Five hundred CCS were enrolled in the present study; 78% (389) were male, 85% (424) belonged to the middle class and 74% (370) were from urban areas. At the time of evaluation, the median age of the survivors was 17 years, 49% (245) were adults >18 years of age, median survival duration was 7 years and 32.6% (163) had survived for >10 years. Based on BMI at diagnosis, the patients were categorized as underweight (130, 26%), normal (295, 59%), overweight (36, 7.2%) and obese (39, 7.8%). The two most common primary diagnoses were acute lymphoblastic leukemia (ALL) (226, 45.2%) and Hodgkin lymphoma (82, 16.4%). Treatment exposures included chemotherapy in all, steroids in 53% (265), radiotherapy (RT) in 32.4% (162), definitive surgery in 23.4% (117) and bone marrow transplant (BMT) in 2.8% (14) of patients (Table 1).
Table 1
Characteristics of childhood cancer survivors with and without metabolic syndrome (MetSyn)
Characteristics
|
No MetSyn
N=439(%)
|
MetSyn
N=61(%)
|
P value
|
Sex
Male
Female
|
335 (76.3)
104 (23.7)
|
54 (88.5)
7 (11.5)
|
0.031
|
Median age at diagnosis (years)
|
8 (IQR:4-12)
|
11 (IQR:6-15)
|
0.003
|
Age at diagnosis
|
|
|
|
<10 years
|
278 (63.3)
|
23 (37.7)
|
<0.001
|
10-18 years
|
161 (36.7)
|
38 (62.3)
|
Median age at evaluation (years)
|
17 (IQR:12-21)
|
22 (IQR:6-15)
|
<0.001
|
<18 years
|
240 (54.7)
|
15 (24.6)
|
<0.001
|
> 18 years
|
199 (45.3)
|
46 (75.4)
|
Median duration from treatment completion (years)
|
6.7±3.6
|
9.2±4.8
|
<0.001
|
Survival time from diagnosis
|
|
|
|
< 10 years
|
306 (69.7)
|
31 (50.8)
|
0.005
|
> 10 years
|
133 (30.3)
|
30 (49.2)
|
BMI at diagnosis
|
|
|
|
Underweight, normal
|
385 (87.7)
|
40 (65.6)
|
<0.001
|
Obese, overweight
|
54 (12.4)
|
21 (34.4)
|
Delta BMI
|
|
|
|
≥50
|
48 (10.9)
|
17 (27.9)
|
0.008
|
<50
|
391 (89.1)
|
44 (72.1)
|
Primary diagnosis
|
|
|
Hematological malignancy
|
319 (72.7)
|
48 (78.7)
|
0.357
|
Solid tumor & brain tumor
|
120 (27.3)
|
13 (21.3)
|
Hematological malignancy
|
|
|
|
Acute lymphoblastic leukemia
|
198 (45.5)
|
28 (43.1)
|
0.906
|
Acute myeloid leukemia
|
17 (3.9)
|
3 (4.6)
|
0.696
|
Non-hodgkin lymphoma
|
35 (8)
|
4 (6.2)
|
0.699
|
Hodgkin lymphoma
|
69 (15.9)
|
13 (20)
|
0.269
|
Solid tumor
|
|
|
|
Osteosarcoma/ Ewing sarcoma
|
51 (11.7)
|
6 (9.2)
|
0.681
|
Rhabdomyosarcoma
|
23 (5.3)
|
0 (0)
|
0.06
|
Wilms tumor
|
15 (3.4)
|
3 (4.6)
|
0.555
|
Neuroblastoma
|
7 (1.6)
|
0 (0)
|
0.32
|
Germ cell tumor
|
17 (3.9)
|
3 (4.6)
|
0.696
|
Others
|
3 (0.7)
|
0 (0)
|
0.517
|
Brain tumor
|
4 (0.9)
|
1 (1.5)
|
0.592
|
Treatment Exposure
Chemotherapy
Alkylating
|
405 (92.25)
|
58 (95.1)
|
0.429
|
|
Antimetabolite
|
271 (61.7)
|
37 (60.65)
|
0.871
|
|
Steroid
|
|
|
|
|
Yes
|
233 (10.9)
|
32 (27.9)
|
0.928
|
|
No
|
206 (89.1)
|
29 (72.1)
|
|
|
Radiotherapy
|
|
|
|
|
Brain
|
68 (15.6)
|
14 (21.5)
|
0.14
|
|
Head & neck not brain
|
24 (5.5)
|
4 (6.2)
|
0.728
|
|
Abdomen & pelvis
|
21 (4.8)
|
1 (1.5)
|
0.261
|
|
Chest
|
10 (2.3)
|
3 (4.6)
|
0.224
|
|
Extremity
|
4 (0.9)
|
3 (4.6)
|
0.012
|
|
Others
|
9 (2.1)
|
1 (1.5)
|
0.829
|
|
Surgery
|
107 (24.4)
|
10 (16.4)
|
0.1713
|
|
Bone marrow transplant
|
12 (2.7)
|
2 (3.3)
|
0.8092
|
|
IQR, interquartile range; BMI, body mass index. Delta BMI is percent change in BMI z-score from diagnosis to evaluation.
