassim
complications often are observed in survivors previously treated with radiation to the head, neck,
Chemaitilly, MD, Division of
Endocrinology, St Jude Children’s
or pelvis. We provide an overview the most common endocrine late effects seen in survivors,
Research Hospital, 262 Danny Thomas Pl, including hypothalamic-pituitary dysfunction, primary thyroid dysfunction, obesity, diabetes
MS 737, Memphis, TN 38105; e-mail: mellitus, metabolic syndrome, and decreased bone mineral density. Primary gonadal injury is
[email protected]. discussed elsewhere in this series. Given a variable latency interval, a systematic approach where
© 2018 by American Society of Clinical individuals are periodically screened on the basis of their risk factors can help to improve health
Oncology outcomes by prompt diagnosis and treatment of evolving endocrinopathies. These recommen-
0732-183X/18/3621w-2153w/$20.00 dations must be revised in the future given changes and improvements in cancer treatment over
time.

J Clin Oncol 36:2153-2159. © 2018 by American Society of Clinical Oncology

INTRODUCTION HP DYSFUNCTION

Endocrine complications are prevalent in child- HP injury can result from the following condi-
hood cancer survivors (CCSs), with 50% expe- tions: growth hormone (GH) deficiency, central
riencing at least one hormonal disorder over the precocious puberty (CPP), luteinizing hormone/
course of their lives.1 Endocrine deficits fre- follicle-stimulating hormone (LH/FSH) deficiency
quently appear as late effects in the years after (hypogonadotropic hypogonadism), thyroid-
cancer treatment.2 Long-term follow-up data stimulating hormone (TSH) deficiency (central
demonstrate that endocrine late effects continue hypothyroidism), and adrenocorticotropic hormone
to appear in adulthood3 at a significantly higher (ACTH) deficiency (central adrenal insufficiency).
rate than in siblings4 and the general pop- Central diabetes insipidus typically is caused by HP
ulation.5 Additional data have revealed frequent damage from tumor growth and/or surgical resec-
delays in the diagnosis and treatment of endo- tion and is seen in the first weeks after intervention.
crine late effects,2 with potential repercussions Central diabetes insipidus is not discussed in this
on general health.3 review because it does not occur as a late effect.15
We provide an overview of the most common The occurrence of HP dysfunction as a late
endocrine late effects, including hypothalamic- effect is primarily a result of radiotherapy.15,16 In
pituitary (HP) dysfunction, primary thyroid contrast to injury from tumor growth or surgery,
dysfunction, obesity, diabetes mellitus (DM), where patients frequently present with HP dis-
metabolic syndrome, and decreased bone min- orders from the onset, radiation-induced HP
eral density (BMD). Sex hormone deficits re- disorders tend to appear sequentially in a dose-
lated to primary gonadal injury are reviewed dependent manner months to several decades
in the articles dedicated to reproductive after radiation.3,15,16 At least one HP deficit after
late effects in this series. Data that pertain cranial radiotherapy was reported in 51% of
to risk factors, screening, and management a cohort followed long term3 (Fig 1). Efforts to
strategies are listed in Table 1. Screening rec- eliminate unnecessary exposures, such as with
ommendations were derived from the most the abandonment of prophylactic CNS irradia-
current version of the regularly updated Chil- tion in acute lymphoblastic leukemia (ALL), or
DOI: https://doi.org/10.1200/JCO.2017. dren’s Oncology Group long-term follow-up to reduce scatter to normal tissue, such as with
76.3268 guidelines.6 the use of protons instead of photons, are likely

