J. Pediatr. (Rio J.) vol.92 número6

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www.jped.com.br

REVIEW

ARTICLE

The

influence

of

antineoplastic

treatment

on

the

weight

of

survivors

of

childhood

cancer

夽

Julia

Ferrari

Carneiro

Teixeira

a

_,

_Priscila

_dos

_Santos

_Maia-Lemos

b

_,

Mônica

dos

Santos

Cypriano

b

_,

_Luciana

_Pellegrini

_Pisani

c,∗

a_Universidade_Federal_de_São_Paulo_(UNIFESP),_Programa_de_{Pós-graduação}_em_Alimentos,_Nutrição_e_Saúde,_Santos,_SP,_Brazil b_Instituto_de_Oncologia_{Pediátrica/Grupo}_de_Apoio_ao_Adolescente_e_à_Criança_com_Câncer_{(IOP/GRAACC),}_São_Paulo,_SP,_Brazil c_Universidade_Federal_de_São_Paulo_(UNIFESP),_Departamento_de_{Biociências,}_Santos,_SP,_Brazil

Received8March2016;accepted23March2016 Availableonline18June2016

KEYWORDS

Neoplasms; Child; Survivors; Obesity; Radiotherapy; Bonemarrow transplantation

Abstract

Purpose: Obesityisalateeffectinsurvivorsofchildhoodcancerandcorrelateswithchronic complications.Survivorsofleukemia,braintumors,andhematopoieticstemcell transplanta-tionaremorelikelytodevelopobesityresultingfromtreatmentmodalitiessuchasradiotherapy andglucocorticoids.Thispaperanalyzesandintegratesthecurrentdataavailabletohealth pro-fessionalsinordertoclarifystrategiesthatcanbeusedtotreatandpreventobesityinchildhood cancersurvivors.

Sources: This isaliterature reviewfrom onscientificallyreliable electronicdatabases.We selectedarticlespublishedinthelastfiveyearsandearlierarticlesofgreatscientific impor-tance.

Datasynthesis: The mechanisms involved in the pathophysiology of obesity in cancer sur-vivors arenot completely understood, butit isbelievedthat damage tothe hypothalamus andendocrinedisorderssuchasinsulinresistance,leptinresistance,andhormonedeficiency maybeinvolved.Thebodycompositionofthisgroupincludesapredominanceofadiposetissue, especiallyinthoseundergoinghematopoieticstemcelltransplantandtotalbodyirradiation. Theuseofbodymassindexinthesepatientsmayleadtoanunderestimationofindividuals’ riskformetaboliccomplications.

Conclusion: Early identificationofgroupsusingaccurateanthropometricassessments, inter-ventional treatment,and/orpreventativemeasures andcounselingis essentialto minimize theadverseeffectsoftreatment.Physicalactivityandhealthyeatingtopromoteadequacyof weightinthewholepopulationshouldbeencouraged.

夽

Pleasecitethisarticleas:TeixeiraJF,Maia-LemosPS,CyprianoMS,PisaniLP.Theinfluenceofantineoplastictreatmentontheweight ofsurvivorsofchildhoodcancer.JPediatr(RioJ).2016;92:559---66.

∗_{Corresponding}_author.

E-mail:[email protected](L.P.Pisani).

http://dx.doi.org/10.1016/j.jped.2016.04.003

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PALAVRAS-CHAVE

Neoplasias; Crianc¸a; Sobreviventes; Obesidade; Radioterapia; Transplantede MedulaÓssea

Ainfluênciadotratamentoantineoplásicosobreopesodesobreviventesdocâncer nainfância

Resumo

Objetivo: Aobesidadeéumefeitotardioemsobreviventesdocâncernainfânciaeestá correla-cionadaacomplicac¸õescrônicas.Ossobreviventesdaleucemia,tumorescerebraisetransplante decélulas-troncohematopoiéticastêm maiorprobabilidadededesenvolverobesidade como resultado dasmodalidadesdetratamento, como radioterapiaeglicocorticoides.Este artigo analisaeintegraosdadosatuaisdisponíveisaprofissionaisdasaúdeparaesclareceras estraté-giasquepodemserutilizadasparatratarepreveniraobesidadeemsobreviventesdocâncer nainfância.

