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Indian Pediatr 2021;58:436-440 |
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Obesity and Sarcopenia
in Survivors of Childhood Acute Lymphoblastic Leukemia
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Payal Malhotra, 1 Gauri
Kapoor,1 Sandeep Jain,1
Silky Jain,1 Anurag Sharma2
From Departments of 1Pediatric Hematology Oncology and
2Biostatistics, Rajiv Gandhi Cancer Institute and Research Centre,
Rohini, Delhi, India.
Correspondence to: Dr Gauri Kapoor, Department of Pediatric
Hematology Oncology, Rajiv Gandhi Cancer Institute and Research Centre,
Rohini Sector 5, Delhi, India.
Email: [email protected]
Received: May 26, 2020;
Initial review: June 29, 2020;
Accepted: September 17, 2020.
Published online: January 02, 2021;
PII:
S097475591600268
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Objective: To describe the prevalence of obesity
and sarcopenia among survivors of childhood acute lymphoblastic leukemia
(ALL) using DEXA scan, and study associated risk factors. Methods:
This case control study was conducted between July, 2013 and June,
2014 at a tertiary care cancer centre in India. Study
participants included 65 survivors of childhood ALL who were <18 years
of age at diagnosis, treated between years 1996 and 2008, and were at
least two years since completion of therapy. The controls included 50
matched siblings. Dual energy X-ray absorptiometry (DEXA)
was used to study the body composition (body fat percentage, BF% and
lean body mass, LBM) of the participants and controls. McCarthy’s body
fat reference data were applied and logistic regression analysis was
used to study various risk factors. Results: At a median (range)
follow-up of 5 (7.2-17.2) years, BF% (DEXA) identified a significantly
higher prevalence of obesity of 21.5% (14/65) and sarcopenic obesity
(14%) among survivors as compared to the controls (0/50, P<0.001),
while the prevalence of sarcopenia as detected by LBM was similar at 60%
(39/65) and 56% (28/50), respectively. On multivariate analysis, age at
evaluation, high-risk disease and cranial irradiation were independently
associated with high likelihood of obesity, while none of the factors
predicted sarcopenia. Conclusion: High prevalence of obesity and
sarcopenic obesity were observed among survivors of childhood ALL.
Keywords: Body composition, Body fat, DEXA, Lean body mass,
Metabolic syndrome.
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Obesity is recognized
as a common chronic health problem in childhood cancer
survivors, and cardiovascular disease has been shown to occur at
an earlier age in survivors of childhood cancer [1-4]. As acute
lympho-blastic leukemia (ALL) is the commonest childhood cancer,
we aimed to study the prevalence of obesity and sarcopenia among
survivors of childhood ALL using DEXA scan, as compared to
sibling controls, and evaluate association with risk factors.
METHODS
This study was conducted between July, 2013
and June, 2014 at the pediatric hemato-oncology department of
our comprehensive cancer center. The study participants (cases)
included survivors of childhood ALL who were less than 18 years
of age at diagnosis, treated between 1996 and 2008, in first
complete remission, and were at least two years after completion
of therapy. Of the total 207 ALL patients that were treated, 122
were eligible for the study and we were able to contact and
obtain consent from 65 children and young adult survivors (52
males). The treatment protocol was based on a Berlin Frankfurt
Munster (BFM) backbone that included a four-drug induction and
prednisolone as the glucocorticoid [5]. Their results were
compared with 50 healthy sibling controls that were matched for
age (±1 year) and sex. The controls were determined to be
healthy and eligible for the study if there was no evidence of
any medical illness on detailed history and physical
examination. The study was approved by the institutional ethics
committee and conducted after obtaining informed consent from
the study participant or parents (in case of minor).
Details of method of measuring anthropometric
indices (weight, height, BMI) and physical activity quotient
(PAQ) have been previously published [5]. Three-compartment body
composition was assessed using DEXA and Hologic Explorer (S/N
91531) software version 13.3:3. The DEXA machine directly
generates absolute values as well as Z scores for bone
mineral content, and lean body mass (LBM) measures, as the
National Health and Nutrition Examination Survey (NHANES)
reference data is integrated into the software.
