4/3/2015. Obesity in Childhood Cancer Survivors: Opportunities for Early Intervention. Cancer in Children. Cancer is the #1 cause of diseaserelated

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1 Obesity in Childhood Cancer Survivors: Opportunities for Early Intervention Fang Fang Zhang, MD, PhD Friedman School of Nutrition Science and Policy, Tufts University UNTHSC Grant Rounds April 8, 2015 Cancer in Children Cancer is the #1 cause of diseaserelated death for children Adamson et al National Academy of Science ~ 12,400 children < 20 yrs diagnosed with cancer each year ~ 3,000 die each year Trends in 5 Year Relative Survival of Childhood Cancer Survivors Year at Diagnosis ~ 80% of children diagnosed with cancer are alive at least five years after diagnosis, and many are considered cured. Jemal et al 2010 CA A Cancer Journal for Clinicians 1

2 Chronic Health Conditions in Adult Survivors of Childhood Cancer and Their Siblings Childhood cancer survivors were three times more likely to have at least one chronic condition than their siblings. Childhood cancer survivors were five times more likely to have two or more chronic conditions than their siblings. Childhood cancer survivors were nine times more likely to have a severe, disabling, or life threatening disease than their siblings. Oeffinger et al 2006 NEJM Cumulative Incidence of Grades 3-5 Chronic Health Conditions in Survivors and Siblings by Age, Childhood Cancer Survivor Study 19.6% 19.6% Cumulative incidence in 24-year-old survivors = 19.6% = Cumulative incidence in 50-year-old siblings = 19.6% Armstrong et al 2014 JCO Cancer Care Faces a Growing Crisis: Obesity Oncologists must begin to play a larger role in addressing overweight and obesity 2

3 Are childhood cancer survivors more obese than their peers? Obesity in Adult Survivors of Acute Lymphoblastic Leukemia (ALL), Childhood Cancer Survivor Study Obesity (%) Survivors Siblings (N = 1,451) (N = 2,167) Baseline Follow up Garmey et al 2008 JCO Systematic Review and Meta analysis: Weight Status in Pediatric ALL Survivors Body mass index (BMI) z-score BMI z-score <0 BMI percentile <50th Below-average BMI BMI z-score >0 BMI percentile >50th Above-average BMI BMI z-score =0 BMI percentile =50th Average BMI Zhang et al 2014 Pediatrics 3

4 Meta Analysis: Weight Status in Pediatric ALL Survivors 20 studies, 1,742 survivors of ALL (<20 years old & off-treatment <10 years) BMI=80 th percentile Zhang et al 2014 Pediatrics BMI Z Score in Pediatric ALL Survivors by Time from Diagnosis, CRT, and Sex Zhang et al 2014 Pediatrics More Questions At which time point do childhood cancer survivors experience unhealthy weight gain? What are the predictors of becoming overweight/obese in childhood cancer survivors? 4

5 Growth Patterns in Pediatric Survivors of ALL Study design: A retrospective cohort Study population: 83 pediatric ALL patients at Tufts Medical Center Median age at dx = 4.0 years Mean time from dx = 13.4 years 16% treated with CRT 52% female Weight and height: Extracted from medical records at several key time points: Diagnosis End of induction End of consolidation Every 6 months during maintenance Yearly up to 5 years post treatment Growth Pattern of Pediatric ALL Survivors at Tufts New slides here end of treatment 5 years post treatment Zhang et al 2014 Pediatric Blood & Cancer Meta-Analysis: Changes in BMI z-score During Treatment in Pediatric ALL Patients A. From dx to start of maintenance B. From start of maintenance to end of treatment C. From dx to end of treatment Zhang et al 2015 Pediatric Blood & Cancer 5

6 Meta-Analysis: Changes in BMI z-score Post Treatment in Pediatric ALL Patients D. From dx to <2 years post tx E. From dx to years post tx F. From dx to 5 years post tx Zhang et al 2015 Pediatric Blood & Cancer Change in BMI z-score during and after treatment in 1,529 pediatric ALL patients Unhealthy weight gain during tx Zhang et al 2015 Pediatric Blood & Cancer Summary Pediatric ALL survivors are more overweight/obese than their peers; They are at risk for becoming overweight or obese early in treatment. Increases in weight are likely to be maintained throughout treatment and beyond; Identifying modifiable risk factors is clearly a major priority for improving their survival and long term health. 6

