domingo, 7 de julio de 2019

Late Effects of Treatment for Childhood Cancer (PDQ®)—Health Professional Version - National Cancer Institute 6/10

Late Effects of Treatment for Childhood Cancer (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

Late Effects of the Endocrine System





Endocrine dysfunction is very common among childhood cancer survivors, especially those treated with surgery or radiation therapy that involves hormone-producing organs and those receiving alkylating agent chemotherapy.


ENLARGEChart showing the prevalence of endocrine disorders at the last follow-up visit by gender.
Figure 8. Prevalence of endocrine disorders at the last follow-up visit, by sex. Copyright © 2013, European Society of Endocrinology.


The prevalence of specific endocrine disorders is affected by the following:[1-3]
  • Patient factors (e.g., age at treatment and sex).
  • Treatment factors (e.g., radiation dose and treatment volume).
  • Time from radiation exposure (typically increases with longer time from radiation exposure [refer to Figure 8]).
Endocrinologic late effects can be broadly categorized as those resulting from hypothalamic/pituitary injury or from peripheral glandular compromise.[4,5] The former are most common after treatment for central nervous system (CNS) tumors, where the prevalence was reported to be 24.8% in a nationwide cohort study of 718 survivors who lived longer than 2 years and all hypothalamic/pituitary axes were effected.[3]
The following sections summarize research that characterizes the clinical features of survivors at risk of endocrine dysfunction that impacts pituitary, thyroid, adrenal, and gonadal function.


Thyroid Gland

Thyroid dysfunction is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma (HL), brain tumors, head and neck sarcomas, and acute lymphoblastic leukemia (ALL). There is considerable evidence linking radiation exposure to thyroid abnormalities, but the prevalence of specific conditions varies widely because studies are limited by cohort selection and participation bias, heterogeneity in radiation treatment approach, time since radiation exposure, and method of ascertainment (e.g., self-report vs. clinical or diagnostic imaging assessment).
Thyroid abnormalities observed in excess in childhood cancer survivors include the following:
  • Primary hypothyroidism.
  • Hyperthyroidism.
  • Goiter.
  • Nodules.

Hypothyroidism

Of children treated with radiation therapy, most develop hypothyroidism within the first 2 to 5 years posttreatment, but new cases can occur later. Reports of thyroid dysfunction differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis.[6] The most frequently reported abnormalities include:
  • Elevated thyroid-stimulating hormone (TSH).
  • Depressed thyroxine (T4).
  • Elevated TSH and depressed T4.
Compensated hypothyroidism includes an elevated TSH with a normal T4 and is asymptomatic. The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T4. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has clinical benefits for cardiovascular, gastrointestinal, and neurocognitive function.
An increased risk of hypothyroidism has been reported among childhood cancer survivors treated with head and neck radiation exposing the thyroid gland, especially among survivors of HL.
Evidence (prevalence of and risk factors for hypothyroidism):
  1. The German Group of Paediatric Radiation Oncology reported on 1,086 patients treated at 62 centers, including 404 patients (median age, 10.9 years) who received radiation therapy to the thyroid and/or pituitary gland.[7] Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values.
    • In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients treated with radiation doses of 15 Gy to 25 Gy to the thyroid gland had a hazard ratio (HR) of 3.072 (P = .002) for the development of pathologic thyroid blood values.
    • Patients treated with more than 25 Gy of radiation to the thyroid gland had an HR of 3.769 (P = .009), and patients treated with craniospinal irradiation had an HR of 5.674 (P < .001).
    • The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups.
  2. In a cohort of childhood HL survivors treated between 1970 and 1986, survivors were evaluated for thyroid disease by use of a self-report questionnaire in the Childhood Cancer Survivor Study (CCSS).[8]
    1. Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality.
    2. For hypothyroidism, there was a clear dose response (refer to Figure 9), with a 20-year risk of:
      • 20% for those who received less than 35 Gy of radiation to the thyroid gland.
      • 30% for those who received 35 Gy to 44.9 Gy of radiation to the thyroid gland.
      • 50% for those who received more than 45 Gy of radiation to the thyroid gland.
    3. Compared to a sibling control group, the relative risk (RR) was 17.1 for hypothyroidism; 8.0 for hyperthyroidism; and 27.0 for thyroid nodules.
    4. Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, with the risk increasing in the first 3 to 5 years postdiagnosis. For nodules, the risk increased beginning at 10 years postdiagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.
    ENLARGEProbability of developing hypothyroidism according to radiation dose in 5-year survivors of childhood cancer; graph shows the proportion not affected in years since diagnosis for no RT, less than 3500 cGy, 3500-4499 cGy, and ≥4500 cGy.
    Figure 9. Probability of developing hypothyroidism according to radiation dose in 5-year survivors of childhood cancer. Data from the Childhood Cancer Survivor Study. Sklar C, Whitton J, Mertens A, Stovall M, Green D, Marina N, Greffe B, Wolden S, Robison L: Abnormalities of the Thyroid in Survivors of Hodgkin's Disease: Data from the Childhood Cancer Survivor Study. The Journal of Clinical Endocrinology and Metabolism 85 (9): 3227-3232, September 1, 2000. Copyright 2000, The Endocrine Society.
  3. In a more recent report from the CCSS that compared self-reported data from 14,290 survivors with data from 4,031 sibling controls.[2]
    • The RR was 3.8 for hypothyroidism and 2.5 for hyperthyroidism; the RR for both remained significantly higher in survivors when compared with controls even in the absence of radiation therapy to the thyroid or pituitary.
    • These results indicate the need for continued and individualized long-term monitoring strategies in childhood cancer survivors.

Thyroid nodules

Any radiation field that includes the thyroid is associated with an excess risk of thyroid neoplasms, which may be benign (usually adenomas) or malignant (most often differentiated papillary carcinoma).[2,8-12] The clinical manifestation of thyroid neoplasia among childhood cancer survivors ranges from asymptomatic, small, solitary nodules to large, intrathoracic goiters that compress adjacent structures. CCSS investigators performed a nested case-control study to evaluate the magnitude of risk for thyroid cancer over the therapeutic radiation dose range of pediatric cancers. The risk of thyroid cancer increased with radiation doses up to 20 Gy to 29 Gy (odds ratio [OR], 9.8; 95% confidence interval [CI], 3.2–34.8), but declined at doses higher than 30 Gy, consistent with a cell-killing effect.[12]
The following factors are linked to an increased risk of thyroid nodule development:
  • Time from diagnosis, female sex, and radiation dose. In a study of HL survivors, CCSS investigators identified time from diagnosis, female sex, and radiation dose of 25 Gy or higher as significant risk factors for thyroid nodule development.[8] Based on a cohort of 3,254 2-year childhood cancer survivors treated before 1986 and monitored for 25 years, the risk of thyroid adenoma increased with the size of the radiation dose to the thyroid during childhood cancer treatment and plateaued at doses exceeding 10 Gy.[10]
  • Age at time of radiation therapy. Based on the same cohort of 3,254 2-year childhood cancer survivors, the risk of thyroid adenoma per unit of radiation dose to the thyroid was higher if radiation therapy had been delivered before age 5 years; the risk was also higher in individuals who were younger than 40 years at the time of the study.[10] Younger age at radiation therapy has also been linked to an excess risk of thyroid carcinoma.[9-12]
  • Exposure to iodine I 131-metaiodobenzylguanidine (131I-MIBG). During childhood and adolescence, there is an increased incidence of developing thyroid nodules, and potentially thyroid cancer, for patients exposed to 131I-MIBG. Children who have been treated with 131I-MIBG should undergo lifelong monitoring, not only for thyroid function but also for the development of thyroid nodules and thyroid cancer.[13]
  • Chemotherapy. Whereas the risk of thyroid cancer is known to be increased by exposure to radiation therapy and 131I-MIBG, an increased risk of thyroid nodules and cancer has also been observed in association with chemotherapy, independent of radiation exposure.[2,9,10]
    In a pooled study of two cohorts of 16,757 survivors that included 187 patients with secondary thyroid cancer, treatments with alkylating agents, anthracyclines, or bleomycin were associated with a significantly increased risk of thyroid cancer in individuals not exposed to radiation therapy.[14] In the CCSS, the RR of developing thyroid cancer was 2.5 (P < .01) in survivors not treated with thyroid radiation when compared with sibling controls.[2] Defining the precise role of exposure to chemotherapy and developing risk prediction models for thyroid cancer in childhood cancer survivors on the basis of demographic and treatment-related risk factors are areas of active research.[15]
Several investigations have demonstrated the superiority of ultrasound to clinical exam for detecting thyroid nodules and thyroid cancers and characterized ultrasonographic features of nodules that are more likely to be malignant.[16-18] However, primary screening for thyroid neoplasia (beyond physical exam with thyroid palpation) remains controversial because of the lack of data indicating a survival benefit and quality-of-life benefit associated with early detection and intervention. In fact, because these lesions tend to be indolent, are rarely life-threatening, and may clinically manifest many years after exposure to radiation, there are significant concerns regarding the costs and harms of overscreening.[19] Expert panels have refrained from specifically endorsing or discouraging the use of ultrasound as a screening tool for thyroid cancer and this continues to be an active area of investigation.[20] Following a systematic assessment of the evidence, the International Guideline Harmonization Group concluded that initiation of surveillance and the type of surveillance modality (thyroid palpation vs. ultrasound) should be determined by shared decision-making between the health care provider and survivor after carefully considering the benefits and harms. A decision aid to facilitate discussion accompanies their recommendations.[21]
(Refer to the Subsequent Neoplasms section of this summary for information about subsequent thyroid cancers.)

