Mini Review
HOR MONE Horm Res Paediatr
RESEARCH I N DOI: 10.1159/000493943
PÆDIATRIC S
Childhood Cancer Treatments and Associated
Endocrine Late Effects: A Concise Guide for the
Pediatric Endocrinologist
Wassim Chemaitilly a, b Charles A. Sklar c
a Department
of Pediatric Medicine, Division of Endocrinology, St. Jude Children’s Research Hospital, Memphis, TN,
USA; b Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA;
c Department of Pediatrics, Memorial-Sloan Kettering Cancer Center, New York, NY, USA
Keywords
Childhood cancer survivor · Endocrine late-effects ·
Endocrine complications · Radiotherapy late-effects ·
Chemotherapy late-effects
Abstract
Endocrine complications are frequently observed in child-
hood cancer survivors (CCS); in many instances, these com-
plications develop months to years after the completion of
cancer therapy. The estimated prevalence of endocrine late
effects is 50% among CCS; the main risk factors are external
beam radiation that includes key endocrine organs (the hy-
pothalamus/pituitary, thyroid and gonads) and/or alkylating
agents. Novel agents targeting tumor growth have increased
the options available to a small number of patients albeit
with the need for treatment over long periods of time. Some
of these agents, such as certain tyrosine kinase inhibitors and
immune system modulators have been shown to cause per-
manent endocrine deficits. This chapter offers a brief sum-
mary of the conventional treatment strategies for the most
common cancers of childhood and a brief overview of the
endocrine late effects most commonly associated with these
exposures. The impact of targeted therapies on the endo-
crine system will also be discussed. The aim of this chapter is
to provide basic guidance to the consulting pediatric endo-
© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/hrp
Received: August 21, 2018
Accepted: September 20, 2018
Published online: November 7, 2018
crinologist in preparation for the clinical encounter with a
CCS. A more detailed discussion of the management of spe-
cific endocrine late effects can be found in the other chap-
ters in this series. © 2018 S. Karger AG, Basel
Introduction
Progress in the treatment of cancer during childhood
has resulted in 5-year survival rates exceeding 80%. The
proportion of patients surviving pediatric cancer has
steadily increased over the last 4 decades; in the United
States, the population of childhood cancer survivors
(CCS) is poised to exceed 500,000 individuals by 2020 [1].
Key to this success has been the use of multi-modal, in-
tensive treatment regimens combining surgery, radio-
therapy, and/or chemotherapy coupled with effective,
multi-disciplinary, supportive care strategies aimed at the
management of acute and frequently severe treatment
complications. Complications of cancer treatments may
also occur in a delayed fashion as chronic health condi-
tions, developing months to years after the completion of
cancer therapy; these are referred to as late effects [2]. En-
docrine conditions are among the most commonly re-
ported late effects in CCS with a prevalence of 50% [3].
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Wassim Chemaitilly, MD
Stockholm University Library
St. Jude Children’s Research Hospital, Division of Endocrinology
262 Danny Thomas Place MS 737
Memphis, TN 38105 (USA)
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E-Mail wassim.chemaitilly @ stjude.org
 The variable latency period between the time of diag-
nosis of cancer and the onset of late effects mandates re-
peated evaluations and lifelong follow-up in many in-
stances [2]. Enhanced knowledge of the risk conferred by
a given cancer diagnosis and its treatment has allowed the
establishment of long-term follow-up guidelines, such as
those proposed by the Children’s Oncology Group –
www.survivorshipguidelines.org. These guidelines assist
medical providers in determining which survivors are at
risk for specific late effects and how best to screen CCS
for various chronic health conditions. Nevertheless, re-
cent reports indicate that a relatively high proportion of
at-risk CCS have undiagnosed and untreated endocrine
conditions [2].
A medical encounter with a CCS requires thorough
preparation by the consulting pediatric endocrinologist.
