FightingChildhoodCancer:TheNationalChildren’sCancerSocietyCallsAttentiontoNewReportOutliningPediatricDrugResearchandtheNeedsofLong-TermSurvivors

WeatTheNationalChildren’sCancerSociety(NCCS)recognizethatdespitebetterchildhoodcancersurvivalratesthaneverbeforeintheUnitedStates,therearemanyfamilieswhoaregrievingthelossofachild.Anewreportaboutthedevelopmentoftreatmentdrugsforpediatriccanceristhefocusofthispaper,withourhopesandprayersthattheinformationincludedherewillinformandeducateparentswhohavefaced,orarefacing,abattleagainstcancerwithachild.

***Morethan14,500Americanchildrenages1to19willfaceacancerdiagnosisthisyearintheU.S.Cancerisstilltheleadingcauseofdeathamongthisagegroup.Althoughcancerinchildrenislesscommonthaninadults,theeffectscanbeworsesinceitoccurssoearlyinlifeandthelateeffectsfromthediseaseandtreatmentscanlastalifetime.Recognizingthatprogressisstillneededintreatingchildhoodcancer,theAmericanCancerSocietyandAllianceforChildhoodCancerdevelopedtheChildhoodCancerResearchLandscapeReport.Thereport,“Translating Discovery into Cures for Children with Cancer,” describestheprocessinwhichchildhoodcancerdrugsaredeveloped.The report is the first time that comprehensive information about childhood cancers has been brought together with a critical analysis of challenges along with opportunities for prevention and treatment. The report includes statistics, trends, a current list of treatment drugs, and details about ongoing pediatric cancer clinical trials and research. It also outlines challenges facing survivors.Thispaperattemptstodistilltheinformationfromthereportintoamorepalatableform.Belowarethehighlights:IncidenceandmortalityAmongchildrendiagnosedwithcancerin2005–2011,theoverallfive-yearsurvivalratewas83%,rangingfrom63%foracutemyeloidleukemiato97%forHodgkinlymphomaandovariangermcelltumors.Howeverwithmanycancersthereisagreatdealofvariationinprognosisdependingontumorsubtypesandotherfactors.Forexample,thefive-yearsurvivalrateamongchildrenwithneuroblastomais78%onaverage,butthesurvivalrateforthosechildrendiagnosedwith“high-risk”neuroblastomadropsto40–50%.Deathratesforallchildhoodandadolescentcancerscombineddeclinedbymorethan50%from1975(51.5permillionpopulation)to2012(24.1permillion).Thedeclineindeathrateswasmorepronouncedforleukemiaandlymphomathanforothertypesofcancer.Unfortunately,selectcancerssuchasadolescentependymomaandneuroblastomahaveseenlittleornodeclinesinmortality.

Althoughfive-yearsurvivalratesaregenerallyusedtobenchmarkprogressincancertreatmentandsurvival,formanycancersmortalityincreasesbeyondthefifthyear,ascomparedtosimilarindividualswhoneverhadcancer.Thisistrueformanychildhoodandadolescentcancersaswellasforadultcancers.Commoncausesofthislatemortalityamongchildhoodandadolescentcancersurvivorsincluderecurrenceorprogressionoftheoriginalcancer,developmentofsubsequentcancersrelatedtotreatmentandothertreatment-relatedtoxicity.Betweendevelopingapproachestocancersthatstillhavenoeffectivetreatments,andreducingthetoxicitiesandside

effectswheretreatmentsaresuccessful,muchworkremainstobedonetoimprovethepediatriccancerlandscape.