Posttransplant thyroid dysfunction

Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at increased risk of thyroid dysfunction, with the risk being much lower (15%–16%) after fractionated total-body irradiation (TBI), as opposed to single-dose TBI (46%–48%). Non–TBI-containing regimens historically were not associated with an increased risk. However, in a report from the Fred Hutchinson Cancer Research Center, the increased risk of thyroid dysfunction did not differ between children receiving a TBI-based or busulfan-based regimen (P = .48).[22] Other high-dose therapies have not been studied.
TSH deficiency (central hypothyroidism) is discussed with late effects that affect the pituitary gland.
Table 7 summarizes thyroid late effects and the related health screenings.
Table 7. Thyroid Late Effectsa
Predisposing TherapyEndocrine/Metabolic EffectsHealth Screening
131I-MIBG = Iodine I 131-metaiodobenzylguanidine; T4 = thyroxine; TSH = thyroid-stimulating hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Radiation impacting thyroid gland; thyroidectomyPrimary hypothyroidismTSH level
Radiation impacting thyroid glandHyperthyroidismFree T4 level
TSH level
Radiation impacting thyroid gland, including 131I-MIBGThyroid nodulesThyroid exam
Thyroid ultrasound

Pituitary Gland

Survivors of childhood cancer are at risk of developing a spectrum of neuroendocrine abnormalities, primarily because of the effect of radiation therapy on the hypothalamus. In addition, tumor development or surgical resection close to the hypothalamus and/or pituitary gland may induce direct anatomical damage to these structures and result in hypothalamic/pituitary dysfunction. Essentially all of the hypothalamic-pituitary axes are at risk.[4,23-25]
Although the quality of the literature regarding pituitary endocrinopathy among childhood cancer survivors is often limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment, the evidence linking this outcome with radiation therapy, surgery, and tumor infiltration is quite compelling because affected individuals typically present with metabolic and developmental abnormalities early in follow-up.

Central diabetes insipidus

Central diabetes insipidus may herald the diagnosis of craniopharyngioma, suprasellar germ cell tumor, or Langerhans cell histiocytosis.[26-28] In these conditions, diabetes insipidus may occur as an isolated pituitary deficiency, although additional pituitary hormone deficiencies may develop with tumor progression. More commonly, however, diabetes insipidus occurs in the context of panhypopituitarism caused by the presence of a tumor in close proximity to the sellar region or as a consequence of surgical procedures undertaken for local tumor control.
Central diabetes insipidus has not been reported as a late effect of cranial irradiation in childhood cancer survivors.

Anterior pituitary hormone deficiency

Deficiencies of anterior pituitary hormones and major hypothalamic regulatory factors are common late effects among survivors treated with cranial irradiation.
Evidence (prevalence of anterior pituitary hormone deficiency):
  1. In a single-institution study, 1,713 adult survivors of childhood cancers and brain tumors (median age, 32 years) were monitored for a median follow-up of 25 years.[25]
    • The prevalence of hypothalamic-pituitary axis disorders was 56.4% in individuals exposed to cranial radiation therapy at doses of 18 Gy or higher.
  2. A study of 748 childhood cancer survivors treated with cranial irradiation and observed for a mean of 27.3 years reported the following:[5]
    • The estimated point prevalence for anterior pituitary hormone deficiency was 46.5% for growth hormone deficiency, 10.8% for luteinizing/follicle stimulating hormone deficiency, 7.5% for thyroid-stimulating hormone deficiency, and 4% for adrenocorticotropin deficiency; the cumulative incidence increased with follow-up.
The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.
Table 8. Anterior Pituitary Hormones and Major Hypothalamic Regulatory Factors
Pituitary HormoneHypothalamic FactorHypothalamic Regulation of the Pituitary Hormone
(–) = inhibitory; (+) = stimulatory.
Growth hormone (GH)Growth hormone–releasing hormone+
Somatostatin–
ProlactinDopamine–
Luteinizing hormone (LH)Gonadotropin-releasing hormone+
Follicle-stimulating hormone (FSH)Gonadotropin-releasing hormone+
Thyroid-stimulating hormone (TSH)Thyroid-releasing hormone+
Somatostatin–
Adrenocorticotropin (ACTH)Corticotropin-releasing hormone+
Vasopressin+

Growth hormone deficiency

Growth hormone deficiency is the earliest hormonal deficiency associated with cranial radiation therapy in childhood cancer survivors. The risk increases with radiation dose and time since treatment. Growth hormone deficiency is sensitive to low doses of radiation. Other hormone deficiencies require higher doses, and their time to onset is much longer than for growth hormone deficiency.[29] The prevalence in pooled analysis was found to be approximately 35.6%.[30]
Growth hormone deficiency is commonly observed in these long-term survivors because of radiation doses used in the treatment of childhood brain tumors. Approximately 60% to 80% of irradiated pediatric brain tumor patients who received doses higher than 30 Gy will have impaired serum growth hormone response to provocative stimulation, usually within 5 years of treatment. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier that growth hormone deficiency will occur after treatment.
Evidence (radiation-dose response relationship of growth hormone deficiency):
  1. A study of conformal radiation therapy (CRT) in children with CNS tumors indicates that growth hormone insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects.[31]
  2. In a report featuring data from 118 patients with localized brain tumors who were treated with radiation therapy, peak growth hormone was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus.[32]
    • The average patient was predicted to develop growth hormone deficiency with the following combinations of time after CRT and mean dose to the hypothalamus: 12 months and more than 60 Gy; 36 months and 25 Gy to 30 Gy; and 60 months and 15 Gy to 20 Gy.
    • A cumulative dose of 16.1 Gy to the hypothalamus would be considered the mean radiation dose required to achieve a 50% risk of growth hormone deficiency at 5 years (TD50/5) (refer to Figure 10).
ENLARGEGraph shows peak growth hormone (in ng/mL) according to hypothalamic mean dose and time (in months) after start of irradiation.
Figure 10. Peak growth hormone (GH) according to hypothalamic mean dose and time after start of radiation. According to equation 2, peak GH = exp{2.5947 + time × [0.0019 − (0.00079 × mean dose)]}. Thomas E. Merchant, Susan R. Rose, Christina Bosley, Shengjie Wu, Xiaoping Xiong, and Robert H. Lustig, Growth Hormone Secretion After Conformal Radiation Therapy in Pediatric Patients With Localized Brain Tumors, Journal of Clinical Oncology, volume 29, issue 36, pages 4776-4780. Reprinted with permission. © (2011) American Society of Clinical Oncology. All rights reserved.
Children treated with CNS-directed therapy for leukemia are also at increased risk of growth hormone deficiency.
Evidence (risk of growth deficits in childhood ALL survivors):
  1. One study evaluated 127 patients with ALL treated with 24 Gy, 18 Gy, or no cranial radiation therapy.[33]
    • The change in height, compared with population norms expressed as the standard deviation score (SDS), was significant for all three groups, with a dose response of -0.49 ± 0.14 for the group that did not receive radiation therapy, -0.65 ± 0.15 for the group that received 18 Gy of radiation therapy, and -1.38 ± 0.16 for the group that received 24 Gy of radiation therapy.
  2. Another study found similar results in 118 ALL survivors treated with 24 Gy of cranial radiation, in which 74% had an SDS of -1 or higher and the remainder had scores of -2 or higher.[34]
  3. Survivors of childhood ALL who are treated with chemotherapy alone are also at increased risk for adult short stature, although the risk is highest for those treated with cranial and craniospinal radiation therapy at a young age.[35] In this cross-sectional study, attained adult height was determined for 2,434 ALL survivors participating in the CCSS.
    • All survivor treatment exposure groups (chemotherapy alone and chemotherapy with cranial or craniospinal radiation therapy) had decreased adult height and an increased risk of adult short stature (height SDS < -2), compared with siblings (P < .001).
    • Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (OR, 3.4; 95% CI, 1.9–6.0).
    • Among survivors, significant risk factors for short stature included diagnosis of ALL before puberty, higher-dose cranial radiation therapy (≥20 Gy vs. <20 Gy), any radiation therapy to the spine, and female sex.
  4. The impact of chemotherapy alone on growth in 67 survivors treated with contemporary regimens for ALL was statistically significant at -0.59 SD. The loss of growth potential did not correlate with growth hormone status in this study, further highlighting the participation of other factors in the growth impairments observed in this population.[36]
  5. In a longitudinal study of 372 survivors of ALL who were treated on a single-institution chemotherapy-only trial, the following was observed:[37]
    • Height z scores declined during treatment and improved after therapy.
    • Younger age at diagnosis (2 to <10 years), or low-risk ALL status, or white blood cell count below 50 × 109/L at diagnosis, or CNS-negative status were associated with significant improvements in z scores for height during the off-therapy period compared with those older at diagnosis (age ≥10 years), or with standard-risk/high-risk ALL status, or a white blood cell count of 50 × 109/L or higher, or CNS-positive status.
    • The loss in height potential in older patients was attributed to attenuation of the growth spurt during treatment without improvement after therapy and to chemotherapy intensity in patients with standard- or high-risk disease features.
Children who undergo HSCT with TBI have a significant risk of both growth hormone deficiency and the direct effects of radiation on skeletal development. The risk is increased with single-dose TBI as opposed to fractionated TBI, pretransplant cranial irradiation, female sex, and posttreatment complications such as graft-versus-host disease (GVHD).[38-40] Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial irradiation for CNS leukemia prophylaxis or therapy.[41] Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies,[40,42] but not others.[43]
Evidence (growth hormone deficiency in childhood HSCT survivors):
  1. The late effects that occur after HSCT have been studied and reviewed by the Late Effect Working Party of the European Group for Blood and Marrow Transplantation. Among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, the following results were observed:[44,45]
    • An overall decrease in final height-SDS value was found, compared with height at transplant and genetic height. The mean loss of height is estimated to be approximately 1 height-SDS (6 cm), compared with the mean height at time of HSCT and mean genetic height.
    • The type of transplantation, GVHD, and growth hormone or steroid treatment did not influence final height.
    • TBI (single-dose radiation therapy more than fractionated-dose radiation therapy), male sex, and young age at transplant were found to be major factors for long-term height loss. Most patients (140 of 181) reached adult height within the normal range of the general population.
Growth hormone deficiency replacement therapy
Growth hormone deficiency replacement therapy provides the benefit of optimizing height outcomes among children who have not reached skeletal maturity. Treatment with recombinant growth hormone (rGH) replacement therapy is generally delayed until 12 months after successful completion of cancer or brain tumor treatments and after a multidisciplinary discussion involving the prescribing pediatric endocrinologist, the primary oncologist, and other providers selected by the patient or family.[46] Safety concerns pertaining to the use of rGH in childhood cancer survivors have primarily been related to the mitogenic potential of the growth hormone stimulating tumor growth in a population with an increased risk of second neoplasms.[47] Most studies that report these outcomes, however, are limited by selection bias and small sample size.
The following study results have been reported in survivors who did or did not receive treatment with growth hormone.
Evidence (growth hormone deficiency replacement therapy):
  1. One study evaluated 361 growth hormone-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of subsequent neoplasm, and risk of death among survivors who did and did not receive treatment with growth hormone.[48]
    • The RR of disease recurrence was 0.83 (95% CI, 0.37–1.86) for growth hormone-treated survivors. Growth hormone-treated subjects were diagnosed with 15 subsequent neoplasms, all solid tumors, for an overall RR of 3.21 (95% CI, 1.88–5.46), mainly because of a small excess number of subsequent neoplasms observed in survivors of acute leukemia.[48] With prolonged follow-up, the elevation of subsequent cancer risk resulting from growth hormone diminished.[49]
    • Compared with survivors not treated with growth hormone, those who were treated had a twofold excess risk of developing a subsequent neoplasm (RR, 2.15; 95% CI, 1.33–3.47; P < .002); meningiomas were the most commonly observed neoplasms (9 of 20 tumors).[48]
  2. A review of existing data suggests that treatment with growth hormone is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia.[50]
  3. A study from the CCSS reported specifically on the risk of subsequent CNS neoplasms after a longer period of follow-up.[51]
    • The adjusted rate ratio of meningioma and gliomas in growth hormone-treated survivors of CNS tumors was 1.0 (95% CI, 0.6–1.8; P = .94) when compared with CNS tumor survivors who were not treated with growth hormone, thus indicating negligible differences between the two groups for this particular risk.
In general, the data addressing subsequent malignancies should be interpreted with caution given the small number of events.[46-48]