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 Chemaitilly et al

Table 1. Risk Factors and Management of Endocrine Late Effects of Childhood Cancers
Late Effect Risk Factor History/Physical* Blood Test Screen* Subsequent Test Treatment
GHD Young age at diagnosis Interval growth No laboratory tests; clinical GH stimulation test GH replacement
HP tumor or surgery Height, weight parameters used for screening
HP RT $ 18 Gy† Growth rate
TBI $ 10 Gy one Sitting height or arm span
fraction (spinal RT)
TBI $ 12 Gy Tanner stage
multifractions
TKI, anti–CTLA-4
mAb
CPP Young age at diagnosis Interval growth and puberty Morning testosterone‡ Bone age x-ray GnRHa
Tumor near HP changes Pelvic US
region Height, weight (females)§
Optic pathway Growth velocity GnRH or
glioma Tanner stage GnRHa test
Hydrocephalus
HP RT $ 18 Gy
LH/FSHD HP tumor or surgery Puberty, sexual function, LH, FSH Bone age x-ray Sex hormone replacement
HP RT $ 30 Gy† menses Estradiol (females) Pelvic US
Anti–CTLA-4 mAb Height, weight Morning testosterone (males) (females)§
Growth velocity
Tanner stage
TSHD HP tumor or surgery Hypothyroidism symptoms TSHk, free T4 — Levothyroxine¶
HP $ 30 Gy† Height, weight
Anti–CTLA-4 mAb Growth rate
ACTHD HP tumor or surgery Failure to thrive Anorexia, 8:00 AM cortisol ACTH stimulation Hydrocortisone¶
HP $ 30 Gy† lethargy test Glucocorticoid stress
Anti–CTLA-4 mAb Dehydration, hypotension dose teaching
Hyperprolactinemia HP tumor or surgery HP Galactorrhea, menses Prolactin — Antidopaminergics
$ 40 Gy Tanner stage
Primary Surgical resection Hypothyroidism symptoms TSH, free T4 — Levothyroxine¶
hypothyroidism Thyroid RT $ 10 Gy Height, weight
Allogeneic HSCT Growth rate
TKI Tanner stage
Anti–CTLA-4 mAb,
interferon
Radioactive iodine, I-
MIBG
Autoimmune Allogeneic HSCT Hypothyroidism or TSH, free T4 Thyroperoxidase, Depending on
thyroid disease Anti–CTLA-4 mAb, hyperthyroidism thyroglobulin Ab consequence (hyper or
interferon symptoms TSH receptor Ab# hypo)
Hyperthyroidism Allogeneic HSCT Hyperthyroidism symptoms TSH, free T4 TSH receptor Ab b-blockers
Thyroid RT $ 30 Gy Height, weight Antithyroid agents
Anti–CTLA-4 mAb,
interferon
Obesity HP tumor or surgery Diet, physical activity No laboratory tests; clinical Fasting lipids, Diet, exercise
HP RT . 20 Gy Height, weight parameters used for screening glucose
Glucocorticoids BMI
DM HSCT Polyuria, polydipsia Fasting glucose Oral glucose Diet, exercise
TBI or abdominal RT Height, weight HbA1c tolerance test Medications as needed
Glucocorticoids BMI
Low BMD Young age at diagnosis Diet, physical activity DXA 25-Hydroxy Diet/calcium, vitamin D,
Leukemia Bone, skeletal pain vitamin D exercise
HSCT 6 TBI Fracture history Height,
Cranial RT weight
Glucocorticoids

NOTE. Recommendations were based on the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult
Cancers Version 4.06 and additional resources.7-14
Abbreviations: Ab, antibody; ACTHD, adrenocorticotropic hormone deficiency; BMD, bone mineral density; BMI, body mass index; CPP, central precocious puberty;
DM, diabetes mellitus; DXA, duel-energy x-ray absorptiometry; GHD, growth hormone deficiency; GnRH, gonadotropin-releasing hormone; GnRHa, gonadotropin-
releasing hormone agonist; HP, hypothalamic-pituitary; HbA1c, hemoglobin A1c; HSCT, hematopoietic stem-cell transplantation; I-MIBG, 131I-metaiodobenzylguanidine;
LH/FSHD, luteinizing hormone/follicle-stimulating hormone deficiency; mAb, monoclonal antibody; RT, radiotherapy; T4, thyroxine; TBI, total body irradiation; TKI,
tyrosine kinase inhibitor; TSHD, thyroid-stimulating hormone deficiency; US, ultrasound.
*Clinical and laboratory screening should be conducted at least every 6 months during childhood and then yearly or more frequently if clinically indicated.
†Condition may appear at a lower dose of RT with longer follow-up.
‡Males exposed to direct testicular radiotherapy and/or gonadotoxic chemotherapy.
§To measure uterine height in girls with discrepant clinical and laboratory data.
kTSH not useful for follow-up.
¶Evaluation for and treatment of ACTHD should always precede that of hypothyroidism in patients at risk for both conditions.
#In case of hyperthyroidism.

