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Late Effects of Treatment for Childhood Cancer (PDQ®)

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Late Effects of the Endocrine System

Thyroid Gland
        Hypothyroidism
        Thyroid nodules
        Posttransplant thyroid dysfunction
Pituitary Gland
        Growth hormone deficiency
        Gonadal abnormalities
        Hypothyroidism
        Adrenal-corticotropin deficiency
        Hyperprolactinemia
Testis and Ovary
Metabolic Syndrome
Changes in Body Composition: Obesity and Body Fatness



Thyroid Gland

Thyroid dysfunction, manifested by primary hypothyroidism, hyperthyroidism, goiter, or nodules, 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.

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.[1] The most frequently reported abnormalities include elevated thyroid-stimulating hormone (TSH), depressed thyroxine (T4), or both.[2-5] 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.

The incidence of hypothyroidism should decrease with lower cumulative doses of radiation therapy employed in newer protocols. In a study of 1,677 children and adults with HL who were treated with radiation therapy between 1961 and 1989, the actuarial risk at 26 years posttreatment for overt or subclinical hypothyroidism was 47%, with a peak incidence at 2 to 3 years posttreatment.[6] In a study of HL patients treated between 1962 and 1979, hypothyroidism occurred in 4 of 24 patients who received mantle doses less than 26 Gy but in 74 of 95 patients who received greater than 26 Gy. The peak incidence occurred at 3 to 5 years posttreatment, with a median of 4.6 years.[7] A cohort of childhood HL survivors treated between 1970 and 1986 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, 30% for those who received 35 Gy to 44.9 Gy, and 50% for those who received greater than 45 Gy to the thyroid gland. The relative risk (RR) for hypothyroidism was 17.1; for hyperthyroidism 8.0; and for thyroid nodules, 27.0. Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, where the risk increased in the first 3 to 5 years after diagnosis. For nodules, the risk increased beginning at 10 years after diagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.[8]

Enlarge
Probability 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 4. Probability of developing hypothyroidism according to radiation dose in 5-year survivors of childhood cancer. Data from the Childhood Cancer Survivor Study.[8] 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.


As might be expected, children treated for head and neck malignancies are also at risk for primary hypothyroidism if the neck is irradiated. 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 had 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. In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients 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 with greater than 25 Gy to the thyroid gland and patients who underwent craniospinal irradiation had HR of 3.768 (P = .009) and 5.674 (P < .001), respectively. The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups.[9]

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).[8,10-13] 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 greater than 30 Gy, consistent with a cell-killing effect.[13] The risk of thyroid nodule development increases with increasing time from radiation exposure. 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.[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. 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 and before the attained age of 4 years.[11] Younger age at radiation therapy has also been linked to an excess risk of thyroid carcinoma.[10-13] An increased risk of thyroid nodules/cancer has also been observed in association with chemotherapy, independent of radiation exposure.[10,11]

During childhood and adolescence, there is an increased incidence of developing thyroid nodules, and potentially, thyroid cancer for patients exposed to iodine I 131 metaiodobenzylguanidine (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.[14]

Several investigations have demonstrated the superiority of ultrasound to clinical exam for detecting thyroid nodules/cancers and characterized ultrasonographic features of nodules that are more likely to be malignant.[15,16] 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.[17]

(Refer to the Subsequent Neoplasms section of this summary for information about subsequent thyroid cancers.)

Posttransplant thyroid dysfunction

Survivors of pediatric hematopoietic stem cell transplant 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 was not different between children receiving a TBI or busulfan-based regimen (P = .48).[18] Other high-dose therapies have not been studied. While mildly elevated TSH is common, it is usually accompanied by normal thyroxine concentration.[19,20]

Table 7. Thyroid Late Effects
Predisposing Therapy  Endocrine/Metabolic Effects Health Screening 
mIBG = metaiodobenzylguanidine; TSH = thyroid stimulating hormone.
Radiation impacting thyroid gland; thyroidectomyPrimary hypothyroidismTSH level
Radiation impacting thyroid glandHyperthyroidismFree thyroxine (Free T4) level
TSH level
Radiation impacting thyroid gland, including mIBGThyroid nodulesThyroid exam
Thyroid ultrasound

Central hypothyroidism is discussed with late effects that affect the pituitary gland.