Disorders of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

Pubertal development can be adversely affected by cranial radiation therapy. Doses higher than 18 Gy can result in central precocious puberty, while doses higher than 30 Gy to 40 Gy may result in LH and FSH deficiency.[52]
Central precocious puberty
Central precocious puberty is defined by the onset of pubertal development before age 8 years in girls and 9 years in boys as a result of the premature activation of the hypothalamic-pituitary-gonadal axis. Aside from the adjustment and psychosocial challenges associated with early pubertal development, precocious puberty can lead to the rapid closure of the skeletal growth plates and short stature. This deleterious effect can be further potentiated by growth hormone deficiency.[53,54] The increased growth velocity induced by pubertal development can mask concurrent growth hormone deficiency with seemingly normal growth velocity; this occurrence may mislead care providers. It is also important to note that the assessment of puberty cannot be performed using testicular volume measurements in boys exposed to chemotherapy or direct radiation to the testes, given the toxic effect of these treatments on germ cells and repercussions on gonadal size. The staging of puberty in males within this population relies on the presence of other signs of virilization, such as the presence of pubic hair and the measurement of plasma testosterone levels.[53]
Children who have tumors that grow near the hypothalamus/pituitary or optic pathways (including those with neurofibromatosis type 1) have the highest risk of developing central precocious puberty.[54,55] Hydrocephalus also seems to increase the risk of this complication.[55] Central precocious puberty has been reported in some children receiving cranial irradiation in doses of 18 Gy or higher.[54,56,57] The impact of central precocious puberty on linear growth can be ascertained by assessing the degree of skeletal maturation (or bone age) using an x-ray of the left hand.[58]
When appropriate, delaying the progression of puberty relies on the use of various gonadotropin-releasing hormone agonist preparations, an approach that has been shown to improve growth prospects—especially when other pituitary abnormalities, including growth hormone deficiency, are concurrently treated.[59]
LH/FSH deficiency
LH/FSH deficiency (also referred to as hypogonadotropic hypogonadism) can manifest through pubertal delay, arrested puberty, or symptoms of decreased sex hormone production, depending on age and pubertal status at the time of diagnosis. The risk of LH/FSH deficiency is highest among patients treated with cranial radiation at doses greater than or equal to 30 Gy; LH/FSH deficiency following the exposure to lower doses can occur at delayed time points.[5] With higher doses of cranial radiation therapy (>35 Gy), deficiencies in LH/FSH can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment.[60,61]
The treatment of LH/FSH deficiency relies on sex-hormone replacement therapy adjusted to age and pubertal status.

TSH deficiency

TSH deficiency (also referred to as central hypothyroidism) in survivors of childhood cancer can have profound clinical consequences and be underappreciated. Symptoms of central hypothyroidism (e.g., asthenia, edema, drowsiness, and skin dryness) may have a gradual onset and go unrecognized until thyroid replacement therapy is initiated. In addition to delayed puberty and slow growth, hypothyroidism may cause fatigue, dry skin, constipation, increased sleep requirement, and cold intolerance. Individuals with TSH deficiency have low plasma free T4 levels and either low or inappropriately normal TSH levels.
The risk of TSH deficiency is highest among patients treated with cranial radiation at doses of 30 Gy or higher; TSH deficiency following the exposure to lower doses can occur at delayed time points.[5] Radiation dose to the hypothalamus in excess of 42 Gy is associated with an increased risk of developing TSH deficiency (44% ± 19% for dose of ≥42 Gy and 11% ± 8% for dose of <42 Gy).[62] It occurs in as many as 65% of survivors of brain tumors, 43% of survivors of childhood nasopharyngeal tumors, 35% of bone marrow transplant recipients, and 10% to 15% of leukemia survivors.[63,64]
Mixed primary and central hypothyroidism can also occur and reflects separate injuries to the thyroid gland and the hypothalamus (e.g., radiation injury to both structures). TSH values may be elevated and, in addition, the secretory dynamics of TSH are abnormal, with a blunted or absent TSH surge or a delayed peak response to TSH-releasing hormone (TRH).[65] In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 patients (7%).[65] Among patients who received TBI (fractionated total doses of 12–14.4 Gy) or craniospinal radiation therapy (fractionated total cranial doses higher than 30 Gy), 15% had mixed hypothyroidism. In one study of 32 children treated for medulloblastoma, 56% developed hypothyroidism, including 38% with primary hypothyroidism and 19% with central hypothyroidism.[66] In 189 children and young adults (aged <26 years) with brain tumors who were treated with proton radiation therapy, the actuarial rate of hypothyroidism was 20.1%, with 90% central TSH deficiency. This is concordant with previous studies.[62] However, the cumulative incidence of primary hypothyroidism was 3% after craniospinal irradiation and 1.6% overall and is substantially lower than previous reports of 56% to 65% incidence after craniospinal irradiation with photons.[62,66,67]
Thyroid hormone replacement therapy using levothyroxine represents the mainstay of treatment of TSH deficiency. The dose of levothyroxine needs to be adjusted solely using plasma free T4 levels; the levels of TSH are expected to remain low during therapy, given the central nature of this deficiency.

