The survival rates in childhood cancer have improved due to early diagnosis, more specific treatment, and better supportive care. The cancer treatments are associated with short-term and long-term effects. The long-term effects that have been described are reduced growth, obesity, decreased fertility, high blood pressure, cardiovascular diseases, impaired glucose, and another form of cancer, endocrine deficiencies and organ dysfunction.1–3 The individual health status and quality of life will be affected by the cumulative long-term effects of the therapy received. Long-term effects of chemotherapy depend on the patient characteristics, type of chemotherapy and cumulative dose. In the case of radiotherapy, the long-term effects are also associated with the dosage and extent of the irradiated field.4,5
Epidemiological reports have revealed clinical features of metabolic syndrome (MS), obesity or overweight in children and young adult cancer survivors.6,7
The International Diabetes Foundation has established the following diagnostic criteria for MS patients: body mass index (BMI) more than the 90th percentile of waist circumference (WC) and 2 factors from the defining criteria. The prevalence of MS in a healthy child population ranges from 3.6% to 4.8%, increasing radically up to 30% among overweight and obese children.8
Antineoplastic drugs used for cancer treatment are cytotoxic substances; most of these agents interfere with DNA replication, transcription, protein synthesis, and microtubule function. Therefore, endocrine cells may result in injured and glandular functions deregulated. Moreover, these agents can interact with receptors or second messengers, causing an increase or an inhibition of hormones. In addition, some of the chemotherapeutic agents can compete for binding sites on carrier proteins, perturbing hormone delivery.9 Consequently, the aforementioned mechanisms may lead to hormone deficiencies, changes in insulin sensitivity, lipid metabolism, inflammatory mediators, and adipokines.8
Cancer and its treatment are associated with systemic inflammation causing damage in adipose tissue, producing an imbalance in adipokines.8 Among survivors of childhood leukemia, higher leptin levels were associated with anthropometric and metabolic changes many years after ALL treatment remain a major health problem facing survivors and may be related to central leptin resistance.
Glucocorticoids produce the relocation of fat deposits.8 High levels of glucocorticoids increase the gluconeogenesis process, and interfere with the action of different insulin antagonist hormones and with insulin postreceptor signaling pathway.9,10 Chow et al11 found a dose-response association between cumulative glucocorticoid dose and the risk of obesity. All survivors had lower lean body mass with more abdominal and visceral fat mass.2 Glucocorticoids and insulin activate lipoprotein lipase, which reduces triglyceride clearance.12,13
Chemotherapy and glucocorticoids modify skeletal muscle glucose uptake and transport, predisposing to inflammation and atherogenic dyslipidemias by producing Radical Oxigen Species and stimulating hepatic de novo lipogenesis.8 De Fine Licht et al,14 showed that 43% of these patients developed an endocrine pathology before 60 years old.
Obesity is a crucial component in MS, and is very common during and after treatment of leukemia; the childhood cancer survivor develops 2 times more obesity compared with healthy children. The BMI increases considerably and associated with different risk factors, such as the radiation dose, female sex, age of diagnosis (≤4 y), the intake of dexamethasone or its derivatives.15 De Has et al,16 showed that 39% of the patients who received chemotherapy associated with radiotherapy developed MS against 8% of those who only received chemotherapy.
The FINDRISC was designed to identify the risk of developing type II diabetes high-risk without using laboratory tests; the criteria included in the test are age, BMI, WC, use of antihypertensive agents, history of hyperglycemia, physical activity, and dietary patterns.17 The FINDRISC is a multivariate analyses and its validation showed that the FINDRISC had a high sensitivity and specificity and about risk of developing type II diabetes in 10 years, the risk increases with increasing FINDRISC values.18
The primary aim of the present study was therefore to examine the prevalence of unhealthy weight status and risk factors associated with MS in a relatively homogenous children group of survivors in México. A secondary aim was to examine whether BMI for age-based estimates of overweight and obesity agreed to metabolic changes that could be related to chemotherapy.