Fontes: Estaéumaanálisedaliteraturadebasesdedadoseletrônicascientificamente con-fiáveis.Selecionamosartigospublicadosnosúltimoscincoanoseartigosmaisantigosdegrande importânciacientífica.

Resumodosdados: Osmecanismosenvolvidosnafisiopatologiadaobesidadeemsobreviventes docâncernão sãocompletamenteentendidos,porémacredita-sequeodanonohipotálamo edisfunçõesendócrinas,como resistênciaàinsulina, resistênciaàleptinaedeficiência hor-monal,possamestarenvolvidos.Acomposiçãocorporaldessegrupoincluiumapredominância detecidoadiposo,principalmenteem pacientessubmetidosatransplantedecélulas-tronco hematopoiéticas e irradiação de todo o corpo. O uso do índice de massa corporal nesses pacientespodesubestimarindivíduosemriscodecomplicaçõesmetabólicas.

Conclusão: Aidentificaçãoprecocedegrupospormeiodeavaliaçõesantropométricasprecisas, tratamentointervencionale/ou medidaspreventivaseaconselhamento éfundamental para minimizarosefeitoscolateraisdotratamento.Aatividadefísicaealimentaçãosaudáveldevem serincentivadasparapromoveraadequaçãodopesonapopulaçãoemgeral.

Introduction

Obesity is an acknowledged late effectin childhood can-cersurvivorsthatisespeciallyobservedincertaingroups, suchassurvivorsofbrain tumorsor leukemia,sincethese cancersareassociatedwithotherchronicdiseasesincluding diabetes,hypertension,depression,cardiovasculardisease, anddyslipidemia.1,2 _Obesity _in_these _groups_of _individuals

iswelldescribedintheliterature;amongallsurvivors, cra-nial radiotherapy(CRT), chemotherapy, and steroids have beendocumentedtocontributetoanalterationinthebody compositionofpatients alreadydischargedfromoncologic treatment.3

Endocrineandmetabolicalterationshavebeenreported ashighlyprevalentin cancersurvivors whohavereceived ahematopoieticstemcelltransplant(HSCT).Contributing factors may include an intense or prolonged immunosup-pressivetreatment,post-transplantendocrinedysfunction, and insulin or leptin resistance. Although there are no studiessuggestingHSCTascausative,preventionandearly treatment of cardiovascular risks in these patients might diminish the incidence of late complications after the transplant.4

The early identification of high-risk groups, followed by a treatment plan based on metabolic and nutritional assessmentsthatincludesincreasedphysical activity,isan essentialcomponentinthepreventionofobesity.5_With_this

knowledge,itisimportanttostudythecausesofobesityin

allsurvivorsofchildhoodcancer,addressingnotonlycauses welldocumentedintheliteratureasinfluential,butalsothe seldomexplored causalfactorsin thisgroup. The authors alsoquestion the efficacy ofbody mass index(BMI)asan indicator to identify patients who are overweight, since theseindividualsexperiencechangesinbodycomposition, andtherefore patientsatrisk formetabolic complications maybeoverlooked.Thus,thegoalofthisreviewisto pro-motediscussiononthethemethroughdatacompilationand understanding possiblecauses, andtoalert health profes-sionalsoftheimportanceofthistopic.Promotionofdebate in the academic communityis essentialto encourage the implementationoffuturepublichealthpoliciestoprevent obesityinchildrenandadolescentswithcancerandinfuture survivors.

Methods

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Table1 Summaryofstudiesonthemainriskfactorsrelatedtoobesityandmetabolicsyndromeinchildhoodcancersurvivors.

Outcomes No.ofstudies

Obesity

Riskfactor Author/Tumortype

Cranialradiotherapy(CRT) Oeffingeretal.(2003)/Leukemia Chowetal.(2013)/Leukemia

Lustigetal.(2003)/Centralnervoussystem(CNS) Ahmetetal.(2006)/CNS

Milleretal.(2010)/Leukemiaandlymphoma

5

FemaleCRT(>20Gy) Oeffingeretal.(2003)/Leukemia 1

Age(<5years) Oeffingeretal.(2003)/Leukemia 1

Age(<10years) Chowetal.(2013)/Leukemia 1

Hematopoieticstemcelltransplant (HSCT)

Chowetal.(2013)/Leukemia Inabaetal.(2012)/Alltypes Rubleetal.(2012)/Alltypes

3

Antineoplastictreatment(anytype andphase)