CCS frequently have complex past medical histories and
multiple coexisting health conditions. It is essential to ob-
tain, whenever possible, detailed information on cancer
history and treatment exposures, as these data are indis-
pensable for accurate assessments and appropriate coun-
seling [4]. The present chapter seeks to provide basic
guidance to the consulting pediatric endocrinologist by
summarizing the treatments employed to treat the most
common cancers in the pediatric age group and the en-
docrine complications associated with these therapeutic
exposures. Treatment modalities most commonly associ-
ated with endocrine late-effects are summarized in Tables
1 and 2.
The Effect of Radiotherapy
Endocrine late effects are most often observed in sur-
vivors previously exposed to external beam radiation that
includes the hypothalamus-pituitary (HP), thyroid, or
gonads. Skeletal growth, bone health, body composition,
and metabolic homeostasis may be impaired as a conse-
quence of radiation-induced endocrine deficits or be-
cause of direct radiation-related toxicity. The effect of ra-
diotherapy on the various endocrine organs is dictated
primarily by the total dose received and the duration
since treatment such that the risk increases with increas-
ing doses and greater elapsed time between exposure and
follow-up [5–7]. Additional considerations include frac-
tion size and number [8] and the method of delivery of
the radiation [9–11].
Efforts to reduce the dose of radiation received by nor-
mal tissue have included over the past 30 years moving
from X-ray based radiotherapy and treatment planning
2 Horm Res Paediatr
DOI: 10.1159/000493943
using 2-dimensional models to photon-based three-di-
mensional “conformal” radiotherapy [9] and intensity-
modulated radiation therapy, a technique that allows the
option to better take into account the shape of the tar-
geted tumor and reduce the amount of scatter to sur-
rounding structures [10]. Proton-based radiotherapy, a
technique that seeks to exploit the decreased propensity
of protons to travel beyond a targeted site in comparison
to photons, has been recently introduced with the aim of
decreasing even further the exposure of normal tissues
located in proximity to the treated tumor [11]. Currently,
only a limited number of institutions offer proton-based
radiotherapy and only a small number of studies, all with
short follow-up durations, have reported data on endo-
crine late effects in children treated with proton-based
radiotherapy, so the long-term risks remain unknown
[12, 13].
Cranial Radiotherapy
Children are exposed to cranial radiotherapy most
commonly for the treatment of central nervous system
(CNS) tumors. The most common childhood CNS tu-
mors treated with radiotherapy include medulloblasto-
ma, craniopharyngioma, ependymoma, high-grade glio-
ma, and low-grade glioma [5, 14]. Other childhood ma-
lignancies that may require cranial radiotherapy include
acute lymphoblastic leukemia (ALL), previously for pro-
phylaxis and currently for treatment of CNS disease [15],
and malignant non-brain solid tumors of the head or
neck (e.g., nasopharyngeal carcinoma, retinoblastoma,
and rhabdomyosarcoma) [16].
Linear Growth Impairment and
Hypothalamic-Pituitary Dysfunction
In contrast to tumor-related or surgically induced HP
deficits, radiation-induced HP dysfunction is limited to
anterior pituitary disorders: growth hormone deficiency,
central precocious puberty, LH/FSH deficiency, TSH de-
ficiency, ACTH deficiency, and hyperprolactinemia; cen-
tral diabetes insipidus has not been described as a com-
plication of radiation [17]. The different HP axes vary in
their vulnerability to radiotherapy [18] (Fig. 1). Growth
hormone deficiency, the most common, and frequently
only, radiation-induced HP deficit has been associated
with radiotherapy doses to the HP region ≥18 Gy [5, 19].
Central precocious puberty may occur following treat-
ment with doses 18–50 Gy [20]. Deficiencies in LH/FSH,
TSH, and ACTH have been associated with HP radio-
therapy at doses ≥30 Gy and hyperprolactinemia with
even higher doses ≥40 Gy [17–19]. Efforts to improve the
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Table 1. Radiotherapy-associated endocrine late effects

