Complete surgical resection improves outcome in INRG high ...

After best surgery, 68.7% of patients achieved complete resection of the primary tumor, 16.8% gross total resection, 14.0% incomplete surgery, ... Skiptomaincontent Advertisement SearchallBMCarticles Search CompletesurgicalresectionimprovesoutcomeinINRGhigh-riskpatientswithlocalizedneuroblastomaolderthan18 months DownloadPDF DownloadPDF Researcharticle OpenAccess Published:04August2017 CompletesurgicalresectionimprovesoutcomeinINRGhigh-riskpatientswithlocalizedneuroblastomaolderthan18 months JaninaFischer  ORCID:orcid.org/0000-0001-6240-24171,AlexandraPohl2,RuthVolland1,BarbaraHero1,MartinDübbers3,GrigoreCernaianu3,FrankBerthold1,DietrichvonSchweinitz2&ThorstenSimon1  BMCCancer volume 17,Article number: 520(2017) Citethisarticle 3292Accesses 35Citations 1Altmetric Metricsdetails AbstractBackgroundAlthoughseveralstudieshavebeenconductedontheroleofsurgeryinlocalizedneuroblastoma,theimpactofsurgicaltimingandextentofprimarytumorresectiononoutcomeinhigh-riskpatientsremainscontroversial.MethodsPatientsfromtheGermanneuroblastomatrialNB97withlocalizedneuroblastomaINSSstage1–3age > 18 monthswereincludedforretrospectiveanalysis.ImagingreportswerereviewedbytwoindependentphysiciansforImageDefinedRiskFactors(IDRF).Operationnotesandcorrespondingimagingreportswereanalyzedforsurgicalradicality.Theextentoftumorresectionwasclassifiedascompleteresection(95–100%),grosstotalresection(90–95%),incompleteresection(50–90%),andbiopsy(<50%)andcorrelatedwithlocalcontrolrateandoutcome.PatientswerestratifiedaccordingtotheInternationalNeuroblastomaRiskGroup(INRG)stagingsystem.SurvivalcurveswereestimatedaccordingtothemethodofKaplanandMeierandcomparedbythelog-ranktest.ResultsAtotalof179patientswereincludedinthisstudy.77patientsunderwentmorethanoneprimarytumoroperation.Afterbestsurgery,68.7%ofpatientsachievedcompleteresectionoftheprimarytumor,16.8%grosstotalresection,14.0%incompletesurgery,and0.5%biopsyonly.Thecumulativecomplicationratewas20.3%andthesurgeryassociatedmortalityratewas1.1%.Imagedefinedriskfactors(IDRF)predictedtheextentofresection.Patientswithcompleteresectionhadabetterlocal-progression-freesurvival(LPFS),event-freesurvival(EFS)andOS(overallsurvival)thantheothergroups.SubgroupanalysesshowedbetterEFS,LPFSandOSforpatientswithcompleteresectioninINRGhigh-riskpatients.Multivariableanalysesrevealedresection(completevs.other),andMYCN(non-amplifiedvs.amplified)asindependentprognosticfactorsforEFS,LPFSandOS.ConclusionsInpatientswithlocalizedneuroblastomaage18 monthsorolder,especiallyinINRGhigh-riskpatientsharboringMYCNamplification,extendedsurgeryoftheprimarytumorsiteimprovedlocalcontrolrateandsurvivalwithanacceptableriskofcomplications. 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BackgroundNeuroblastomaisthemostcommonsolidextracranialmalignancyofchildhoodandthemostcommonmalignanttumorininfants[1].Despitetheadvancesinmultidrugtherapy,surgerystillplaysamajorroleintreatmentofneuroblastoma(NB)[2].Childrenpresentingwithlocalizeddiseasehaveanoverallbetterprognosis,mainlydependingonthedegreeoftumorresection[3].Indeed,completelyresectedtumors(INSSstage1)rarelyrelapseanddonotrequirepostoperativechemotherapy[4,5].Thereis,however,stillacontroversyregardingthevalueofradicalsurgeryforextendedlocaldisease[2].Biologicalandclinicalprognosticmarkersmayhelptostratifyrisksandguidetherapyinthesepatients,butprospectiverandomizedtrialswithsurgicalendpointsarestillmissing.In2008,theINRGgroupimplementedapretreatmentriskstratificationconsideringage,MYCNamplification,histologicaltumorgrade,ImageDefinedRiskFactorsand11qdeletiontoclassifyNBpatientsintoverylow-,low-,intermediate-andhigh-riskpatients[6].Inthisstudy,weanalyzedtheimpactoftheextentoftumorresectiononoutcomeofpatientsolderthan18 