Metabolic Syndrome in Childhood Cancer Survivors: Does Delta BMI Predict Risk in Lower-middle-income Countries?

Purpose Metabolic syndrome (MetSyn) is an important late effect of childhood cancer. The combination of rising obesity and high prevalence of under-nutrition at diagnosis, make this a unique population to study in LMIC (lower middle-income countries). Methods Children <18 years of age at cancer diagnosis, in a single-centre in a LMIC, who were disease free and had completed treatment at least 2 years prior to study were included. MetSyn was dened using International Federation for Diabetes criteria for Asian Indians. Logistic regression analyses were carried out to evaluate the inuence of various risk factors, including delta BMI (increase in body mass index from diagnosis to evaluation), on MetSyn. Results A high prevalence of MetSyn (12.2%), central obesity (33%), and dyslipidemia (61.8%) was found in a cohort of 500 Asian Indian childhood cancer survivors (CCS) at a median follow-up age of 17 years. Multivariable analysis revealed older age at diagnosis >10 years, OR 2.9(1.6-5), longer survival duration >10 years, OR 2.2(1.3-3.8), high BMI at diagnosis OR 3.2(1.5-6.9) and large delta BMI >50, OR 3.15(1.7-5.9) to be independent predictors of MetSyn. Patients who were under-weight or normal at diagnosis with large Delta BMI > 50 had very high odds (OR, 12.5,1.7-92) of developing MetSyn compared to those with lower Delta BMI. Conclusions and implications for cancer survivors: A high prevalence of MetSyn was observed in CCS with early age at onset. Timely screening and early intervention are proven to be benecial and delta BMI could be a useful screening tool for LMIC.


Introduction
With improved survival of childhood cancers, late effects have emerged as a serious area of concern. As a result, survivors of childhood cancer are at an increased risk of chronic health conditions such as cardio-metabolic disorders, pulmonary problems, stroke, diabetes and second neoplasms. This is true even in the lower middle-income countries (LMIC) as evidenced by an ever-increasing number of survivors, particularly in Asian Indians [1][2][3]. Of concern is the substantially elevated risk of cardiovascular diseases (CVD) observed in numerous investigations worldwide [4][5][6][7][8] and Oe nger et al observed this risk to be 10 times higher in childhood cancer survivors (CCS) in the US as compared to their siblings [8]. Metabolic syndrome (MetSyn) is an important predictor of CVD and constitutes a cluster of risk factors including obesity, glucose intolerance, insulin resistance, dyslipidemia, and hypertension [9]. Although the epidemiology of MetSyn is multifactorial, it is to a large extent determined by modi able factors like obesity, dietary habits and sedentary life style.
Recent data shows that obesity, is rising in every region of the world, and may in fact be increasing more rapidly in the LMIC than in the high-income countries (HIC) [10][11][12]. Furthermore, the majority of undernourished children live in LMIC [13]. Hence, child under-nutrition and adult obesity coexist in many LMIC (e.g., India), leading to sarcopenic obesity wherein de cits of muscle mass relative to fat persist into adulthood. This dual combination has been implicated as a risk factor for cardio-metabolic disorders unique to LMIC [14][15][16][17]. Recent studies indicate that even among those who are not overweight or obese, the increase in BMI (delta) during growth and development should be closely monitored, as it may predict early onset MetSyn [18]. Hence, we planned to study delta BMI in this context as it has not previously been evaluated among CCS. The present study aims to address this knowledge de cit by analyzing the prevalence of MetSyn in CCS in a LMIC setting and determine the risk factors associated with it.

