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To join the call dial (866) 740-1260, code 8055841#.All participants are placed on mute for the duration of the webinar.If you have questions, type them in the chat box at the bottom left hand side of your screen. They will be answered at the end of the presentation.This conference is being recorded for future use.The recording will be made available on the ASPHO website afterwards.
Welcome!
Slide2Copyright (C) 2017 by ASPHOImpact of Obesity on Outcomes in Childhood ALL Survivors
Jill Simmons, MD
Associate Professor of Pediatrics
Vanderbilt University Medical Center
Emily
Tonorezos
, MD, MPH
Clinical Director, Adult Long-Term Follow-Up Program
Memorial Sloan Kettering Cancer Center
Slide3Learning ObjectivesDescribe the multifactorial physiologic mechanisms for obesity in pediatric ALL survivorsDiscuss the impact of obesity on childhood ALL survivors and long-term health-related outcomes into adult yearsExamine potential prevention and treatment strategies
Slide4Obesity in Pediatric ALL: Begins Early and Persists Beyond Treatment Completion1-3Prevalence in ALL survivors is 34-46%3Mean BMI in survivors is the 80th percentile31Esbenshade, Simmons et al. Pediatr Blood Cancer 2011; 2Zhang et al, Pediatr
Blood Cancer 2015;
3
Zhang et al, Pediatrics
2014.
Slide5Obesity: Risk FactorsSimply having ALLExcessive weight gain occurs in patients with pediatric ALL regardless of treatment received, sex, and weight status at diagnosis (meta-analysis 1,514 ALL survivors)1Cancer treatment attributes <50% to the elevated obesity risk in CCS21Zhang et al Pediatr Blood Cancer 2015; 2 Hudson et al JAMA 2013
Slide6Obesity: Risk FactorsHigh-dose glucocorticoid (GC) therapy1Cranial radiation2Chemotherapy?Female sex?3Age at diagnosis?1Zhang et al. Pediatr Blood Cancer 2014; 2Garmey et al. JCO 2008; 3Veringa et al. Pediatr Blood Cancer 2012;
Slide7Mechanisms of Obesity: GC TherapyIncreases energy intake (food) 1,2During maintenance therapy (on dexamethasone), ALL patients consumed 2126 kcal/ day Healthy controls consumed 1775 kcal/ day (p<0.05)1Pediatric ALL patients consumed 20% more calories on GC therapy during maintenance compared with days without steroid therapy 2Increases visceral adipose tissue31 Jansen et al, Support Care Cancer 2009; 2 Reilly et al JCEM 2001; 3 Stimson et al Diab Ob Metab 2017
Slide8Mechanisms of Obesity: Anthracyclines and Vincristine1,2Theoretically:Impaired cardiovascular fitness Decreased muscle strengthReduced levels of physical activityStudies show:No difference between physical activity levels and treatment with anthracyclines in survivors1 Florin et al Cancer Epidemiol Biomarkers Prev 2007; 2 Ness et al Cancer 2009;
Slide9Obesity in Pediatric ALL Survivors: A Meta-AnalysisZhang et al, Pediatrics 2014
Slide10Mechanisms of Obesity: CRT / HSCTUntreated concomitant pituitary/ hypothalamic dysfunctionGH deficiencyThyroid hormone/ TSH deficiencyHypogonadismLeptin resistance?11Follin et al, PLOS 2016
Slide11Leptin-Melanocortin Pathway
Stomach
Adipose
Tissue
Hypothalamus
POMC
Agrp
/
Npy
MC4R
PVN
Arcuate
Ghrelin
Ghsr
+
-
+
Leptin
Lepr
Lepr
Mc4r
+
↑ Energy
Expenditure
↓Food intake
-
Slide courtesy of Ashley Shoemaker, MD MCSI
Slide12Leptin-Melanocortin Pathway
Stomach
Adipose
Tissue
Hypothalamus
POMC
Agrp
/
Npy
MC4R
PVN
Arcuate
Ghrelin
Ghsr
+
-
+
Leptin
Lepr
Lepr
Mc4r
+
↑ Energy
Expenditure