to modify the prevalence of HP dysfunction in survivors treated have been reported in patients treated with the newer targeted
more recently.17 Conventional chemotherapy agents have not chemotherapy agents such as imatinib, a tyrosine kinase inhibitor
been shown consistently to cause HP dysfunction.18 HP deficits (TKI),7 and immune system modulators.8 Whether the deleterious

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 Endocrine Late Effects of Childhood Cancer

but patients may not achieve their genetic potential because of other
GHD (n = 262)
factors, such as spinal25 irradiation, TBI,27 scoliosis, or direct growth
LH/FSHD (n = 21) plate injury from agents such as cis-retinoic acid.28 Treatment with
TSHD TSHD (n = 8) hGH may improve cardiovascular risk factors, such as dyslipidemia,
n = 55 ACTHD (n = 1) and quality of life in adult CCSs similar to the non-CCS population,
(n = 26)
ACTHD but studies are lacking in children, and results are variable and
(n = 13)
n = 29
(n = 3)
limited.29,30 Long-term data from the Childhood Cancer Survivor
GHD
n = 336 (n = 2) Study have suggested no significant association between hGH and
(n = 1) recurrence of the primary cancer.31 Data on the association between
LH/FSHD (n = 1) hGH and secondary neoplasia are conflicting,31,32 and more studies
n = 77 (n = 10)
are needed.
(n = 2)
(n = 6)
(n = 1)
CPP
(n = 14)
CPP is the onset of puberty before 8 years (girls) or 9 years
(boys) of age as a result of the activation of the HP-gonadal axis.33
Fig 1. Overlap among anterior pituitary deficiencies after cranial radiotherapy. Left untreated, CPP may result in psychosocial dysfunction and
ACTHD, adrenocorticotropic hormone deficiency; GHD, growth hormone de- short stature.34 Up to 15.2% of CNS tumor survivors have been
ficiency; LH/FSHD, luteinizing hormone/follicle-stimulating hormone deficiency;
TSHD, thyroid-stimulating hormone deficiency. Reproduced with permission.3
reported to experience CPP.15,34 The prevalence is even higher
Copyright © 2015 American Society of Clinical Oncology. (30%) in children with a history of tumors near the HP region.34,35
Other risk factors include the exposure of the HP region to ra-
diotherapy at doses of 18 to 50 Gy and increased intracranial
effects of these newer targeted agents are reversible after their pressure.15,34-36
discontinuation has yet to be fully elucidated. The diagnosis of CPP follows the same steps as in the non-
CCS population,9,33 with two exceptions. First, the clinical di-
agnosis of puberty in boys treated with gonadotoxic modalities (eg,
GH Deficiency
direct testicular radiotherapy, alkylating agent chemotherapy)
GH deficiency is the most common pituitary hormone deficit
should rely on findings other than testicular volume (eg, phallic
in CCSs with a reported prevalence of 12.5% overall15 and 46.5%
enlargement, pubarche, scrotal thinning) because patients may
after HP radiotherapy.3 An increased likelihood and earlier de-
have inappropriately small testes as a result of germ cell and Sertoli
velopment of GH deficiency are directly related to radiation dose
cell depletion and yet still be able to produce testosterone.37
and inversely related to the number of fractions.19 GH deficiency
Additional confirmation should be sought by measuring morn-
frequently develops after HP radiotherapy doses $ 30 Gy3,20 but
ing plasma testosterone levels. Second, CPP and GH deficiency
can develop after 18 to 24 Gy, doses that have been used to treat
have been shown to co-occur frequently in CCSs; thus, growth
ALL and lymphoma.21 GH deficiency also is reported after lower
velocity assessment should be interpreted with this association in
doses with a single fraction of 10 Gy and fractionated doses of 12 to
mind because delays in the diagnosis and treatment of either
18 Gy when administered as total body irradiation (TBI) in the
condition can result in irreversible losses in final height.34 The first
context of hematopoietic stem cell transplantation (HSCT).22 Al-
line of therapy is a gonadotropin-releasing hormone agonist.
though the development of GH deficiency after chemotherapy
The timing of discontinuation of pubertal suppression needs to
alone18 is controversial, autoimmune hypophysitis that results in GH
be individualized, but treatment after 12 years of age rarely is
deficiency is increasingly recognized with the use of the immune
indicated.9
checkpoint inhibitor ipilimumab (an anti–CTLA-4 monoclonal
antibody).8 Imatinib mesylate, a TKI used in the treatment of
children with certain forms of leukemia, impairs growth, but LH/FSH Deficiency
whether the mechanism is through GH deficiency, GH resistance,23 Patients with LH/FSH deficiency experience a lack of gonadal
or skeletal toxicity is unclear.24 sex hormones (estrogen, progesterone in females; testosterone in
GH deficiency should be suspected when linear growth failure males) because of lack of stimulation of the gonads by the HP axis.
(height trajectory that crosses to lower percentile lines) or lack of Children and adolescents may present with pubertal delay (absence
growth acceleration during puberty are seen after ruling out of pubertal development past the ages of 13 [girls] or 14 [boys]
hypogonadism, hypothyroidism, inadequate nutritional intake, or years).10 Later in life, manifestations include arrested puberty,
excess glucocorticoid exposure. Measuring the sitting height or primary or secondary amenorrhea, or symptoms related to low
determining the ratio of upper to lower segment are helpful to rule testosterone or estrogen levels. The prevalence of LH/FSH de-
out poor spinal growth after radiation.25 Insulin-like growth factor I ficiency was reported at 6.5% in CCSs overall38 and 11% after HP
levels are not always low in the context of radiation-induced GH radiotherapy.3 The main risk factors of LH/FSH deficiency are HP
deficiency and should not be used to screen patients at risk.26 When tumor, surgery, or radiotherapy at doses $ 30 Gy within or near the
GH deficiency is suspected, a referral to a pediatric endocrinologist is HP region.3,39 Association with doses of 20 to 29 Gy was reported
indicated for additional evaluation with stimulation testing. in cohorts with an extended duration of follow-up.3,34
Replacement with recombinant human GH (hGH) results in The diagnosis of LH/FSH deficiency in CCSs follows the same
a significant improvement in height in children with GH deficiency, guidelines as in the non-CCS population.10,11 Lower-than-normal