Mayeretal.(2000)/Leukemia Esbenshadeetal.(2011)/Leukemia

2

Overweight(initiationoftreatment) Zhangetal.(2014)/Leukemia 1 Overweight(regardlessofother

characteristics)

Zhangetal.(2014)/Leukemia 1

Local/Extensivesurgery Lustigetal.(2003)/CNS Ahmetetal.(2006)/CNS

2

Deficiencyofgrowthhormone(GH) Lustigetal.(2003)/CNS Ahmetetal.(2006)/CNS

2

Reducedenergyexpenditure Harzetal.(2003)/CNS 1

Functionalcapacitycompromised (reducedmobilityand/ormuscle weakness)

Nessetal.(2014)/CNS Pietiläetal.(2009)/CNS Hoffmanetal.(2008)/Sarcoma

3

Watchtelevision Milleretal.(2010)/LeukemiaandLymphoma 1

Inadequatenutrition Berdanetal.(2014)/Alltypes

Shams-Whiteetal.(2015)/Leukemiaandlymphoma

2

Metabolicsyndrome No.ofstudies

Riskfactor Author/Typeoftumor

HSCT(includingtotalbody irradiation[TBI])

VanWaasMetal.(2010)/LeukemiaandCNS Oudinetal.(2011)/Leukemia

Taskinenetal.(2000)/Alltypes Frisketal.(2011)/Alltypes ScottBakeretal.(2007)/Alltypes

5

n,numberofstudiesevaluated.

participants, typeof tumor, aim of the study,and results obtained.Belowisasummaryofmajorstudiesthatwillbe addressedanddescribedinthisreview(Table1).

Itwasdecidedtodividethediscussiontopicsaccording tothetumorandtreatmentbecausetheyarethemaintypes describedintheliteraturecorrelatedwithobesity.

Results

and

discussion

Acutelymphoblasticleukemia(ALL)

Acute lymphoblastic leukemia (ALL) is the most common malignantchildhoodcancer andit hasbeen consideredan importantmodel for thestudy ofmetabolic disordersand

theircorrelationwithcardiovascularevents,suchasstrokes andchronichealthconditionsamongsurvivorsofALL.6

ExcessiveweightgainoccurringduringtreatmentforALL is usuallyrelated tothe use of steroids, appetite regula-tiondisorders,radiotherapytothecentralnervoussystem (CNS), and reduced energy expenditure due to physical inactivity.3_{Post-treatment}_weight_gain_conditions_have_also

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addition,boystreatedwith20Gyhadanalmosttwotimes increasedchance of being obesecompared to their male siblings.7,8

In agreementwiththisobserved influence of radiothe-rapyonweight,Mayeretal.reportthattheprevalenceof obesitywassignificantlyhigherafterALLtherapywhenthe factorsofALLpost-therapyobesitywereevaluatedduringa transversalstudywith39survivorsofthedisease.In compar-isonwithnon-irradiatedpatients,thosewhohadundergone therapyhadhighlyreducedbasalmetabolicrates(BMR)as wellasareductionintheirphysicalactivitylevels,andlower concentrationsofinsulin-likegrowthfactorbindingprotein 3andfreethyroxin.9

In itsanalysis of thedifferential effects of CRT,spinal radiotherapy,andtotalbodyirradiation(TBI)ongrowthand endocrinefunction in 3467 ALLsurvivors, the CCSS found thatpatientstreatedwithTBIweresignificantlymorelikely toreportthemselvesasunderweightthanthosewhohadnot receivedany dose of radiotherapy.It wasalsofound that thosetreatedwithCRTweresignificantlymorelikelytobe overweightorobese.Thestudyshowedthatage<10years atdiagnosisandHSCTareindependentcharacteristics asso-ciatedwithBMIalterationsandan increasedrisk of being overweightorobese.Otherfindingsfromthestudyinclude thefollowing:supplementationwithgrowthhormone(GH) was associated with being underweight, and female sur-vivors, contrary to previous studies, were less likely to beoverweight or obesethan malesurvivors. The authors concludedthatpatientstreatedwithanyofthe aforemen-tionedtherapieshadanincreasedriskofalterationsinbody composition.10