↓Food intake
-
Slide courtesy of Ashley Shoemaker, MD MCSI
Slide13Mechanisms of Obesity: CRT / HSCTLeptin levels ↑ in female ALL survivors treated with CRT compared with controls33 ug/L vs 13 ug/L (p<0.001)1Leptin/ kg fat mass ↑in ALL survivors treated with CRT compared with controls (possible evidence of leptin resistance)Females: 1.09 vs 0.6, p<0.0011Males: 0.5 vs 0.3 (P<0.01)21 Follin C, et al. PLOS ONE 2016; 2 Tonorezos et al Pediatr Blood Cancer 2011
Slide14Hypothalamic Size and Leptin/ kg in ALL Survivors Treated with CRTFollin C, et al. PLOS ONE 2016
Slide15Mechanisms of Obesity: CRT / HSCTPediatric HSCT survivors have higher % body fat mass and lower lean body mass but no difference in BMI compared to similar-aged controls 1 ALL HSCT survivors have higher waist-to-hip ratio but not a higher BMI than ALL survivors who did not require HSCT 21Slater et al, Biol Blood Marrow Transplant 2015; 2 Chow et al, Biol Blood Marrow Transplant 2010
Slide16Risk Factors for Obesity: Female Sex (Meta-analysis)Studies reporting z-scores for BMIBMI z-score for female ALL survivors: +1.0 (95% CI 0.7-1.4)BMI z-score for male ALL survivors: +0.7 (95% CI 0.3-1.1)Not all studies agreePrevalence of overweight/ obesity by sex 7/22 reported a higher prevalence of obesity in females than in males15/ 22 report no differenceZhang et al Pediatrics 2014
Slide17Risk Factors for Obesity: Younger Age at Diagnosis (Meta-Analysis)11 studies report effect of age at diagnosis on obesity in ALL survivors5 report higher prevalence in younger patients 6 did not find an effect of age Younger age at diagnosis is not universally definedZhang et al Pediatrics 2014
Slide18Behavior Patterns: Long-TermChildren have difficulty reversing unhealthy eating habits and sedentary behaviors after treatment completion 1-3All long-term pediatric cancer survivors4: Survivors less likely than siblings to meet CDC physical activity guidelines (46% vs 52%)Survivors more likely than siblings to report no leisure-time physical activity in the past month (23% vs 14%)1 Florin et al Cancer Epidemiol Biomarkers Prev 2007; 2 Stern et al Clinical Practice in Pediatric Psychology 2013; 3 Arroyave et al Oncol Nurs Forum 2008; 4Ness et al Cancer 2009
Slide19Behavior Patterns: Long-TermCompared with controls, pediatric ALL survivors more likely to:Not meet CDC recommendations for physical activity (OR 1.44, 95% CI 1.32-1.57) Report no leisure-time physical activity in the past month (OR 1.74, 95% CI 1.56-1.94)11 Florin et al Cancer Epidemiol Biomarkers Prev 2007;
Slide20Methods for Diagnosis of ObesityBody fat by DXA is gold standard; is expensive and leads to increased radiation exposureTriceps-skinfold measurements1 or waist-hip ratio2 have been reportedBMI, triceps-skinfold measurements and waist-hip ratio all misclassify CCS as non-obese compared to DXA3,41Collins et al., J Adolesc Young Adult Oncol 2017; 2Chow et al., Biol Blood Marrow Transplant 2010; 3Blijdorp et al, PLoSOne 2012; 4Karlage et al., Cancer 2015
Slide21BMI May Not Be Best Indicator of ObesityBMI compared with % body fat by DXA; 46% false negative in men and 53% false negative in womenSkinfolds compared with % body fat by DXA; 35% false negative in men and 27% false negative in womenWaist-hip ratio compared with % body fat by DXA; 13% false negative in men and 30% false negative in womenKarlage RE, et al. Cancer. 2015 Jun 15;121(12):2036-43.