Adrenal-corticotropin (ACTH) deficiency

ACTH deficiency is less common than other neuroendocrine deficits but should be suspected in patients who have a history of brain tumor (regardless of therapy modality), cranial radiation therapy, growth hormone deficiency, or central hypothyroidism.[29,62,68-70] Although uncommon, ACTH deficiency can occur in patients treated with intracranial radiation doses of less than 24 Gy and has been reported to occur in fewer than 3% of patients after chemotherapy alone.[70]
The diagnosis should be suspected when low plasma levels of morning cortisol are measured (a screening cortisol level collected at 8 a.m. that is 10 µg/dL or more is reassuring for ACTH sufficiency, whereas a value of 5 µg/dL or lower is suspicious for insufficiency). Confirmation is necessary using dynamic testing such as the low-dose ACTH stimulation test.[69] Because of the substantial risk of central adrenal insufficiency among survivors treated with cranial radiation doses exceeding 30 Gy to the hypothalamic-pituitary axis, endocrine monitoring with periodic dynamic testing as clinically indicated is recommended for this high-risk group.
Patients with partial ACTH deficiency may have only subtle symptoms unless they become ill. Illness can disrupt these patients’ usual homeostasis and cause a more severe, prolonged, or complicated course than expected. As in complete ACTH deficiency, incomplete or unrecognized ACTH deficiency can be life-threatening during concurrent illness.
The treatment of ACTH deficiency relies on replacement with hydrocortisone, including stress dosing in situations of illness to adjust to the body’s physiologically increased need for glucocorticoids.

Hyperprolactinemia

Hyperprolactinemia has been described in patients who received radiation therapy to the hypothalamus in doses higher than 50 Gy or who underwent surgery that disrupted the integrity of the pituitary stalk. Primary hypothyroidism may lead to hyperprolactinemia as a result of hyperplasia of thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. The prolactin response to TRH is usually exaggerated in these patients.[29,71]
In general, hyperprolactinemia may result in delayed puberty, galactorrhea, menstrual irregularities, loss of libido, hot flashes, infertility, and osteopenia. However, hyperprolactinemia resulting from cranial radiation therapy is rarely symptomatic and is frequently associated with hypogonadism (both central and primary).
Hyperprolactinemia rarely requires treatment.
Table 9 summarizes pituitary gland late effects and the related health screenings.
Table 9. Pituitary Gland Late Effectsa
Predisposing TherapyEndocrine/Metabolic EffectsHealth Screening
BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone; T4 = thyroxine; TSH = thyroid-stimulating hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
bTesticular volume measurements are not reliable in the assessment of pubertal development in boys exposed to chemotherapy or direct radiation to the testes.
cAppropriate only at diagnosis. TSH levels are not useful for follow-up during replacement therapy.
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis.Growth hormone deficiencyAssessment of nutritional status
Height, weight, BMI, Tanner stageb
Tumor or surgery affecting hypothalamus/pituitary or optic pathways; hydrocephalus. Radiation impacting hypothalamic-pituitary axis.Precocious pubertyHeight, weight, BMI, Tanner stageb
FSH, LH, estradiol, or testosterone levels
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis.Gonadotropin deficiencyHistory: puberty, sexual function
Exam: Tanner stageb
FSH, LH, estradiol or testosterone levels
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis.Central adrenal insufficiencyHistory: failure to thrive, anorexia, episodic dehydration, hypoglycemia, lethargy, unexplained hypotension
Endocrine consultation for those with radiation dose ≥30 Gy
Radiation impacting hypothalamic-pituitary axis.HyperprolactinemiaHistory/exam: galactorrhea
Prolactin level
Radiation impacting hypothalamic-pituitary axis.Overweight/obesityHeight, weight, BMI
Blood pressure
Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism)Fasting blood glucose level and lipid profile
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis.Central hypothyroidismTSHc free thyroxine (free T4) level

Testis and Ovary

Testicular and ovarian hormonal functions are discussed in the Late Effects of the Reproductive System section of this summary.

Metabolic Syndrome

An increased risk of metabolic syndrome or its components has been observed among cancer survivors. The evidence for this outcome ranges from clinically manifested conditions that are self-reported by survivors to retrospectively assessed data in medical records and hospital registries to systematic clinical evaluations of clinically well-characterized cohorts. Studies have been limited by cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment. Despite these limitations, compelling evidence indicates that metabolic syndrome is highly associated with cardiovascular events and mortality.
Definitions of metabolic syndrome are evolving but generally include a combination of central (abdominal) obesity with at least two of the following features:
  • Hypertension.
  • Atherogenic dyslipidemia (elevated triglycerides, reduced high-density lipoprotein [HDL] cholesterol).
  • Abnormal glucose metabolism (fasting hyperglycemia, hyperinsulinism, insulin resistance, diabetes mellitus type 2).[72]
Evidence (prevalence of and risk factors for metabolic syndrome in childhood cancer survivors):
  1. A study monitored 784 long-term childhood ALL survivors (median age, 31.7 years) for a median follow-up of 26.1 years.[73]
    • The prevalence of metabolic syndrome was 33.6%, which was significantly higher than that in a cohort of age-, sex-, and race-matched controls (n = 777) from the National Health and Nutrition Examination Survey (RR, 1.43; 95% CI, 1.22–1.69).
    • Risk factors associated with metabolic syndrome in this study included older age and past exposures to cranial radiation therapy.
    • Components of metabolic syndrome with significantly higher prevalence in ALL survivors than in controls included obesity, insulin resistance, hypertension, and decreased HDL levels.
  2. French investigators evaluated the overall and age-specific prevalence of and risk factors for metabolic syndrome and its components among 650 adult survivors of childhood leukemia treated without hematopoietic stem cell transplantation.[74]
    1. The overall prevalence of the condition was 6.9%, with the following age-specific cumulative prevalence:
      • 20 years—1.3%.
      • 25 years—6.1%.
      • 30 years—10.8%.
      • 35 years—22.4%.
    2. The prevalence of individual components of the metabolic syndrome was as follows:
      • Increased fasting glucose—5.8%.
      • Increased triglycerides—11.7%.
      • Increased abdominal circumference—16.7%.
      • Decreased high-density lipoprotein cholesterol—26.8%.
      • Increased blood pressure—36.7%.
    3. Clinical factors significantly predicting the risk of metabolic syndrome included male sex (OR, 2.64; 95% CI, 1.32–5.29), age at last evaluation (OR, 1.10; 95% CI, 1.04–1.17) and body mass index (BMI) at diagnosis (OR, 1.15; 95% CI, 1.01–1.32), but not cumulative steroid dose. Irradiated and nonirradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in nonirradiated patients.
  3. Abdominal irradiation is an additional risk factor for metabolic syndrome. Survivors of developmental or embryonal tumors treated with abdominal irradiation are also at an increased risk of developing components of metabolic syndrome. In a prospective study of 164 long-term survivors (median follow-up, 26 years), nephroblastoma (OR, 5.2) and neuroblastoma (OR, 6.5) survivors had more components of metabolic syndrome than did controls.[75]
    • Compared with nonirradiated survivors, survivors treated with abdominal irradiation had higher blood pressure, triglycerides, low-density lipoprotein (LDL) cholesterol, and total fat percentage, which were assessed by dual-energy x-ray absorptiometry.
Long-term survivors of ALL, especially those treated with cranial radiation therapy, may have a higher prevalence of some potentially modifiable risk factors for cardiovascular disease such as impaired glucose tolerance or overt diabetes mellitus, dyslipidemia, hypertension, and obesity.[73,76-81] The contribution of modifiable risk factors associated with metabolic syndrome to the risk of major cardiac events suggests that survivors are good candidates for targeted screening and lifestyle counseling regarding risk-reduction measures.[82]
Several studies have provided support for the potential benefits of lifestyle modifications in reducing cardiovascular disease risk.
Evidence (lifestyle modifications to reduce cardiovascular risk in childhood cancer survivors):
  1. Survivors participating in the St. Jude Lifetime Cohort Study who were adherent to a heart-healthy lifestyle had a lower risk of metabolic syndrome. Females (RR, 2.4; 95% CI, 1.7–3.3) and males (RR, 2.2; 95% CI, 1.6–3.0) in the cohort who did not follow recommended dietary and physical activity guidelines had a more than twofold excess risk of having clinical features of the metabolic syndrome.[83]
  2. A CCSS investigation evaluated the impact of exercise on cardiovascular disease risk among survivors of HL.[84]
    • Vigorous exercise was associated with a lower risk of cardiovascular events in a dose-dependent manner, independent of cardiovascular risk profile and treatment.
    • Survivors who were adherent to national vigorous-intensity exercise guidelines had a 51% reduction in the risk of any cardiovascular event compared with those not meeting the guidelines.
  3. Another CCSS investigation evaluated the association of exercise with mortality in adult survivors of childhood cancer.[85]
    • After adjusting for chronic health conditions and treatment exposures, all-cause mortality was inversely associated with survivor-reported exercise quartiles (0, 3–6, 9–12, and 15–21 metabolic equivalent task [MET] hours/week).
    • Survivors who endorsed recommended levels of vigorous exercise (≥9 MET hours/week) in early adulthood and those who increased exercise over 8 years had a lower risk of mortality.