Radiotherapy Treated conditions Possible complications

– Field

Cranial CNS tumors Anterior pituitary disorders*

Includes: Acute lymphoblastic leukemia with CNS disease Obesity
– Whole brain Non brain solid tumors:
– Infratemporal Rhabdomyosarcoma
– Nasopharyngeal Nasopharyngeal carcinoma
– Orbital Retinoblastoma
– Waldeyer’s ring
Craniospinal Medulloblastoma/PNET Anterior pituitary disorders*
Skeletal dysplasia – short stature
Primary hypothyroidism
Hyperthyroidism
Thyroid cancer
Premature ovarian insufficiency
Total body irradiation Conditioning for hematopoietic stem cell transplantation Growth hormone deficiency
Acute leukemia Skeletal dysplasia – short stature
Neuroblastoma Primary hypothyroidism
Thyroid cancer
Premature ovarian insufficiency
Male germ cell failure
Decreased bone mineral density
Abnormal glucose metabolism
Metabolic syndrome
Neck, thorax, mediastinum Hodgkin lymphoma Primary hypothyroidism
Includes: Solid tumor located within field: Hyperthyroidism
– Neck Rhabdomyosarcoma Thyroid cancer
– Chest Neuroblastoma
– Lung Ewing sarcoma
– Mantle Nasopharyngeal carcinoma
– Nasopharyngeal
– Oropharyngeal
– Supraclavicular
Abdominal, pelvic, genitourinary Hodgkin lymphoma Premature ovarian insufficiency
Includes: Solid tumor located within field: Male germ cell failure
– Flank or hemi abdomen Rhabdomyosarcoma Leydig cell failure
– Whole abdomen Neuroblastoma Abnormal glucose metabolism
– Inverted Y Acute lymphoblastic leukemia with testicular relapse
– Bladder
– Vaginal (females)
– Prostate, testes (males)
– Iliac
– Inguinal, femoral (males)
131-I-MIBG
Neuroblastoma Primary hypothyroidism
Thyroid cancer
Premature ovarian insufficiency

*  Includes deficiencies in growth hormone, LH/FSH, TSH, and/or ACTH, central precocious puberty and hyperprolactinemia.
Adapted from the Children’s Oncology Group Long-Term Follow-Up Guidelines version 4.0 www.survivorshipguidelines.org.
CNS, central nervous system; PNET, primitive neuroectodermal tumors.
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Table 2. Chemotherapeutic agents associated with endocrine late effects

Category Drug Possible complication

Alkylating agents Busulfan Premature ovarian insufficiency

Carmustine Male germ cell failure
Chlorambucil Leydig cell dysfunction (most commonly subclinical)
Cyclophosphamide
Dacarbazine
Ifosfamide
Lomustine
Mechlorethamine
Melphalan
Procarbazine
Temozolomide
Thiotepa
Heavy metals Carboplatin Premature ovarian insufficiency
Cisplatin Male germ cell failure
Glucocorticoids Dexamethasone Obesity
Prednisone Decreased bone mineral density
Tyrosine kinase inhibitors Imatinib Impaired linear growth
Sorafenib Primary hypothyroidism
Sunitinib
Immunomodulator Interferon Auto-immune thyroid disease
Immune checkpoint inhibitor – Ipilimumab Immune hypophysitis:
Anti-CTLA4 monoclonal antibody Growth hormone deficiency
LH/FSH deficiency
TSH deficiency
ACTH deficiency
Auto-immune thyroid disease
Other Retinoic acid Skeletal dysplasia – short stature
Hedgehog pathway inhibitors

