Childhood cancer survival rates have improved greatly and 5-year survival now exceeds 80%.1 These survivors often develop chronic health conditions directly related to their cancer or their therapy. Of these chronic conditions, endocrine-related disorders are among the most common. Data from the Childhood Cancer Survivor Study, a retrospective longitudinal cohort study involving survivors of childhood malignancies and their siblings, revealed that endocrine sequelae are cumulative with time. Over a 35-year time span after diagnosis, 44% of survivors developed one endocrinopathy, 16.7% developed at least two, and 6.6% had three endocrine disorders. Among specific cancer diagnoses, the risk of endocrinopathy may be even greater; 60% of Hodgkin lymphoma survivors and 54% of central nervous system (CNS) tumor survivors have an endocrinopathy.2
Children may develop complications from the tumor itself, or from treatment of the cancer. After therapy, complications may take years to develop. Primary care providers and endocrinologists should be aware of the increased risk and delayed presentation for endocrinopathies in this population.
In addition to direct damage to endocrine organs from surgical resection (ie, hypothalamic or pituitary damage for CNS tumors), the most common modalities associated with endocrinopathies include radiation therapy, chemotherapy, and stem cell transplantation. Immune checkpoint inhibitors are not yet commonly used in children but cause autoimmune endocrine disorders.
Radiation therapy directly damages DNA of targeted tissues, creates free radicals that damage DNA, damages cells involved in neuronal support and vascular supply, and may also trigger chronic inflammation, contributing to damage that may not show itself for years.3
Compared to conventional external beam radiation, proton beam therapy has the advantage of more localized delivery of radiation, with the potential of sparing surrounding local tissues from incidental damage. In general, radiation delivered in smaller doses and more fractions over a longer duration of time causes less injury, except for testicular radiation.3 Age, gender, and pubertal status may also determine the extent of damage. Commonly targeted areas of radiation that result in endocrine sequelae include craniospinal (short stature, hypopituitarism, low bone mineral density for age, thyroid or ovarian dysfunction); total body irradiation (TBI) prior to stem cell transplantation (growth hormone deficiency, direct thyroid toxicity, reproductive dysfunction, metabolic syndrome, low bone mineral density); mantle or neck radiation (direct thyroid toxicity, hyperparathyroidism); abdominal and pelvic (metabolic syndrome, reproductive dysfunction); and testicular radiation (infertility, hypogonadism).4,5 One form of radiation therapy, I-131 linked to metaiodobenzylguanidine (MIBG), is used to treat high-risk neuroblastoma and may result in primary thyroid dysfunction, thyroid cancer, and rarely, premature ovarian insufficiency.6,7Table 1 summarizes radiation effects on the endocrine system.
Radiation Therapy and Endocrine Risks
Conventional chemotherapy directly damages cancer cells. Alkylating agents attach alkyl groups to DNA causing DNA breakage and cell death and affect rapidly proliferating cells preferentially. Thus, they not only affect cancer cells, but also disproportionately affect gonadal tissue. One of the most commonly used alkylators is cyclophosphamide, and exposure to other alkylating agents can be calculated as cyclophosphamide equivalents to better determine risk for gonadal dysfunction.8 Heavy metals (platinum-based compounds) are believed to have similar effects on gonadal tissue by crosslinking purines in DNA. In addition, alkylating agent therapy may be an additional risk factor for hypothyroidism and thyroid cancer.9,10
Asparaginase is commonly used in childhood acute lymphoblastic leukemia and reduces protein synthesis in leukemic cells. All three forms may cause hyperglycemia, hypertriglyceridemia, and pancreatitis, but on occasion the pancreatitis is followed by permanent diabetes mellitus.11
Methotrexate is a DNA nucleotide analogue that inhibits cell mitosis and particularly affects osteoblasts, leading to lower bone mineral density.12
Tyrosine kinase inhibitors (TKIs) block phosphorylation of tyrosine residues and thereby alter pathways associated with cell proliferation and cell death. TKIs can be nonspecific inhibitors that affect multiple tyrosine kinases, or can be selective monoclonal antibodies, which are associated with fewer side effects. The most common endocrinopathy is hypothyroidism, although persistent hyperthyroidism may occur.13 Other less well-known side effects include direct impairment of linear growth, potential impairment of fertility, subclinical adrenal insufficiency, and hypo or hyperglycemia.13,14
Glucocorticoids may cause hyperglycemia, obesity and metabolic disorder, and low bone mineral density. Depending on duration and dosing, transient iatrogenic adrenal insufficiency may ensue.