Slide22Screening for ObesityDue to expense and no clearly better alternative, annual BMI measurement is recommendedcovert to age- and sex- specific z-score
Slide23Glucose Abnormalities: HSCT SurvivorsInsulin resistance and glucose abnormalities occur without the presence of obesity 1,252% of long-term HSCT survivors have insulin resistance35% of HSCT recipients have DM at 11 years post-transplant41Chow et al, Pediatr Blood Cancer 2013; 2Neville et al, JCEM 2006;3Taskinen et al, Lancet 2000; 4Hoffmeister et al J Pediatr Hematol Oncol 2004
Slide24Glucose Abnormalities in ALL HSCT Survivors: MechanismPancreatic islet cell injury due to TBI1Atypical body fat distribution (partial lipodystrophy) 2Adipose tissue is damaged ↓ subcutaneous with ↑visceral and ↑intramuscular fat distribution↑ total fat mass and ↓ lean mass↑ risk of abnormal glucose tolerance and ↓insulin sensitivity1 Wei et al ClinEndocrinol 2015; 2 Wei et al, Pediatr Blood Cancer 2015
Slide25Screening for DiabetesIn patients who have had XRT to include the abdomen:Fasting BG or HbA1c every 2 yearsSooner if medically indicated www.survivorshipguidelines.org
Slide26ConclusionsPediatric ALL survivors are at risk for obesityTreatment FactorsPatient factorsHaving ALL Obesity begins early in treatment and continues throughout the lifespan Evaluate for obesity using BMI Remember that BMI may miss patients at risk for metabolic abnormalitiesEvaluate patients who have received XRT (TBI/ abdominal) for glucose abnormalities
Slide27Copyright (C) 2017 by ASPHODiet and Physical Activity Interventions for Childhood ALL Survivors
Emily
Tonorezos
, MD, MPH
Clinical Director, Adult Long-Term Follow-Up Program
Memorial Sloan Kettering Cancer Center
Slide28Behavior Patterns: Long-TermChildren have difficulty reversing unhealthy eating habits and sedentary behaviors after treatment completion 1-3All long-term pediatric cancer survivors4: Survivors less likely than siblings to meet CDC physical activity guidelines (46% vs 52%)Survivors more likely than siblings to report no leisure-time physical activity in the past month (23% vs 14%)1 Florin et al Cancer Epidemiol Biomarkers Prev 2007; 2 Stern et al Clinical Practice in Pediatric Psychology 2013; 3 Arroyave et al Oncol Nurs Forum 2008; 4Ness et al Cancer 2009
Slide29Behavior Patterns: Long-TermCompared with controls, pediatric ALL survivors more likely to:Not meet CDC recommendations for physical activity (OR 1.44, 95% CI 1.32-1.57) Report no leisure-time physical activity in the past month (OR 1.74, 95% CI 1.56-1.94)11 Florin et al Cancer Epidemiol Biomarkers Prev 2007;
Slide30ALLIFE Diet Study117 adult survivors of childhood ALLComprehensive metabolic testingHarvard food frequency questionnaireAdherence to the Mediterranean Diet plan was determined using the Med Diet IndexTrichopoulou et al. NEJM 2003; 348:2599.Tonorezos et al. Cancer Causes Control 2013; 24:313.
Slide31Mediterranean DietEat lots of: Fruits, vegetables, nuts, monounsaturated (versus saturated) fats, legumes, fish and seafood, whole grainsDrink a little alcoholDon’t eat too much: meat or dairy Trichopoulou et al. BMJ 2009;338:b2337.
Slide32Mediterranean DietOverall mortalityDiabetes mellitusCardiovascular disease and strokeAlzheimer’s diseaseCancerSofi Am J Clin Nutr 2010;92:1189.Renaud Am J Clin Nutr 1995;61(Suppl):1360S.Scarmeas Arch Neurol 2006;63:1709.Estruch NEJM 2013; 368:1279-1290.
Slide33Mediterranean Diet after ALLGreater adherence to a Mediterranean diet pattern was associated with:Lower visceral adiposity (p = 0.07)Less subcutaneous adiposity (p < 0.001)Smaller waist circumference (p = 0.005)Lower body mass index (p = 0.04).Trichopoulou et al. NEJM 2003; 348:2599.Tonorezos et al. Cancer Causes Control 2013; 24:313.