Child-AdultDifferencesAnumberofcancersareseenalmostexclusivelyinchildren,andthesechildhood-specificcancersoftenarisefromembryonalcells.Beginningwitheggfertilization,embryosstartfromasinglecellandeventuallybecomethebillionsofcellsthatmakeupanewbornchild.Embryonalcellsmultiplyrapidlyanddifferentiateintoallofthedifferentorgansandpartsofthehumanbodyaccordingtocomplexbiologicalcontrolmechanisms.Whilemuchofthecellulardifferentiationofembryonalcellshasstoppedbybirth,significantcellularreproductioncontinuesthroughadolescence,atwhichpointhumansareessentiallyphysicallymature.Embryonaltumorscomefromembryonalcellswhosecontrolmechanismsfailtoworkproperly,resultinginthecellscontinuingtoreproduceinanuncontrolledmannertobecomecancer.Thesecancersoftenappearduringtheperiodnotlongafterbirth,asseenbythefactthatembryonalcancersincludingneuroblastoma(nervoussystem),retinoblastoma(retina),rhabdomyosarcoma(muscle),medulloblastoma(brain)andWilmstumor(kidney)havethehighestincidenceinchildrenbetweenbirthandfouryearsofage,andoccurprogressivelymorerarelyafterthat.Themajorcancersthatareonlyfoundinadultsmostcommonlyarisefromtissuesliningtheinnerandoutersurfacesofthebody,andarearesultofmultiplechangesincellsandtissuesthattakealongtimetooccur.Combinationsofexternalexposuressuchastobaccosmoke,infectionsorradiationmaycausesomeofthesechanges;orinternalexposuressuchashormonesproducedbythebody.Otherchangesincellsthatcontributetocancerdevelopmentcanoccurrandomly,withoutbeingcausedbyaparticularexposure.AmongthecancersthatareseeninbothchildrenandadultsareAcuteMyeloidLeukemia(AML),AcuteLymphoblasticLeukemia(ALL),Hodgkinandnon-Hodgkinlymphoma,thyroidcancer,melanoma,andglioblastoma(anaggressivetypeofbraintumor).Whilethesecancersinchildrenandadultssharethesamegeneralnames,theadultandpediatricversionsofthesamecancerareoftendistinctbiologicalsubtypes.Sometimesevenwithinthechildhoodagegroup(birthto19years)therearedifferencesinthesamecancerbetweenyoungerchildrenandolderones.Asanexample,ALLcanhaveadistinctlydifferentoutlookatdifferentages,partlyduetovaryinggeneticsubsetsthattendtooccurasachilddevelops.Evenwhereadultandchildhoodcancersareverysimilaratthemolecularlevel,differentapproachestotreatmentmaybe

necessarybecauseoffundamentalbiologicaldifferencesbetweenadultsandchildren,includingthegreaterpotential

forharminchildrenwhosebodiesarestilldeveloping.Long-termSurvivalforChildhoodandAdolescentCancerAlthoughtheincidenceofchildhoodcancerhasbeenslightlyincreasing,atanaverageof0.6%peryearfrom1975to2012,thenumberofchildhoodcancersurvivorshasalsoincreased.Anestimated398,967survivorsofchildhoodandadolescentcancer(diagnosedatages0-19)werealiveintheU.S.asofJanuary1,2012.ThetopthreetypesofcanceramongchildhoodcancersurvivorsareAcuteLymphocyticLeukemia,brainandCNStumors,andHodgkin’slymphoma.Mostsurvivorsofchildhoodandadolescentcancer(71%)are20yearsofageorolder.Approximatelyonein513youngadultsbetweentheagesof20and39isachildhoodcancersurvivor.BiologicalCausesofLateEffectsofTreatmentResearchhasdocumentedthevulnerabilitypediatriccancerpatientshavetosideeffectsoverthelongterm,whicharecausedbymultipletoxicitiesofcancertreatments.Priorresearchhasshownthatnearly40%ofchildhoodcancersurvivorsaged35orolderhaveexperiencedasevereillness,life-threateningcondition,orhavedied.Thisisarateoverfivetimeshigherthanseeninthesiblingsofthesesurvivorswhowerenottreatedforcancerbutwhopresumablycarryotherwiseequivalentriskforseverehealthconditionsduetogeneticsandenvironmentalexposures.CytotoxicchemotherapyandradiationtreatmentstypicallykillorinhibitcancercellsbydamagingtheirDNAandinterruptingnormalcellularreproductionprocesses.Whilesuchdamageanddisruptioncankillcancercells,itcansimilarlydamagehealthycells.Eventargetedtherapies,whichtypicallyonlyinterruptselectprocessesthattendtobeoveractiveincancercells,canleadtolong-termsideeffectsthatappearlaterinasurvivor’slife.Infact,acurrentconcernisthatitisdifficulttopredictorstudythelong-termeffectsoftargetedtherapiesinchildrenduetothenewnessofthesetherapiesandthesmallnumberofchildrenwhohavereceivedaspecifictreatment.OrganizationslikeTheNationalChildren’sCancerSocietynowprovidewide-rangingsupportandeducationforsurvivorsfacinglateeffects.TheNCCSevencreatedanonlineassessmenttooltohelpsurvivorsdeterminepossiblephysical,cognitiveandemotionallateeffectsfromtheircancerortreatment.Theorganization’sBeyondtheCureprogramalsoprovideshelptosurvivorswithissuesrelatedtoeducation,relationships,medicalcare,employment,insuranceandhealthyliving.“Familiesareoftenunpreparedfordealingwithlateeffects,”explainedMarkStolze,presidentandCEOoftheNCCS.“Manydon’tevenrealizetheproblemstheirchildishavingseveralyearsafterendingtreatmentaredirectlyrelatedtothetreatmenttheyreceived.“BecausetheNCCSoffersresourcestofamiliesdealingwithlateeffects,wecontinuallyseeknewinformationabouttreatmentdrugsandchallengesthatsurvivorsfacesothatwecanbetterhelpthemidentify,treatandultimatelyovercomethosechallenges,”Stolzeadded.Additionalinformationaboutlateeffectscanbefoundhere.