Study participants’ body mass index (BMI)
status was determined by using WHO BMI growth charts and
categorized as normal weight (BMI >5th to <85th percentile),
overweight (>85th to <95th percentile), or obese (BMI
³95th
percentile) [6,7]. High adiposity was defined as body fat
percentage (BF%) levels higher than the 85th percentile of
McCarthy BF% reference data (NHANES) for each age-sex group
(overweight ³85th
percentile and obesity ³95th
percentile) [8,9]. Sarcopenia was defined as LBM <5th percentile
of reference data (NHANES). Sarcopenic obesity was defined as
participants fulfilling criteria for sarcopenia and obesity by
BF% and LBM [8]. Body fat mass index (BFMI) and lean body mass
index (LBMI) were calculated from DEXA-measured body-composition
data as BF or LBM in kg per m2 height.
Statistical analyses: The body
compositions of two groups such as weight, height, BMI, BF %
etc. were compared using independent t test and
chi-square test. Analysis of variance (ANOVA) was used to
compare delta BMI change among thin, average and overweight
patients at diagnosis. Univariate and multivariate logistic
regressions were used to study the influence of various
demographic and disease-related factors for obesity and
sarcopenia among the survivors. The results were interpreted
using odds ratio (OR) and 95% confidence interval (CI). The
Statistical Package for Social Sciences for Window’s software
(IBM SPSS Statistics version 23.0) was used for all analyses.
Significance was set at P<0.05.
RESULTS
At the time of evaluation, the 65 study
participants [median (range) age, 15 (7.7-27.5) years] were
median (range) 4.3 (2-14.8) years from treatment completion, and
had a median (range) follow-up of 7.2 (5-17.2) years.
The values for body composition for the
survivors and the control groups are provided in Table I.
The mean (SD) BF% was significantly higher among ALL survivors
as compared to the controls [35.2 (7.4) vs 30.2 (8.0);
P=0.001], and a similar trend was observed when analyzed by
gender. Using BF%, obesity was observed among 21.5% (14/65) of
study participants and none of the controls (P=0.00) and
overweight among 55% (36/65) and 48% (24/50) of cases and
controls respectively (P=0.7). On the other hand BMI
under-estimated obesity (6%, 4/65, P=0.02) and overweight
(26%, 17/65, P=0.01) among the study participants. It
also detected fewer control participants to be overweight (6%,
3/50, P=0.01).
Table I Body Composition by DEXA Scan and Anthro-pometry of Survivors of Childhood
Acute Lymphoblastic Leukemia and Sibling Controls (N=115)
| Characteristics |
ALL survivors |
Controls |
P value |
|
(n=65) |
(n=50) |
|
| Weight, kg |
50.9 (16) |
48.5 ( 16.3) |
0.42 |
| Height, cm |
154.6 (15.3) |
156 (14.9) |
0.61 |
| BMI, kg/cm2 |
20.8 (3.7) |
19.3 (3.8 ) |
0.03 |
| Body fat, % |
35.2 (7.4) |
30.2 (8.0) |
<0.001 |
| BFMI |
7.26 (2.4) |
5.8 (2.3 ) |
<0.001 |
| Lean body mass |
30355.9 (9886.1) |
32092.7 (10644.6) |
0.38 |
| LBMI |
12.3 (2.1) |
12.5 (2.5) |
0.68 |
| Trunk/Leg fat % |
0.9 (0.6) |
0.8 (0.5) |
1.0 |
| Trunk lean mass |
14861 (5000.9) |
15835.93 (5509.8) |
0.33 |
| All values in mean
(SD). DEXA: Dual energy X-ray absorptiometry; ALL: Acute
lymphoblastic leukemia; BMI: Body mass index at
evaluation; BF%: Body fat percentage; BFMI: Body fat
mass index; LBMI: Lean body mass index. |
We further looked at WHO BMI z-scores
at diagnosis and noted that 10/65 (15%) were underweight/thin,
9/65 (14%) were overweight, and none was obese. While at
evaluation, these proportions changed to 26.1% (n=17)
overweight and 6.1% (n=4) obese, respectively. No
participant was underweight/thin. Delta BMI change was
calculated from baseline BMI percentile, which revealed that the
highest mean (SD) delta change occurred among thin [2067(882)]
followed by normal [273(50)] and overweight [45(30)] patients, (P<0.001).
The absolute values for LBM and LBMI for the
study participants’ were lower than the controls but this was
not statistically significant (P=0.38, 0.68) (Table I).