7 Energy Balance in Childhood Cancer Survivors High energy intake (overeating) Cancer treatment received at a young age Low energy expenditure (physical inactivity) Treatment Exposure & Obesity Radiotherapy (cranial irradiation) Leptin resistance Chemotherapy (steroids, anthracyclines,mtx) Increased appetite Reduced cardiac fitness Energy intake > Energy expenditure Psychosocial factors Prevalence of Clinically Ascertained Health Outcomes in Adult Survivors of Childhood Cancer, SJLIFE Cohort 16% Attributable Fraction (%) 42% 9% 42% Hudson et al 2013 JAMA 7

8 We need a better understanding on energy balance profiles in childhood cancer survivors Nutritional Intake in childhood cancer survivors Poor diet quality? Suboptimal intake of key nutrients and food groups? Energy expenditure in childhood cancer survivors Reduced energy expenditure? How do cancer- and treatment-related factors affect nutritional intake and energy expenditure in childhood cancer survivors? Are nutritional intake and energy expenditure associated with chronic health conditions in childhood cancer survivors? Differ by at risk for treatment exposure? A Pilot Study: the Healthy Living Study Pediatric ALL and lymphoma patients/survivors Baseline 6-month 12-month Weight / height Body composition Diet Food craving Energy Expenditure Weight/height Diet Food craving Weight/height Body composition Diet Food craving Characteristics of Childhood Cancer Survivors the Healthy Living Study, Characteristics N=22 Age at study enrollment, years, median (Q1, Q3) 11.5 (7.0, 19.0) Female, N (%) 7 (32) Non-Hispanic white, N (%) 17 (77) Age at diagnosis, years, median (Q1, Q3) 4.5 (3.0, 7.0) Years since diagnosis, median (Q1, Q3) 5.6 (2.8, 8.3) BMI z-score, mean (SD) 0.8 (1.0) Overweight/obese, N (%) 9 (41) Fat-free mass, kg, mean (SD) 34.2 (17.4) Percentage of body fat, mean (SD) 29.2 (6.6) 8

9 Doubly Labeled Water (DLW) Method DLW: water where the hydrogen and oxygen have been replaced for tracing purpose with a common isotope ( 18 O and 2 H 2 ) INPUT Dose 2 H 18 2 O 2 H 18 2 O 2 H 2 Body Water Atmospheric 18 O Water Vapor CO 2 Food and Water OUTPUT WATER WATER + CO 2 Remaining Isotope Enrichment, o / oo Water Turnover Deuterium Oxygen Water + CO 2 Turnover Time, days Differential elimination of DLW dose 18 oxygen leaves the body as carbon dioxide (CO 2 ) and water Deuterium leaves the body as water CO 2 production calculated by difference in elimination rates TEE calculated based on energy equivalent of a liter of CO2 to be 3.815/RQ DLW Protocol dose Baseline 4 h 5 h 7-10 d A subject is given a dose of DLW and measured the elimination rates of 18-oxygen and deuterium over time through sampling of isotope concentrations in the body water such as urine Urine samples analyzed for TEE using the gas-isotoperatio mass spectrometry Total Energy Expenditure (TEE) in Childhood Cancer Survivors Mean TEE = 2,073 kcal/day Zhang et al 2014 J Pediatr Hematol Oncol 9

10 TEE Adjusted for Weight by Age and CRT 56 vs. 39, p= vs. 50, p=0.049 Young Old (<12 yrs) ( 12 yrs) CRT + CRT - Zhang et al 2014 J Pediatr Hematol Oncol Energy Gap: Difference between TEE and EER ID Age Gender TEE EER (kcal/day) (kcal/day) 1 9 F 1,834 2, F 2,364 2, M 2,826 3, M 1,208 2, M 1,479 1, M 3,283 3, M 1,274 1, M 2,598 3, M 1,866 2, F 1,909 2, M 2,282 3, M 3,362 3, F 1,375 1, M 1,505 1, M 1,794 2, M 2,475 3, M 1,804 2,210 Mean 2,073 2,565 TEE Growth Diet induced Thermogenesis Activity Energy Expenditure (AEE) Resting Energy Expenditure (REE) mean difference = 492 kcal/day Healthy Eating Index (HEI) 2010 in Childhood Cancer Survivors Adequacy Component Moderation Component Zhang et al 2015 Pediatric Blood & Cancer 10