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cells are harvested from either the peripheral blood or bone marrow. Transplantation may involve using the patient's own cells (autologous) if the cancer is a solid tumor, thereby avoiding the risk of graft versus host disease (GvHD). Allogeneic transplant uses donor stem cells for hematologic malignancies and immunodeficiencies. Transplantation follows preconditioning regimens that involve chemotherapy and/or TBI. Chemotherapy with alkylating agents (busulfan and cyclophosphamide) or TBI increases risk for later endocrinopathies, as does GvHD prophylaxis with tacrolimus, or treatment with glucocorticoids.15
Recently, alemtuzumab, an anti-CD52 monoclonal antibody used for preconditioning, has been reported to cause thyroid dysfunction (predominantly autoimmune hyperthyroidism) in 41% of patients with multiple sclerosis.16
Checkpoint inhibitor immunotherapy is increasingly used in adults but occasionally may be used in children. Immunotherapy inhibits checkpoints on T cell activation, mainly the cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 pathways. The resultant activation of the immune system targets cancer cells but also may cause autoimmune primary hypothyroidism or hyperthyroidism, hypophysitis resulting in central hypothyroidism or adrenal insufficiency, primary adrenal insufficiency, or even autoimmune diabetes mellitus.17
The thyroid gland may be within the field of external radiation during treatment of childhood cancer. Head and neck radiation, TBI, and mantle radiation increase the risk for primary hypothyroidism or hyperthyroidism as well as thyroid nodules and thyroid cancer.2 Cranial radiation also increases the risk for central hypothyroidism but thyrotroph cells are relatively more resistant to radiation effects compared to other pituitary cell lines.3
I-131-MIBG therapy for high-risk neuroblastoma is also associated with primary hypothyroidism, thyroid nodules, and thyroid cancer.6 Alkylating chemotherapy exposure as conditioning for stem cell transplantation has been independently associated with thyroid dysfunction.9
The risk for thyroid dysfunction is more than double for survivors as compared to siblings.2 Annual thyroid function testing with thyroid-stimulating hormone (TSH), free thyroxine (free T4), and physical examination are recommended for survivors with a history of head and neck radiation.5
However, thyroid dysfunction is treated and followed similarly to thyroid dysfunction for others unless a central component (TSH deficiency) is suspected. If central hypothyroidism is suspected due to high dose cranial radiation exposure and inappropriate TSH level for low free T4, then these patients should be observed by keeping free T4 in mid to upper normal range, rather than relying on the TSH level.
Thyroid cancer is 2.5 times more likely in survivors of childhood cancer.2 Therefore, the presence of thyroid nodules, which is almost 4-fold more likely in survivors compared to siblings, should prompt more careful monitoring, and quicker consideration for fine needle aspiration to rule out malignancy. The risk for thyroid cancer increases with increasing radiation exposure up to 30 Gy then declines thereafter, likely due to higher chance of absolute destruction of the thyroid gland.2 Luckily, thyroid cancer in survivors due to radiation exposure is no more aggressive than that in the general population,18 and routine surveillance by thyroid examination may be sufficient based on current guidelines.5,18
Unlike radiation therapy, surgery for CNS tumors may have immediate effects on hypothalamic-pituitary function and can also affect the posterior pituitary, leading to diabetes insipidus. Diabetes insipidus is typically treated with desmopressin, unless it is partial and mild.
Radiation effects on pituitary function are both dose-dependent and age-dependent, and the risk for dysfunction increases with time. They also appear to be related to both hypothalamic and pituitary damage. Growth hormone (GH) secretion as well as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion are affected at lower doses, whereas adrenocorticotropin hormone (ACTH) and TSH secretion are relatively spared until radiation exposure exceeds 30 to 40 Gy. In contrast, diabetes insipidus almost never occurs with the radiation doses used for childhood cancer.3
GH secretion is the most vulnerable to radiation, and risk of deficiency increases at cranial exposure ≥18 Gy and TBI ≥10 Gy. In addition, the younger the age at exposure, the higher the risk for GH deficiency.3 In the past, there were concerns that GH replacement could theoretically increase the risk of recurrence of the primary neoplasm, or enhance the risk for secondary neoplasms, particularly CNS neoplasms such as meningioma. However, more recent data suggest that the enhanced risk for secondary neoplasm is due to the radiation exposure that caused the GH deficiency in the first place.19 Endocrine Society guidelines published in 2018 recommend offering GH therapy for those with proven GH deficiency who are at least 1 year in remission from their cancer.20
LH and FSH secretion effects depend on dose of radiation, gender, and age. Risk for precocious puberty or rapidly progressive puberty occurs in girls at lower doses of radiation of 18 to 24 Gy, by altering inhibitory pathways that normally suppress pubertal onset until a later age. This risk is higher at younger ages of exposure.21 However, at doses >25 to 30 Gy, LH and FSH secretion may be decreased, leading to hypogonadotropic hypogonadism and either lack of pubertal onset or lack of pubertal progression. Children may even start with rapidly progressive puberty, which then stalls.3 Early or delayed activation of the hypothalamic-pituitary-gonadal axis can be initially assessed with morning levels of gonadotropins and estradiol or testosterone using appropriate pediatric-sensitive assays. Testicular volume is not reliable as an indicator of puberty in those who have received alkylating agent therapy or testicular radiation due to preferential damage to Sertoli cells, which contribute the bulk of testicular volume.20 Precocious puberty may be halted by gonadotropin-releasing hormone (GnRH) agonist therapy for psychosocial reasons or to maximize growth potential. Hypogonadism is typically treated with hormone replacement, using estrogen and usually a progestin, or testosterone. The exact dosing and escalation depend on the age and growth potential of the child and is managed by an endocrinologist.