|
Prevalence of MetSyn and its components
The prevalence of MetSyn in the CCS was 12.2% (61) at a median age of 22 years, their characteristics are detailed in categorical Table 1. The prevalence was lower in children/ adolescents (<18 years, 6%) and higher in adults >18 years (19%). Figure 1 clearly demonstrates the age-wise increment in both males and females. Among the children 6-10 years of age, 28.5% (13/49) were obese by BMI and 22.4% (11/49) had central obesity (WC> 90th centile). Those with family history for cardiovascular risk factors were further assessed and 3 (all were male) of these survivors were observed to have HT (> 90th centile for age and height), elevated TG (>150 mg/dL) and low HDL-c (< 40 mg/dL), hence for the purpose of this analysis they were considered to have MetSyn.
Derangements in individual components [central obesity, impaired fasting glycemia (IFG), hypertriglyceridemia (high TG), low HDL-c, HT] of MetSyn were observed in 68.6% (343) of CCS, one component was abnormal in 40.2% (201) and two components in 16.2% (81). Low values for HDL-c and high WC (central obesity) were the most frequently observed derangements (Table 2). Their frequency and mean values were significantly higher among survivors with MetSyn and in those with high delta BMI (Table 2). It is noteworthy that, 40/61 survivors who developed MetSyn were non-obese/overweight at diagnosis.
Table 2
Prevalence of components of metabolic syndrome (MetSyn) and their mean values among childhood cancer survivors by presence of MetSyn and delta body mass index (BMI)
Components of MetSyn
|
No MetSyn N=439(%)
|
MetSyn N=61(%)
|
P- value
|
Delta BMI <50
N=435 (%)
|
Delta BMI ≥50
N=65 (%)
|
P- value
|
Prevalence of individual components
|
Central obesity (WC)
|
104 (23.7)
|
61 (100)
|
<0.001
|
87 (20.0)
|
40 (61.5)
|
<0.001
|
Hypertriglyceridemia
|
19 (4.3)
|
29 (47.5)
|
<0.001
|
36 (8.3)
|
12 (18.5)
|
0.021
|
Low HDL-c
|
242 (55.1)
|
55 (90.2)
|
<0.001
|
250 (57.5)
|
47 (72.3)
|
0.030
|
IFG
|
8 (1.8)
|
13 (21.3)
|
0.002
|
13 (3.0)
|
8 (12.3)
|
0.003
|
Hypertension
|
23 (5.2)
|
39 (63.9)
|
<0.001
|
50 (11.5)
|
12 (18.5)
|
0.153
|
Mean values
|
Mean±SD
|
Mean±SD
|
|
Mean±SD
|
Mean±SD
|
|
WC
|
75.1±12.8
|
96.7±8.0
|
<0.001
|
76.2±13.9
|
92.1±8.7
|
<0.001
|
TG
|
77.3±36.6
|
132.6±65.6
|
<0.001
|
81.2±41.8
|
103.1±59
|
<0.001
|
HDL-c
|
40.1±9.1
|
34.9±6.2
|
<0.001
|
39.9±9.1
|
36.5±7.7
|
<0.001
|
FBG
|
83.8±7.0
|
94.8±26.2
|
0.002
|
84.5±8
|
89.4±24.9
|
<0.001
|
SBP
|
108.2±13.1
|
126.5±12
|
<0.001
|
109.8±13.4
|
116.5±11.7
|
<0.001
|
DBP
|
67±9.4
|
78.3±9
|
<0.001
|
68±9.6
|
72±8.4
|
<0.001
|
No of components
|
|
|
|
|
|
|
0
|
157 (35.8)
|
0 (0)
|
<0.001
|
154 (35.4)
|
4 (6.2)
|
<0.001
|
1
|
201(45.8)
|
0 (0)
|
<0.001
|
180 (41.4)
|
21 (32.3)
|
0.18
|
2
|
81 (18.5)
|
0 (0)
|
<0.001
|
58 (13.3)
|
26 (40)
|
<0.001
|
≥3
|
0 (0)
|
61 (100)
|
<0.001
|
43 (9.9)
|
14 (21.5)
|
<0.001
|
SD, standard deviation; WC, Waist circumference; IFG, Impaired fasting glycemia; TG, Triglycerides; HDL-c, High-density lipoprotein cholesterol; FBG, fasting blood glucose; SBP, Systolic Blood Pressure; DBP; Diastolic Blood Pressure. |
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 3
Metabolic syndrome by nutritional status at diagnosis and Delta BMI
BMI at Diagnosis
|
Prevalence of MetSyn
|
p value
|
OR (95% CI) of MetSyn when Delta BMI >50
|
Delta BMI <50
|
Delta BMI >50
|
Under-weight, Normal (N=428)
|
7.4% (28/377)
|
23.5% (12/51)
|
0.0002
|
12.5 (1.7-92.2)
|
Overweight, Obese (N=72)
|
27% (16/58)
|
35% (5/14)
|
0.5
|
2.0 (0.6-8.1)
|
BMI, body mass index; OR, odds ratio; CI; confidence interval. Delta BMI is percent change in BMI z-score from diagnosis to evaluation. |
Risk Factors for MetSyn and its individual components
Of the various risk factors studied, multivariable analysis revealed older age at diagnosis (OR 2.78,1.43-5.4), longer survival duration (OR 2.74, 1.43-5.26), high BMI (obese) at diagnosis (OR 3.2, 1.64-6.2) and high delta BMI (OR 2.26, 1.13-4.55) to be independent predictors of MetSyn (Table 4, supplemental Table 2).
