Metabolic Syndrome in Childhood Cancer Survivors

Over 200,000 children under the age of fifteen are diagnosed with cancer worldwide every year. Cancer is the second most common cause of death among children between the ages of 1 and 14 years in developed countries, surpassed only by accidents.Nearly one third of the cancers diagnosed in children are leukemias (particularly acute lymphoblastic leukemia (ALL)), followed by cancer of the brain or central nervous system (21%), soft tissue sarcomas (including neuroblastoma (7%) and rhabdomyosarcoma (3%)), renal (nephroblastoma) tumors (5%), and non-Hodgkin lymphoma (4%). Childhood cancer survival has increased significantly over the past few decades (Figure 1). Especially the advent of combination chemotherapy in the late 1960s and 1970s brought about large increases in survival for many childhood cancers. Furthermore, improved surgery, radiotherapy, stem cell transplantation, supportive care and better stratification of therapy regimens played an important role. Population-based statistics show the probability of fiveyear survival of cancer in those under the age of 20 in the United States to be 80%. This success in therapy translates into a growing and aging population of long-term survivors. To date, 1 out of 640 young adults in the United States is a childhood cancer survivor. In the Netherlands, currently 7000 adults are long-term childhood cancer survivors

Adrenal function in adult long-term survivors of nephroblastoma and neuroblastoma

AbstractBackgroundAdrenal insufficiency, or relative insufficiency, might partly explain increased mortality rates in nephroblastoma and neuroblastoma survivors after unilateral adrenalectomy.ObjectiveTo assess adrenal function and its metabolic effects in survivors after adrenalectomy.MethodsIn this cross-sectional study, 67 adult long-term survivors of nephroblastoma, 36 survivors of neuroblastoma and 49 control subjects participated. Adrenal function was assessed by a 1μg short Synacthen-test. Levels of cortisol, adrenocorticotrophic hormone (ACTH), low (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), triglycerides, apolipoprotein-B, glucose and insulin were assessed in blood samples taken at baseline. In addition, cortisol levels were assessed after 30 (t=30) and 60min. Homoeostatic Model Assessment (HOMA) was calculated.ResultsAdrenal insufficiency was not present in survivors. Interestingly, baseline serum cortisol levels were higher in survivors after unilateral adrenalectomy (mean 503nmol/l) (N=46) than in survivors with both adrenals intact (mean 393nmol/l, P=0.002) (N=52), and than in controls (mean 399nmol/l, P=0.013) (N=49). After correcting for age, sex and use of oral oestrogens, unilateral adrenalectomy was independently associated with elevated baseline cortisol and ACTH levels. Baseline cortisol levels were positively associated with triglycerides (P<0.001), LDL-C (P=0.004), apolipoprotein-B (P<0.001) and HOMA (P=0.008).ConclusionsNo adrenal insufficiency was observed in survivors of nephroblastoma and neuroblastoma. Survivors treated with unilateral adrenalectomy had relatively high basal cortisol and ACTH levels, indicating a higher central setpoint of the hypothalamic-pituitary-adrenal axis. This higher setpoint was associated with lipid concentrations and insulin resistance and can therefore influence the cardiovascular risk profile in long-term survivors of nephroblastoma and neuroblastoma

Metabolic syndrome detection with biomarkers in childhood cancer survivors

Purpose: Augmented survival of childhood nephroblastoma and neuroblastoma has increased long-term side effects such as metabolic syndrome (MetS). Risk stratification is difficult after abdominal radiation because waist circumference underestimates adiposity. We aimed to develop a strategy for determining MetS in irradiated survivors using an integrated biomarker profile and vascular ultrasonography. Methods: The NCEP-ATPIII MetS-components, 14 additional serum biomarkers and 9 vascular measurements were assessed in a single-centre cohort of childhood nephroblastoma (n = 67) and neuroblastoma (n = 36) survivors and controls (n = 61). Multivariable regression models were used to study treatment effects. Principal component analysis (PCA) was used to study all biomarkers in a combined analysis, to identify patterns and correlations. Results: After 27.5 years of follow-up, MetS occurred more often in survivors (14%) than controls (3%). Abdominal radiotherapy and nephrectomy, to a lesser extent, were associated with MetS and separate components and with several biomarker abnormalities. PCA of biomarkers revealed a pattern on PC1 from favourable lipid markers (HDL-cholesterol, adiponectin) towards unfavourable markers (triglycerides, LDL-cholesterol, apoB, uric acid). Abdominal radiotherapy was associated with the unfavourable biomarker profile (β = 1.45, P = 0.001). Vascular measurements were not of added diagnostic value. Conclusions: Long-term childhood nephro-and neuroblastoma survivors frequently develop MetS. Additional assessment of biomarkers identified in PCA – adiponectin, LDL, apoB, and uric acid – may be used especially in abdominally irradiated survivors, to classify MetS as alternative for waist circumference. Vascular ultrasonography was not of added value