Patient selection
This was a cross-sectional, observational, single-centre study, conducted over a period of 18 months, from July 2018 to December 2019, in a tertiary care cancer centre. The Pediatric Oncology department of our Institute runs an after completion of therapy (ACT) clinic, where all off-therapy patients are registered.
The hospital and ACT e-database were mined to identify CCS who were ≤18 years at diagnosis, in complete remission and at least two years from treatment completion. Among 1430 patients registered in the hospital, data for 954 patients was available in the ACT e-database, of these 714 could be contacted telephonically; 500 consented and were evaluated at the ACT clinic. The evaluation comprised a complete history (including details of anti-hypertensive and anti-hyperglycemic medication), physical examination, anthropometry, and laboratory tests. Demographic, socioeconomic, disease and treatment details were extracted from the e-medical records. Exposure to various classes of chemotherapeutic agents (anthracycline, alkylating agent, anti-metabolite), steroids and cumulative equivalence doses of anthracycline were calculated. Radiation elds and doses were obtained and categorized as cranial, head and neck (not brain), chest, abdomen/pelvis, extremity and other). Assessment of urban/ rural residence and socioeconomic class was done based on the Kuppuswamy scale (based on overall family income, occupation and education) [19]. The study received approval from the Institute's ethics committee and written informed consent was obtained from patients/parents (for minors).
BMI was calculated as: BMI= weight (kg)/ height 2 (m 2 ). Nutritional status was de ned as per Centre for Disease Control (CDC) and WHO criteria using Asia-Paci c guidelines for South Asians: age 5-19 years, BMI <5 th percentile was de ned as underweight, BMI = 5 th to <85 th percentile de ned as normally nourished, BMI > 85 th to <95 th percentile as overweight and >95th percentile as obese, adjusted for age and sex; age >19 years, BMI <18.5 kg/m 2 were de ned as underweight, normal BMI range was 18. 5-22.9 kg/m 2 , BMI >23 kg/m 2 to <25 kg/m 2 was de ned as overweight and those with BMI >25 kg/m 2 as obese [20,21]. Delta BMI was calculated as the percentage change in BMI z-score from diagnosis to follow-up evaluation. Delta BMI = [(BMI z-score at evaluation -BMI z-score at diagnosis) / BMI z-score at diagnosis] x 100. Waist circumference (WC) was measured midway between the lowest rib and the top of the iliac crest at the end of expiration in a standing position using a berglass tape with an accuracy of 1 mm. For survivors <18 years of age at evaluation, age-and sex-speci c reference percentiles for WC reported in Indian children by Khadilkar et al. were utilized as normative data for de ning central obesity [22].
International Diabetes Federation (IDF) criteria for Asian Indians were utilized for adults [23]. Blood pressure (BP) was measured in the right upper arm in sitting position using mercury sphygmomanometer with an appropriate size cuff. Hypertension (HT) was de ned as systolic or diastolic values ≥90th percentile for age, sex, and height. Blood biochemistries included fasting blood glucose (FBG) and lipid pro le after 12 hours of overnight fasting.

Statistical analysis
The participants' demographic, disease and treatment details were analysed by descriptive statistics and mean (± standard deviation, SD) or median (inter quartile range, IQR) were used as appropriate. Fischer's exact test and chi-square test were utilized for categorical variables. Quantitative variables were compared using the Student t-test or the Mann-Whitney test. Analysis of variance (ANOVA) was used to compare delta BMI among various nutrition categories (underweight and normal versus overweight and obese). Logistic regression analysis was done to investigate the in uence of various pre-treatment and treatment related factors on MetSyn among the survivors. Adjusted OR was calculated to study the impact these factors on individual components of MetSyn. Factors with p value <0.05 on univariate analysis were included for multivariable analysis. A receiver operating characteristic (ROC) curve was plotted to determine the cut-off value of delta BMI to predict MetSyn. The results were interpreted using odds ratio (OR) and 95% con dence interval (CI), and the signi cance threshold was set as p-value of <0.05. Statistical analysis was performed using the SPSS software (version 23.0, 2011; IBM, Armonk, NY, USA).

Delta BMI and Nutritional status
Calculation of means and SD of percent BMI z-score increment from diagnosis to evaluation (delta BMI) revealed that the highest delta BMI occurred among those who were underweight (74+2) and normally nourished (123+53) at diagnosis, followed by those who were obese (15.8+1.4) and overweight (7.9+1.5), p, 0.04 (Supplemental Table 1). The ROC curve analysis (Supplemental Figure 1) revealed that underweight and normal patients who had >50 percent increase in delta BMI, had 12.5 (1.69-92) times higher odds of MetSyn compared to those with a smaller delta BMI (<50); and the odds were 43 (5.8-315) times for those with delta BMI of 108 percent (Table 3).  Table   2). , when compared to those not exposed to CRT of the same age.

