Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
Corresponding author: Kirsten K. Ness, PhD, Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Pl, MS735, Memphis, TN 38105-2794; Fax: (901) 595-5845; firstname.lastname@example.org
Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS.
CCS who were ≥ 10 years from diagnosis, aged > 18 years, and participating in the St. Jude Lifetime Cohort Study completed medical and laboratory tests and a food frequency questionnaire. The Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria were used to classify participants with MetSyn. Anthropometric, food frequency questionnaire, and self-reported physical activity data were used to characterize lifestyle habits according to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations. Those who met ≥ 4 of 7 recommendations were classified as having followed guidelines. Sex-stratified log-binomial regression models were used to evaluate associations between dietary/lifestyle habits and MetSyn, adjusted for age, age at cancer diagnosis, receipt of cranial radiotherapy, education, and household income.
Among 1598 CCS (49.2% of whom were male, with a median age of 32.7 years [range, 18.9 years-60.0 years]), 31.8% met criteria for MetSyn and 27.0% followed WCRF/AICR guidelines. Females who did not follow WCRF/AICR guidelines were 2.4 times (95% confidence interval, 1.7-3.3) and males were 2.2 times (95% confidence interval, 1.6-3.0) more likely to have MetSyn than those who followed WCRF/AICR guidelines.
There are over 360,000 childhood cancer survivors (CCS) in the United States, 70% of whom will experience at least 1 chronic health condition. Therefore, the long-term health of survivors has become a focus of both observational and interventional research. One of the most significant findings among adult CCS is an increased risk of developing cardiovascular disease, including coronary artery disease.2,4,5 Anthracycline chemotherapy and chest radiation are known risk factors for cardiomyopathy,[6, 7] likely worsened by modifiable risk factors including obesity, dyslipidemia, and insulin resistance, which are common in this population.[2, 4] Metabolic syndrome (MetSyn) is a constellation of physical and laboratory abnormalities associated with the risk of cardiovascular disease. The reported prevalence of MetSyn among CCS ranges from 7% to 60%. Those individuals with a history of cranial radiotherapy (CRT) are at highest risk.[10, 11]
Poor nutritional habits, specifically diets high in fat and simple sugars, are associated with the development and progression of MetSyn in the general population. Because CCS report consuming less than the recommended amounts of fruits and vegetables and high amounts of fat,[12, 13] an evaluation of the contribution of poor dietary habits to MetSyn is important in this population. Other than small studies of adult survivors of childhood acute lymphoblastic leukemia (ALL),[14, 15] to our knowledge few studies to date have investigated the association between dietary/lifestyle habits and the presence of MetSyn among CCS.
The purpose of the current study was to evaluate the association between the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines and MetSyn among adult CCS of varying diagnoses.
MATERIALS AND METHODS
Participants were members of the St. Jude Lifetime Cohort Study, a study of adult CCS who were treated at St. Jude Children's Research Hospital using previously described recruitment strategies.[16, 17] The primary aim of the St. Jude Lifetime Cohort Study is to prospectively evaluate health outcomes among CCS as they age. Participants must be aged ≥ 18 years, 10 years from cancer diagnosis, and willing to return to St. Jude Children's Research Hospital for evaluation. Potentially eligible study participants were recruited and attended their on-campus evaluation between October 2007 and October 2012 (Fig. 1). All participants provided informed consent for participation in this Institutional Review Board-approved study.
MetSyn was defined using the Third Report of the National Cholesterol Education Program Adult Treatment Panel. Individuals having or being treated for ≥ 3 of the following were classified as having MetSyn: 1) abdominal obesity (waist circumference of > 102 cm in males and > 88 cm in females); 2) triglycerides ≥ 150 mg/dL; 3) high-density lipoprotein (HDL) cholesterol < 40 mg/dL in males and < 50 mg/dL in females; 4) hypertension (systolic pressure ≥ 130 mm Hg or diastolic pressure ≥ 85 mm Hg); and 5) fasting plasma glucose ≥ 100 mg/dL.
Abdominal circumference at the narrowest point between the xiphoid process and the navel was determined with a Gulick tape measure. The measure was repeated twice and recorded to nearest tenth of a centimeter. The highest circumference was used for analysis. Resting blood pressure was taken with the participant seated with both feet on the floor after a 5-minute rest period. The lowest of 3 measurements was used for analysis.
Blood samples were collected after an overnight fast. Glucose, triglycerides, and HDL were measured using an enzymatic spectrophotometric assay (Roche Diagnostics, Indianapolis, Ind).
