Late Effects of the Endocrine System
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. It is manifested by the following:
- Primary 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. 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 Hodgkin lymphoma. Results from selected studies include the following:
- In a study of 1,713 adult survivors of childhood cancers and brain tumors (median age, 32 years) monitored in a single institution (median follow-up duration, 25 years), the prevalence of primary hypothyroidism among individuals exposed to neck radiation was 13.8%.
- 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 gland and/or hypophysis. Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values. The following was observed:
- In comparison to patients treated with prophylactic cranial radiation (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 radiation had an HR of 5.674 (P < .001).
- The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups.
- 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). Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality. For hypothyroidism, there was a clear dose response, 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.
The relative risk (RR) was 17.1 for hypothyroidism; 8.0 for hyperthyroidism; and 27.0 for thyroid nodules. 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.
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).[4-8] 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.
The following factors are linked to an increased risk of thyroid nodule development:
- Time from diagnosis, female gender, and radiation dose. In a study of HL survivors, CCSS investigators identified time from diagnosis, female gender, and radiation dose of 25 Gy or more as significant risk factors for thyroid nodule development. 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.
- 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. Younger age at radiation therapy has also been linked to an excess risk of thyroid carcinoma.[5-8]
- 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.
- 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.[5,6]
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. Defining the precise role of exposure to chemotherapy and developing risk prediction models for thyroid cancer in childhood cancer survivors based on demographic and treatment-related risk factors are areas of active research.
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.[12,13] 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.
(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 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). Other high-dose therapies have not been studied.
|Predisposing Therapy||Endocrine/Metabolic Effects||Health Screening|
|mIBG = metaiodobenzylguanidine; T4 = thyroxine; TSH = thyroid-stimulating hormone.|
|Radiation impacting thyroid gland; thyroidectomy||Primary hypothyroidism||TSH level|
|Radiation impacting thyroid gland||Hyperthyroidism||Free T4 level|
|Radiation impacting thyroid gland, including mIBG||Thyroid nodules||Thyroid exam|
TSH deficiency (central hypothyroidism) is discussed with late effects that affect the pituitary gland.
Survivors of childhood cancer are at risk for 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.[2,16-18]
Central diabetes insipidus
Central diabetes insipidus may herald the diagnosis of craniopharyngioma, suprasellar germ cell tumor, or Langerhans cell histiocytosis.[19-21] 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 radiation 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. In a study of 1,713 adult survivors of childhood cancers and brain tumors (median age, 32 years) monitored in a single institution (median follow-up duration, 25 years), the prevalence of hypothalamic-pituitary axis disorders was 56.4% in individuals exposed to cranial radiation therapy at doses of 18 Gy or more. The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.
|Pituitary Hormone||Hypothalamic Factor||Hypothalamic Regulation of the Pituitary Hormone|
|(–) = inhibitory; (+) = stimulatory.|
|Growth hormone (GH)||Growth hormone–releasing hormone||+|
|Luteinizing hormone (LH)||Gonadotropin-releasing hormone||+|
|Follicle-stimulating hormone (FSH)||Gonadotropin-releasing hormone||+|
|Thyroid-stimulating hormone (TSH)||Thyroid-releasing hormone||+|
|Adrenocorticotropin (ACTH)||Corticotropin-releasing hormone||+|
Growth hormone deficiency
Growth hormone deficiency (GHD) is the earliest hormonal deficiency associated with cranial radiation in childhood cancer survivors. The risk increases with radiation dose and time since treatment. GHD is the earliest hormone deficiency observed and is sensitive to low doses of radiation. Other hormone deficiencies require higher doses, and their time to onset is much longer than for GHD. The prevalence in pooled analysis was found to be approximately 35.6%.
GHD 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 (GH) 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 GHD will occur after treatment.
- A study of conformal radiation therapy (CRT) in children with central nervous system (CNS) tumors indicates that GH insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects.
- In a report featuring data from 118 patients with localized brain tumors that were treated with radiation therapy, peak GH was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus. The average patient was predicted to develop GHD 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 GHD at 5 years (TD50/5).
Children treated with CNS-directed therapy for leukemia are also at increased risk of GHD. Results from selected studies of childhood acute lymphocytic leukemia (ALL) survivors are as follows:
- One study evaluated 127 patients with ALL treated with 24 Gy, 18 Gy, or no cranial radiation. 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.
- Another study found similar results in 118 ALL survivors treated with 24 Gy cranial radiation, in which 74% had SDS scores of -1 or higher and the remainder had scores of -2 or higher.