MATERIAL AND METHODS
The present study recruited cancer survivors who had at least 1 year of having finished their chemotherapy and had been treated at the Una Nueva Esperanza, during the period 2015 to 2017. The sample consisted of 52 patients, 25 men and 27 women; the mean group age was 10.7±4.9 years old.
In the absence of a FINDRISC type test for children, we decided to apply it, modifying the question about the consumption of antihypertensive drugs by the consumption of steroids during cancer treatment.
The following parameters of each of the children were collected: age, sex, neoplasia diagnosed, chemotherapy received, FINDRISC score, glycosylated hemoglobin, cholesterol, triglycerides, blood pressure, WC, weight, height. For each child and parameter, the international percentiles tables recommended by WHO and does published for Mexican children were used to determine the real values according to sex and age of the child for each parameter.
Height and weight were measured to 0.1 cm and 0.1 kg, respectively, using a BAME 5282 scale with stand on scale. The BMI was calculated and expressed as an age and sex-specific percentile. We used the anthropometric data recommended for Mexican boy’s and girl’s population using percentile charts. Also, we used international BMI for age reference data provided by WHO.19–23
Overweight and obesity were defined by the Cole-IOTF approach, based on BMI for age.20–23
Metabolic Changes Measurements
The presence or absence of the MS was defined by the International Diabetes Federation as having central obesity assessed by WC plus 2 or more of the following criteria elevated HDL-Cholesterol, triglycerides, blood pressure, glycosylated hemoglobin.24
Capillary blood lipid and glycosylated hemoglobin concentrations were determined in the morning after an overnight fasting period of at least 8 hours. Capillary total cholesterol and triglycerides concentrations were determined with the Accutrend Plus.25 Glycosylated hemoglobin was measured with the DCA 2000 (Bayer Diagnostics, Milan, Italy). This system uses an immunochemical technique with a monoclonal antibody.26
Blood pressure (BP) was measured using a BP cuff (Hewlett Packard, Palo Alto) with a specific size to child/pediatric. The measurements were taken 2 times on the right arm with short intervals between readings, and the average of the 2 BP readings was calculated and used for analysis according to international guidelines.27,28
All the statistical analyses were performed using the SSPS statistical software (version 21.0. Armonk, NY: IBM Corporation).
Because of the absence of the control group, it is only possible to carry out a qualitative descriptive analysis of the data obtained from the children’s data.
An analysis of variance was performed to determine the correlation between variables (triglycerides, cholesterol, and WC) to determine the presence of MS. Statistical significance was accepted at the P<0.05 level.
The protocol was approved by the University bioethics committee and all the patient’s tutors signed an informed consent. Patient data are protected confidentially. The bioethics committee did not authorize to obtain blood from healthy children as the study control.
The population of children studied was composed of 52.27% of girls and 47.72% of boys with an average age of 10.7±4.9 years old (11.3±7 y old for boys and 10.6±4.9 y old for girls). The average of surveillance time after chemotherapy was 2.09±0.7 years.
The Cancer distribution of the population is presented in Figure 1, as expected in children, the most common cancer was leukemia with 65%.
The population was then studied according to the height and weight percentile, those who were below the 30th percentile was considered with a low height, between 30 and 70 considered normal and those who were above the percentile 70 were classified as high height (Table 1). The data show that more than a half of the sample was of unhealthy weight status (underweight, overweight, obese).
Afterward, with the height and weight data, the BMI was calculated and the group was classified according to the BMI percentile by age and sex, considering those in the below the percentile 5 with low BMI, from 5 to 85 percentile with normal BMI, those between 85 and 95 with overweight and above the percentile 95 were in obesity (Table 2).
The WC was calculated, those who the WC were <90 were considered normal, and with overweight, all those who the WC were >90 (Table 2).
The blood pressure of all the children was measured and it was evaluated according to the percentile in which they were found according to their age and sex, to calculate if they were in normal levels obtaining that there were 3 prehypertensive girls and 2 hypertensive boys.
According to the quantification of glycosylated hemoglobin, we found that 9 children had high levels of glycosylated hemoglobin (7 females and 2 males). Only both of them have previous Knowledge about glucose high levels.