precision of the delivery of radiotherapy, as with the use
of protons instead of photons, are likely to decrease scat-
ter to the HP region and may hopefully reduce or delay
the appearance of HP dysfunction especially in individu-
als treated for tumors located outside the HP region [13].
Primary Thyroid Disorders
Scatter from cranial radiation, especially in children
exposed at a very young age has the potential to reach the
thyroid gland. A history of prophylactic cranial irradia-
tion for ALL does not seem to be associated with a higher
risk of primary hypothyroidism [21]. However, thyroid
carcinoma has been reported in CCS treated with this
modality [21] possibly as a result of exposure at a young
age and increased scatter due to older radiotherapy deliv-
ery techniques [22]. Survivors of various malignant non-
brain solid tumors of the head and neck whose thyroid
was exposed to radiotherapy were also reported to have
developed thyroid cancer [23].
Craniospinal Irradiation
Children may receive craniospinal irradiation (CSI)
for the treatment of CNS malignancies such as medullo-
blastoma or primitive neuroectodermal tumors. In addi-
tion to a standard dose delivered to the whole neuraxis,
patients may receive additional “boosts” to specific sites
of disease [14].
Linear Growth Impairment and Skeletal Dysplasia
In addition to the complications related to the cranial
component of CSI, exposed CCS may experience subop-
timal growth due to the direct injury of the vertebral body
growth plates and develop a skeletal dysplasia where spi-
nal growth is more impaired than that of the legs [24].
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 own pre-harvested hematopoietic stem cells after treat-
■ GHD (n = 262) ment with myeloablative chemotherapy for a non-hema-
■ LH/FSHD (n = 21)
■ TSHD (n = 8)
tological cancer such as a solid tumor (e.g., medulloblas-
■ ACTHD (n = 1) toma or neuroblastoma) [14].
GHD
TSHD ■ ■ (n = 26) In patients treated for malignant hematological disor-
(n = 55)
(n = 336) ■ ■ (n = 13) ders, conditioning may involve TBI in addition to alkylat-
ACTHD ■ ■ (n = 3)
(n = 29) ing agent-based chemotherapy. The delivery of TBI has
■ ■ (n = 2)
■ ■ (n = 1) evolved over the past decades from single-dose to divided
LH/FSHD ■ ■ (n = 1) doses or fractions given via multiple sessions a day over
(n = 77) ■ ■ ■ (n = 10) 3–4 days in order to decrease treatment toxicity [8, 27].
■ ■ ■ (n = 2)
■ ■ ■ (n = 6) Other types of conditioning include non TBI-based-che-
■ ■ ■ (n = 1) motherapy-alone regimens as with fludarabine, melpha-
■ ■ ■■ (n = 14) lan, and thiotepa. Reduced intensity conditioning regi-
mens may use lower doses of fludarabine and busulfan or
fludarabine with low-dose TBI for the preparation of pa-
Fig. 1. Prevalence and overlap between anterior pituitary deficits
following cranial radiotherapy. Overlap among hypothalamic pi-
tients who are unable to tolerate traditional regimens
tuitary deficits after cranial radiotherapy in 748 adult survivors of [28].
childhood cancer survivors followed for a mean 27.3 years. Repro-
duced with permission [19]. Copyright © 2015 American Society Linear Growth Impairment and Hypothalamic
of Clinical Oncology. Pituitary Dysfunction
The risk of short stature is highest among CCS treat-
ed with HSCT who have a history of prior exposure to
cranial irradiation and conditioning with TBI [27, 29].
Primary Thyroid Disorders A subset of patients may not be able to experience an
The thyroid gland may be exposed to scatter radio- adequate pubertal growth spurt with lasting conse-
therapy after CSI. Thyroid complications observed after quences on adult height [29]. This is due, at least in part,
CSI include primary hypothyroidism, hyperthyroidism, to radiation-induced vertebral body growth plate dam-
and thyroid cancer [7, 25]. The use of proton-based ra- age [27]. HP dysfunction other than growth hormone
diotherapy for CSI holds promise in terms of decreasing deficiency is rare in HSCT recipients treated with TBI
the amount of scatter to the thyroid [13]. and who do not have a history of prior cranial radio-
therapy [29].
Primary Gonadal Disorders
Female survivors of childhood CNS tumors may expe- Primary Thyroid Disorders
rience premature ovarian insufficiency (POI) because of Primary hypothyroidism and thyroid cancer have
scatter from CSI [26]. The use of proton-based radiother- been reported following TBI-based conditioning for var-