Pituitary Gland

Survivors of childhood cancer are at risk for a spectrum of neuroendocrine abnormalities, primarily due to the effect of radiation therapy on the hypothalamus. Essentially all of the hypothalamic-pituitary axes are at risk.[21-23] 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 Hormone  Hypothalamic Factor Hypothalamic Regulation of the Pituitary Hormone 
(–) = inhibitory; (+) = stimulatory.
Growth hormoneGrowth hormone-releasing hormone+
Somatostatin
ProlactinDopamine
Luteinizing hormoneGonadotropin-releasing hormone+
Follicle-stimulating hormoneGonadotropin-releasing hormone+
Thyroid-stimulating hormoneThyroid-releasing hormone+
Somatostatin
AdrenocorticotropinCorticotropin-releasing hormone+
Vasopressin+

Growth hormone deficiency

Growth hormone deficiency (GHD) is the first and most common side effect of cranial irradiation in brain tumor survivors. The risk increases with radiation dose and time after treatment. GHD is the earliest hormone deficiency and is sensitive to low doses. Other hormone deficiencies require higher doses and their time to onset is much longer than for GHD.[24] The prevalence in pooled analysis was found to be approximately 35.6%.[25] The potential for neuroendocrine damage is likely to decrease because of the use of more focused radiation therapy and a decrease in dose for some malignancies such as medulloblastoma.

Approximately 60% to 80% of irradiated pediatric brain tumor patients who have received doses greater 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 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.[26] In a recent report from the St. Jude Children’s Research Hospital on 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 conformal radiation therapy (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).[27]

Enlarge
Graph shows peak growth hormone (in ng/mL) according to hypothalamic mean dose and time (in months) after start of irradiation.
Figure 5. Peak growth hormone (GH) according to hypothalamic mean dose and time after start of irradiation. According to equation 2, peak GH = exp{2.5947 + time × [0.0019 − (0.00079 × mean dose)]}.[27] 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 irradiation for leukemia are also at increased risk of GHD. One study evaluated 127 patients with acute lymphocytic leukemia (ALL) treated with 24 Gy, 18 Gy, or no cranial irradiation. 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 no radiation therapy group, -0.65 ± 0.15 for the 18 Gy radiation therapy group, and -1.38 ± 0.16 for the 24 Gy group.[28] Another study found similar results in 118 ALL survivors treated with 24 Gy cranial irradiation, in which 74% had SDS score of -1 or greater and the remainder had -2 or greater.[29] However, 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.[30] 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.

GHD has been reported in 14% of survivors of childhood nasopharyngeal carcinoma, which is secondary to the hypothalamic/pituitary radiation.[31] This incidence is likely an underestimate since screening was selective.

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. Risk is increased with single-dose as opposed to fractionated TBI, pretransplant cranial irradiation, female gender, and posttreatment complications such as graft-versus-host disease (GVHD).[32-34] Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies,[34,35] but not others.[36] Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial radiation for CNS leukemia prophylaxis or therapy.[37]

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, 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, 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.[38,39]

GHD should be treated with replacement therapy. Some controversy surrounds this, with a concern over increased risk of primary tumor recurrence and subsequent malignancies. Most studies, however, are limited by selection bias and small sample size. 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.[40] With prolonged follow-up, the elevation of subsequent cancer risk due to GH diminished.[41] 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), and 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.[42] In general, the data addressing subsequent malignancies should be interpreted with caution given the small number of events.[40]