The prevalence of sarcopenia was similar in both the groups
(39/65, 60%; 28/50, 56%), respectively (P=0.10). However,
the female survivors (11/13, 85%) were more sarcopenic compared
to their male counterparts (28/52, 54%) (P=0.05).
Sarcopenic obesity was observed among 14% (9/65) of study
participants and none of the controls (P=0.00). Of these
9 patients, 1 was thin and none were overweight or obese based
on baseline BMI, this difference was not statistically
significant (P=0.29).
Table II Demographic and Disease Characteristics of Obese and Sarcopenic Survivors of
Childhood Acute Lympho-blastic Leukemia (All)
| Characteristic |
Survivors |
Obese |
Sarcopenic |
|
(n=65) |
(n=14) |
(n= 39) |
| Male |
52 (80) |
6 (42.9) |
29 (74.4) |
| Age at diagnosis <10 y |
19 (29.2) |
14 (100) |
26 (66.7) |
|
T cell immunophenotype |
14 (21.5) |
4 (28.6) |
8 (20.5) |
| High NCI risk |
30 (46.2) |
5 (35.7) |
19 (48.7) |
| Cranial radiation |
31 (47.7) |
4 (28.6) |
19 (48.7) |
| >5 y after therapy |
29 (44.6) |
4 (28.6) |
19 (48.7) |
| Age at evaluation <10 y |
10 (15.4) |
6 (42.9) |
7 (17.9) |
| High BMI |
21 (32.3) |
14 (100) |
1 (2.6) |
| Sarcopenic LBM |
39 (60) |
9 (64.3) |
39 (100) |
| Normal PAQ score |
21 (32.3) |
13 (92.9) |
27 (69.2) |
| All values in no. (%).
DEXA: Dual energy X-ray absorptiometry; NCI: National
Cancer Institute; BMI: Body mass index at evaluation;
LBM: Lean body mass; PAQ: Physical activity quotient. |
Distribution of demographic, disease and
treatment exposure among participants who were obese or
sarcopenic is displayed in Table II. The study
participants had a 28 times higher odds of being obese compared
to the controls [OR (95% CI) 28 (1.7 to 490); P=0.002] .
On univariate logistic regression analysis female gender, age at
diagnosis less than 10 years, T immunophenotype, high NCI risk,
receiving cranial irradiation, more than 5 years since therapy,
younger age at evaluation, being sarcopenic, and PAQ>2 were
significantly associated with obesity. On multi-variate
analysis, only female gender [OR (95% CI) 7.3 (1.1-50.1); P=0.04],
high NCI risk category [OR (95% CI) 6.7 (1.1-43.5); P=0.04],
cranial irradiation [OR (95% CI) 9.9 (1.2-83.3); P=0.04],
and younger age [OR (95% CI) 10.2 (1.1-91.4); P=0.04],
had a significant association with obesity.
Table III Multivariate Logistic Regression Analysis of Obese and Sarcopenic Survivors of
Childhood Acute Lymphoblastic Leukemia (N=65)
| Variables |
Odds ratio (95% CI) |
P value |
| Female |
7.3 (1.1-50.1) |
0.04 |
| Age at diagnosis (<10y) |
1.2 (0.2-7.5) |
0.85 |
|
T Immunophenotype |
1.9 (0.1-25.6) |
0.63 |
| High NCI risk |
6.7 (1.1-43.5) |
0.04 |
| Cranial radiation |
9.9 (1.2-83.3) |
0.04 |
| >5y after therapy |
1.6 (0.3-8.6) |
0.59 |
| Age at evaluation (<10y) |
10.2 (1.1-91.4) |
0.04 |
| High BMI |
2.1 (0.4-11.5) |
0.38 |
|
LBMI-Sarcopenic |
1.3 (0.3-5.6) |
0.72 |
| PAQ >2 |
8.2 (0.8-83.3) |
0.07 |
| NCI: National Cancer
Institute; yr: year; BMI: Body mass index at evaluation;
LBM: Lean body mass; LBMI: Lean body mass index;
PAQ: Physical activity quotient. |
Among 31 children exposed to cranial RT,
doses of 12.6 Gy were administered to 27 of whom one was obese.
Four children received cranial RT at doses of 18 Gy and three of
them were obese. None of the four obese survivors suffered from
endocrinopathies or short stature to account for obesity. None
of the baseline characteristics were associated with higher
prevalence of sarcopenia.