Abnormal glucose metabolism

Abdominal radiation therapy and TBI are increasingly recognized as independent risk factors for diabetes mellitus in childhood cancer survivors.[2,75,77,81,86-90]
Evidence (risk factors for diabetes mellitus in childhood cancer survivors):
  1. A single-center cohort study of 532 long-term (median follow-up, 17.9 years) adult (median age, 25.6 years) survivors observed the following:[88]
    • Treatment, but not genetic variation, was strongly associated with the occurrence of the components of metabolic syndrome.
    • Metabolic syndrome was more frequent in cranially (23.3%, P = .002) and abdominally (23.4%, P = .009) irradiated survivors than in nonirradiated survivors (10.0%).
  2. A cross-sectional study evaluated cardiovascular risk factors and insulin resistance in a clinically heterogeneous cohort of 319 childhood cancer survivors 5 or more years since diagnosis and 208 sibling controls.[91]
    • Insulin resistance was significantly higher in survivors treated with cisplatin plus cranial irradiation (92% brain tumors) and in those who received steroids but no cisplatin (most leukemia survivors), compared with siblings.
    • Insulin resistance did not differ between survivors treated with surgery alone and siblings.
    • Among survivors, analysis of individual chemotherapy agents failed to find associations with cardiovascular risk factors or insulin resistance. However, compared with siblings, nearly all chemotherapeutic agents, when examined individually, seemed to be associated with a high cardiovascular risk profile, characterized by lower total lean body mass, higher percentage fat mass, and insulin resistance.
  3. In a European multicenter cohort of 2,520 childhood cancer survivors (median follow-up, 28 years), significant associations were found between diabetes mellitus and increasing doses of radiation therapy to the tail of the pancreas. These data support the contribution of radiation-induced islet cell injury to impairments of glucose homeostasis in this population.[89]
  4. A report from the CCSS compared 8,599 childhood cancer survivors with 2,936 randomly selected sibling controls, and adjusted for age, BMI, and several demographic factors.[92]
    • The risk of diabetes mellitus was 1.8 times higher in survivors (95% CI, 1.3–2.5; P < .001).
    • Significant associations were found between diabetes mellitus and young age at diagnosis (0–4 years), the use of alkylating agents and abdominal radiation therapy or TBI.
    • Survivors were significantly more likely to be receiving medication for hypertension, dyslipidemia, and/or diabetes mellitus than were sibling controls.
Table 10 summarizes metabolic syndrome late effects and the related health screenings.
Table 10. Metabolic Syndrome Late Effectsa
Predisposing TherapyPotential Late EffectsHealth Screening
BMI = body mass index.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Abdominal irradiation. Total-body irradiation.Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism)Height, weight, BMI, blood pressure
Labs: fasting glucose and lipids

Body Composition: Underweight, Overweight, and Obesity

Childhood cancer survivors are at risk of experiencing abnormal body composition, which includes being underweight (BMI, <18.5), overweight (BMI, >25.0 to BMI, <30.0), or obese (BMI, ≥30.0). BMI at diagnosis has been identified as a significant predictor of being underweight or overweight at follow-up, suggesting that genetic or environmental factors contribute to the development or persistence of abnormal body composition.[93,94]
CCSS investigators identified treatment-related risk factors for being underweight, including TBI (females) or abdominal irradiation (males), use of alkylating agents, and use of anthracyclines.[94] Among a cohort of 893 Dutch childhood cancer survivors monitored for a median of almost 15 years, being underweight was linked to a high prevalence of moderate to extreme adverse health statuses and reports of a major medical condition.[93]
To date, cancer patients with an increased incidence of being overweight and obese are primarily ALL [93,95-101] and CNS tumor [4,23] survivors who were treated with cranial radiation therapy.[94,102] The development of obesity after cranial radiation therapy is multifactorial and includes the following:[98,103,104]
  • Growth hormone deficiency.
  • Leptin sensitivity.
  • Reduced levels of physical activity and energy expenditure.
The cumulative glucocorticoid dose received during therapy does not affect the risk of long-term childhood cancer survivors being overweight, as investigated in Swiss childhood cancer survivors with ALL, non-Hodgkin lymphoma, and Hodgkin lymphoma. In a study of 1,936 childhood cancer survivors surveyed at a median of 17 years from diagnosis and compared with siblings and the general population, there was no evidence of a relationship between cumulative glucocorticoid dose and being overweight. Additionally, there was no evidence that the use of cranial radiation therapy modified the effect of the cumulative glucocorticoid dose on being overweight.[105]
Also, craniopharyngioma survivors have a substantially increased risk of extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection.[106-111]
In addition to treatment factors, lifestyle factors and medication use can also contribute to the risk of obesity. CCSS investigators reported the following independent risk factors for obesity in childhood cancer survivors:[112]
  • Cancer diagnosed at ages 5 to 9 years (RR, 1.12; 95% CI, 1.01–1.24).
  • Abnormal physical functioning (RR, 1.19; 95% CI, 1.06–1.33).
  • Hypothalamic/pituitary radiation dose of 20 Gy to 30 Gy (RR, 1.17; 95% CI, 1.05–1.3; P = .01).
  • Specific antidepressant use (paroxetine) (RR, 1.29; 95% CI, 1.08–1.54).
Survivors who adhered to the U.S. Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82–0.97; P = .01) and who had a medium amount of anxiety (RR, 0.86; 95% CI, 0.75–0.99; P = .04) had a lower risk of obesity.[112]

Body composition alterations after childhood ALL

Moderate-dose cranial radiation therapy (18–24 Gy) among ALL survivors is associated with obesity, particularly in females treated at a young age.[78,96,98,113] Female adult survivors of childhood ALL who were treated with cranial radiation therapy of 24 Gy before age 5 years are four times more likely to be obese than are women who have not been treated for a cancer.[96] In addition, women treated with 18 Gy to 24 Gy cranial radiation therapy before age 10 years have a substantially greater rate of increase in their BMI through their young adult years than do women who were treated for ALL with only chemotherapy or women in the general population.[98] It appears that these women also have a significantly increased visceral adiposity and associated insulin resistance.[114,115]
These outcomes are attenuated in males. However, a study of long-term male survivors of ALL (mean age, 29 years) observed significantly higher body adiposity than in age-matched controls, despite normal weight and BMI. Potential indicators of increased adiposity included high leptin and low sex hormone–binding globulin levels. Serum testicular endocrine markers (testosterone, FSH, or inhibin B) did not correlate with body adiposity.[116]
ALL therapy regimens are associated with increases in BMI shortly after completion of therapy, and possibly with a higher risk of obesity in the long term.[99-101,117,118] Several studies have reported that survivors of childhood ALL treated with chemotherapy alone also exhibit long-term changes in body composition, with relative increases in body fat [115,119-121] and visceral adiposity in comparison to lean mass.[114] These changes cannot be detected if BMI alone is used in the assessment of metabolic risk in this population.
Evidence (body composition changes in adult survivors of childhood ALL):
  1. A cohort study of 365 adult survivors of ALL (149 treated with cranial radiation therapy and 216 treated without cranial radiation therapy) compared body composition, energy balance, and fitness with age-, sex-, and race-matched peers.[122]
    • Female survivors who were not exposed to cranial irradiation had comparable body composition values to that of peers. However, waist circumference, waist-to-height ratio, and total and percent fat mass were higher among male survivors and cranial radiation–exposed female survivors than among comparison group members.
    • Survivors of both sexes exposed to cranial radiation therapy had higher BMI and percent body fat than did survivors not exposed to cranial radiation therapy.
    • Although survivors who did not receive cranial radiation therapy had energy balance similar to the matched peer group, they had significantly higher measures of impaired fitness (impaired flexibility, peripheral sensorimotor deficits, proximal muscle weakness, and poor exercise tolerance).
    • These results suggest that elimination of cranial radiation from ALL therapy has improved, but not eliminated, adverse body composition outcomes and underscores the importance of attention to interventions to preserve function in this group as they age.
  2. In contrast, in a report from the CCSS, adult survivors of childhood ALL treated with chemotherapy alone did not have significantly higher rates of obesity than did sibling controls,[96] nor were there differences in BMI changes between these groups after a subsequent period of follow-up that averaged 7.8 years.[98]
Results from the CCSS, however, were based on self-reported height and weight measurements. Likewise, Children’s Oncology Group investigators also did not observe an increased risk of being overweight and obese based on BMI measurements in 269 patients with standard-risk ALL (age, 3.5 years at diagnosis and 13.3 years at follow-up) compared with peers without cancer. Again, these variable outcomes likely relate to the use of BMI as the metric for abnormal body composition, which does not adequately assess visceral adiposity that can contribute to metabolic risk in this population.[123]

Body composition alterations after treatment for CNS tumors

Among brain tumor survivors treated with higher doses of cranial radiation therapy, only females treated at a younger age appear to be at increased risk for obesity.[124]

Body composition alterations after hematopoietic cell transplantation

Survivors of childhood cancer treated with TBI in preparation for an allogeneic HSCT have increased measures of body fatness (percent fat) while often having a normal BMI.[86,90,125,126] Longitudinal decline in BMI related to substantial decrease in lean mass has been observed among survivors of hematological malignancies treated with allogeneic HSCT. This finding was largely attributable to TBI conditioning and severity of chronic GVHD.[127]

Body composition and frailty

Young adult childhood cancer survivors have a higher-than-expected prevalence of frailty, a phenotype characterized by low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Individuals are termed prefrail if they have two of these five characteristics and frail if they have three or more of these characteristics. The frailty phenotype increases in prevalence with aging, and has been associated with excess risk of mortality and onset of chronic conditions.[128] Ongoing research aims to elucidate the pathophysiology of frailty and develop/test interventions to prevent or reverse this condition.
Table 11 summarizes body composition late effects and the related health screenings.
Table 11. Body Composition Late Effectsa
Predisposing TherapyPotential Late EffectsHealth Screening
BMI = body mass index.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Cranial radiation therapyOverweight/obesityHeight, weight, BMI, blood pressure
Labs: fasting glucose and lipids
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for endocrine and metabolic syndrome late effects information, including risk factors, evaluation, and health counseling.