Gonadal abnormalities

Pubertal development can be adversely affected by cranial radiation. Doses greater than 30 Gy to 40 Gy may result in gonadotropin deficiency, while doses greater than 18 Gy can result in precocious puberty.[43] Precocious puberty has been reported in some children receiving cranial irradiation, mostly in girls who receive 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.[44,45] Another study showed that the age of pubertal onset is positively correlated with age at the time of cranial irradiation. The impact of early puberty in a child with radiation-associated GHD is significant, and timing of GH therapy is especially important for GH-deficient females also at risk of precocious puberty.[45] With higher doses of cranial irradiation (>35 Gy), deficiencies in the gonadotropins can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment.[46-48]

Hypothyroidism

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. Radiation dose to the hypothalamus in excess of 42 Gy is associated with an increase in the risk of developing TSH deficiency, 44% ± 19% (dose ≥42 Gy) and 11% ± 8% (dose <42 Gy).[49] 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.[31,50]

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 thyrotropin-releasing hormone (TRH).[22,51] In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 (7%) patients.[51] Among patients who received TBI (fractionated total doses of 12 Gy–14.4 Gy) or craniospinal irradiation (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.[52]

Adrenal-corticotropin deficiency

Adrenocorticotropic hormone (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 irradiation, GH deficiency, or central hypothyroidism.[22,24,49,53-56] Although uncommon, ACTH deficiency can occur in patients who have received intracranial radiation that did not exceed 24 Gy and has been reported to occur in less than 3% of patients after chemotherapy alone.[56] 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.

Hyperprolactinemia

Hyperprolactinemia has been described in patients who have received doses of radiation higher than 50 Gy to the hypothalamus or who have undergone surgery disrupting the integrity of the pituitary stalk. Hyperprolactinemia may result in delayed puberty. In adult women, hyperprolactinemia may cause galactorrhea, menstrual irregularities, loss of libido, hot flashes, infertility, and osteopenia; in adult men, impotence and loss of libido. 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.[22,24,53]

Table 9. Pituitary Gland Late Effects
Predisposing Therapy Endocrine/Metabolic Effects  Health Screening 
BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
Radiation impacting hypothalamic-pituitary axisGrowth hormone deficiencyAssessment of nutritional status
Height, weight, BMI, Tanner stage
Radiation impacting hypothalamic-pituitary axisPrecocious pubertyHeight, weight, BMI, Tanner stage
Radiation impacting hypothalamic-pituitary axisGonadotropin deficiencyHistory: puberty, sexual function
Exam: Tanner stage
FSH, LH, estradiol or testosterone levels
Radiation impacting hypothalamic-pituitary axisCentral 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 axisHyperprolactinemiaHistory/exam: galactorrhea
Prolactin level
Radiation impacting hypothalamic-pituitary axisOverweight/obesity; metabolic syndromeHeight, weight, BMI
Blood pressure
Fasting blood glucose level and lipid profile
Radiation impacting hypothalamic-pituitary axisCentral hypothyroidismFree thyroxine (Free T4) level

Testis and Ovary

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

Metabolic Syndrome

The metabolic syndrome is highly associated with cardiovascular events and mortality. Definitions of the metabolic syndrome are evolving, but generally include a combination of central (abdominal) obesity with at least two or more 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).[57]

An increased risk of metabolic syndrome or its components has been observed among cancer survivors.

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, dyslipidemia, hypertension, and obesity.[58-60]

In a cross-sectional study that compared cardiovascular risk factors and insulin resistance among 319 childhood cancer survivors (median age, 14.5 years; median time from diagnosis, 10.1 years) and 208 sibling controls, no differences were observed in weight and body mass index (BMI), although survivors had greater adiposity, percent fat, and lower lean body mass than siblings. Childhood cancer survivors also had higher total- and low-density lipoprotein cholesterol (LDL-C) and triglycerides and lower insulin sensitivity than siblings.[61]

In a young-adult cohort of ALL survivors (mean age 30 years), 62% had at least one cardiovascular risk factor and 30% had two or more.[62] Another study observed no difference in prevalence of metabolic syndrome in 75 ALL survivors compared with a population-based control group.[63] However, survivors with metabolic syndrome were more likely to have GH insufficiency or GHD. Those treated with cranial radiation therapy also had an association with GH abnormalities and were more likely to have two or more components of the metabolic syndrome than were survivors who were not treated with cranial radiation therapy.