Despiteampleevidencefortheassociationbetween obe-sityandRT,studieshavealsoshownthatpatientspresenta riskofbecomingoverweightduringallphasesoftreatment, regardlessofthetreatmentmodality.WhentheBMIof183 ALLpatientswasevaluatedduringallphasesoftreatment (diagnosis, induction, consolidation, and maintenance),it hasbeen observed that,at diagnosis, 36% of thepatients wereoverweightand 19%were obese.The median BMIz -scoreincreasedduringtheinduction phaseandthenlater returnedtobaseline;however,itincreasedagain through-outthefirst22monthsofmaintenance.Bytheendofthe treatment, 49% of the patients were overweight and 21% wereobese.TheincreaseintheBMIz-scoreduringthe diag-nosis wasassociated withthe z-score increase duringthe maintenancephase.Thestudyconcludedthatpatientsare at risk of an elevation in BMI at all phases of treatment, whichplacesthematgreaterriskforadversehealth condi-tionsintheirfuture.11

Anothersimilarstudy examinedtheBMIof83pediatric survivorsofALLandobservedthatweightatdiagnosisand BMIz-score weretwo important predictors of overweight andobesityattheendofthetreatment.Patientswhowere overweight or obese at diagnosis were 11.9 times more likelytobeoverweightorobesebytheendoftheir treat-mentthan thosewhowereunderweightor normal weight at diagnosis. An increase of one unit in the BMI z-score at diagnosis was associated with a tripling in the risk of being overweight or obese by the end of the treatment. ThestudyfinallyconcludesthatALLsurvivorsareatriskof becomingoverweightatthebeginningoftreatmentandthat theirweightincreaseismaintainedthroughouttreatment,

making early intervention necessary.12 _Reaffirming _these

findings,the sameauthorfound ina meta-analysisofALL survivorsthatobesityisprevalentinthisgroupandis inde-pendent of patient characteristics such as sex or age at diagnosis,andtreatments,suchascranialirradiation.Thus, health professionalsmay need topayspecial attentionto thesesurvivors.13

Besidesobesity,metabolicsyndrome(MetS)isalso expe-rienced by childhood cancer survivors as a consequence of anti-neoplastic treatments. MetS can be defined as a group of interrelatedrisk factorsof metabolic origin that contribute directly to the development of cardiovascular disease(CVD)and/ordiabetesmellitustype2.Well-known riskfactorsforMetSincludeatherogenicdyslipidemia,high blood pressure, and high plasmatic glucose levels. Indi-viduals withthese characteristics commonly present with apro-thrombosisand pro-inflammatorystate. Atherogenic dyslipidemiacomprises a seriesof alterations in levels of lipoproteins,includingariseintriacylglycerol, apolipopro-tein B (apo B), and low-density lipoprotein (LDL), and a decreaseinhigh-densitylipoprotein(HDL).Abdominal obe-sity, insulinresistance (IR), physical inactivity,aging, and hormonalimbalancecanpromotemetabolicriskfactors.14

Childhoodcancersurvivors,especiallythosetreatedwith cranialirradiation,faceahigherriskofdevelopingMetSas adults,15 _particularly_those_who _had_ALL _and_CNS _cancers

and presentedwithrisk factorssuch asvisceraladiposity, dyslipidemia,IR,andhypertension.16,17_The_authors_of_one

studydeterminedthattheprevalenceofMetSinFrenchALL survivorswas9.2%,whichwasdoubletherateinthegeneral populationofFrenchyoungadults.Therewasnoassociation found betweentheprevalenceofMetSandgender,ageat diagnosis,leukemiasubtype,ortreatmentwithsteroidsor CNSradiation.18

Endocrinedisordersobserved insurvivorswhoreceived an HSCT are multifactorial andare correlatedto the age ofthepatient,basedisease,andtypeoftransplant (autol-ogous or allogeneic). The HSCTconditioning regimen that useshighdosesofchemotherapyagentsaloneorin combina-tionwithradiotherapy,whichisintendedtoeliminateactive andresidualmalignantcells,maybeacontributingfactorin thedevelopmentofendocrinedisorders.Another contribut-ing factor could be administration of immunosuppressive agents,whichcanproduceeitherearlyorlate hematopoi-etictoxicity,asprophylaxisagainstgraft-versus-hostdisease (GVHD).19,20