Table 4
Univariate and multivariable logistic regression analysis: risk factors for metabolic syndrome
Variable
|
Univariate
|
|
Multivariable
|
|
|
OR
|
95% CI
|
P
|
OR
|
95% CI
|
P
|
Gender Female
|
1
|
|
|
|
|
|
Gender Male
|
2.4
|
1.1-5.4
|
0.04
|
1.93
|
0.83-4.52
|
0.13
|
Age at diagnosis <10 years
|
1.0
|
|
|
|
|
|
Age at diagnosis 10-18 years
|
2.9
|
1.6-5
|
0.00
|
2.78
|
1.43-5.4
|
0.00
|
Age at eval <18 years
|
1.0
|
|
|
|
|
|
Age at eval >18 years
|
3.7
|
2.0-14.5
|
0.82
|
|
|
|
Survival time from diagnosis < 10 years
|
1.0
|
|
|
|
|
|
Survival time from diagnosis > 10 years
|
2.2
|
1.3- 3.8
|
0.00
|
2.74
|
1.43-5.26
|
0.00
|
BMI at diagnosis, underweight, normal
|
1.0
|
|
|
|
|
|
BMI at diagnosis, Obese, overweight
|
3.2
|
1.5-6.9
|
0.00
|
3.19
|
1.64-6.2
|
0.00
|
Delta BMI <50
|
1
|
|
|
|
|
|
Delta BMI ≥50
|
3.15
|
1.7-5.9
|
0.00
|
2.26
|
1.13-4.55
|
0.02
|
Primary Diagnosis
|
|
|
|
|
|
|
Hematological malignancy
|
1.0
|
|
|
|
|
|
Solid tumor & brain
|
0.7
|
0.4-1.4
|
0.32
|
|
|
|
Treatment exposure*
|
|
|
|
|
|
|
Chemotherapy
Steroid
Surgery
|
1.0
0.9
0.6
|
0.6-1.7
0.3-1.2
|
0.90
0.17
|
|
|
|
RT
|
1.7
|
1-2.9
|
0.07
|
|
|
|
BMT
|
1.2
|
0.3-5.5
|
0.81
|
|
|
|
OR, Odds ratio; CI, confidence interval; P, p-value; eval, evaluation; BMI, body mass index; RT, radiotherapy; BMT, bone marrow transplant.* All patients received chemotherapy. |
Results of chemotherapy exposure showed that use of steroids, anthracyline (>120mg/m2), alkylators or antimetabolites did not influence the occurrence of MetSyn. Patients receiving RT at various sites (cranial, abdominal or pelvic), had similar prevalence of MetSyn. Childhood cancer survivors with ALL treated with cranial RT (CRT) had a low OR (1.9, 0.85-4.24) for developing MetSyn, except in very young children (< 5 years), OR (5.48, 1.5-20), p, 0.01), when compared to those not exposed to CRT of the same age.
On multivariable analysis, adjusted OR revealed that HT (OR 3.9,1.6-9.6) and obesity (OR 2,1-3.8) were more likely in adult survivors (compared to children); hypertriglyceridemia was more in males than females (OR, 3.8;1.1-12.6) and IFG was more likely in survivors of solid tumor (OR 3.7, 1.4-9.6) .Central obesity (OR 2.4, 1.3-4.7) and low HDL-c (OR 1.7, 1-2.8) were more common in the longer surviving patients(Supplemental Table 2).