apy for CSI holds promise in terms of decreasing the ious disorders in children and adolescents [30, 31].
amount of scatter to the ovaries [13]. The effect of scatter
from CSI to the testes seems to be minor and unlikely to Primary Gonadal Disorders
affect Leydig cell function, though it can potentially affect Nearly all female CCS treated with TBI after the age of
sperm production [26]. 10 develop POI, while a subset among those treated be-
fore the age of 10 years may experience a spontaneous
Total Body Irradiation onset for puberty or menarche [32]. Males exposed to TBI
Total body irradiation (TBI) is used for the condition- are at a great risk for impaired spermatogenesis and in-
ing of patients for hematopoietic stem cell transplanta- fertility [33]. Gonadal shielding has been reported to pos-
tion (HSCT). Allogeneic HSCT is used to treat different sibly protect the testes from the effects of TBI, but fertil-
disorders including hematological malignancies such as ity preservation via sperm banking prior to HSCT should
relapsed or high risk leukemia [15], nonmalignant blood be offered whenever feasible [34]. In contrast to germ cell
disorders such as Fanconi anemia as well as certain in- function, Leydig cell function (testosterone secretion) is
born errors of metabolism. Autologous HSCT is used to rarely affected in individuals without a history of prior
repopulate the bone marrow of an individual with her/his exposure to direct testicular irradiation [35].
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 Other Types of Exposure to Radiotherapy
Neck, Thoracic, and Mediastinal Radiotherapy Sites
The most common reason for the exposure of the
neck, thorax, or mediastinum to radiotherapy in pediatric
oncology is for the treatment of Hodgkin Lymphoma.
Treatments for pediatric Hodgkin lymphoma include ra-
diotherapy of involved regions and multi-agent chemo-
therapy, with a major ongoing effort to limit the use of
radiotherapy and adapt the intensity of chemotherapy to
individual risk factors [36]. Treatment with radiotherapy
may also be necessary in children diagnosed with malig-
nant solid tumors of the neck or chest [37]. Survivors
whose treatment involved neck irradiation are at high risk
for primary hypothyroidism, hyperthyroidism, and thy-
roid cancer [6, 38, 39].
Abdominal, Pelvic, and Genitourinary Radiotherapy
Sites
The treatment of pediatric Hodgkin Lymphoma may
require the exposure of the abdomen or pelvis to radio-
therapy [36]. Individuals may also be exposed to abdom-
inal, pelvic, or genitourinary irradiation for the treatment
of solid tumors such as neuroblastoma and rhabdomyo-
sarcoma located within or near these regions [16]. Male
survivors of childhood ALL may require testicular radio-
therapy for the treatment of disease relapse in the testes
[35].
Radiotherapy exposures involving the ovaries repre-
sent a major risk factor of POI in female CCS [40–42].
Individuals whose testes have been exposed to radiother-
apy for the treatment of Hodgkin Lymphoma or solid tu-
mors located nearby are at risk for germ cell and Leydig
cell failure [40, 43, 44]. Abdominal radiotherapy may also
increase the risk of abnormal glucose metabolism, includ-
ing insulin resistance and diabetes mellitus [45].
Treatment with (131)-I-Metaiodobenzylguanine
Children diagnosed with neuroblastoma may require
treatment with (131)-I-metaiodobenzylguanine (131–I-
MIBG) and HSCT and have a high risk of developing pri-
mary hypothyroidism [46]. Thyroid cancer has also been
reported after treatment with 131-I-MIBG for neuroblas-
toma without neck irradiation and despite prophylaxis
with potassium iodide [47]. Treatment with 131-I-MIBG
for neuroblastoma has more recently been shown to pos-
sibly be associated with POI [48].
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The Effect of Chemotherapy
Alkylating Agents
Alkylating chemotherapy agents are a group of drugs
that inhibit cell multiplication by adding an alkyl group
to DNA. Abnormally proliferating cells, such as cancer
cells are vulnerable to alkylating agents. Alkylating agents
may also be toxic to normally multiplying nonmalignant
cells, which explains their gonadal toxicity and associa-
tions with POI in females and germ cell dysfunction in
males [40–42, 49–51]. Leydig cell failure may affect 10–
57% of survivors of childhood ALL after treatment with