Endocrine Effects in Survivors of Cancer in Adolescence and Young Adulthood

In one of the first studies of late effects in survivors of adolescent and young adult (AYA) cancers, based on 32,548 AYA 1-year cancer survivors from the Danish Patient Registry, investigators found that AYA cancer survivors are at 73% higher risk of developing endocrine disease than are the general population. The dominating endocrine diseases are thyroid diseases, testicular dysfunction, and diabetes, which reflect the most common cancers in the AYA population and treatment during the time period of 1975 to 2009. This study highlights the importance of counseling and monitoring of AYA cancer survivors to guide future preventive measures.[129]


References
  1. Brignardello E, Felicetti F, Castiglione A, et al.: Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. Eur J Endocrinol 168 (3): 465-72, 2013. [PUBMED Abstract]
  2. Mostoufi-Moab S, Seidel K, Leisenring WM, et al.: Endocrine Abnormalities in Aging Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 34 (27): 3240-7, 2016. [PUBMED Abstract]
  3. Clement SC, Schouten-van Meeteren AY, Boot AM, et al.: Prevalence and Risk Factors of Early Endocrine Disorders in Childhood Brain Tumor Survivors: A Nationwide, Multicenter Study. J Clin Oncol 34 (36): 4362-4370, 2016. [PUBMED Abstract]
  4. Constine LS, Woolf PD, Cann D, et al.: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328 (2): 87-94, 1993. [PUBMED Abstract]
  5. Chemaitilly W, Li Z, Huang S, et al.: Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study. J Clin Oncol 33 (5): 492-500, 2015. [PUBMED Abstract]
  6. Gleeson HK, Darzy K, Shalet SM: Late endocrine, metabolic and skeletal sequelae following treatment of childhood cancer. Best Pract Res Clin Endocrinol Metab 16 (2): 335-48, 2002. [PUBMED Abstract]
  7. Bölling T, Geisenheiser A, Pape H, et al.: Hypothyroidism after head-and-neck radiotherapy in children and adolescents: preliminary results of the "Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence" (RiSK). Int J Radiat Oncol Biol Phys 81 (5): e787-91, 2011. [PUBMED Abstract]
  8. Sklar C, Whitton J, Mertens A, et al.: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85 (9): 3227-32, 2000. [PUBMED Abstract]
  9. Bhatti P, Veiga LH, Ronckers CM, et al.: Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 174 (6): 741-52, 2010. [PUBMED Abstract]
  10. Haddy N, El-Fayech C, Guibout C, et al.: Thyroid adenomas after solid cancer in childhood. Int J Radiat Oncol Biol Phys 84 (2): e209-15, 2012. [PUBMED Abstract]
  11. Ronckers CM, Sigurdson AJ, Stovall M, et al.: Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers. Radiat Res 166 (4): 618-28, 2006. [PUBMED Abstract]
  12. Sigurdson AJ, Ronckers CM, Mertens AC, et al.: Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 365 (9476): 2014-23, 2005 Jun 11-17. [PUBMED Abstract]
  13. van Santen HM, Tytgat GA, van de Wetering MD, et al.: Differentiated thyroid carcinoma after 131I-MIBG treatment for neuroblastoma during childhood: description of the first two cases. Thyroid 22 (6): 643-6, 2012. [PUBMED Abstract]
  14. Veiga LH, Lubin JH, Anderson H, et al.: A pooled analysis of thyroid cancer incidence following radiotherapy for childhood cancer. Radiat Res 178 (4): 365-76, 2012. [PUBMED Abstract]
  15. Kovalchik SA, Ronckers CM, Veiga LH, et al.: Absolute risk prediction of second primary thyroid cancer among 5-year survivors of childhood cancer. J Clin Oncol 31 (1): 119-27, 2013. [PUBMED Abstract]
  16. Vivanco M, Dalle JH, Alberti C, et al.: Malignant and benign thyroid nodules after total body irradiation preceding hematopoietic cell transplantation during childhood. Eur J Endocrinol 167 (2): 225-33, 2012. [PUBMED Abstract]
  17. Li Z, Franklin J, Zelcer S, et al.: Ultrasound surveillance for thyroid malignancies in survivors of childhood cancer following radiotherapy: a single institutional experience. Thyroid 24 (12): 1796-805, 2014. [PUBMED Abstract]
  18. Brignardello E, Felicetti F, Castiglione A, et al.: Ultrasound surveillance for radiation-induced thyroid carcinoma in adult survivors of childhood cancer. Eur J Cancer 55: 74-80, 2016. [PUBMED Abstract]
  19. Metzger ML, Howard SC, Hudson MM, et al.: Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma. Pediatr Blood Cancer 46 (3): 314-9, 2006. [PUBMED Abstract]
  20. Francis GL, Waguespack SG, Bauer AJ, et al.: Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 25 (7): 716-59, 2015. [PUBMED Abstract]
  21. Clement SC, Kremer LCM, Verburg FA, et al.: Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 63: 28-39, 2018. [PUBMED Abstract]
  22. Sanders JE, Hoffmeister PA, Woolfrey AE, et al.: Thyroid function following hematopoietic cell transplantation in children: 30 years' experience. Blood 113 (2): 306-8, 2009. [PUBMED Abstract]
  23. Gurney JG, Kadan-Lottick NS, Packer RJ, et al.: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer 97 (3): 663-73, 2003. [PUBMED Abstract]
  24. Sklar CA: Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am 44 (2): 489-503, 1997. [PUBMED Abstract]
  25. Hudson MM, Ness KK, Gurney JG, et al.: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309 (22): 2371-81, 2013. [PUBMED Abstract]
  26. Ramelli GP, von der Weid N, Stanga Z, et al.: Suprasellar germinomas in childhood and adolescence: diagnostic pitfalls. J Pediatr Endocrinol Metab 11 (6): 693-7, 1998 Nov-Dec. [PUBMED Abstract]
  27. Vinchon M, Baroncini M, Leblond P, et al.: Morbidity and tumor-related mortality among adult survivors of pediatric brain tumors: a review. Childs Nerv Syst 27 (5): 697-704, 2011. [PUBMED Abstract]
  28. Fahrner B, Prosch H, Minkov M, et al.: Long-term outcome of hypothalamic pituitary tumors in Langerhans cell histiocytosis. Pediatr Blood Cancer 58 (4): 606-10, 2012. [PUBMED Abstract]
  29. Darzy KH, Shalet SM: Hypopituitarism following radiotherapy. Pituitary 12 (1): 40-50, 2009. [PUBMED Abstract]
  30. Mulder RL, Kremer LC, van Santen HM, et al.: Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: a systematic review. Cancer Treat Rev 35 (7): 616-32, 2009. [PUBMED Abstract]
  31. Merchant TE, Goloubeva O, Pritchard DL, et al.: Radiation dose-volume effects on growth hormone secretion. Int J Radiat Oncol Biol Phys 52 (5): 1264-70, 2002. [PUBMED Abstract]
  32. Merchant TE, Rose SR, Bosley C, et al.: Growth hormone secretion after conformal radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol 29 (36): 4776-80, 2011. [PUBMED Abstract]
  33. Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 123 (1): 59-64, 1993. [PUBMED Abstract]
  34. Schriock EA, Schell MJ, Carter M, et al.: Abnormal growth patterns and adult short stature in 115 long-term survivors of childhood leukemia. J Clin Oncol 9 (3): 400-5, 1991. [PUBMED Abstract]
  35. Chow EJ, Friedman DL, Yasui Y, et al.: Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr 150 (4): 370-5, 375.e1, 2007. [PUBMED Abstract]
  36. Vandecruys E, Dhooge C, Craen M, et al.: Longitudinal linear growth and final height is impaired in childhood acute lymphoblastic leukemia survivors after treatment without cranial irradiation. J Pediatr 163 (1): 268-73, 2013. [PUBMED Abstract]
  37. Browne EK, Zhou Y, Chemaitilly W, et al.: Changes in body mass index, height, and weight in children during and after therapy for acute lymphoblastic leukemia. Cancer 124 (21): 4248-4259, 2018. [PUBMED Abstract]
  38. Ogilvy-Stuart AL, Clark DJ, Wallace WH, et al.: Endocrine deficit after fractionated total body irradiation. Arch Dis Child 67 (9): 1107-10, 1992. [PUBMED Abstract]
  39. Willi SM, Cooke K, Goldwein J, et al.: Growth in children after bone marrow transplantation for advanced neuroblastoma compared with growth after transplantation for leukemia or aplastic anemia. J Pediatr 120 (5): 726-32, 1992. [PUBMED Abstract]
  40. Wingard JR, Plotnick LP, Freemer CS, et al.: Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation. Blood 79 (4): 1068-73, 1992. [PUBMED Abstract]
