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Body Mass Index of Adolescent and Adult Survivors of Pediatric Acute Lymphoblastic Leukemia – A Meta-Analysis
1. Body Mass Index of
Adolescent and Adult Survivors of
Pediatric Acute Lymphoblastic
Leukemia – A Meta-Analysis
Gina Nam, BA, BS
Research Assistant
HuntsmanCancer Institute, Cancer Control and Population Sciences
2. INTRODUCTION
• Over 60% of adolescent or adult survivors of pediatric cancer
experience at least one late effect in first decade following their
diagnosis.
• Late effects include cardiovascular disease, second cancers, and
alterations in growth and development.
• A possible late effect is the development of an abnormal body
composition (e.g., being overweight or obese) that can potentially
increase the risk of developing other chronic health conditions.
3. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
3%
57%
78%
92%
Survival Rates
1964 20091987
• ALL is the most common pediatric
cancer in the U.S.
• About 3,000 children and adolescents
are diagnosed in the U.S. with ALL every
year.
Source:American Childhood Cancer Organization
4. BODY MASS INDEX (BMI)
Adults Adolescents
Underweight ≤ 18.5 kg/m2 ≤ 5th percentile
Normal 18.5 – 25 kg/m2 5th – 85th percentile
Overweight 25 – 30 kg/m2 85th – 95th percentile
Obese ≥ 30 kg/m2 ≥ 95th percentile
5. EXISTING LITERATURE
• Existing systematic reviews suggest that during childhood, survivors
of pediatric ALL have higher BMIs than normative populations.
• However, mixed evidence exists on the risk of overweight/obesity
among adolescent and adult survivors of pediatric ALL.
• No meta-analyses on BMI among adolescent and adult survivors of
pediatric ALL.
6. OBJECTIVES
• Conduct a meta-analysis of studies that investigate the BMI of
adolescent and adult survivors of pediatric ALL.
• Systematically summarize literature.
• Quantify overall effect size and effect sizes for sex differences.
• Critical assessment of existing gaps in literature.
7. METHODS
Identified Studies
(N=109)
• PRISMA Guidelines.
• Multiple search engines.
• Search phrases: e.g.
ALL, body
composition, BMI, overwe
ight, adiposity etc.
• Time frame: 1994-2014.
InclusionCriteria (N=11)
• ALL diagnosed at <21
years of age.
• Age at study ≥16 years.
• BMI at the end of the
primary therapy phase.
• Comparison sample or
population norms.
• Peer-reviewed.
Coding & Analyses
• Coding into Excel by 2
investigators.
• Cross-checked by 2 other
researchers.
• Reliability analysis in
progress.
• Effect size analysis in Stata
and R.
8. STUDY EFFECT SIZE
Long-Term BMI Health Outcome in
Adolescents or Adults
Overweight/Obese Normal
ALL Survivors a b
Controls c d
BMI cutoff points for overweight/obese are based on BMI
classification guidelines for adolescents and adults as appropriate.
9. STUDIES (N=11)
Author Year Location N ALL Survivors N Controls Stratification
Birkebæk et al 1998 Denmark 33 NA Treatment
Garmey et al 2008 U.S. 1,451 2,167 Sex, Treatment
Geenen et al 2010 Netherlands 141 69 Treatment
Jarfelt et al 2005 Sweden 35 5,439 Sex, Treatment
Meacham et al 2005 U.S. 1,665 40,899 Sex
Ness et al 2007 U.S. 75 NA Sex
Oeffinger et al 2003 U.S. 1,765 2,565 Sex, Age, Treatment
Shaw et al 2000 United Kingdom 33 66 Sex
Tylavsky et al 2010 U.S. 164 NA Age
Veringa et al 2012 Netherlands 68 6,555 Sex, Treatment
Warner et al 2013 U.S. 165 5,410 Sex
10. FOREST PLOT for ODDS RATIO (N=7*)
STUDY OR Plot OR (95% CI) %WEIGHT
*4 studies do not provide enough information to compute OR.