Adherence to WCRF/AICR Guidelines
Anthropometrics, dietary intake data, and self-reported physical activity information were used to calculate a score based on the WCRF/AICR guidelines. The 7 components that make up this scale are shown in Table 1. Participants received 1 point for each recommendation met. Based on a previous report, participants who followed a majority of recommendations (≥ 4 of 7) were considered adherent.
Table 1. WCRF/AICR Scoring
Abbreviations: BMI, body mass index; WCRF/AICR, World Cancer Research Fund/American Institute for Cancer Research.
Guidelines from Centers for Disease Control and Prevention recommend 150 minutes per week of moderate physical activity.
Height and weight were measured using a wall-mounted stadiometer and an electronic scale, respectively. Body mass index was calculated by dividing weight in kilograms (kg) by height in meters squared (m2). Body mass index was defined as underweight (< 18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥ 30 kg/m2).
Participants completed the Block 2005 Food Frequency Questionnaire to estimate customary intake of nutrients and food groups over the past year. The data were processed using the Block Dietary Data Systems (Berkeley, Calif), which uses a food list from the National Health and Nutrition Examination Survey (NHANES) and a nutrient database from the US Department of Agriculture Food and Nutrient Database for Dietary Studies.[21-23]
Self-reported physical activity was obtained by having participants complete the NHANES Physical Activity Questionnaire, which asks questions about physical activity over the past 7 days. Minutes per week of moderate physical activity were assigning 1 minute for each reported minute of moderate activity and 1.67 minutes for each minute of reported vigorous activity. Participants who met or exceeded the Centers for Disease Control and Prevention's recommendation for physical activity (150 minutes per week) were classified as physically active.
Demographic and Treatment Information
Demographic and cancer treatment data were obtained from participant questionnaires and from medical records by trained abstractors.
Associations between adherence to the WCRF/AICR guidelines and MetSyn or components were analyzed in log-binomial regression models, with MetSyn or individual components treated as dependent variables in sex-stratified models. Adherence to the WCRF/AICR guidelines was the primary independent variable, with current age, race, CRT, education, smoking status, and age at diagnosis included as potential confounders. Final models were determined using Akaike information criteria to select the best subset of covariates among all possible models. Adherence to the WCRF/AICR guidelines was retained in all final models. The interaction between CRT exposure and adherence to the WCRF/AICR guidelines was evaluated but not found to be significant. Results are presented as relative risks with 95% confidence intervals (95% CIs). Descriptive analyses were completed in SAS statistical software (version 9.2; SAS Institute Inc, Cary, NC). Model selection was conducted in R statistical software (R Project Foundation, Vienna, Austria).
Study Population and Characteristics
Among 2654 potentially eligible survivors, 1639 (61.8%) agreed to participate. Nonparticipants included 46 patients (1.7%) who were lost to follow-up, 707 patients (26.6%) who actively (245 patients) or passively (462 patients) chose not to participate, and 162 patients (6.1%) who completed the surveys but did not complete a campus visit. An additional 41 patients (1.5%) had incomplete or inaccurate dietary or MetSyn status data, leaving 1598 participants for this analysis (Fig. 1). Participants were more likely than the source population to be female (Table 2). Approximately one-half of the survivors were female (50.8%) and just less than one-half were survivors of leukemia (49.4%). The mean age at diagnosis was 7.9 years ± 5.5 years and the mean time since diagnosis was 25.6 years ± 7.6 years. Approximately 20% of the survivors were current smokers; < 40% were college graduates. Greater than one-half of survivors were overweight (28.2%) or obese (38.1%). Greater than one-third of survivors had been exposed to CRT.
Table 2. Population Characteristics
Study Participants (n=1639)
Total No. (%)
Females No. (%)
Males No. (%)
Abbreviations: BMI, body mass index; CNS, central nervous system; CRT, cranial radiotherapy.
Comparison for race (white vs black and other); P values were derived from the chi-square test.
MetSyn was present in 32.5 % of males and 31.0% of females. Among males, the most prevalent MetSyn component was high blood pressure (53.0%), followed by elevated fasting glucose (38.2%) and low HDL (38.2%). Among females, low HDL was the most prevalent component (42.6%), followed by increased waist circumference (42.6%) and high blood pressure (40.6%) (Fig. 2). Table 3 includes detailed information by sex and age group for each MetSyn component.
Table 3. Components of Metabolic Syndrome by Sex, Age, and Treatment Statusa
Abbreviation: HDL, high-density lipoprotein.
There is no standard treatment for elevated waist circumference; therefore, it was not included in the table.