Source:TheNationalAcademiesPress,“Identifyingandaddressingtheneedsofadolescentsandyoungadultswith

cancer:Workshopsummary,”Copyright2013,NationalAcademyofSciences.DrugResearch,PreclinicalResearchintothebasicbiologyofcancercanprovideanunderstandingofwhatmayhaveledtothedevelopmentofagiventypeofcancerandwhatmakesacancergrowandsurvive.Armedwiththeknowledgeofwhatdrivesagivencancer,researcherscancreatedrugsthatcanexploitweaknessesorattackbiologicalprocessesthatarecriticaltocancergrowth.Thefirststepofthistranslationofbasicsciencetoausabletreatmentbeginswithpreclinicalresearch.Preclinicalresearchisconductedincell-oranimal-modelsystemsthataremeanttomimiccancerinhumansorthatotherwisemightprovideinsightsintohowadrugmightworkinapersonwithoutactuallyadministeringthedrugtoahuman.Thiskindofresearchprovidesmeaningfulinformationabouttheimpactofadrugonaparticularcancerwithoutexposingpeopletopotentialharmandtheunknownbenefitofbeinganexperimentaldrugcandidate.Preclinicalresearchcanbethoughtofasafilteringstepthatdetermineswhetheraparticulardrugisabletokilltargetedcancercellsinatesttubeoranimalmodel.Inchildhoodcancerthepreclinicalphaseofdrugdevelopmentiscritical,asthereareveryfewchildrenonwhomnewtherapiescanbetested,andfederallawsprotectchildrenfromresearchthatmaybetoorisky.Therefore,thedrugsthateventuallymoveforwardintopediatricclinicaltrialsmustbethosewiththehighestprobabilityofworking.Beforenewdrugsaretestedinchildren,mostundergotesting

inadulthumanstudiespriortoexposingchildrentotheunknowntoxicitiesofnovelagents.

