Introduction

Survival in childhood cancer has significantly increased above 80% in developed nations of the world. As the survivors of childhood cancer continue to increase, there is an exponential need for evidence-based surveillance of the long-term effects of cancer therapy. Endocrine and metabolic complications are more prevalent in childhood cancer survivors (CCSs). Bhatia et al reported in their recent review that the most common adverse effects in individuals who survived childhood cancer are endocrine disorders, such as hypothyroidism (HT) or growth hormone deficiency (GHD; 44%).1 There is a need for clinicians and patients to have heightened awareness of these complications to diagnose them promptly and early intervention is very important.

Methods

This hospital-based descriptive study was conducted in the Department of Pediatric Hemato-oncology at our tertiary care institution from August 2015 to August 2017. Children between the ages of 2 and 18 years who have completed at least 1 year after cancer treatment (chemotherapy/radiotherapy/surgery/combination of these) were included in the study. Written consent was obtained from the parents.

After enrolment, anthropometric parameters (height, weight, body mass index [BMI], pubertal evaluation, systolic and diastolic blood pressure). All anthropometric measurements were measured (as per-existing protocols) in triplicate and averaged. For all anthropometric data, World Health Organization (WHO) 2006 charts were used for children aged 2 to 5 years and revised Indian Academy of Pediatrics 2015 charts were used for children aged 5 to 18 years of age.2 Height, weight, and BMI were converted to standard deviation scores for ease of analysis across different ages in the study population. For pubertal stage assessment, Tanner's sexual maturity rating was used.34 For further statistical analysis, all children with Tanner stage 1 were grouped as prepubertal and children with Tanner staging 2 to Tanner staging 5 were grouped as pubertal. Ethical approval was obtained from the institutional ethics committee (Ref. no. CSP-MED/15/AUG/24/46).

As per study protocol, 8 mL blood was drawn for lipid profile (total cholesterol, triglycerides, high-density cholesterol, and low-density cholesterol), fasting glucose, fasting insulin, thyroid-stimulating hormone (TSH), and FreeT4 (FT4). NHLBI (National Heart, Lung, and Blood Institute) cutoffs were used for lipid profile.5 For defining metabolic syndrome, WHO definition was used.6 Fasting hyperinsulinism was defined by fasting insulin level >15 mIU/mL for prepubertal children or >26 mIU/mL for pubertal children.7 Insulin resistance was analyzed by homeostasis model assessment of insulin resistance (HOMA-IR) using the formula [FBG (mg/dL) × FI (μU/mL)/405].8 Fasting insulin, TSH, and FT4 were analyzed by chemiluminescence immunoassay. Fasting glucose was done by the glucose oxidase peroxidase method. Lipid profile was analyzed using cholesterol oxidase and enzymatic end-point analysis.

All descriptive data were expressed as mean ± standard deviation. Qualitative data were compared by the Chi-square test. Comparison of means was done using Student's t-test. Statistical significance was taken as p <0.05. All statistical analyses were performed using SPSS version 16.

Results

Clinical and biochemical data are described in Table 1. The mean age of study population is 9.4 ± 4.8 years; 64% in the study were boys. Fifty-six children (57.7%) had hemato-lymphoid malignancies, and 41 children (42.3%) had solid tumors. In this cohort, 52 children were prepubertal (53.6%) and 45 children (46.4%) were in pubertal stage of Tanner 2 and above. Fig. 1 represents the distribution of malignancies observed in the study population.

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Fig. 1: Common malignancies observed in the study population. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; GCT, germ cell tumor; HL, Hodgkin's lymphoma; NHL, non-Hodgkin's lymphoma; PNET, primitive neuroectodermal tumor.

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Among treatment options, chemotherapy alone was received by 54 children (55.6%), 2 children received radiotherapy alone (2.1%), surgical approach alone was needed in 4 children (4.1%). Combined therapies like chemotherapy + radiation, chemotherapy + surgery, and chemotherapy + radiotherapy + surgery were received by 12 (12.4%), 20 (20.6%), and 5 (5.2%), respectively.