Baseline characteristics of study participants.

<p>Data expressed as median (range) unless specified otherwise.</p>*<p>Time after cessation of treatment.</p>**<p>Data expressed as median (interquartile range).</p><p><b>n.a.</b> = not applicable, Gy = gray, TCD =  total cumulative dose.</p

Components of the metabolic syndrome in survivors treated with and without abdominal irradiation.

<p>Frequency of the metabolic syndrome determined according to the definition of NCEP but instead of waist circumference, total percentage fat was used as an alternative marker for adiposity. Prevalence of metabolic syndrome (≥3 components) in abdominally irradiated survivors is significantly higher than in controls (P = 0.018) (Chi-squared test). Each group in total (0, 1, 2, ≥3 components) equals 100%.</p

Prevalence of components of the metabolic syndrome in nephroblastoma and neuroblastoma survivors compared with controls.

*<p>Or treatment.</p>**<p>Waist circumference is imprecise in irradiated survivors.</p><p>¹Nephroblastoma survivors compared with controls.</p><p><b>²</b>Neuroblastoma survivors compared with controls (Chi-squared test). All subjects are included. Frequency of fasting glucose does not include one survivor with diabetes type 1.</p

The black box indicates a schematic interpretation of the radiation field. A

<p>Part of pancreas (i.e. head and part of tail) and part of liver in radiation field <b>B</b> Total pancreas (i.e. head and tail) and part of liver in radiation field <b>C</b> Part of pancreas (i.e. head and part of tail) and total liver in radiation field <b>D</b> Total pancreas (i.e. head and tail) and total liver in radiation field <b>Categories: B+D</b> Total pancreas in radiation field <b>A+C</b> Part of pancreas in radiation field <b>C+D</b> Total liver in radiation field <b>A+B</b> Part of liver in radiation field Original figure was retrieved from <a href="http://openlearn.open.ac.uk" target="_blank">http://openlearn.open.ac.uk</a>.</p

Influence of treatment components and diagnosis on parameters.

*<p>subjects with treatment for diabetes excluded.</p>**<p>subjects with treatment for dyslipidemia excluded.</p><p>¹Corrected for age, sex, BMI, physical activity.</p><p>²Corrected for age, sex, BMI, smoking, physical activity.</p>3<p>Corrected for age, sex, BMI, smoking.</p>4<p>corrected for age, sex, SES, BMI.</p>5<p>corrected for age, sex, physical activity. Glucose, insulin, HOMA and triglycerides levels were normally distributed after log-transformation and were expressed in percentages. ref = reference value (control subjects).</p><p>Multiple linear regression analyses were performed using the following strategy: Model 1: the effects of both diagnoses (dummy variables) were added. Model 2: the effects of chemotherapy, nephrectomy, adrenalectomy, abdominal radiotherapy (dummy variables) were added. Additional linear regression analyses were performed according to the following strategy: Model 3: the effects of radiotherapy to the total pancreas and on part of the pancreas (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052237#pone-0052237-g001" target="_blank">Figure 1</a>) (dummy variables) were added. Model 4: the effect of radiotherapy on the total liver and on part of the liver (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052237#pone-0052237-g001" target="_blank">Figure 1</a>) (dummy variables) were added. Model 3 and 4 were additionally corrected for the treatment components that were significant in Model 2. P-values indicate the significance of the difference with control subject.</p