  41. Huma Z, Boulad F, Black P, et al.: Growth in children after bone marrow transplantation for acute leukemia. Blood 86 (2): 819-24, 1995. [PUBMED Abstract]
  42. Bernard F, Bordigoni P, Simeoni MC, et al.: Height growth during adolescence and final height after haematopoietic SCT for childhood acute leukaemia: the impact of a conditioning regimen with BU or TBI. Bone Marrow Transplant 43 (8): 637-42, 2009. [PUBMED Abstract]
  43. Chemaitilly W, Sklar CA: Endocrine complications of hematopoietic stem cell transplantation. Endocrinol Metab Clin North Am 36 (4): 983-98; ix, 2007. [PUBMED Abstract]
  44. Socié G, Salooja N, Cohen A, et al.: Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101 (9): 3373-85, 2003. [PUBMED Abstract]
  45. Cohen A, Rovelli A, Bakker B, et al.: Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood 93 (12): 4109-15, 1999. [PUBMED Abstract]
  46. Raman S, Grimberg A, Waguespack SG, et al.: Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol Metab 100 (6): 2192-203, 2015. [PUBMED Abstract]
  47. Chemaitilly W, Robison LL: Safety of growth hormone treatment in patients previously treated for cancer. Endocrinol Metab Clin North Am 41 (4): 785-92, 2012. [PUBMED Abstract]
  48. Sklar CA, Mertens AC, Mitby P, et al.: Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 87 (7): 3136-41, 2002. [PUBMED Abstract]
  49. Ergun-Longmire B, Mertens AC, Mitby P, et al.: Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab 91 (9): 3494-8, 2006. [PUBMED Abstract]
  50. Bogarin R, Steinbok P: Growth hormone treatment and risk of recurrence or progression of brain tumors in children: a review. Childs Nerv Syst 25 (3): 273-9, 2009. [PUBMED Abstract]
  51. Patterson BC, Chen Y, Sklar CA, et al.: Growth hormone exposure as a risk factor for the development of subsequent neoplasms of the central nervous system: a report from the childhood cancer survivor study. J Clin Endocrinol Metab 99 (6): 2030-7, 2014. [PUBMED Abstract]
  52. Nandagopal R, Laverdière C, Mulrooney D, et al.: Endocrine late effects of childhood cancer therapy: a report from the Children's Oncology Group. Horm Res 69 (2): 65-74, 2008. [PUBMED Abstract]
  53. Chemaitilly W, Sklar CA: Endocrine complications in long-term survivors of childhood cancers. Endocr Relat Cancer 17 (3): R141-59, 2010. [PUBMED Abstract]
  54. Chemaitilly W, Merchant TE, Li Z, et al.: Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes. Clin Endocrinol (Oxf) 84 (3): 361-71, 2016. [PUBMED Abstract]
  55. Gan HW, Phipps K, Aquilina K, et al.: Neuroendocrine Morbidity After Pediatric Optic Gliomas: A Longitudinal Analysis of 166 Children Over 30 Years. J Clin Endocrinol Metab 100 (10): 3787-99, 2015. [PUBMED Abstract]
  56. Didcock E, Davies HA, Didi M, et al.: Pubertal growth in young adult survivors of childhood leukemia. J Clin Oncol 13 (10): 2503-7, 1995. [PUBMED Abstract]
  57. Shalet SM, Crowne EC, Didi MA, et al.: Irradiation-induced growth failure. Baillieres Clin Endocrinol Metab 6 (3): 513-26, 1992. [PUBMED Abstract]
  58. Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of Hand and Wrist. 2nd ed. Stanford, Ca: Stanford University Press, 1959.
  59. Gleeson HK, Stoeter R, Ogilvy-Stuart AL, et al.: Improvements in final height over 25 years in growth hormone (GH)-deficient childhood survivors of brain tumors receiving GH replacement. J Clin Endocrinol Metab 88 (8): 3682-9, 2003. [PUBMED Abstract]
  60. Chow EJ, Friedman DL, Yasui Y, et al.: Timing of menarche among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 50 (4): 854-8, 2008. [PUBMED Abstract]
  61. Armstrong GT, Whitton JA, Gajjar A, et al.: Abnormal timing of menarche in survivors of central nervous system tumors: A report from the Childhood Cancer Survivor Study. Cancer 115 (11): 2562-70, 2009. [PUBMED Abstract]
  62. Laughton SJ, Merchant TE, Sklar CA, et al.: Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26 (7): 1112-8, 2008. [PUBMED Abstract]
  63. Rose SR: Cranial irradiation and central hypothyroidism. Trends Endocrinol Metab 12 (3): 97-104, 2001. [PUBMED Abstract]
  64. Cheuk DK, Billups CA, Martin MG, et al.: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117 (1): 197-206, 2011. [PUBMED Abstract]
  65. Rose SR, Lustig RH, Pitukcheewanont P, et al.: Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. J Clin Endocrinol Metab 84 (12): 4472-9, 1999. [PUBMED Abstract]
  66. Paulino AC: Hypothyroidism in children with medulloblastoma: a comparison of 3600 and 2340 cGy craniospinal radiotherapy. Int J Radiat Oncol Biol Phys 53 (3): 543-7, 2002. [PUBMED Abstract]
  67. Vatner RE, Niemierko A, Misra M, et al.: Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors. J Clin Oncol 36 (28): 2854-2862, 2018. [PUBMED Abstract]
  68. Patterson BC, Truxillo L, Wasilewski-Masker K, et al.: Adrenal function testing in pediatric cancer survivors. Pediatr Blood Cancer 53 (7): 1302-7, 2009. [PUBMED Abstract]
  69. Kazlauskaite R, Evans AT, Villabona CV, et al.: Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 93 (11): 4245-53, 2008. [PUBMED Abstract]
  70. Rose SR, Danish RK, Kearney NS, et al.: ACTH deficiency in childhood cancer survivors. Pediatr Blood Cancer 45 (6): 808-13, 2005. [PUBMED Abstract]
  71. Constine LS, Rubin P, Woolf PD, et al.: Hyperprolactinemia and hypothyroidism following cytotoxic therapy for central nervous system malignancies. J Clin Oncol 5 (11): 1841-51, 1987. [PUBMED Abstract]
  72. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106 (25): 3143-421, 2002. [PUBMED Abstract]
  73. Nottage KA, Ness KK, Li C, et al.: Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia - From the St. Jude Lifetime Cohort. Br J Haematol 165 (3): 364-74, 2014. [PUBMED Abstract]
  74. Saultier P, Auquier P, Bertrand Y, et al.: Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study. Haematologica 101 (12): 1603-1610, 2016. [PUBMED Abstract]
  75. van Waas M, Neggers SJ, Raat H, et al.: Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS One 7 (12): e52237, 2012. [PUBMED Abstract]
  76. Chow EJ, Simmons JH, Roth CL, et al.: Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with total body irradiation. Biol Blood Marrow Transplant 16 (12): 1674-81, 2010. [PUBMED Abstract]
  77. Surapolchai P, Hongeng S, Mahachoklertwattana P, et al.: Impaired glucose tolerance and insulin resistance in survivors of childhood acute lymphoblastic leukemia: prevalence and risk factors. J Pediatr Hematol Oncol 32 (5): 383-9, 2010. [PUBMED Abstract]
  78. Veringa SJ, van Dulmen-den Broeder E, Kaspers GJ, et al.: Blood pressure and body composition in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 58 (2): 278-82, 2012. [PUBMED Abstract]
  79. Steinberger J, Sinaiko AR, Kelly AS, et al.: Cardiovascular risk and insulin resistance in childhood cancer survivors. J Pediatr 160 (3): 494-9, 2012. [PUBMED Abstract]
  80. Gurney JG, Ness KK, Sibley SD, et al.: Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 107 (6): 1303-12, 2006. [PUBMED Abstract]
  81. Oudin C, Simeoni MC, Sirvent N, et al.: Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. Blood 117 (17): 4442-8, 2011. [PUBMED Abstract]
  82. Armstrong GT, Oeffinger KC, Chen Y, et al.: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 31 (29): 3673-80, 2013. [PUBMED Abstract]
  83. Smith WA, Li C, Nottage KA, et al.: Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Cancer 120 (17): 2742-50, 2014. [PUBMED Abstract]
  84. Jones LW, Liu Q, Armstrong GT, et al.: Exercise and risk of major cardiovascular events in adult survivors of childhood hodgkin lymphoma: a report from the childhood cancer survivor study. J Clin Oncol 32 (32): 3643-50, 2014. [PUBMED Abstract]
  85. Scott JM, Li N, Liu Q, et al.: Association of Exercise With Mortality in Adult Survivors of Childhood Cancer. JAMA Oncol : , 2018. [PUBMED Abstract]
  86. Neville KA, Cohn RJ, Steinbeck KS, et al.: Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab 91 (11): 4401-7, 2006. [PUBMED Abstract]