DISCUSSION
In the present analysis, using DEXA we
observed that more than one-fifth of the survivors of childhood
ALL were obese and half of them were overweight at a median
follow-up of 7 years. A wide variation in prevalence rates of
obesity (18-80%) has been reported among childhood cancer
survivors in studies using DEXA scans. The St Jude life time
cohort study [10] reported obesity in 63% male and 85% female
ALL survivors at a mean follow up of 25 years, while Barr, et
al. [11] from Canada reported obesity and overweight rates of
12% and 18% respectively at a median follow-up of 21 years. The
range in findings may be attributed to differences in
definitions of obesity, treatment protocol and gluco-corticoid
doses, duration of follow-up, ethnicity, and social factors as
well as the prevalence of obesity in the normal population of
the region. Comparison with a control population helped obviate
many of these factors. The main advantage of using sibling
controls was to avoid confounding biases due to constitutional
and environmental factors.
Published studies form India have used
weight- and height-based indices and reported lower prevalence
rates of obesity (2.5-12%) and overweight (19-20%) [12,13]. In
order to be comparable with these data, we adopted the BMI
criteria and observed similar rates of obesity (6%) and
overweight (24%) among our ALL survivors. Hence, BMI
underestimated the prevalence of adiposity as it is unable to
identify normal and underweight individuals with high body fat.
Blijorg, et al. [14] used total fat percentage as the gold
standard, and reported that 42% of male survivors and 65% of
female survivors were misclassified as non-obese using BMI [9].
It is noteworthy that the prevalence of
obesity and overweight was not influenced by the study
participants’ nutritional status at diagnosis, since the thin
and normally nourished children treated for ALL were equally
predisposed. However, we observed that the delta change in BMI
was highest amongst those who were under-weight/thin at
diagnosis, and they probably require close monitoring during
follow-up.
Various investigators have described muscle
mass loss during the treatment for ALL and its progression
throughout therapy and after treatment completion [15,16]. This
is attributed mainly to the degradation and decreased synthesis
of myosin heavy chains, and steroid use, which causes increased
glycogen and lipid levels in muscle cells. The prevalence of
sarcopenia was equally high amongst our control population,
which possibly indicates that ethnically, our population has
lower muscle mass compared to Western counterparts. We did;
how-ever, observe a high prevalence of sarcopenic obesity (14%)
among the survivors that was not seen among the controls. This
assumes importance in the context of current literature that
highlights the combination of the two to be more detrimental and
an important contributor to the development of metabolic
syndrome [16].
The observed gender difference has previously
also been reported [10,11,17]. Hyperleptinemia, which occurs in
girls during puberty, has been linked to body fat and has been
described as a possible mechanism for obesity. Although many
investigators have reported the association of cranial RT with
obesity, it remains a controversial point [17]. Disturbances
influencing the satiety centre and dysfunction of
hypothalamic-pituitary axis have been found to cause obesity as
well. However, with modern treatment protocols, wherein smaller
doses of radiation are delivered with better techniques, recent
papers have revealed no association of cranial radiation with
the incidence of obesity in survivors of childhood ALL [18]. The
increased incidence of obesity among children with NCI high risk
disease status may be attributed to the use of higher doses of
glucocortico-steroid therapy, poor physical activity and use of
cranial radiation in this subset.
The results of our analysis should be
interpreted in light of the small sample size and skewed gender
ratio, in addition to the fact that influence of unknown
psychosocial factors on the controls could not be completely
excluded. However, our use of DEXA to accurately identify
adiposity and sarcopenia as well as use of matched controls
strengthens our findings.
The findings of the present study highlight
the high prevalence of obesity and sarcopenic obesity in our
population of survivors of childhood ALL. Since these are
believed to be forerunners of cardio-metabolic syndrome our
results emphasize the need for early recognition and aggressive
preventive strategies. Larger interventional studies may
identify strategies that have an impact on reducing obesity in
this sub-population of children.
Acknowledgements: Dr Uma Athale and Dr
Julia Challinor in editing and proof-reading the manuscript.
Ethical clearance: Institutional Review
Board; No. RGCIRC/IRB/77/2013, dated 10 September, 2013.