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 Chemaitilly et al

levels of sex hormones that coincide with low or inappropriately At-risk patients should be screened by assessing their symp-
normal levels of LH and/or FSH are generally suggestive of LH/FSH toms and with annual measurement of an 8:00 AM plasma
deficiency.10,11 Hyperprolactinemia, a known complication of cortisol level. Values , 83 nmol/L (3 mg/dL) suggest ACTH de-
high-dose HP irradiation, should be ruled out as a possible cause.39 ficiency, whereas values . 413 nmol/L (15 mg/dL) indicate normal
Treatment relies on sex hormone replacement therapy.10,11 Al- ACTH-adrenal function.11 Confirmatory testing may include
though hypogonadism is known to decrease the risk of secondary low- (1 mg) or high- (250 mg) dose ACTH stimulation or insulin
breast cancer in female CCSs treated with chest irradiation, recent tolerance testing.11,42 Treatment of ACTH deficiency includes
reports have shown that full replacement with estrogen and daily replacement of glucocorticoids to mimic normal physio-
progesterone either had no effect40 or resulted in a moderately logic production, additional oral steroids at times of mild to
increased risk that nevertheless remained lower (hazard ratio, 0.47; moderate illness, and parenteral steroids during severe illness.
95% CI, 0.23 to 0.94) than that of CCSs without hypogonadism Medical alert identification information should be carried or
who underwent chest irradiation.41 Prescribers should be aware of worn to notify emergency personnel of the need for rapid steroid
drug interactions between estrogen and antiepileptic drugs as well treatment.11
as other hormone replacement therapies (GH, levothyroxine) and
plan appropriately for monitoring and dosage adjustment.11 Adult
CCSs with hypogonadism should be encouraged to consult with PRIMARY THYROID DYSFUNCTION
fertility specialists with regard to reproductive options.12,13
Thyroid disorders are among the most common endocrine se-
quelae after treatment of childhood cancer.4 CCSs are at risk for the
TSH Deficiency development of hypothyroidism and hyperthyroidism as well as for
Individuals with TSH deficiency experience hypothyroidism thyroid neoplasia (reviewed elsewhere in this series).
because of lack of stimulation of the thyroid by the HP axis. Primary hypothyroidism is one of the most frequently ob-
Presentation may include fatigue, slow linear growth, and/or ab- served late effects in CCSs; its prevalence has been reported at
normal weight gain. Rates of TSH deficiency have been reported at 13.8% to 20.8% in the overall population of survivors (Fig 2).1,2,4,43
7.5% to 9.2% in survivors of childhood brain tumors and those The highest incidence was reported in survivors of Hodgkin
exposed to HP radiotherapy.1,3,15 Risk factors include tumors or lymphoma after neck irradiation . 45 Gy, with up to 50% di-
surgery in the HP region and HP radiation doses $ 30 Gy.3,15,16 agnosed after 20 years of follow-up.43 Patients treated with cra-
Longer time since treatment and the presence of other central niospinal radiotherapy represent another high-risk population.16
endocrinopathies increase the likelihood of TSH deficiency.3,35 Treatment with 131I-metaiodobenzylguanidine can cause primary
Low, normal, or marginally elevated plasma TSH levels in hypothyroidism because of radionuclide uptake in the thyroid