Non U.S. Studies
1.11 (1.04-1.19)
11. FEMALE SURVIVORS in the U.S. (N=4)
STUDY OR Plot OR (95% CI) %WEIGHT
Overall (I-squared = 74.3%, p = 0.001)
Warner
Oeffinger
Study
Oeffinger
ID
Oeffinger
Garmey
Oeffinger
Meacham
1.32 (1.20, 1.45)
1.14 (0.73, 1.78)
1.29 (0.62, 2.67)
1.76 (1.31, 2.36)
OR (95% CI)
1.67 (1.05, 2.65)
1.72 (1.42, 2.07)
1.32 (0.93, 1.88)
1.04 (0.91, 1.20)
100.00
4.76
1.69
%
9.32
Weight
3.71
22.70
7.26
50.55
1.32 (1.20, 1.45)
1.14 (0.73, 1.78)
1.29 (0.62, 2.67)
1.76 (1.31, 2.36)
OR (95% CI)
1.67 (1.05, 2.65)
1.72 (1.42, 2.07)
1.32 (0.93, 1.88)
1.04 (0.91, 1.20)
100.00
4.76
1.69
%
9.32
Weight
3.71
22.70
7.26
50.55
10 1 3
12. MALE SURVIVORS in the U.S. (N=4)
STUDY OR Plot OR (95% CI) %WEIGHT
Overall (I-squared = 77.5%, p = 0.000)
Oeffinger
Warner
Oeffinger
Meacham
Oeffinger
ID
Study
Garmey
Oeffinger
0.93 (0.85, 1.03)
1.46 (1.11, 1.92)
1.29 (0.85, 1.95)
0.80 (0.49, 1.29)
0.76 (0.66, 0.87)
2.60 (0.97, 6.97)
OR (95% CI)
1.03 (0.84, 1.26)
0.89 (0.63, 1.26)
100.00
9.99
4.56
4.19
51.90
0.70
Weight
%
20.84
7.82
0.93 (0.85, 1.03)
1.46 (1.11, 1.92)
1.29 (0.85, 1.95)
0.80 (0.49, 1.29)
0.76 (0.66, 0.87)
2.60 (0.97, 6.97)
OR (95% CI)
1.03 (0.84, 1.26)
0.89 (0.63, 1.26)
100.00
9.99
4.56
4.19
51.90
0.70
Weight
%
20.84
7.82
10 1 7
13. GAPS IN EXISTING LITERATURE
• Identified only 11 quality studies, of which 6 were conducted in the U.S.
• Reporting standards not unique.
• 9 studies report BMI proportions.
• 7 studies report mean BMI.
• 2 studies report BMI Z-score relative to reference values.
• Missing information on a host of important variables.
• Cancer relapse.
• Detailed treatment and BMI.
• Family medical history.
• Sample size of controls.
14. CONCLUSIONS/RECOMMENDATIONS
• Overall effect size for survivors in the U.S.
• OR= 1.11; 95% CI= 1.04-1.19.
• Female survivors (OR=1.32; 95% CI=1.20-1.45 ) may be overweight/obese at
greater numbers than male survivors (OR=0.93; 95% CI=0.85-1.03).
• Recommendations:
• Long-term health management programs for adolescent and adult survivors
of pediatric ALL.
• More emphasis on addressing weight-related health behaviors for female
survivors of pediatric ALL.
• Standardized reporting of results for robust meta-analyses.
15. LIMITATIONS
• BMI is an indirect measurement of body fat, and does not reflect
changes in muscle mass or changes that occur with age in adulthood.
• With the limited number of available studies, characteristics of
control population, treatment etc. are inconclusive.
Cancer has been and still is the leading cause of death in the US. However, survival rates have increased for past decades and over 60% of adolescent or adult survivors of ped cancer experience at least one late effect such as cadiovascular disease, secondary cancers, and developing abnormal body composition that can further increase the risk of developing other chronic health conditions.
Our study focused on Pediatric Acute Lymphoblastic Leukemia, or ALL, because it is the most common childhood cancer diagnosis in the US. It accounts for about 30% of childhood cancer diagnosis, and about 3,000 children and adolescents are diagnosed in the US with ALL every year. With the improvement of treatment, survival rate today has been improved from 3% to 90%, meaning that many survive well into adulthood when late-effects become an issue.
To examine abnormal body composition as a possible late effect in ALL survivors such as overweight and obesity, BMI is the most simple and easy way to screen for possible weight issues, and also a reliable indicator of body fatness for most people. It is calculated by dividing weight by height. Even though BMI is measured in the same way, BMI of adults and adolescents are interpreted using different guidelines. And the studies we looked at followed guidelines accordingly.