Increased blood pressure
Increased fasting glucose
On average, males reported consuming 2419.9 ± 1549.9 kilocalories and females reported consuming 1905.3 ± 1122.9 kilocalories per day (Table 4). Daily caloric intake from fat and sugars was similar among males and females. The mean fruit intake was nearly 1 serving per day and vegetable intake was just over 2.5 servings per day among males and females. Sodium intake was higher in males than females.
Abbreviations: RDI, recommended daily intake; SD, standard deviation.
RDI is based on US Department of Agriculture and US Department of Health and Human Services. Dietary Guidelines for Americans, 2010. 7th ed. Washington, DC: US Government Printing Office; 2010. www.dietaryguidelines.gov. Accessed December 10, 2013.
Nutrient intake, daily
1905.3 ± 1122.9
2419.9 ± 1549.9
76.6 ± 49.7
98.4 ± 69.3
Energy fat, %
35.8 ± 6.0
36.2 ± 5.9
Energy saturated fat, %
12.1 ± 3.0
11.4 ± 2.5
72.6 ± 45.7
94.3 ± 70.1
235.7 ± 137.2
287.5 ± 172.9
Energy from sugar, %
4.6 ± 1.9
4.7 ± 2.1
Total fiber, g
17.8 ± 11.4
3151.3 ± 1916.5
3979.2 ± 2672.9
Daily no. of servings from each food group servings
1.2 ± 0.9
1.0 ± 0.8
3.0 ± 2.2
2.8 ± 2.1
2.6 ± 4.6
2.0 ± 5.2
0.6 ± 0.7
0.6 ± 0.8
1.3 ± 1.0
1.5 ± 1.2
Meat, poultry, fish (in oz)
3.9 ± 3.4
5.8 ± 5.5
Adherence to Dietary Guidelines
Only 25.2 % of males and 28.8% of females met ≥ 4 of 7 components of the WCRF/AICR guidelines (Table 5). Obesity, excessive consumption of red meat and sodium, and inadequate servings of fruits and vegetables were common among both males and females. Greater than one-half of survivors reported activity levels below recommended guidelines. Less than one-half of females (39.9%) consumed > 400 g per day of complex carbohydrates.
Associations Between Meeting Guidelines and MetSyn
Among those with MetSyn, 87.8% of men and 87.2% of women did not follow the WCRF/AICR guidelines. Of the men with hypertension (53.0%), 78.9% did not follow WCRF/AICR guidelines. Of the nearly 40% of men with elevated fasting glucose, 80.8% were not adherent to the WCRF/AICR guidelines. Similarly, among the 42.6% of women with low HDL, 81.6% did not follow the WCRF/AICR guidelines. Greater than 40% of the women had an elevated waist circumference, 87.0% of whom were not adherent to the WCRF/AICR guidelines (Fig. 2).
Survivors who did not follow the WCRF/AICR guidelines were more likely to have MetSyn than those who followed the guidelines, with relative risks of 2.2 (95% CI, 1.6-3.0) among males and 2.4 (95% CI, 1.7-3.3) among females (Table 6). Among female survivors, advanced age, lower educational attainment, and receipt of CRT were also found to be associated with an increased risk of MetSyn. Among male survivors, white race, advanced age, and lower educational attainment were also associated with an increased risk of developing MetSyn.
Table 6. Association Between Dietary Intake and Metabolic Syndrome
Abbreviations: 95% CI, 95% confidence interval; CRT, cranial radiotherapy; Ref, reference group; RR, relative risk; WCRF/AICR, World Cancer Research Fund/American Institute for Cancer Research.
RRs were estimated using the log-binomial model. Final models are based on Akaike information criteria.
Among a large, well-characterized cohort of adult CCS, nearly one-third had evidence of MetSyn that was associated with not following dietary and lifestyle guidelines recommended by the WCRF/AICR. This association persisted even after adjusting for race, age, smoking status, educational attainment, and CRT in multivariable models. Importantly, the association between an unhealthy lifestyle and MetSyn was even stronger than the association between CRT and MetSyn in females, suggesting that individuals predisposed to adverse cardiovascular outcomes after treatment for childhood cancer may be able to modify this risk through behavioral changes.