association with low free thyroxine (T4) levels generally suggest gland. Thyroid protection through potassium iodide; perchlorate;
TSH deficiency.11 Treatment with levothyroxine should target free or the combination of potassium iodide, T4, and a thiamazole
T4 levels in the mid to upper half of the normal range for age, and decreases but does not entirely eliminate the risk of 131 I-
TSH values should not be used to adjust doses.11,14 The addition of metaiodobenzylguanidine–induced hypothyroidism.44 Conven-
antiepileptic drugs, estrogens, and/or glucocorticoids may require tional chemotherapy agents, especially busulphan and cyclo-
adjustments in levothyroxine doses.11 The adrenal axis should be phosphamide, are associated with transient and often mild forms
evaluated in patients at risk for central endocrinopathies before of hypothyroidism.18 More recently, hypothyroidism has been
beginning thyroid hormone replacement lest the thyroid supple- recognized as among the most common adverse effects of TKIs,
mentation precipitate adrenal insufficiency.11 especially sorafenib, sunitinib, and imatinib.7 The precise mech-
anism of TKI-induced hypothyroidism is unknown. A subset of
CCSs may experience hypothyroidism as a consequence of auto-
ACTH Deficiency immune thyroid disease, which has been reported after HSCT and
Individuals with ACTH deficiency have insufficient cortisol likely is due to the transfer of autoimmunity from the graft do-
secretion because of inadequate stimulation of the adrenal cortex nor.45 It may occur as an adverse effect of treatment with immune
by the HP axis. Aldosterone production typically is preserved. system modulators, such as interferon and anti–CTLA-4 mono-
Presentation may include fatigue, weight loss, and/or low blood clonal antibodies (ipilimumab, tremelimumab, nivolumab, and
glucose levels. Patients are at risk for adrenal crisis in times of pembrolizumab).8 Hyperthyroidism is significantly less common
significant physical illness.11 Estimates of the prevalence of ACTH than hypothyroidism in CCSs; it can present after neck or cra-
deficiency in CCSs have varied widely partly because of the use of niospinal irradiation (Fig 2) and in patients with autoimmune
different testing modalities. The 5-year cumulative incidence of thyroid disease.4,43
ACTH deficiency has been reported at 2.9% in a cohort of CNS Patients at risk for primary thyroid dysfunction should be
tumor survivors.15 Risk factors for ACTH deficiency include tumor screened by assessing their symptoms and measuring plasma free
growth and/or surgery that involved the HP region as well as HP T4 and TSH levels at least yearly (Table 1). Screening with thyroid
radiation doses $ 30 Gy.3 Longer time since treatment and the autoantibody titers is not advised because the development of
presence of other central endocrinopathies increase the likelihood hypothyroidism or hyperthyroidism cannot be predicted on the
of ACTH deficiency.3,42 Subclinical forms of ACTH deficiency have basis of the presence or absence of these antibodies. However, these
been reported in individuals treated with imatinib, but the clinical can be used to investigate the etiology of hypo- or hyperthyroidism
implications of this observation are unclear.7 further. Patients administered targeted therapies should be screened