There are a few meta-analytic reviews available suggesting that children survivors of pediatric ALL have higher BMIs than age-matched comparison populations. However, we do not have a conclusive evidence on the risk of overweight/obesity among adolescent and adult survivors of pediatric ALL as a long term late-effect. And no meta-analyses on these age groups either.
So, our study conduct a meta-anlaysis of studies that investigate the BMI of adolescent and adult survivors of pediatric ALL to systematically summarize existing literature, quantify overall effect size as well as effect sizes for sex differences, because women tend to have a higher BMIs than men in general population, and finally critical assess gaps in literature.
We initially identified 109 studies using PRISMA guidelines. We used Google Scholary, Embase, PubMed and other search engines with search phrases including ALL with terms related to change in body composition, such as body mass index, overweight, obesity, adiposity and so on.Then, we further distilled studies specific to our topic by using these following inclusion criteria, which gave us total of 11 studies for us to code and analyze. Coding is primarily done by 2 investigators with cross-check by 2 others. And we have a preliminary results, where we looked at effect sizes using Stata and R. We are currently checking reliability of the data.
So our primary effect size wasodds ratio of a prevalence of overweight/obesity, as one combined category, of ALL survivors compared to control groups with 95% Confidence Interval. And the proportion of overweight/obese are categorized based on BMI classification guidelines accordingly.
These are the studies we identified. And as you can see, the location, number of subjects, and stratification are vary. Also, quite a few does not report the total sample size of control groups. 6 US Studies8 Studies stratified by Sex6 Studies stratified by Therapy4 Studies that have mixed age group of adolescent and adult survivors.
Here is the forest plot for all studies that provided odds ratios where you can see it visually and numerically. So there were7 studies out of 11 studies provided enough information for us to compute OR. Some have multiple outcomes because of a stratification (either based on sex or age). Of 7 studies, 3 were non U.S. studies and they were either too low or too high. Weighted Overall odds ratio was 1.13, meaning ALL survivors are 13% more prone to develop overweight/obese than controls.
Because women tend to achieve higher BMI than men in general population, we looked at female and male survivors of pediatric ALL separately. As the European studies appeared to be outliers, we only included the U.S. studies. Also, there are multiple outcomes for Oeffinger, because they were stratified by not only sex, but also age group as well. So when we looked at female only, all of the studies had odds ratio over 1, and the weighted overall OR was 1.32. Meaning female adolescent and adult survivors have a higher prevalence of obesity/obese than controls by 32 %.
For male survivors, we have a mixed results. 3 studies had OR lower than 1, and the other had IR higher than 1. As for overall OR, it was 0.93 which is actually a reverse of what we anticipated.
Within the studies we looked at, there were a few gaps that we would like to discuss. Among 11 studies that we examined, there were only 6 conducted in the US and 3 used Childhood Cancer Survivor Study data, which can overlap the results. Also, BMI outcome measurements in each study were vary from BMI proportions, mean BMI to BMI z-score relative to reference values. Finally, there were missing information that may be crucial to look at such as relapse among ALL survivors that are known to have a risk of even higher BMI, family medical history that can be associated with change in BMI such as down syndrome, diabetes, and growth hormone deficiency, and sample size of control groups.
By looking at 4 studies in the US that provided OR, overall odds ratio was 1.11 with 95% confidence interval of 1.04-1.19. Similar to female children survivors of ALL, female adolescent and adult survivors are more likely to develop overweight/obesity than male survivors. Looking into a prevalence of overweight/obese in adolescent and adult survivors of pediatric ALL, we have a few suggestions for future studies. As our preliminary result shows abnormal body composition in ALL survivors, long-term health management programs for those survivors is highly recommended, especially for female survivors. Also, standardized reporting of results will be helpful for more robust meta-analyses in the future.
We also had a few limitations to consider. BMI is a commonly used too to screen a possible weight issues, but it does not reflect changes in muscle mass or changes that occur with age in adulthood. There are other studies that used xxx to measure body fat accurately, but the number is very limited at the moment. We found that the we don’t fully understand a prevalence of overweight and obesity among adolescent and adult survivors of pediatric ALL despite the fact that abnormal weight change is commonly known as a late-effect in this population. And so it was not challenging to look at other factors that could cause overweight/obese in ALL survivors.