11 Comparison of Survivors Dietary Intake with 2010 Dietary Guidelines of Americans (DGA) Macronutrients 0%! Intake/DGA = 63% Intake/DGA = 112% Intake/DGA = 115% Zhang et al 2015 Pediatric Blood & Cancer Comparison of Survivors Dietary Intake with 2010 Dietary Guidelines of Americans (DGA) Minerals Zhang et al 2015 Pediatric Blood & Cancer Comparison of Survivors Dietary Intake with 2010 Dietary Guidelines of Americans (DGA) Vitamins Zhang et al 2015 Pediatric Blood & Cancer 11

12 St. Jude Lifetime (SJLIFE) Cohort Study Design: A retrospective cohort that systematically and prospectively assesses health outcomes among CCS as they age Study Population (N=2,600): Mean age = 32.6 years (range: 18 65) Mean time from dx = 24.3 years Mean age at dx = 8.3 years 48% female; 83% non Hispanic white 38% leukemia, 19% lymphoma, 13% embryonal tumor, 13% sarcoma, 9% CNS tumor, 8% others 29 % treated with CRT Cardiometabolic conditions: risk based medical assessments Dyslipidemia: 59% Hypertension: 37% Insulin resistance (HOMA IR): 49% Obesity: 35% St. Jude Lifetime (SJLIFE) Cohort Nutritional Intake: Assessed using Block Food Frequency Questionnaire at study enrollment Consumption of 110 food items during the past 12 months Frequency asked in 8 categories + portion size Validated with three 24 hour diet recalls (r= ) 12

13 Fiber intake & cardiometabolic conditions in childhood cancer survivors P trend=0.03 P trend=0.007 Only 6.4 % of the survivors met the recommended intake of dietary fiber. P trend=0.01 P trend=0.06 High fiber intake of fiber was inversely associated with the prevalence of cardiometabolic conditions in childhood cancer survivors. Jia et al 2015 Experimental Biology Sodium Intake in Childhood Cancer Survivors The mean sodium intake in adult survivors of childhood cancer was 3,566 mg/d, slightly higher than the national average and substantially higher than the recommended upper limit (2,300 mg/d). Liu et al 2015 Experimental Biology Sodium Intake and CVD Risk Factors Odds Ratio Elevated Triglyceride Odds Ratio Reduced HDL 0 3, < Odds Ratio HOMA-IR Odds Ratio Hypertension 0 3, < Odds Ratio Abdominal Obesity Odds Ratio Metabolic Syndrome 0 3, <

14 Summary CCS have a high prevalence of obesity Excessive weigh gain occurs early in treatment; and increases in weight are maintained throughout the treatment and beyond CCS have suboptimal energy balance profiles They have reduced levels of energy expenditure, likely due to reduced levels of physical activity; They also have poor diet quality and poor adherence to dietary guidelines for saturated fat, fiber, sodium, vitamin D, vitamin E, calcium, and potassium; Call for clinicians screening for obesity early in survivorship, and interventions to improve diet quality and avoid physical inactivity early in survivorship. Tufts University Susan Parsons, MD, MRP Edward Saltzman, MD Michael Kelly, MD, MPH,MS Susan Roberts, PhD Aviva Must, PhD Mei Chang, PhD Angie Rodday, MS Shanshan Liu Yinan Jia Acknowledgement Cook Children s Medical Center Paul Bowman, MD Rachel Hill, RD St. Jude Children s Research Hospital Kevin Krull, PhD Rohit Ohja, DrPH Jennifer Lanctot, PhD Wassim Chemaitilly, MD Melissa Hudson, MD Funding Boston Nutrition and Obesity Research Center (BNORC)P30 DK46200, National Center for Research Resources Grant UL1 RR025752, National Center for Advancing Translational Sciences UL1 TR Tufts Collaborates Grant 14

15 Thank You! 15