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 Endocrine Late Effects of Childhood Cancer

A B
Radiation exposure Thyroid radiation dose

Cumulative Incidence (%)

Cumulative Incidence (%)

60
Thyroid ≥ 20 Gy (n = 1,802) 10 ≥ 40 Gy (n = 705)

50 HP ≥ 40 Gy (n = 545) 0 to < 40 Gy (n = 11,386)

Both (n = 259) 8
*
40 Neither (n = 9,370) *
* 6
30

20
* 4

10 2

0 0

5 10 15 20 25 30 35 5 10 15 20 25 30 35
Time Since Primary Cancer Time Since Primary Cancer
Diagnosis (years) Diagnosis (years)
Fig 2. Cumulative incidence of thyroid disorders. (A) Underactive thyroid and (B) overactive thyroid in survivors stratified by treatment exposure. Thin lines represent 95%
CIs. *P , .01 for comparison versus the non–high-risk exposure group. HP, hypothalamic pituitary. Reproduced with permission.4 Copyright © 2016 American Society of
Clinical Oncology.

per their treatment protocols.7 Treatment of hypothyroidism with 5 years of follow-up to 28.4% at 10 years), especially among those
levothyroxine is indicated for lowered free T4 values in combination treated with cranial radiotherapy in addition to TBI.57 Abdominal
with elevated TSH values, after evaluation of the adrenal axis in radiotherapy also has been associated with an increased risk of
patients who also are at risk for adrenal insufficiency.11 The benefit glucose intolerance and DM in survivors of solid tumors.58,59
of treatment of compensated (subclinical) hypothyroidism (ie, el- Annual screening for overweight and obesity is recommended
evated TSH accompanied by normal free T4 values) remains by using height, weight, and body mass index measurements.
controversial; normalization of TSH may decrease the growth of Fasting blood glucose or hemoglobin A1c at least every 2 years is
thyroid nodules in at-risk patients, although data are inconsistent.46 recommended to screen for DM in CCSs treated with abdominal
Management of persistent and symptomatic hyperthyroidism fol- radiotherapy or TBI, regardless of body mass index.59 Treatments
lows similar steps as with hyperthyroidism as a result of Graves of hypothalamic obesity have included octreotide,49 diazoxide,60
disease, with the understanding that it is frequently transient.45 amphetamine derivatives,61 glucagon-like peptide 1 receptor ag-
onists,62 and bariatric surgery,63 but data on long-term efficacy are
lacking. Physical activity may prevent additional deterioration of
OBESITY, DM, AND METABOLIC SYNDROME metabolic control55; the risk/benefit ratio of pharmacotherapy (eg,
metformin) is unknown in CCSs.64
The risks of obesity and DM are significantly higher in CCSs than
in their siblings.4 Metabolic syndrome, a constellation of cardio-
vascular (hypertension) and metabolic (obesity, abnormal glucose LOW BMD
metabolism, and dyslipidemia) abnormalities associated with
cardiovascular mortality, also has been shown to affect a sizeable The prevalence of low BMD has been reported at 9% to 18% in
proportion of CCSs (31.8%) and at a higher rate than in the general general cohorts of CCSs.1,2 High-risk groups include survivors of
population of adults younger than 40 years of age (18.3%).47,48 pediatric ALL, CNS tumors, and HSCT.65-67 Several factors con-
Patients with hypothalamic injury as a result of tumor or tribute to poor bone acquisition and alterations in bone resorption
surgical resection are at the highest risk for obesity, which can be in CCSs, including the following: the direct impact of cancer
severe (hypothalamic obesity).49 Survivors of childhood ALL diagnosis (eg, leukemia) on the skeleton, glucocorticoid treatment,
represent another high-risk group because of treatment with osteotoxic chemotherapy, and radiation as well as comorbid
cranial radiation and high-dose glucocorticoids. Up to 46% of ALL conditions such as treatment-induced endocrine deficits (eg, GH
survivors have been reported to be obese at 10 years of follow-up.50 deficiency, hypogonadism), malnutrition, physical impairment,
Patients treated with HSCT have higher-than-expected rates of and reduced muscle strength.66,67 Adverse skeletal growth out-
abnormal glucose metabolism, independently from obesity.51 The comes have more recently been reported in individuals treated with
prevalence of insulin resistance and DM in HSCT recipients has retinoid derivatives28 and with TKIs such as imatinib, sunitinib,
been reported at 52%52 and 5%,53 respectively. Treatment with dasatinib, and vandetanib7; additional data are needed to better
TBI, decreased lean mass (sarcopenia),54,55 and atypical body fat understand and address the detrimental effects of these agents on
distribution may explain the prevalence of abnormal glucose the developing skeleton.
metabolism after HSCT.56 Longitudinal follow-up data from young Dual-energy x-ray absorptiometry (DXA) is recommended
HSCT survivors have suggested an increase in the prevalence for bone health assessment after childhood cancer therapy.68 The
of metabolic syndrome/cardiovascular risk over time (10.6% at BMD of shorter individuals and those with pubertal delay may be