Preclinicaltestingisapowerfultool,butonewithimportantlimitations.Well-characterizedcelllinesandanimalmodelsdonotexistforallpediatriccancers,leavingimportantgapsintheabilitytodevelopdrugsforsomecancers.Preclinicaltestingintheacademicsettingisalso

oftenlimitedbyalackofaccesstocommercialdrugmoleculelibraries.Additionally,constrainedfundingandresourcesmeansthattherateatwhichdrugcandidatesaretestedinacademicsettingsismuchslowerthanisthecasewithpharmaceutical-sponsoredpreclinicalscreeningprograms.Drugsthatdowellpreclinicallydonotalwaystranslateintodrugsthatworkinhumans.ClinicalResearchClinicaltrialsfordrugdevelopmentareoftendividedintothreephases.Phase1isfocusedontestingforsafety;Phase2helpsoptimizedosageanddeterminesinitialefficacy,andPhase3isdesignedtoconfirmwhetheradrugworks,especiallyascomparedtothestandardtreatmentinuseatthetimeofthetrial.Eachsubsequentphasetypicallyenrollsmoreparticipantsthanthepreviousone,andissizedonlyaslargeasnecessarytoanswerthebasicquestionsposedineachphase(safety,dosing,efficacy,etc.).Poorresultsinonephasemeanthatagivendrugtypicallydoesnotprogresstothenextphase.

Manycancerdrugshavesignificantsideeffects,soitisconsideredunethicaltotesttheminhealthyindividuals.

Theclassicparadigmforclinicalresearchisoftenmodifiedincancerclinicaltrials.Forexample,whentestingdrugsfornon-life-threateningdiseases,Phase1trialsareoftendonewithhealthyvolunteerstofindouthowwelladrugistoleratedandhowfastitisclearedfromthebody.Manycancerdrugshavesignificantsideeffects,soitisconsideredunethicaltotesttheminhealthyindividuals.Instead,Phase1safetytrialsforcancerdrugsareconductedinpatientswithcancer.Insomecases,Phase1trialsarefocusedsolelyonpatientswhosecancerthedrugisdesignedtotreat.Ifadrugsuccessfullyworksagainstaparticularcancertype,itsefficacycansometimesbeobservedatthesametimeassafetyisbeingtested.Inbothadultandchildhoodcancers,itissometimespossibletocollectsufficientinformationaboutadrug’ssafety,dosing,andefficacytosatisfyFDA’sapprovalcriteriaafterPhase2studies.Ifadrugisparticularlyeffective,itcanevenbeapprovedafteranexpandedPhase1study.Asaresult,theclassicalparadigmofsequentialandseparatePhase1,2,and3studiesmaynotalwaysapplyforcancerdrugdevelopment.Cancerclinicaltrialsrarelyuseplacebosastheonlytreatment.Whensomeonehasaseriousdiseaselikecanceritisunethicaltowithholdtreatmentaspartofanexperiment,soincancerclinicaltrialsanewdrugisusuallytestedagainstwhatevertreatmentisconsideredstandardatthetime.InarandomizedPhase3clinicaltrial,halfofthepatientstypicallygetthestandardtreatment,whiletheotherhalfgetthenewdrugbeingtested.Insomecases,thenewdrugisadministeredinadditiontothestandardtherapyratherthaninplaceofit.Ifthepatientsreceivingthenewdrugfarebetter,thenitistypicallyapprovedandbecomesthenewstandardtreatmentforpatientswiththattypeofcancer.ClinicaltrialsdonotnecessarilystoponcetheFDAhasapprovedadrug.Onceonthemarket,manydrugsundergoadditionaltestingtodetermineoptimumdosingamounts,frequency,durationorsequencing,andtodetectuncommonsideeffects.Multipleapproveddrugsarealsosometimescomparedagainsteachother,orcomparedagainstothertreatmentmodalitieslikeradiationorsurgery.Thesepost-marketstudiesaresometimesreferredtoasPhase4studies,andtheyareintendedtofurtherrefineandoptimizetheuseofatreatmentthathasalreadybeenshowntobeeffectiveagainstagivencancer.