Among the cancer survivors, 84 children (84.5%) had at least one endocrine or metabolic complication and 41 children (42.3%) had more than two endocrine or metabolic complications. Among the complications, HT was observed in 5 (5.1%), short stature in 6 (6.2%), and precocious puberty in 6 children (6.2%). Overt HT was observed in one child with short stature. Among metabolic complications, 8 children (8.8%) had obesity, 11 children (11.3%) had systolic hypertension, 18 children (18.6%) had diastolic hypertension, 4 children (4.1%) had impaired fasting glucose, 31 children (32%) had fasting hyperinsulinism, 66 children (68%) had dyslipidemia, and 8 children (8.2%) had metabolic syndrome (Table 2). Among children less than 5 years of age, moderate acute malnutrition was observed in 3 children (3.1%) and severe acute malnutrition was observed in 2 children (2.1%).

As shown in Table 3, HT was frequently observed in children receiving radiotherapy (3 children out of 19 children receiving radiotherapy, odds ratio [OR]: 7.13, 95% confidence interval: 1.1–46.2, p = 0.019).

Metabolic syndrome was frequently observed in children treated with L-asparaginase compared with those not treated with L-asparaginase (16.2 vs. 3.3% respectively, OR: 5.61, 95% confidence interval: 1.07–29.5, p = 0.025) and details are shown in Table 4.

No significant differences were observed with the incidence of endocrine and metabolic complications based on the type of tumor, gender, and pubertal status (Tables 234).

Discussion

Nearly two-thirds of all CCSs will suffer some late effect, and the endocrine system is commonly involved.910 Wheeler et al in their systematic review of the risk of radiation-related central endocrine effects including 4,629 publications, with a total of 570 patients, showed 18 cohorts reporting GHD, 7 reporting for central HT, and 6 reported adrenocorticotropic hormone deficiency.11

These are further influenced by the age at which treatment was initiated, the length of time since treatment, and gender.1213 HT, pituitary disorders, and pubertal disorders are the most common endocrine sequelae observed in several studies.141516 Our study shows that endocrine and metabolic complications are observed as early as 1 year of survival.

In the study by Sánchez González et al14 among 55 CCSs enrolled with minimum of 2-year survival period, primary hypogonadism was the common endocrine sequelae, followed by pituitary and thyroid disorders. Similar observations were seen in studies by Shalitin et al.15 However, in our study, obesity, short stature, precocious puberty, and HT were observed to be the commonest endocrine abnormalities and dyslipidemias, the commonest observed metabolic abnormality. This could be due to the differences in the study population enrolled and the type of therapies received.

Survivors who have received 20-Gy cranio-spinal radiotherapy had the highest risk for developing HT.1617 The Childhood Cancer Survivor Study cohort had observed a cumulative incidence of HT of 1.6%.17 In our study, HT was observed in 15.8% of patients receiving radiotherapy.

The risks of obesity and diabetes mellitus are significantly higher in CCS than in their siblings.13 Metabolic syndrome has been shown to affect a sizeable proportion of survivors (31.8%) and at a higher rate than in the general population of adults younger than 40 years of age (18.3%).1718 Alkylating agents, glucocorticoids, and irradiation are observed to be the most common causes of metabolic complications. However, in our study, metabolic syndrome was observed to be more frequent in children receiving L-asparaginase therapy (16.2%). To the best of our knowledge, no such associations have been shown for L-asparaginase therapy. Steroids being the backbone of acute lymphoblastic leukemia management could be a confounder for this observation.

Ours was a single-center study with a small sample size. Long-term follow-up is needed to confirm the study findings. Nevertheless, our study adds up to the observation of endocrine and metabolic complications in CCS in as early as 1 year following cancer treatment.

Conclusion

Significant endocrine and metabolic complications are observed among CCSs, as early as 1 year from the completion of treatment. Timely and appropriate recognition of these complication is necessary for optimal health care of these children.