  87. Baker KS, Ness KK, Steinberger J, et al.: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 109 (4): 1765-72, 2007. [PUBMED Abstract]
  88. van Waas M, Neggers SJ, Uitterlinden AG, et al.: Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors. Eur J Cancer 49 (3): 668-75, 2013. [PUBMED Abstract]
  89. de Vathaire F, El-Fayech C, Ben Ayed FF, et al.: Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 13 (10): 1002-10, 2012. [PUBMED Abstract]
  90. Armenian SH, Chemaitilly W, Chen M, et al.: National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report. Biol Blood Marrow Transplant 23 (2): 201-210, 2017. [PUBMED Abstract]
  91. Baker KS, Chow EJ, Goodman PJ, et al.: Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors. Cancer Epidemiol Biomarkers Prev 22 (11): 1954-63, 2013. [PUBMED Abstract]
  92. Meacham LR, Chow EJ, Ness KK, et al.: Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 19 (1): 170-81, 2010. [PUBMED Abstract]
  93. van Santen HM, Geskus RB, Raemaekers S, et al.: Changes in body mass index in long-term childhood cancer survivors. Cancer 121 (23): 4197-204, 2015. [PUBMED Abstract]
  94. Meacham LR, Gurney JG, Mertens AC, et al.: Body mass index in long-term adult survivors of childhood cancer: a report of the Childhood Cancer Survivor Study. Cancer 103 (8): 1730-9, 2005. [PUBMED Abstract]
  95. Mayer EI, Reuter M, Dopfer RE, et al.: Energy expenditure, energy intake and prevalence of obesity after therapy for acute lymphoblastic leukemia during childhood. Horm Res 53 (4): 193-9, 2000. [PUBMED Abstract]
  96. Oeffinger KC, Mertens AC, Sklar CA, et al.: Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 21 (7): 1359-65, 2003. [PUBMED Abstract]
  97. Sklar CA, Mertens AC, Walter A, et al.: Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukemia: role of cranial irradiation. Med Pediatr Oncol 35 (2): 91-5, 2000. [PUBMED Abstract]
  98. Garmey EG, Liu Q, Sklar CA, et al.: Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 26 (28): 4639-45, 2008. [PUBMED Abstract]
  99. Chow EJ, Pihoker C, Hunt K, et al.: Obesity and hypertension among children after treatment for acute lymphoblastic leukemia. Cancer 110 (10): 2313-20, 2007. [PUBMED Abstract]
  100. Withycombe JS, Post-White JE, Meza JL, et al.: Weight patterns in children with higher risk ALL: A report from the Children's Oncology Group (COG) for CCG 1961. Pediatr Blood Cancer 53 (7): 1249-54, 2009. [PUBMED Abstract]
  101. Dalton VK, Rue M, Silverman LB, et al.: Height and weight in children treated for acute lymphoblastic leukemia: relationship to CNS treatment. J Clin Oncol 21 (15): 2953-60, 2003. [PUBMED Abstract]
  102. Nathan PC, Jovcevska V, Ness KK, et al.: The prevalence of overweight and obesity in pediatric survivors of cancer. J Pediatr 149 (4): 518-25, 2006. [PUBMED Abstract]
  103. Oeffinger KC: Are survivors of acute lymphoblastic leukemia (ALL) at increased risk of cardiovascular disease? Pediatr Blood Cancer 50 (2 Suppl): 462-7; discussion 468, 2008. [PUBMED Abstract]
  104. Brennan BM, Rahim A, Blum WF, et al.: Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf) 50 (2): 163-9, 1999. [PUBMED Abstract]
  105. Belle FN, Kasteler R, Schindera C, et al.: No Evidence of Overweight in Long-Term Survivors of Childhood Cancer After Glucocorticoid Treatment. Cancer : , 2018. [PUBMED Abstract]
  106. Sahakitrungruang T, Klomchan T, Supornsilchai V, et al.: Obesity, metabolic syndrome, and insulin dynamics in children after craniopharyngioma surgery. Eur J Pediatr 170 (6): 763-9, 2011. [PUBMED Abstract]
  107. Müller HL: Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother 10 (4): 515-24, 2010. [PUBMED Abstract]
  108. Simoneau-Roy J, O'Gorman C, Pencharz P, et al.: Insulin sensitivity and secretion in children and adolescents with hypothalamic obesity following treatment for craniopharyngioma. Clin Endocrinol (Oxf) 72 (3): 364-70, 2010. [PUBMED Abstract]
  109. May JA, Krieger MD, Bowen I, et al.: Craniopharyngioma in childhood. Adv Pediatr 53: 183-209, 2006. [PUBMED Abstract]
  110. Müller HL, Gebhardt U, Teske C, et al.: Post-operative hypothalamic lesions and obesity in childhood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up. Eur J Endocrinol 165 (1): 17-24, 2011. [PUBMED Abstract]
  111. Tosta-Hernandez PDC, Siviero-Miachon AA, da Silva NS, et al.: Childhood Craniopharyngioma: A 22-Year Challenging Follow-Up in a Single Center. Horm Metab Res 50 (9): 675-682, 2018. [PUBMED Abstract]
  112. Green DM, Cox CL, Zhu L, et al.: Risk factors for obesity in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30 (3): 246-55, 2012. [PUBMED Abstract]
  113. Didi M, Didcock E, Davies HA, et al.: High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood. J Pediatr 127 (1): 63-7, 1995. [PUBMED Abstract]
  114. Janiszewski PM, Oeffinger KC, Church TS, et al.: Abdominal obesity, liver fat, and muscle composition in survivors of childhood acute lymphoblastic leukemia. J Clin Endocrinol Metab 92 (10): 3816-21, 2007. [PUBMED Abstract]
  115. Oeffinger KC, Adams-Huet B, Victor RG, et al.: Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 27 (22): 3698-704, 2009. [PUBMED Abstract]
  116. Jahnukainen K, Heikkinen R, Henriksson M, et al.: Increased Body Adiposity and Serum Leptin Concentrations in Very Long-Term Adult Male Survivors of Childhood Acute Lymphoblastic Leukemia. Horm Res Paediatr 84 (2): 108-15, 2015. [PUBMED Abstract]
  117. Kohler JA, Moon RJ, Wright S, et al.: Increased adiposity and altered adipocyte function in female survivors of childhood acute lymphoblastic leukaemia treated without cranial radiation. Horm Res Paediatr 75 (6): 433-40, 2011. [PUBMED Abstract]
  118. Zhang FF, Rodday AM, Kelly MJ, et al.: Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 61 (7): 1263-9, 2014. [PUBMED Abstract]
  119. Warner JT, Evans WD, Webb DK, et al.: Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol 38 (3): 165-72, 2002. [PUBMED Abstract]
  120. Miller TL, Lipsitz SR, Lopez-Mitnik G, et al.: Characteristics and determinants of adiposity in pediatric cancer survivors. Cancer Epidemiol Biomarkers Prev 19 (8): 2013-22, 2010. [PUBMED Abstract]
  121. Jarfelt M, Lannering B, Bosaeus I, et al.: Body composition in young adult survivors of childhood acute lymphoblastic leukaemia. Eur J Endocrinol 153 (1): 81-9, 2005. [PUBMED Abstract]
  122. Ness KK, DeLany JP, Kaste SC, et al.: Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia. Blood 125 (22): 3411-9, 2015. [PUBMED Abstract]
  123. Lindemulder SJ, Stork LC, Bostrom B, et al.: Survivors of standard risk acute lymphoblastic leukemia do not have increased risk for overweight and obesity compared to non-cancer peers: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (6): 1035-41, 2015. [PUBMED Abstract]
  124. Gurney JG, Ness KK, Stovall M, et al.: Final height and body mass index among adult survivors of childhood brain cancer: childhood cancer survivor study. J Clin Endocrinol Metab 88 (10): 4731-9, 2003. [PUBMED Abstract]
  125. Nysom K, Holm K, Michaelsen KF, et al.: Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 27 (8): 817-20, 2001. [PUBMED Abstract]
  126. Ketterl TG, Chow EJ, Leisenring WM, et al.: Adipokines, Inflammation, and Adiposity in Hematopoietic Cell Transplantation Survivors. Biol Blood Marrow Transplant 24 (3): 622-626, 2018. [PUBMED Abstract]
  127. Inaba H, Yang J, Kaste SC, et al.: Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 30 (32): 3991-7, 2012. [PUBMED Abstract]
  128. Ness KK, Krull KR, Jones KE, et al.: Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J Clin Oncol 31 (36): 4496-503, 2013. [PUBMED Abstract]
  129. Jensen MV, Rugbjerg K, Licht SDF, et al.: Endocrine late effects in survivors of cancer in adolescence and young adulthood: a Danish population-based cohort study. JAMA Netw Open 1 (2): e180349, 2018. Also available online. Last accessed April 17, 2019.
Publicado por en

No hay comentarios:

Publicar un comentario

Suscribirse a: Enviar comentarios (Atom)