Slide34Mediterranean Diet after ALLFor each point higher on the Mediterranean Diet Score, the odds of having the metabolic syndrome fell by 31 % (OR 0.69; 95 % CI 0.50, 0.94; p = 0.019).Trichopoulou et al. NEJM 2003; 348:2599.Tonorezos et al. Cancer Causes Control 2013; 24:313.
Slide35Mediterranean Diet after ALLFindings were independent of measured physical activity energy expenditureDifferences of 0.5 servings of vegetables a day, or one serving of fish a week, were associated with improved body mass index, adiposity, and blood pressure, and lower risk of the metabolic syndrome.Trichopoulou et al. NEJM 2003; 348:2599.Tonorezos et al. Cancer Causes Control 2013; 24:313.
Slide36Observational StudiesSurvivors are inactive and do not comply with dietary recommendations.Small improvements in diet appear to be beneficial.What about intervention studies?clinicaltrials.gov
Slide37IDEAL Weight in ALLDietary and exercise intervention for 10-18 year old patients with newly diagnosed with B-precursor ALLCurrently enrolling at CHLAPrimary Aim: Reduce fat gained during induction therapy, measured with DXA
Slide38IDEAL Weight in ALLDietary Intervention Beginning at time of diagnosis, the dietary component of the intervention uses a personalized menu to implement high protein, moderate fat, and low glycemic index/high fiber diet to achieve a minimum net -10% daily caloric deficit during the induction phase of chemotherapy.
Slide39IDEAL Weight in ALLActivity and Exercise Intervention Beginning at the time of diagnosis, the exercise and activity component uses an "activity menu" to implement a target level of 200 minutes per week of moderate exercise activity (as estimated by metabolic equivalents) during the induction phase of chemotherapy
Slide40Let’s Play! Healthy Kids After CancerThe goals of this pilot study are to evaluate the feasibility, acceptability, and potential efficacy of a parent-targeted, phone-delivered nutrition and physical activity program to prevent unhealthy weight gain among 60 childhood ALL survivors, 4-10 years of age.
Slide41Let’s Play! Healthy Kids After CancerParticipants will be randomly assigned to either the phone-delivered parent-targeted nutrition and physical activity intervention or a standard-of-care control group.
Slide42Let’s Play! Healthy Kids After CancerPrimary outcome is feasibility and acceptability but adherence to program and biomarkers/body composition also measured.Completed, awaiting publication of results.
Slide43Low GI Diet in Children and Adolescents with ALLThis study aims to determine the feasibility, measured by compliance to a low-GI diet, of a 6-month low glycemic dietary intervention in children and adolescents undergoing treatment for ALL. Currently recruiting at Columbia and expanding to other sites.
Slide44Low GI Diet in Children and Adolescents with ALLThe proposed work will be used for the design and implementation of a multi-center nutritional intervention aimed at improving dietary intake during treatment and its effect on clinically important outcomes.
Slide45ALL-ActiveFamily-based intervention study at Vanderbilt.To evaluate feasibility, adherence, completion rates and participant satisfaction associated with a family based lifestyle intervention for overweight pediatric acute lymphoblastic leukemia (ALL) patients or those at high risk to become so (body mass index [BMI] >= 50th percentile) in the first three months of maintenance therapy.
Slide46ALL-ActiveARM I: Patients receive standard of care individualized diet and exercise plan and monthly booster follow-up sessions from the nutritionist and exercise physiologist and weekly phone counseling with a trained health coach to address barriers to improve plan adherence.
Slide47ALL-ActiveARM II: Patients receive standard of care individualized diet and exercise plan.After completion of study treatment, patients are followed up at 3 and 6 months.Recruitment is finished but study is ongoing.
Slide48Physical Activity InterventionsCurrently, six trials of physical activity interventions among children with ALL.Exergaming, web-based, and home-based interventions.Aims include increasing aerobic activity, balance, or strength training.