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 the 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%).[64]

Survivors of developmental or embryonal tumors treated with abdominal irradiation are also at an increased risk for developing components of the 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 the metabolic syndrome than did controls. Compared with nonirradiated survivors, survivors treated with abdominal irradiation had higher blood pressure, triglycerides, LDL-C, and total fat percentage, which were assessed by dual energy X-ray absorptiometry.[65]

A high frequency of cardiovascular risk factors has also been observed among hematopoietic cell transplant recipients.[66,67] French investigators reported an overall 9.2% (95% CI, 5.5–14.4) prevalence of metabolic syndrome in a cohort of 184 ALL survivors (median age 21.2 years).[68] Gender, age at diagnosis, corticosteroid therapy, or cranial radiation were not significant predictors of metabolic syndrome. However, hematopoietic cell transplantation with TBI was a major risk factor for metabolic syndrome (OR, 3.9, P = .03). Other investigators have reported a significantly increased risk of hyperinsulinemia, impaired glucose tolerance, or diabetes mellitus associated with exposure to TBI.[59,69] The association between TBI and excess risk for diabetes has also been observed by other investigators.[70] These data suggest that survivors might benefit from targeted screening and lifestyle counseling regarding risk reduction measures.

Table 10. Metabolic Syndrome Late Effects
Predisposing Therapy Potential Late Effects Health Screening 
BMI = body mass index.
Total-body irradiationMetabolic syndromeExam (annual): height, weight, BMI, blood pressure
Labs: fasting glucose and lipids every 2 years

Changes in Body Composition: Obesity and Body Fatness

To date, the primary cancer groups recognized with an increased incidence of treatment-related obesity are ALL [71-85] and CNS tumor [21,22,86] survivors treated with cranial radiation therapy.[87,88] In addition, craniopharyngioma survivors also have a substantially increased risk of extreme obesity due to the tumor location and the hypothalamic-pituitary-adrenal damage resulting from surgical resection.[89-95]

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:[96]

  • 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.[96]

Moderate-dose cranial radiation therapy (18–24 Gy) among ALL survivors is associated with obesity, particularly in females treated at a young age.[60,75,81,97] 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 in comparison with women who have not been treated for a cancer.[75] 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 in comparison with women who were treated for ALL with only chemotherapy or with women in the general population.[81] It appears that these women also have a significantly increased visceral adiposity and associated insulin resistance.[98,99] These outcomes are attenuated in males. Interestingly, 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.[100] The development of obesity after cranial radiation therapy is multifactorial, with factors including GHD, leptin sensitivity, reduced levels of physical activity, and energy expenditure.[81,101,102] Importantly, 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.[69,103] 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.[104]

It remains controversial whether contemporary ALL therapy, without cranial radiation therapy, is associated with a sustained increase in BMI. During and soon after completion of therapy, there appears to be an increase in BMI z-scores among children treated for ALL with only chemotherapy.[82-84,105] However, investigators from the CCSS did not find a significant association among adult survivors of childhood ALL between chemotherapy-only protocols and risk of obesity or change in BMI over time. Notably, while there may not be an increased incidence of obesity, as measured by BMI, among adult survivors of childhood ALL, there does appear to be an increase in percent body fat [80,85,99,106] and visceral adiposity.[98]

Table 11. Body Composition Late Effects
Predisposing Therapy Potential Late Effects Health Screening 
BMI = body mass index.
Cranial radiation therapyOverweight/obesityExam (annual): height, weight, BMI, blood pressure
Labs: fasting glucose and lipids every 2 years

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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