Centralnervoussystem

Hormonal deficiencies and obesity are common complications after treatment of CNS tumors. Currently, themainriskfactorsthatseemtopredictthedevelopment ofobesity insurvivorsofCNStumorsareageatdiagnosis, irradiationofthehypothalamusgreaterthan51Gy,location ofthetumor,extensivenessofthesurgery,histologyofthe tumor,andthepresenceofendocrinediseases,particularly GHdeficiency.21,22

Craniopharyngiomas are rare tumors accounting for 2%---5% of CNS tumors and originate from remnants of thesquamousepitheliumof Rathke’spouch.23 _Survivors_of

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extremeobesityduetothelocationoftheirbraintumorand thehypothalamicdamageresultingfromsurgicalresection. Theseindividualsexperienceastateof hypothalamic obe-sity,definedasanydamagetothe energycontrolcenters of the hypothalamus, which is responsible for the regu-lation of body weight through balancing food ingestion, energyexpenditure,andamountofadiposetissue.24_These

lesions,whichmaybepresentontheventromedial hypothal-amus,paraventricularnucleus,arcuatenucleus,andlateral hypothalamus, can result from surgical procedures, anti-neoplastictreatments,orthetumoritself.Thedamagemay be structural, functional, or genetic in nature, and ulti-mately compromises hypothalamic functions, leadingto a stateofsevereobesity.25

Theresultingmorbidityfromradicaltumorresection per-formed toreduce the chances of relapse is explainedby theintimateanatomicrelationofcraniopharyngiomaswith the neurohypophysis and particularlywith the hypothala-mus.Hypothalamic-hypophysisdisorder----characterizedby pan-hypopituitarism, obesity, hyperphagia,obsession with thepursuitoffood,andneuropsychologicaldisorders---- dra-maticallyaffectsthequalityoflifeofaffectedchildrenand theirfamilies.26

Although the dose andthe duration of treatment with peri-surgicaldexamethasonehasashort-terminfluenceon post-surgicalweightgainofcraniopharyngiomapatients,it cannot be saidto affect long-term morbid obesity.Other factorscanbecorrelatedtotheweightgaininthisgroup, asobservedbyHarzandcollaborators,whofoundthattheir obesecraniopharyngiomapatientshadnearlynormalcaloric ingestionbutreducedenergyexpenditureincomparisonto thecontrolgroupwithasimilarBMI.Theauthors hypothe-sizethatthis phenomenonmayberelatedtoneurological andvisualdeficits,aswellastoanuncontrolledproduction ofmelatoninleadingtoanincreaseindaytimesleepiness.27

Treatments have been proposedtominimizethe hypo-thalamic obesity present in this group of patients. In a double-blindrandomizedcontrolledstudyusingoctreotide therapyforpediatrichypothalamicobesity,itwasobserved that,analogoustosomatostatin,itresultedinstabilization of weight and BMI. Furthermore, the placebo treatment didnot resultinany alterationin weightgainindex, sug-gesting beneficial effects of octreotide in this group.28

Another study evaluated the effect of combined therapy with diazoxide-metformin for hypothalamic obesity, and observedareductioninBMIandareaundertheinsulincurve, whichisapredictoroftheefficacyofthetreatment.29

Besidesmedicinaltherapies,gastricbypasshasbeen pro-posedasanefficientandsafemethodtotreathypothalamic obesity,asithasbeendescribedinacasestudyofanadult manwhohadundergonecraniopharyngiomaresectionatthe ageofeight.Eighteenmonthsafterthebypasstherewasa reductioninBMIfrom52kg/mto31.9kg/m,aswellasfull remissionoftype2diabetesandexpressimprovementofhis apnea.30

Other CNS tumor types can also affect metabolism in an important way.Heikens etal. investigatedrisk factors for CDV in a mixed group of long-term survivors of CNS tumorsanddescribedanalteredriskprofilefor thisgroup of patients due to dyslipidemia,central obesity,and ele-vatedsystolicbloodpressure,especiallyforthosesuffering fromaGHdeficiency.31_Additional_mechanisms_contribute_to

excessweightinthisgroup,includingreducedmobility, mus-cleweakness,andreducedtolerancefor physical activity, compromisingtheirability tofullyparticipatein anormal dailyroutine.32,33

Othertypesofcancer

Excessweighthasnotonlybeendemonstratedinsurvivorsof ALLorCNStumors.Otherstudiesexploringisolatedgroups oftumortypes,inadditiontogroupedstudiesonsurvivorsof childhoodcancer, haveshownchangesin theBMIpatterns ofsurvivors.