- 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. In this cross-sectional study, attained adult height was determined among 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 standard deviation score < -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 gender.
- 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 GH status in this study, further highlighting the participation of other factors in the growth impairments observed in this population.
Children who undergo hematopoietic stem cell transplantation (HSCT) with TBI have a significant risk of both GHD and the direct effects of radiation on skeletal development. The risk is increased with single-dose TBI as opposed to fractionated TBI, pretransplant cranial radiation, female gender, and posttreatment complications such as graft-versus-host disease (GVHD).[30-32] Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies,[32,33] but not others. Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial radiation for CNS leukemia prophylaxis or therapy.
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:[36,37]
- 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 GH or steroid treatment did not influence final height.
- TBI (single-dose radiation therapy more than fractionated-dose radiation therapy), male gender, 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.
GHD replacement therapy provides the benefit of optimizing height outcomes among children who have not reached skeletal maturity. Treatment with recombinant GH (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. Safety concerns pertaining to the use of rGH in childhood cancer survivors have primarily been related to the mitogenic potential of the GH stimulating tumor growth in a population with an increased risk of second neoplasms. 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 GH:
- One study evaluated 361 GH-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 GH.
- The RR of disease recurrence was 0.83 (95% CI, 0.37–1.86) for GH-treated survivors. GH-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. With prolonged follow-up, the elevation of subsequent cancer risk due to GH diminished.
- Compared with survivors not treated with GH, 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 (9 of 20 tumors).
- A review of existing data suggests that treatment with GH is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia.
- A recent study from the CCSS reported specifically on the risk of subsequent CNS neoplasms after a longer period of follow-up. The adjusted rate ratio of meningioma and gliomas in GH-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 GH, thus indicating negligible differences between the two groups for this particular risk.
Disorders of luteinizing hormone (LH) and follicle-stimulating hormone (FSH): Central precocious puberty and LH/FSH deficiency
Pubertal development can be adversely affected by cranial radiation. 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.
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 GHD. The increased growth velocity induced by pubertal development can mask concurrent GHD 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.
Central precocious puberty has been reported in some children receiving cranial radiation in doses of 24 Gy or higher. Earlier puberty and earlier peak height velocity, however, have been observed in girls treated with 18 Gy cranial radiation.[45,46] 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.
When appropriate, delaying the progression of puberty relies on the use of various gonadotropin-releasing hormone (GnRH) agonist preparations, an approach that has been shown to improve growth prospects—especially when other pituitary abnormalities, including GHD, are concurrently treated.
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. With higher doses of cranial radiation (>35 Gy), deficiencies in LH/FSH can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment.[49,50] The treatment of LH/FSH deficiency relies on sex-hormone replacement therapy adjusted to age and pubertal status.
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.
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). 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.[52,53]
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). In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 patients (7%). Among patients who received TBI (fractionated total doses of 12–14.4 Gy) or craniospinal radiation (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.
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, GHD, or central hypothyroidism.[22,51,56-58] 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. 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 mcg/dl or more is reassuring for ACTH sufficiency, whereas a value of 5 mcg/dl or lower is suspicious for insufficiency). Confirmation is necessary using dynamic testing such as the low-dose ACTH stimulation test. 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 has been described in patients who received radiation 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.[22,59]
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, given its frequent associations with hypogonadism (both central and primary), rarely requires treatment.
|Predisposing Therapy||Endocrine/Metabolic Effects||Health Screening|
|BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone; TSH = thyroid-stimulating hormone.|
|aTesticular volume measurements are not reliable in the assessment of pubertal development in boys exposed to chemotherapy or direct radiation to the testes.|
|bAppropriate only at diagnosis. TSH levels are not useful for follow-up during replacement therapy.|
|Radiation impacting hypothalamic-pituitary axis||Growth hormone deficiency||Assessment of nutritional status|
|Height, weight, BMI, Tanner stagea|
|Radiation impacting hypothalamic-pituitary axis||Precocious puberty||Height, weight, BMI, Tanner stagea|
|FSH, LH, estradiol, or testosterone levels|
|Radiation impacting hypothalamic-pituitary axis||Gonadotropin deficiency||History: puberty, sexual function|
|Exam: Tanner stagea|
|FSH, LH, estradiol or testosterone levels|
|Radiation impacting hypothalamic-pituitary axis||Central adrenal insufficiency||History: failure to thrive, anorexia, episodic dehydration, hypoglycemia, lethargy, unexplained hypotension|
|Endocrine consultation for those with radiation dose ≥30 Gy|
|Radiation impacting hypothalamic-pituitary axis||Hyperprolactinemia||History/exam: galactorrhea|
|Radiation impacting hypothalamic-pituitary axis||Overweight/obesity||Height, weight, BMI|
|Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism)||Fasting blood glucose level and lipid profile|
|Radiation impacting hypothalamic-pituitary axis||Central hypothyroidism||TSHb 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.