Slide49Physical Activity InterventionsAll six studies are in the pediatric population and most take place at the time or soon after diagnosis.Thus far, no results have been published and some trials are still recruiting.
Slide50The EQUAL StudyExercise and QUality diet After Leukemia.A 24-month randomized controlled trial comparing the effect of a web- and telephone-based weight loss intervention (led by Healthways at Hopkins) to general information about weight loss and healthy living (control).
Slide51The EQUAL StudyParticipants are from a nationwide sample of obese adult survivors of childhood ALL in the Childhood Cancer Survivor Study.Diagnosed with ALL from 1970-2000 and treated on a variety of protocols.
Slide52The EQUAL StudyInvited participants were obese by self-reported measures (CCSS questionnaire).Those assigned to the control group will receive brochures from the American Cancer Society and the CDC about achieving a healthy weight.
Slide53Goals of the InterventionOverall goal is weight loss, which is achieved through diet and physical activity modification.Participants are encouraged to eat a low-calorie, low-salt diet with 7-12 daily servings of fruits and vegetables and Build to 180 minutes of vigorous physical activity per week.
Slide54Components of the InterventionCoaches focus on key weight management behaviors (diet and physical activity).Use motivational interviewing techniques including open-ended questions, exploring ambivalence, and supporting optimism.Follow re-engagement procedures when participants have not logged in.
Slide55Components of the InterventionWebsite provides learning modules with games, quizzes, and worksheets.Provides self-monitoring tools and graphs (to record weight, minutes of vigorous exercise per day, and calories consumed).Displays feedback regarding weight loss progress including change since last log-in and overall change.
Slide56Healthways at Hopkins
Slide57Healthways at Hopkins
Slide58The POWER TrialWeight loss at 24 months was the same in the two intervention groups.The remote intervention delivered by Healthways at Hopkins provided clinically significant weight loss (4.6kg) that was not different from what was achieved the addition of in-person support (5.1kg).The control group lost 0.8kg.
Slide59The POWER TrialAppel Clark et al. NEJM 2011.
Slide60The POWER Trial
Slide61The EQUAL Study: All ParticipantsHome visit for anthropometric measures and fasting blood work at 0, 12, and 24 months.Detailed web-based questionnaires at 0, 12, and 24 months.
Slide62The EQUAL Study AimsSpecific Aim 1: Determine the effectiveness of a 24-month remotely-delivered diet and physical activity intervention, compared to self-directed weight loss, among a nationwide sample of obese adult survivors of childhood acute lymphoblastic leukemia (ALL).Hypothesis 1: Obese ALL survivors randomized to the call-center directed intervention will lose on average 2.75kg more than those engaged in self-directed weight loss.
Slide63The EQUAL Study AimsSpecific Aim 2: Calculate the effect of the diet and physical activity intervention, compared to self- directed weight loss, on three key metabolic biomarkers:a. Fasting insulinb. Leptin:adiponectin ratioc. Small, dense LDLHypothesis 2: Improvements in biomarkers will be greater among participants in the intervention group.
Slide64The EQUAL Study AimsSpecific Aim 3: Calculate the relative contribution of diet and physical activity to weight loss and the three key metabolic parameters.Hypothesis 3: A diet rich in fruits and vegetables and with little meat consumption will result in the greatest benefit.Specific Aim 4: Assess the roles of self-efficacy and risk perception on meeting activity and diet goals.Hypothesis 4: Subjects with high self-efficacy and enhanced risk perception will be more likely to make behavioral and nutritional changes.
Slide65The EQUAL Study: All ParticipantsPrimary outcome: weight loss at 24 months.Other outcomes: serum lipids, fasting glucose, and leptin/adiponectin levels.Other outcomes: meeting dietary and physical activity goals (understanding behavioral change in this population).
Slide66ConclusionsObesity and type 2 diabetes mellitus is a common and serious problem among children with acute lymphoblastic leukemia.These intervention studies will help us understand how kids who have had ALL can achieve a healthy weight, and what might stand in their way.
Slide67Questions?Type them in the chat box at the bottom left hand side of your screen.
Slide68Copyright (C) 2017 by ASPHO