The prevalence of MetSyn and its components in the current study cohort were higher than that documented by previous investigators in younger cohorts of CCS, but similar to those documented in the general population among much older adults. In a cohort of 75 survivors of childhood ALL (mean age, 30.2 years ± 7.1 years), the authors reported that 16.6% had MetSyn, 8.0% had abnormal fasting glucose, and 20.0% had hypertension, compared with the 31.5%, 31.9%, and 46.9%, respectively, reported in the current study cohort. Similarly, Van Waas et al described a MetSyn prevalence of 13% among of 500 adult CCS with a younger age distribution (5% aged > 40 years) than the current study cohort. The overall prevalence (31.5%) of MetSyn in the current study cohort, 22% of whom were aged > 40 years, was similar to that (34%) reported in the general population, 68% of whom were aged > 40 years. Elevated blood pressure (53.0% vs 43.4% in males and 40.6% vs 35.2% in females) and low HDL cholesterol (38.2% vs 21.6% in males and 42.6% vs 27.8% in females) were more prevalent, whereas increased waist circumference (29.9% vs 44.8% in males and 41.6% vs 60.2% in females) and impaired fasting glucose (38.2% vs 45.8% in males and 24.9% vs 31.3% in females) were less prevalent among CCS when compared with the general population.
Significant findings in the current study were that the association between poor lifestyle choices and MetSyn persisted even after taking into account cancer survivor-specific (eg, CRT) and other known risk factors (eg, smoking, age, etc), and that the influence of lifestyle on each MetSyn component was apparent for both male and female survivors. These results are concordant with those of Tonorezos et al, who reported that among 117 adult survivors of childhood ALL, each unit increase in adherence to the Mediterranean diet increased the odds of MetSyn by 31%, but expanded their findings by accounting for CRT exposure and including survivors of a variety of diagnoses. Although reports from large cohort studies such as the Atherosclerosis Risk in Communities study and the NHANES indicate that the association between poor dietary habits and the incidence of MetSyn is a general population phenomenon,[28, 29] results in the younger CCS population in the current study are particularly troubling. Recent data have indicated that CCS who have both a cardiotoxic treatment exposure and a known population-based cardiovascular risk factor (eg, hypertension) have a more than additive risk for an adverse cardiac outcome, including death.
The findings of the current study that the majority (> 70%) of adult CCS do not follow diets that promote heart health are in concordance with what to our knowledge are the few studies to date documenting dietary habits among CCS.[12, 13] Robien et al evaluated dietary intake among 72 adult survivors of childhood ALL and noted that few met WCRF/AICR guidelines. Similar to the participants in the current study, these authors reported that their cohort consumed excessive red meat, sodium, and dietary fat. Another study reported that nearly 80% of 209 CCS did not consume recommended servings of fruits and vegetables per day. The body of literature regarding dietary habits among CCS is not yet robust. However, there is a pattern of evidence that suggests that survivors' dietary habits are not optimal for heart health.
The current study has limitations that should be considered when interpreting the results. Dietary intake data may be underreported.[30, 31] To address this, we applied a critical evaluation of energy intake to allow us to exclude from analysis those patients (1.3%) with unrealistic values based on physiological energy demands. In addition, not all eligible individuals participated. Although Ojha et al previously assessed selective nonparticipation in this cohort and reported no substantial differences between participants and nonparticipants, it is possible that those who were unable to participate differed from study participants. Rates of obesity (38.1% vs 33.3%) and smoking (20.3% vs 24.1%) among survivors were fairly similar to those of the population in the southeastern United States. However, generalizability to other regions may be limited. In addition, although we used the WCRF/AICR guidelines as our model for a heart-healthy lifestyle, to the best of our knowledge an optimal dietary strategy to reduce disease risk has not been identified.[34, 35] It is possible that other diet or lifestyle guidelines may have a greater impact on MetSyn.
MetSyn was prevalent in > 30% of the adult CCS in the current study cohort, and only 28% reported a lifestyle consistent with WCRF/AICR guidelines. Even after adjusting for known treatment and demographic risk factors, failure to follow a heart-healthy lifestyle was associated with a > 2-fold increased risk of developing MetSyn. These data suggest that a heart-healthy lifestyle is associated with improved metabolic control in CCS, even in individuals treated with CRT. Additional work is needed to evaluate the impact of lifestyle interventions on risk for MetSyn among CCS, especially in individuals predisposed to adverse cardiovascular outcomes after treatment for childhood cancer.
Support provided by Cancer Center Support (CORE) grant CA 21765 from the National Cancer Institute (NCI) and by the American Lebanese Syrian Associated Charities (ALSAC).
CONFLICT OF INTEREST DISCLOSURES
Dr. Lanctot was supported by an NCI grant for work related to the current study. Dr. Robison received personal fees for acting as a scientific advisor for Novo Nordisk. Dr. Ness was supported by grant CA21765 from the NCI to St. Jude Children's Research Hospital, as well as the American Lebanese Syrian Associated Charities (ALSAC) for work related to the current study.