Drugdevelopmentforchildrenoccursinseveraldifferentways.A)Clinicaltestinginchildrencanoccur

simultaneouslywithtestinginadults.Researchonadruginchildrenmaylagbehindresearchinadults-inthiscasebyoneortwophases,butnonethelessbeginsbeforetheadultindicationisapproved.B)Testinginchildren

sometimesonlystartsafteragivendrughasalreadybeenapprovedforuseinadults.C)Whileitrarelyoccurs,drugdevelopmentforchildhoodcancerscanbeginatthepreclinicalphaseandcontinuethroughtodrugapproval

completelyinchildrenandwithoutparalleladultdrugdevelopment.D)Somedrugsapprovedforadultcancersmaybetestedinchildren,andiffoundsuccessful,beusedinchildhoodcancerswithoutanyformalFDAreviewor

inclusionofdataintothelabel.Source:ChildhoodCancerResearchLandscapeReport

Pediatric-specificRequirementsAdultscanvaryinhowmuchrisktheyarewillingtotakeonbyparticipatinginresearch.Forexample,anindividualmaybewillingtoreceiveanexperimentaldruginaPhase3trialafterithasbeenshowntobesafeinotherpatientsandhasshownsomeevidenceofeffectiveness,butthatsamepersonmaybetotallyunwillingtoparticipateinaPhase1trialwheresafetyofadrugislargelyunknown.Participationinresearchisvoluntaryforadults,andalonghistoryofethicalargumentsconfirmthatnoonecanbeforcedtoparticipateinresearchwithouthisorherconsent.Noteveryone,however,isabletoprovideconsentinthesameway.Recognizingthatcertainsegmentsofthepopulationhaveareducedabilitytoprovideconsent,federalregulationsandstandardshavebeendevelopedforvulnerableadultsandchildren.Becausechildrenbelowage18arepresumednottocomprehendfullythenatureofaresearchstudy,parentstechnically“givepermission”fortheirchildrentoparticipate.Childrenandadolescentsofmaturemindalsoareexpectedto“assent”toparticipateinresearchstudies,givensufficientexplanationofitspurposeandprocedures.Federallawprovidesspecialprotectionsforchildrenwhentheyparticipateinresearchstudies.Researchinchildrencannotbeconductedsolelytoanswerscientificquestions,regardlessofhowimportanttheymaybe.Ateachphaseintestingnewcanceragentsinchildren,lawandethicsrequirethatanindividualchildparticipatinginresearchmusthavetheprospectofdirectbenefitfromthestudyascomparedtootheravailabletreatmentalternatives.

Federalregulationsprovidespecialprotectionstochildrenwhoparticipateinresearch.Theabilitytoconductpediatricresearchdependsonthenatureoftheresearchanditsanticipatedrisksandbenefitsforchildren.

Source:ChildhoodCancerResearchLandscapeReport

FederalFundingofChildhoodCancerResearchThefederalgovernmentisthelargestsinglesourceofchildhoodcancerresearchfundingintheU.S.TheNationalCancerActof1937establishedTheNationalCancerInstitute(NCI)astheprimaryU.S.governmentagencyresponsibleforaddressingtheresearchandtrainingneedsrequiredtodiscoverthecauses,diagnosisandtreatmentsforcancer.TheActalsocalledforNCItoassistwithandpromotesimilarresearchconductedatotherpublicandprivateinstitutions.PassageofthePublicHealthServiceActof1944,andlatertheNationalCancerActof1971,furthershapedNCI,placingitasanoperatingdivisionoftheNationalInstitutesofHealth(NIH).AmongtheNIH’smanyduties,itwaschargedwithdistributingresearchgrantsandcontracts,collaboratingwithotherpublicagenciesandprivateindustry,conductingcancercontrolactivities,aswellasappointingadvisorycommitteestoexplorenewissuesandopportunities.NCIhasauniquestatusamongtheotherinstitutesandcentersatNIHbecauseitsdirectorisappointedbythepresidentoftheUnitedStates.TheNCIhastheabilitytoproduceitsownbudgetproposalseparatefromtheadministration’sofficialbudget.Thisseparatedocumenthasnoformalroleintheappropriationsprocess,butitdoesprovidetheNCIdirectorwiththeopportunitytoemphasizeNCI’sresearchpriorities.NCI’sbudgetremainedrelativelyflatfromfiscalyear(FY)2005-2015,averaging$4.9billionperyear.Atthesametime,researchcostsincreased.Thesefactorshaveposedseriouschallengesforcancerresearchinrecentyears.However,theNCIFY2016budgetincreasedoverlastyearby$250.5millionto$5.21billion,anencouragingupswing.ResearchFundingandEconomicForcesCreatingevenfurtherfinancialincentivesfordrugcompaniestodevelopdrugsforrarepediatricconditions,CongresspassedtheCreatingHopeActin2011.Modeledonaprogramto