When analyzing survivors of childhoodsarcoma ---- pre-dominantlyEwingsarcoma----intheUnitedStates,survivors were more likely to have two or more criteria for MetS whencomparedwiththeircontrols.Ananalysisofindividual MetScriteria revealed a greater prevalence of hyperten-sionandhypertriglyceridemia.Regardingnutritionalstatus basedontheBMI,22%ofsurvivorswereobeseand28%were overweight.Bothmaleandfemalesurvivorshadincreased total body fat as measured by dual-energy X-ray absorp-tiometry (DEXA). Other parameters, such as testosterone levelsand physical activity,were alsoassessed, revealing thatamongmalesurvivors,totaltestosteronewasreduced. In addition, free testosterone and mean activity z-scores had a strong tendency todecline as the number of MetS indicatorsincreased.Theauthorsconcludedthatthisgroup of patients had an increase in the prevalence of MetS, especially among those younger than 40 years of age. The development of MetS in this population was associ-ated with reduced levels of testosterone and functional capacity.34

Bothchangesinbodycompositionofsurvivorsandissues relatedtotheuseofBMIhave beendescribed. Astudyof 170ALL andlymphoma survivors sought tocompare body fat indicators andmetabolic factors associatedwithbody fat,and todetermine therisk of adiposity insurvivors of childhoodcancerwhohadreceivedadiverserangeof treat-ments.Theauthorsconcludedthattotalbodyandabdominal fat are higher in malesurvivors of pediatric cancer than insibling controls, and that BMIis not a sensitive indica-torof adiposity.Forboth maleandfemale survivors,CRT andthehabitofwatching televisionwere associatedwith adiposity.35

Cancer treatments may have an impact on the hypothalamic-pituitary brain region, causing long-term changes in consumption and binge eating, as suggested by authors using a modified version of the Food Craving Inventory in 22 survivors of pediatric leukemia and lym-phoma.Comparedtosurvivorsdiagnosedatayoungerage (<4.5years), thosediagnosed at an older age had signifi-cantly greater total cravings and cravings for fast-foods, sweets,carbohydrates, andfat; therefore,age at diagno-sismaypotentiallyaffectfoodcravingsinchildhoodcancer survivors.36

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controlgroup.Only35.8%ofthesurvivingpatientsfellwithin ahealthyBMI range,while 2.9%wereunderweight, 28.9% wereoverweight,and32.4%wereclassifiedasobese. His-panicsurvivorshadahigherBMIthanCaucasians.Inregards tofoodconsumption, only 4.8%of survivors fullyadhered totherecommendationsof theACS. Only 10.2%complied withthe recommended intakeof dietary fiber and 17.7% consumedfive fruits and vegetablesper day, while 46.2% mettherecommendationforprocessedredmeat.37

Hematopoieticstem-celltransplant(HSCT)

HSCT,includingautologousandallogeneic stemcell trans-plantsfrombone marrow, peripheralblood, andumbilical cord blood, has increased considerably in recent years. HSCTis appliedmainly in the treatment of leukemiaand solid tumors, but it is also effective in the treatment of hematological, immunological, and genetic disorders, andin the cureof non-hematological metabolic diseases. Advancesin transplant technology andtreatment support practiceshaveledtoprogressiveimprovementsinthe sur-vival of HSCT recipients; however, due to patients living longer after the transplant, the risk of developing late complications related to pre-, peri-, and post-transplant exposures has increased. These complications may cause substantialmorbidity,worsenpatients’qualityoflife,and contributetolatemortalityintheseindividuals.Themost commonadverse effects,whichgenerallyresultfrom pre-transplantconditioningregimes,includegrowthandthyroid disorders, metabolic changes, gonadal insufficiency, and osteoporosis.4,38