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 Chemaitilly et al

underestimated by DXA.69 A single DXA measurement alone is treatments over time will necessitate future revisions of these
insufficient to dictate the initiation of specific therapeutic in- recommendations.
terventions, and emphasis should be placed on fracture history,
risk factors, and BMD changes over time.70 Treatment for low
BMD includes prompt recognition and treatment of hormonal AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
deficiencies, repletion of vitamin D insufficiency/deficiency, and OF INTEREST
supplementation of poor calcium intake. Furthermore, CCSs
should be counseled about the benefits of regular physical activity Disclosures provided by the authors are available with this article at
jco.org.
on bone remodeling and the deleterious effects of smoking and
alcohol consumption.71
In conclusion, endocrine complications are among the
AUTHOR CONTRIBUTIONS
most common late effects in CCSs. Given a variable latency in-
terval, a systematic approach where individuals are periodically Conception and design: All authors
screened on the basis of their risk factors can help to improve Manuscript writing: All authors
health outcomes by prompt diagnosis and treatment of evolv- Final approval of manuscript: All authors
ing endocrinopathies. Changes and improvements in cancer Accountable for all aspects of the work: All authors

the assessment and management of female repro- imatinib on the skeleton of growing rats. PLoS One
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Affiliations
Wassim Chemaitilly, St Jude Children’s Research Hospital, Memphis; Jill H. Simmons, Vanderbilt University Medical Center,
Nashville, TN; Laurie E. Cohen, Boston Children’s Hospital, Boston, MA; Sogol Mostoufi-Moab, University of Pennsylvania,
Philadelphia, PA; Briana C. Patterson and Lillian R. Meacham, Emory University School of Medicine and Aflac Cancer and Blood
Disorders Center of Children’s Healthcare of Atlanta, Atlanta, GA; Hanneke M. van Santen, University Medical Center Utrecht, Utrecht,
the Netherlands; and Charles A. Sklar, Memorial Sloan Kettering Cancer Center, New York, NY.

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 Chemaitilly et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Endocrine Late Effects in Childhood Cancer Survivors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Wassim Chemaitilly Jill H. Simmons
Honoraria: Pfizer Honoraria: Alexion Pharmaceuticals
Consulting or Advisory Role: Pfizer Research Funding: Alexion Pharmaceuticals, Ultragenyx Pharmaceutical
Travel, Accommodations, Expenses: Alexion Pharmaceuticals
Laurie E. Cohen
Honoraria: Scherer Clinical Communications (who received grant from Lillian R. Meacham
Novo Nordisk) No relationship to disclose
Research Funding: Versartis (Inst), Ascendis Pharma (Inst), OPKO Health
(Inst) Hanneke M. van Santen
Travel, Accommodations, Expenses: Ferring
Sogol Mostoufi-Moab
No relationship to disclose Charles A. Sklar
No relationship to disclose
Briana C. Patterson
No relationship to disclose

© 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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