Discussion
The present study demonstrates a high prevalence of MetSyn and its components in long term Asian Indian survivors of various childhood cancers. The prevalence of MetSyn was age dependent (Figure 1), being lower among children and adolescents (6%) and higher among the adult (19%) survivors. The data from published National studies on healthy individuals revealed that the prevalence of MetSyn in children/adolescents (1-3%) and adults of similar age (11-13%) was signi cantly lower than in the present analysis [25][26][27][28][29][30]. It is well established that MetSyn increases with increasing age, however the higher prevalence in survivors compared to the healthy population is noteworthy and concerning [29][30][31][32][33].
Furthermore, the prevalence of MetSyn and its components in CCS are known to vary with ethnicity, and duration of follow-up, in addition to age. Compared to published literature from Asia, and Europe (France, Netherlands) the current analysis reveals a higher prevalence of MetSyn and at an earlier age [34,35]. However, it is lower than that reported from US by the St Jude Lifetime Cohort Study (34%) although they had a much longer follow-up and older age at evaluation [6]. The present study demonstrates a 12.2% prevalence of MetSyn in a cohort of 500 CCS in a tertiary care centre in a LMIC at a median followup age of 17 years at evaluation. This is higher than that previously reported from Asia (including India), wherein MetSyn was observed in 1.3-8% of pediatric and 10-12% of adult CCS [36][37][38]. This may be partly explained due to the fact that these studies had a shorter follow-up and younger age at evaluation. High prevalence of MetSyn at an early age among CCS in our study and its potential adverse implications on health and quality of life reinforces the need for increasing awareness for its early identi cation. This assumes greater signi cance as it is often an ignored and underestimated late effect and early institution of preventive strategies and lifestyle modi cation may signi cantly delay or reverse the associated longterm morbidities.

Components of MetSyn
Two MetSyn components, low HDL-c (61.8%) and central obesity (33%) were observed in a large number of CCS and were much higher than values reported from HIC [6,35]. This observation may be explained by ethnic differences in patterns of dyslipidemia and obesity in Asian Indians and also the trend of increasing obesity in LMIC in recent times. Investigators have shown that compared to other ethnic groups, children with ancestral origin in South Asia manifest central adiposity, insulin resistance and metabolic perturbations earlier in life and these derangements are of higher magnitude than white Caucasian children [30]. Both these components are associated with high odds of developing MetSyn and known to predispose to atherosclerotic heart disease [6, 31,35]. Therefore, regular assessment of these individual components may aid in early identi cation of CCS at risk of developing MetSyn. This may also facilitate streamlining ACT activity and allocation of adequate manpower and resources to institute frequent monitoring, and counselling for aggressive risk-reduction strategies.

The risk factors
Delta BMI It is well established that obesity is the central factor in the pathogenesis of insulin resistance and MetSyn [35]. However, it is noteworthy that most of our CCS who developed MetSyn were nonobese/overweight at diagnosis and a high delta BMI at follow-up strongly predicted MetSyn (OR 12.  34,[40][41][42]. Despite having a large cohort of ALL survivors we were unable to elicit cranial RT as a risk factor. The primary mediator of MetSyn associated with CRT is believed to be growth hormone de ciency leading to obesity and dyslipidemia and has been reported with RT doses of 18-24 Gy for ALL and > 25 Gy for brain tumor. The CRT doses administered to majority of our ALL patients was lower (12.6 Gy) and may explain our observation that, except for exposure to CRT in very young children (<5 years) with ALL, we did not observe it to be a risk factor. Furthermore, our cohort included small numbers of survivors of brain tumor and BMT that precluded meaningful analysis.
The main limitation of our study is that it was a cross-sectional cohort study and lacked serial, annual BMI assessments during follow-up. Furthermore we did not have age-and sex-matched control group for comparison. Nonetheless it has a number of strengths, it is one of the largest studies from a single LMIC centre wherein MetSyn was classi ed based on IDF criteria. It provides valuable insight into the risk factors of MetSyn in CCS and highlights the novel predictive role of delta BMI in LMIC.

Conclusion
The present study demonstrates Asian Indian CCS to be at high risk for MetSyn and its components at an early age. Obesity and dyslipidemia were the two major contributing factors for its development and are both modi able with lifestyle changes. Monitoring delta BMI during follow-up can be a useful tool for early identi cation of non-obese/overweight CCS, at risk of MetSyn that needs validation in larger longitudinal cohort. Due to the manifold increased risk of morbidity and mortality as a consequence of MetSyn, there is an overwhelming medical and ethical imperative for its early detection and timely intervention. Further research into the genetic landscape of MetSyn may help to better predict risk and individualize cancer treatment thereby leading to lower toxicities in the future.

Abbreviations
Not applicable • Con icts of interest/Competing interests: none • Ethics approval (include appropriate approvals or waivers): The study was approved by the ethical committee of the institute • Consent to participate: Informed consent was obtained from all individual participants/guardians included in the study.
• Consent for publication: The participant has consented to the submission of the data in the manuscript to the journal.
• Availability of data and material (data transparency):