Whenthefrequencyoflateeffectsonglucoseandlipid metabolismafterchildhoodtransplantationwasevaluated, 52%ofthepatientswithtransplantswereobservedtohave IR.ThemainindicatorsofMetS(combinedhyperinsulinemia andhypertriglyceridemia)werefoundin39%of transplant patients, compared to 8% in a control group of ALL sur-vivors treated only withchemotherapy (noHSCT) and 0% inhealthycontrols.ThefrequencyofIRincreasedwithtime aftertheHSCTwasperformed.Abdominalobesitywas com-monamong patients withIR. The authors concludedthat long-termsurvivorswhohave undergoneHSCT areat sub-stantialriskofIR,glucoseintolerance,andtype2diabetes mellitus, even withnormal weight and at a young age.39

The authors suggest that the decrease in insulin sensitiv-ity can be explained by adverse body composition after HSCT,asassessedinacross-sectionalstudyof18survivors ofbloodcancer(leukemiaandlymphoma)inchildhoodwho underwenttransplantationandcompleted10yearswithout treatment.UsingDEXA,itwasshownthatfatmasswas sig-nificantlyhigherandleanbodymass significantlylowerin thesurvivors than in controlpatients, and these parame-terscorrelatedinverselywithinsulinsensitivity.Themedian BMIofthesurvivorswas21.6kg/m2_._BMI_tended_to_be_lower inthesurvivor group duetoreducedleanbody mass,but theirhigherpercentagesoffatmasswereassociatedwitha decreaseininsulinsensitivity.40

InadditiontotheHSCTitself,TBIasapreparative ther-apyforHSCThasbeendescribedasplayinganessentialrole inthegenesisofIR,aswaspointedoutbyalargemulticenter studythatincluded adult andpediatricsurvivorsof trans-plantation.Theriskofdevelopingtype2diabetesmellitus

wasthreetimeshigherinpatientswhounderwentHSCT,and thisriskwasassociatedwithTBI.41

Althoughendocrinecomplicationsinpatients whohave receivedaHSCThavebeenwell-describedintheliterature, the causes of excess weight in this group have remained controversial. Such controversy possiblyexists due to the compromised specificity ofusing BMIasa markerof MetS inchildhoodcancersurvivors,especiallyinthosewhohave undergone transplantation.Onestudymeasured longitudi-nal weight and body composition changes in survivors of malignanthematologicdiseasesinchildhoodandobserved asignificantdecreaseinBMIinsurvivorsafterHSCT,mainly due to a reduction in lean body mass. According to the authors, the findings of the study may be attributableto TBIand/orthedegreeofchronicGHVD.Furthermore,they suggest thathealth professionalsshould bealerttolosses innotonlyBMI,butalsoinleanmassinthesesurvivorsin ordertoensureearlyandappropriateinterventionbasedon nutritionaleducationandphysicalactivity.42

Corroborating these findings, Rubles and collaborators observedthat54%ofthesurvivorshadbodyfatpercentages (measured by DEXA) that exceeded the recommendations forahealthybodycomposition,and31%qualifiedashaving centralobesity.PrevioustreatmentwithTBIwasassociated withagreaterpercentageofbodyfatandcentralobesity, andGHVDwasassociatedwithalowerpercentageofbody fat.TheBMIcriteriadidnotcorrectlyidentifytheHSCT sur-vivorswithahighbodyfatpercentage.Thestudyconcluded thatsurvivorswhoreceivedaHSCTinchildhoodareatrisk ofobesityandcentralobesity,whichisnoteasilyidentified bythestandardBMIcriteria.43

Conclusion

SurvivorsofALLandCNStumorsaremoreproneto devel-oping obesity due tothe employedtreatment modalities, butantineoplastictreatmentsinfluencetheappearanceof excessweightinallsurvivorsofchildhoodcancer,regardless oftumor type.As inthegeneralpopulation,other factors contributetoweightgaininsurvivors,giventhatobesityisa multi-factorialdisease;thesefactorsincludepoornutrition, physicalinactivity,andindividualgeneticcharacteristics.In addition, theadministration of HSCT and TBI affect body composition by increasing adiposity, reducing lean body mass,andincreasingmetaboliccomplications.Clearlythere is need for assistance in this group. Strategies for early identificationofhigh-riskpatientsanddevelopmentof inter-ventional models, includingnutritional counseling, should be offered by health professionals in order to minimize and/orpreventthischroniccomplicationofantineoplastic therapy.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

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role of thefunding source is toencourage education and researchdevelopmentinBrazil.

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