alkylating agents but the majority of cases are subclinical
or compensated with individuals experiencing with
elevated LH but normal serum testosterone levels [52].
The most commonly used alkylating agents are listed in
Table 2.
Heavy Metals
Heavy metal chemotherapy drugs include cisplatin
and carboplatin and are used for the treatment of differ-
ent solid tumors such as germ cell tumors of the CNS and
gonads as well as medulloblastoma. The use of heavy met-
als has been associated with a higher risk of primary go-
nadal injury in both males and females [49, 50].
Prolonged Exposure to Systemic Glucocorticoids
Children may be exposed to high-dose systemic ste-
roids for many months to treat ALL [15], with potential-
ly lasting consequences on bone health [53] and metabo-
lism [54].
Novel Targeted Chemotherapy Agents
In contrast to conventional cytotoxic chemotherapies,
novel strategies for cancer treatment include targeted
agents designed to interfere with specific molecular path-
ways to inhibit tumor growth. These agents may be used
over long periods of time as maintenance therapy. De-
spite the intent for new treatment strategies to limit the
collateral damage to normal tissue by targeting tumor-
specific pathways, long-term endocrine and skeletal com-
plications have been reported in individuals exposed to
such therapies.
Tyrosine Kinase Inhibitors
Imatinib mesylate, a tyrosine kinase inhibitor, has be-
come a frontline therapy option for children with chron-
ic myeloid leukemia, a myeloproliferative disorder with
an activated BCR-ABL tyrosine kinase fusion protein [55,
56]. Children may be treated with imatinib for other con-
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ditions such as relapsed solid tumors [57]. Treatment
with imatinib has been shown to cause linear growth de-
celeration [56]. The mechanism of growth failure in chil-
dren treated with tyrosine kinase inhibitors such as ima-
tinib is not well understood and may involve perturba-
tions of the GH-IGF-I axis and direct skeletal effects [55].
Primary hypothyroidism is also among the most com-
monly reported side effects of treatment with tyrosine ki-
nase inhibitors, especially imatinib, sorafenib, and suni-
tinib; the mechanism by which these agents cause hypo-
thyroidism is unknown and may involve multiple
pathways [57].
Immune System Modulators
Anti-CTLA-4 monoclonal antibodies including ipili-
mumab, which are increasingly used for the treatment of
relapsed solid tumors, have been reported to cause im-
mune-related hypophysitis and various HP deficits
(mostly central hypothyroidism and central adrenal in-
sufficiency); these were reported to be permanent in up
to 50% of cases [58]. Patients treated with immunomodu-
lators such as interferon and immune check point inhib-
itors including ipilimumab, nivolumab, tremelimumab,
and pembrolizumab may develop autoimmune thyroid
disease with subsequent hypothyroidism or, more rarely
hyperthyroidism [58].
cal trials to treat a subset of patients with malignancies
believed to be driven by the aberrant activation of this
pathway, have recently been shown to also cause growth
plate damage and premature epiphyseal fusions [60].
Conclusion
Endocrine late effects are frequently observed in CCS,
primarily as a result of the therapies used to treat their
primary cancer. The optimal management of these pa-
tients mandates obtaining detailed information regard-
ing the survivor’s therapeutic exposures such as radiation
fields, doses of radiation to key endocrine organs as well
type and doses of chemotherapy. As endocrine complica-
tions may develop months to years following a cancer di-
agnosis, survivors at risk may require lifelong screening
for various adverse endocrine outcomes. Changes and
improvements in cancer treatments necessitate a sus-
tained effort in the investigation of long-term endocrine
and general health outcomes in this population.
Acknowledgment
Wassim Chemaitilly, MD and Charles A. Sklar MD contrib-
uted to the drafting and review of the manuscript.

Others
Children treated with 13-cis-retinoic acid for neuro- Disclosure Statement
blastoma may have irreversible damage to their growth
plates and are at risk of significantly impaired final adult The authors have no conflicts of interest to disclose.
height [59]. Hedgehog pathway inhibitors, used in clini-

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