The triglycerides analysis showed that 25% of the population had high levels of triglycerides and the cholesterol shows that 7% of the group has high levels (Table 2).
We decided to analyze each parameter of the FINDRISC test first, and we find that 60% of the children do not do any physical activity and neither consumes vegetables and fruits daily.
Regarding the modified question about whether children consumed steroids, we found that 77% of children had received steroids during their treatment, and the 15.3% received radiotherapy in head and trunk.
Only 5.7% of the mothers remember to be diagnosed with gestational diabetes and 30% of the population has familiar diabetes antecedents.
Also the birth weight was evaluated, taking as a reference the value of 2500 g to be considered as low weight or 3500 for high weight, the results show that 19.23% of the group had high birth weight (22.2% girls vs. 16% boys) and 11.5% were classified as low birth weight (7.4% girls vs. 16% boys).
When the total FINDRISC score was calculated we found that 17.3% of the children had high-risk FINDRISC scores, 23% moderate risk, and the rest of the population were normal.
The International Diabetes Federation defines the MS for children from 10 to 16 years old when the individual has abdominal obesity (defined by the WC percentile ≥90) and 2 of the following criteria triglycerides and cholesterol above 150 mg/dL, hypertension (percentile ≥90), and abnormal arterial pressure or carbohydrate metabolism (glucose). We did a variable correlation with an analysis of variance, and the correlation between triglycerides, cholesterol, and WC in our group was P<0.00001 with an F ratio equal to 25.92.
One of the main limitations of the present study was the absence of a control group due to bioethical limitations associated with the use of blood from healthy children, so the data reported in the literature for healthy children were used as reference data.
Cancer in children is a relatively rare disease, but it is considered one of the most important causes of death by disease among children, the highest leukemia rates correspond to Hispanic children. The children survival comes with a “cost,” 75% of those who survive will face a chronic health condition, in children these late effects are more aggressive than when the treatment is applied in an adult.29
Our data showed that the population presented abnormal anthropometric data such as high percentile weight (42.3%), high weight percentile (21%), and 50% of the child were classified in the percentile ≥90 for WC. Among 21.5% of our population had overweight or obesity (BMI ≥85% percentile). These data are similar to those reported by Esbenshade10 and Reisi et al30 who found an increase in obesity in children with chemotherapy. Childhood cancer survivor studies showed that patients treated with chemotherapy had an increment in their weight, as high as 40% five years after cancer treatment, plus 21.2% of the survivors were classified as obese (BMI >95th) and 20% as overweight (BMI >85th).30–32 Meacham et al,33 suggests that both treatment-related cardiovascular risk factors and obesity are increasing among survivors of childhood cancer, their results showed that children survivors are 7 times more likely to die as adults from cardiac-related diseases than those in the general population.34
These anthropometric data are a strong predictor of cardiovascular disease risk in children.35
The metabolic data showed that 5 children already had hypertension and the lipid results were worrying because >50% of our population showed increased triglycerides levels and 14.8% abnormal cholesterol levels, which are associated with diabetes mellitus and cardiovascular disease.
The FINDRISC data found that 40.3% of the children surveyed have the possibility of developing type II diabetes in the future; the FINDRISC is probably one of the most effective tools to prevent diabetes. The International diabetes federation, proposes that in children under 10 years old, it is difficult to define the presence of MS, but after the 10 years is possible to establish MS, with the following criteria abdominal obesity plus the presence of 2 or more other components (elevated triglycerides, low high–density lipoprotein, high cholesterol, high blood pressure, elevated plasma glucose), our data showed that almost 30% of our population are detectable with MS development.
On the basis of our study findings, unhealthy weight status and body composition appear to be quite common among the children cancer survivors. MS as a highly morbid disease and should be considered important in childhood cancer survivors, all these data suggest that it is necessary a metabolic follow-up of children cancer patients, even years after treatment.
The authors thank all the children that assist to Una Nueva Esperanza ABP, and Francisco Alvarez for his unconditional support.
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