An increased risk of metabolic syndrome or its components has been observed among cancer survivors. 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 or more of the following features:
- Atherogenic dyslipidemia (elevated triglycerides, reduced high-density lipoprotein [HDL] cholesterol).
- Abnormal glucose metabolism (fasting hyperglycemia, hyperinsulinism, insulin resistance, diabetes mellitus type 2).
Long-term survivors of ALL, especially those treated with cranial radiation, 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.[61-67] Results of selected studies are as follows:
- In a study of 784 childhood long-term ALL survivors (median age, 31.7 years; median follow-up duration, 26.1 years), 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.
- In a European cohort of 184 adult survivors of childhood leukemia (81.5% had ALL; median age, 21.2 years; median follow-up duration, 15.4 years), the prevalence of metabolic syndrome was 9.2%. In this study, exposure to TBI was found to be significantly associated with metabolic syndrome, with significant associations between TBI and hypertriglyceridemia, and low HDL and impaired fasting glucose.
Abdominal radiation is an additional risk factor for metabolic syndrome as seen by the following:
- Survivors of developmental or embryonal tumors treated with abdominal radiation are also at an increased risk of developing components of metabolic syndrome. In a prospective study of 164 long-term survivors (median follow-up time, 26 years), nephroblastoma (OR, 5.2) and neuroblastoma (OR, 6.5) survivors had more components of metabolic syndrome than did controls. Compared with nonirradiated survivors, survivors treated with abdominal radiation had higher blood pressure, triglycerides, LDL-C, and total fat percentage, which were assessed by dual-energy x-ray absorptiometry.
- Abdominal radiation therapy and TBI in the context of hematopoietic stem cell transplantation are increasingly recognized as independent risk factors for diabetes mellitus in childhood cancer survivors.[62,67-72]
A single-center cohort study of 532 adult (median age, 25.6 years) long-term (median follow-up time, 17.9 years) survivors observed that 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%). In a cross-sectional study evaluating 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, 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.
Studies of glucose metabolism have observed the following:
- In a European multicenter cohort of 2,520 childhood cancer survivors (median follow-up duration, 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.
- In a report from the CCSS that compared 8,599 childhood cancer survivors to 2,936 randomly selected sibling controls, and after adjustment for age, body mass index (BMI), and several demographic factors, 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 or TBI. Also, survivors were significantly more likely to be receiving medication for hypertension, dyslipidemia, and/or diabetes mellitus than were sibling controls.
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.
|Predisposing Therapy||Potential Late Effects||Health Screening|
|BMI = body mass index.|
|Total-body irradiation||Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism)||Height, weight, BMI, blood pressure|
|Labs: fasting glucose and lipids|
Obesity and Being Overweight
To date, the primary cancer groups recognized with an increased incidence of treatment-related obesity are ALL [76-85] and CNS tumor [16,17] survivors treated with cranial radiation therapy.[86,87] In addition, craniopharyngioma survivors have a substantially increased risk of extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection.[88-93]
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:
- 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.
- Leptin sensitivity.
- Reduced levels of physical activity and energy expenditure.
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.[63,79,82,97] 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. 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. It appears that these women also have a significantly increased visceral adiposity and associated insulin resistance.[98,99] These outcomes are attenuated in males.
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.[83-85,100,101] Survivors of childhood ALL treated with chemotherapy alone also exhibit long-term changes in body composition, with relative increases in body fat [99,102-104] and visceral adiposity in comparison to lean mass. These changes cannot be detected if BMI alone is used in the assessment of metabolic risk in this population. 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, nor were there differences in BMI changes between these groups after a subsequent period of follow-up that averaged 7.8 years. It is important to note, however, that results from the CCSS were based on self-reported height and weight measurements.
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.
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.[69,106] 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.
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. The frailty phenotype increases in prevalence with aging, and has been associated with excess risk of mortality and onset of chronic conditions. Ongoing research aims to elucidate the pathophysiology of frailty and develop/test interventions to prevent or reverse this condition.
|Predisposing Therapy||Potential Late Effects||Health Screening|
|BMI = body mass index.|
|Cranial radiation therapy||Overweight/obesity||Height, 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.
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