Central adrenal insufficiency is less common but potentially life-threatening if not diagnosed. Survivors exposed to ≥30 Gy of cranial radiation should undergo annual screening for adrenal sufficiency with an 8 am cortisol level.5 Suspicion for adrenal insufficiency should be heightened in those exposed to ≥24 Gy who are more than 10 years post-exposure or who have suggestive symptoms of adrenal insufficiency such as fatigue, weakness, poor appetite and weight loss, or symptoms suggestive of low blood pressure or hypoglycemia. Confirmatory testing may involve insulin tolerance testing or cosyntropin stimulation testing to confirm. Central adrenal insufficiency, unlike primary adrenal insufficiency, requires replacement with glucocorticoid alone, typically with hydrocortisone. Patients who are found to have adrenal insufficiency should be educated regarding the need for stress dosing of steroids and emergency identification indicating the diagnosis of adrenal insufficiency.20
Hyperprolactinemia may also be present after higher doses of radiation (≥40 Gy). Although typically asymptomatic, hyperprolactinemia should be ruled out when evaluating for hypogonadism.3,20
In addition to GH deficiency, other contributing factors to short stature include direct radiation effects, chemotherapy, malnutrition, and illness. Radiation to the spine may cause stunted vertebral growth, and CNS radiation can result in precocious or rapidly progressive puberty, causing premature epiphyseal closure. Hypogonadism due to radiation may prevent the typical pubertal growth spurt. Chemotherapeutic agents that exacerbate short stature include glucocorticoids, TKI, and retinoic acid. Indirect complications such as avascular necrosis may lead to leg length discrepancy. However, the 2018 Endocrine Society guideline on hypothalamic-pituitary disorders in survivors advises against the use of GH therapy in the absence of GH deficiency.20
Gonadal Dysfunction and Infertility
Primary hypogonadism occurs with both chemotherapy (alkylating agents) and radiation (abdominal, pelvic, testicular, spinal, or TBI) and the combination of both therapies increases the risk.21 For female survivors, exposure affects estrogen production and fertility equally, but for male survivors, the risk of infertility occurs with lower levels of chemotherapy and radiation compared with the levels needed to affect testosterone production.21,22 Because seminiferous tubule development comprises the majority of testicular volume and is more sensitive to gonadotoxic therapy, it is important to remember that in patients exposed to alkylating agents and/or testicular radiation, testicular growth is not a reliable indicator of puberty onset and may not correlate with increasing testosterone levels.20
Age of exposure also determines risk for hypogonadism after radiation therapy. For females, risk for acute ovarian insufficiency increases with pelvic radiation ≥5 Gy in pubertal girls but ≥10 Gy in pre-pubertal girls.21 Cyclophosphamide exposure between ages 13 and 20 years is another independent risk factor, particularly at a cumulative dosing of ≥7.5 g/m2. Risk increases with any dose of alkylating agent in combination with radiation. However, there are no factors that absolutely predict whether ovarian insufficiency will be transient or permanent and therefore, in the absence of symptoms, it is reasonable to delay hormone replacement for a year to see if ovarian function will return. Anti-Mullerian hormone may be useful as an indicator of ovarian reserve.21
In addition to direct ovarian damage, pelvic radiation may injure the uterus and decrease the likelihood of a successful intrauterine pregnancy, as well as negatively affect sexual function.21
For males, age of radiation exposure is inversely related to likelihood of infertility. Testicular radiation ≥3 to 6 Gy is associated with irreversible azospermia.22 Cyclophosphamide exposure ≥5 to 7.5 g/m2 may cause oligospermia and exposure >19 g/m2 is typically associated with azospermia.22 For males, Leydig cell function (testosterone production) is more likely to be affected by radiation ≥20 Gy, but increases over time with doses of ≥12 Gy.23 Unlike females, risk is greater when exposure occurs prior to puberty (≥24 G) compared with during puberty (≥30 Gy).22,23
However, there is growing recognition of the importance of fertility preservation prior to cancer therapy, when feasible. There are mixed results regarding efficacy of GnRH agonist therapy during chemotherapy in reducing gonadal toxicity. Depending on the urgency of starting therapy, survivors may have undergone procedures such as oophoropexy (ovarian transposition) or oocyte cryopreservation prior to gonadotoxic treatment.21 For pubertal males, the most effective method is sperm banking. For prepubertal males, there are no established options.23
When observing children exposed to alkylating agents and/or radiation (cranial, pelvic, testicular, spinal, or TBI), growth and puberty (Tanner staging) should be monitored yearly. Sexual function should also be assessed by asking about libido, erectile function, or vaginal dryness. Further evaluation or referral to endocrinology is recommended if no puberty has occurred by age 13 years for girls, age 14 years for boys, or if pubertal progression has halted.5