stimulatedrugstotreattropicaldiseases,thislawcreatedapriorityreviewvoucherprogram.Vouchersareawardedtonewlyformulateddrugsthattreatanyrarediseaseinchildren(notjustcancers).ApriorityreviewvoucherentitlesacompanytoobtainashorterFDAdrugreviewtime,cuttingitfrom10monthstosixmonths.Afasterreviewallowsadrugsponsortobeginsellingitsproductsooner.Federalfundingforbasicscienceandforsomeoftheresearchinfrastructureneededforclinicaltrialsprovidesalaunchingpointforprivateindustrytocarryoutdrugdevelopment,andinpediatriccancertheroleoffederalandphilanthropic

fundingismoresignificantthaninadultcancer.SummaryIncreasedunderstandingofthebasicbiologyofpediatriccancerscanleadtopromisingnewdrugs.Inordertoturnthesepromisingideasintosafe,usableandeffectivedrugs,however,alargeinvestmentinclinicalresearchanddrugdevelopmentiscritical.Privateindustrytypicallyfundsmostofthelaterstagesofdrugdevelopment,largelydrivenbyanexpectationofeventualprofitsfromthesaleofanapproveddrugoveraperiodoftime.However,pediatriccancersarerare,meaningthatthesalespotentialandincentivefordevelopingpediatriccancerdrugsislowerthanforadultdrugs.Inadditiontodirectlyfundingresearchandunderwritingthecostsofpediatricclinicaltrials,thefederalgovernmenthascreatedanumberofincentiveprogramstoaugmenttheotherwiselimitedeconomicincentivesinherentforanydrugforasmallpatientpopulation,likechildhoodcancer.Allorphandrugs(thosethatremainundevelopedbecausetheyhavelimitedpotentialforprofitability)receivetwoextrayearsofexclusivitycomparedtonon-orphandrugs,andtheapplicationsforapprovalhavemanyoftheirapplicationfeeswaived.Despitetheseincentives,fundingresearchanddrugdevelopmentforchildhoodcancerremainschallenging.

Developingeffectivedrugstotreatchildrenwithcancerpresentsdauntingchallenges.Itrequiresthecollectiveengagementofresearch,advocacy,andregulatory

communitiesinordertorecognizeandaddressthespectrumofhurdlesdescribedinthisreport.

ConclusionChildrentypicallydevelopcancersthatarequitedifferentfromcancersthatoccurinadults.Theyalsoundergotreatmentduringatimeofvitalphysicalandmentaldevelopment,leavingthemvulnerabletoalifetimeofsideeffects,eveniftheircancershavebeencured.Consequently,developingeffectivedrugstotreatchildrenwithcancerpresentsdauntingchallenges.Itrequiresthecollectiveengagementofresearch,advocacy,andregulatorycommunitiesinordertorecognizeandaddressthespectrumofhurdlesdescribedinthisreport.Challengesrangingfrombiologicaltologisticaltoethicalandeconomicrequire

enhancedcollaborationamongstakeholderswhosharethecommongoalofadvancingtreatmentstocurechildhoodcancers.AboutTheNationalChildren’sCancerSocietyThemissionofTheNationalChildren'sCancerSocietyistoprovideemotional,financialandeducationalsupporttochildrenwithcancer,theirfamiliesandsurvivors.TolearnmoreabouttheNCCSanditssupportservices,visitthenccs.org.TheNationalChildren’sCancerSocietyisa501C(3)organizationthathasprovidedover$63millionindirectfinancialassistancetomorethan40,000childrenwithcancer.TocontacttheNCCS,call(314)241-1600.YoucanalsofindtheNCCSonFacebookandTwitter.