Contributors: PM: data acquisition,
interpretation, drafting the manuscript; GK: study design, data
interpretation, reviewing and finalizing manuscript; SJ: data
interpretation, reviewing manuscript; SJ: data acquisition,
reviewing manuscript; AS: data analysis and interpretation,
reviewing manuscript.
Funding: None; Competing
interests: None stated.
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WHAT THIS STUDY ADDS?
• Body composition analysis by DEXA scan showed that
21.5% survivors of childhood ALL were obese and 60% had
sarcopenia on follow-up.
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REFERENCES
1. Tamilselvan St, Scott JX, Sneha L,
Divyalakshmi J. Metabolic syndrome in childhood cancer
survivors. J Clin Oncol. 2017;35:145.
2. Chueh HW, Yoo JH. Metabolic syndrome
induced by anticancer treatment in childhood cancer survivors.
Ann Pediatr Endocrinol Metab. 2017;22:82-9.
3. Barnea D, Raghunathan N, Friedman DN,
Tonorezos ES. Obesity and metabolic disease after childhood
cancer. Oncology (Williston Park). 2015;29:849-55.
4. Commission on ending childhood obesity:
Taking action on childhood obesity
report. 2018;WHO/NMH/PND/ECHO/18.1.
5. Jain S, Jain S, Kapoor G, Virmani A,
Bajpai R. No impact of disease and its treatment on bone mineral
density in survivors of childhood acute lymphoblastic leukemia.
Pediatr Blood Cancer. 2017;64.
6. World Health Organization. World Health
Organization Child Growth Standards. 2006. Accessed March 5,
2012. https://www.who.int/childgrowth/en/
7. Krebs NF, Himes JH, Jacobson D, et al.
Assessment of child and adolescent overweight and obesity.
Pediatrics. 2007;120:S193-228.
8. McCarthy HD, Cole TJ, Fry T, Jebb SA,
Prentice AM. Body fat reference curves for children. Int J Obes
(Lond). 2006;30:598-602.
9. Ogden CL, Li Y, Freedman DS, Borrud LG,
Flegal KM. Smoothed percentage body fat percentiles for U.S.
children and adolescents, 1999-2004. Natl Health Stat Report.
2011;1-7.
10. Karlage RE, Wilson CL, Zhang N, et al.
Validity of anthropometric measurements for characterizing
obesity among adult survivors of childhood cancer: A report from
the St. Jude Lifetime Cohort Study. Cancer. 2015;121: 2036-43.
11. Marriott CJC, Beaumont LF, Farncombe TH,
et al. Body composition in long-term survivors of acute
lymphoblastic leukemia diagnosed in childhood and adolescence: A
focus on sarcopenic obesity. Cancer. 2018;124:1225-31.
12. Prasad M, Arora B, Chinnaswamy G, et al.
Nutritional status in survivors of childhood cancer: Experience
from Tata Memorial Hospital, Mumbai. Indian J Cancer.
2015;52:219-23.
13. Mohapatra S, Bansal D, Bhalla AK, et al.
Is there an increased risk of metabolic syndrome among childhood
acute lymphoblastic leukemia survivors? A developing country
experience. Pediatr Hematol Oncol. 2016;33:136-49.
14. Blijdorp K, van den Heuvel-Eibrink MM,
Pieters R, et al. Obesity is underestimated using body mass
index and waist-hip ratio in long-term adult survivors of
childhood cancer. PLoS One. 2012;7:e43269.
15. Orgel E, Mueske NM, Sposto R, et al.
Limitations of body mass index to assess body composition due to
sarcopenic obesity during leukemia therapy. Leuk Lymphoma.
2018;59:138-45.
16. Rayar M, Webber CE, Nayiager T, Sala A,
Barr RD. Sarcopenia in children with acute lymphoblastic
leukemia. J PediatrHematol Oncol. 2013;35:98-102.
17. Garmey EG, Liu Q, Sklar CA, et al.
Longitudinal changes in obesity and body mass index among adult
survivors of childhood acute lymphoblastic leukemia: A report
from the Childhood Cancer Survivor Study. J Clin Oncol.
2008;26:4639-45.
18. Withycombe JS, Post-White JE, Meza JL, et al. Weight
patterns in children with higher risk ALL: A report from the
Children’s Oncology Group (COG) for CCG 1961. Pediatr Blood
Cancer. 2009;53:1249-54.
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