Diabetes Mellitus and Obesity
Obesity is not more prevalent in the childhood cancer survivor population overall compared with siblings. However, survivors exposed to cranial radiation ≥18 Gy are more likely to be obese than other survivors.2 Therefore, survivors with a history of cranial radiation should be screened for obesity yearly.5
Diabetes, on the other hand, is 1.8 times more likely to be present in cancer survivors compared to siblings, despite similar rates of obesity.2 Patients who have undergone stem cell transplantation may have a predilection for central adipose accumulation while overall preserving normal body mass index.24 Risk for diabetes also increases with both TBI and abdominal radiation exposure.2 For these reasons, in addition to emphasizing a healthy lifestyle, patients exposed to TBI or abdominal radiation should be screened for diabetes and dyslipidemia every 2 years after therapy is complete.5
Low Bone Mineral Density
Low bone mineral density (BMD) is more common in survivors compared to siblings. Risk factors include glucocorticoid exposure, methotrexate therapy, craniospinal irradiation or TBI, hypogonadism, GH deficiency, and calcineurin inhibitors used to prevent GvHD after stem cell transplant (SCT).5,12,15 However, according to the Childhood Cancer Survivor Study, BMD tended to normalize with time and there was no increased risk for fractures when compared to siblings among overall survivors.12,25 Nevertheless, the data were limited by the reliance on survivor recall, and certain populations appear to be at higher risk for fracture.26 In one study, 26% of children undergoing treatment for acute lymphoblastic leukemia were found to have vertebral fractures, of which 39% were asymptomatic.27 All children and adolescents should aim for adequate calcium intake (ideally through diet but with supplements if needed), vitamin D sufficiency, and weight-bearing exercise, when possible. BMD should be evaluated at baseline 2 years after completion of cancer therapy or 1 year after SCT.5,15
The breadth of chronic endocrine disorders affecting childhood cancer survivors adds a layer of complexity when transitioning health care. Recent guidelines on transition published by the American Academy of Pediatrics28 emphasize principles that include focusing on self-determination and self-management, caregiver support, early and continued preparation to transition to the adult health care model, acknowledgement of individual differences, and communication and coordination between pediatric and adult practices. The transition process includes Six Core Elements and a suggested timeline starting with introduction of a transition policy between ages 12 and 14 years, followed by tracking of transition goals, assessment of readiness, and development of a transition plan between ages 14 and 18 years. The final two elements include transfer to an adult care model or practice by age 18 to 21 years, and confirmation of transition and feedback from the young adult after transition.28
The age at which the transition process begins for children who have experienced cancer may be delayed depending on age of diagnosis and whether relapse has occurred. Barriers to transitioning survivors of childhood cancer include the complex needs of some survivors (including cognitive or developmental delay), incomplete understanding of therapy received, and the lack of awareness of the possibility of delayed complications. In addition, the survivors may face knowledge gaps in adult providers unfamiliar with the additional risks associated with cancer therapy.29
According to one small survivorship study on transition from the survivor perspective, young adults felt inadequately prepared to assume their own care, and although they are interested in independence, they simultaneously recognized the value of ongoing assistance from family in coordinating care, particularly when this involved follow-up with multiple subspecialists.30 The ideal model of transition for this population is not known and depends on the complexity of the medical history. However, in patients at risk for multiple comorbidities, long-term survivorship clinics, often located in the same hospital where care was received, facilitate transition. Access may be limited by distance, medical insurance, and the limited number of such clinics, however. At minimum, a medical summary with a timeline of specific surveillance recommendations should be provided to the patient and to the medical providers assuming care.29
The Children's Oncology Group publishes long-term follow-up guidelines periodically. These guidelines5 summarize the different disorders that survivors may develop and describe appropriate screening and surveillance based on therapy exposure. They were developed for survivors who are at least 2 years in remission from their cancer or 1 year past stem cell transplantation. Thus, they provide an invaluable resource for primary care providers and subspecialists caring for this complex population.