monthswithlocalizednon-metastaticNBaged,whoweretreatedaccordingtotheGermanprospectiveclinicaltrialNB97.MethodsAllpatientsregisteredbytheGermanprospectiveclinicaltrialNB97betweenNovember1,1996,andSeptember30,2004,wereincludedinthisanalysiswhentheymetthefollowingcriteria:stage1–3neuroblastomadiagnosedaccordingtotheInternationalNeuroblastomaStagingSystemcriteria[7];ageatdiagnosis>18 monthsbutlessthan21 years.Writteninformedconsentwasobtainedfrompatientsortheirguardiansforparticipationinthestudydesign,datacollectionandtreatment(Registrationnumber:NCT00017225,ClinicalTrials.gov).TheNB97trialwasarandomizedtrialcomparingASCT(autologousstemcelltransplantation)andoralmaintenancechemotherapyinhigh-riskpatients.AccordingtotheNB97protocol,thepatientswithlocalizedNBwereprospectivelystratifiedinNB97high-risk,NB97standard-riskorNB97low-risksubgroupsaccordingtoINSSstage,age,MYCN-Statusandthreateningsymptoms.NB97standard-riskpatientsreceived4 cyclesofchemotherapyafterfirstsurgeryandasecondresectionwhennecessarywhereasNB97low-riskpatientswereobservedforupto12 monthswithexaminationsandstagingevery6 weeks.NB97high-riskpatientswererandomizedandreceivedASCTororalmaintenancetherapy.ThetrialprotocolhadbeenevaluatedbytheInstitutionalEthicalBoardsoftheUniversityofCologneandparticipatinghospitals.Allpatientsparticipatedinthetrialafterinformedconsentandonvoluntarybasis.Trialprotocolandresultsoftheprimarytrialendpointhavebeenpublishedbefore[8,9].TheNB97protocolalsoprovidedclearrecommendationsontimingandextentoftumorresection.Forexample,initialordelayedcompleteresectionwasadvisedwhennovascularstructuresoradjacentorganswereinvolved.Incompleteresectionwasacceptabletoreducetheriskofacutecomplicationsandlong-termorganimpairments.Nephrectomyorinsertionofvascularprostheseswasdiscouraged.Therefore,completeinitialresectionwasreservedonlyforpatientswithwell-encapsulatedprimarytumors.Allotherpatientswererecommendedtoundergosecondlookoperationsafterfourtosixcyclesofinductionchemotherapy.Moreover,radiationtherapyof40 Gywasadvisedforpatientswithunresectableresidualsoftheprimarytumorpresentafterinductionchemotherapy.Finally,radiationdoseslessthan40 Gywereappliedtoprotectadjacentstructureswithlowradiationtolerance[10].Dataonextentandcomplicationsofresectionwerecollectedprospectivelyusingcasereportforms.Forthisanalysis,imagingreports,operationnotesandpathologyreportswereretrospectivelyreviewedbytwoindependentexperiencedphysicians,anddiscrepantresultswereclarifiedafterrepeatedjointreviewofthepatients’files.Inthisstudy,wedistinguishedbetweentwotypesofoperations,asdescribedbefore[11].Briefly,firstoperationwasthetumoroperationperformedbeforeorwithinthefirstsixcyclesofinductionchemotherapy,andbestoperationwasthemostextensiveremovalofprimarytumortissuedoneatanytimeduringfirst-linetherapy.Foroutcomeanalysis,theextentofresectionwasclassifiedasfollows:nooperationorbiopsyremovinglessthan50%oftumortissue;incompleteresectionof50%tolessthan90%oftumorvolumepresentatthetimeofsurgery;grosstotalresectionremovingmorethan90%ofthetumor;orcompleteresectionwithoutmacroscopicpostoperativetumorresiduals.Itwasnotpossibletoincludethecategoryofmicroscopiccompleteresectionbecauseneuroblastomaswererarelyremovedintoto,andtherefore,thepathologistoftenreceivedseveraltumorfragments,makingconfirmationofmicroscopiccompleteresectionimpossible.IDRFwerenotestablishedin1997,andtherefore,theyhadtobeassessedretrospectivelybyreviewofinitialimagingandoperationnotesbasedonthedefinitionspublishedbytheEuropeanInternationalSocietyofPediatricOncologyNeuroblastomaGroup[12]andtheInternationalNeuroblastomaRiskGroup[13,14].Duringinductionchemotherapy,re-staging,includingmagneticresonanceimagingoftheprimarytumorsite,bonemarrowassessment,andmetaiodobenzylguanidine(MIBG)scintigraphy,wasscheduledafterfourtosixchemotherapycycles.Ifprogressionorrelapsewassuspected,completestagingwasnecessary.Diseasestatusandresponsetotreatmentwerecategorizedascompleteremission,verygoodpartialremission,partialremission,stabledisease,orprogressionaccordingtothepublishedInternationalNeuroblastomaResponseCriteria[7].PretreatmentRiskStratificationwasperformedretrospectivelyaccordingtoINRGstagingsystem[6]consideringage,MYCNamplification,histologicalgrade,IDRFand11qdeletionstratifyingallpatientsintoINRGverylow-,INRGlow-,INRGintermediate-andINRGhigh-risk.HistologywasdefinedbyINPCguidelinesasdescribedbefore[15].StatisticalanalysisForstatisticalanalysis,theIBMSPSSsoftware(Version24.0.0;Armonk,NY,IBMCorp.)andRversion3.3.1wereused.ProportionswerecomparedbyFisher’sexacttest.SurvivalcurveswereestimatedaccordingtothemethodofKaplanandMeierandcomparedbythelog-ranktest.Event-freesurvival(EFS)timewascalculatedasthetimefromdiagnosistoeventorlastexaminationifthepatienthadnoevent.Relapse,progression,anddeathfromdiseaseorsurgery-relatedwereregardedasevents.Localprogression–freesurvival(LPFS)wascalculatedfromdiagnosistorelapseorprogressionoftheprimarytumorsiteorlastexaminationifthepatienthadnolocalrecurrence.ThismeansthatpatientswhodiedfrommetastaticdiseasewithoutprogressionattheprimarytumorsitewerecensoredatthetimeofdeathforLPFSanalysis.Overallsurvival(OS)wascalculatedasthetimefromdiagnosistodeathfromdiseaseorsurgery-relatedorlastexaminationifthepatientsurvived.MultivariablebackwardselectedCoxregressionanalyseswereperformedtoanalyzetheprognosticvalueofthefollowingfactors:stage(1or2vs.3),extentofbestresection(completevs.other),MYCNstatus(amplifiedvs.notamplified)andIDRF(novs.>1).Thelikelihoodratiotestp-valueforinclusionwasp ≤ 0.05.ResultsPatientsAmong1121patientsintheNB97trial,191patientswithINSSstage1–3 >18 monthswereeligibleforanalysis.PatientswithINSSstage4disease(n = 383)andpatientswithnon-stage4neuroblastoma<18 monthsofage(n = 547)didnotmeetinclusioncriteria.Twopatientswithganglioneuromaand10patientswithanearlyprogressionwithinthefirst40 daysofchemotherapywereexcludedfromthestudy.179patientswithlocalizedneuroblastomametallinclusioncriteria(Fig.1).Themedianageatdiagnosiswas3.64 years(range,1.5to20.8 years),andthemedianobservationtimeofthesurvivingpatientswas10.2 years(range,0.5to17.3 years).105eventswererecorded.Among30relapses,therewere9localrelapsesandin35patientswithprogression,wefound27localizedprogressionsoftheprimarytumorsite.Thirty-threepatientsdied.Table1listsdetailsofthepatients’keycharacteristics.Fig.1PatientflowdiagramFullsizeimage Table1Keydemographicandclinicalcharacteristicsof179patientswithlocalizedNB>18 monthsFullsizetable Beforeorduringinductionchemotherapy,completeresectionwasachievedin83patients(46.4%),grosstotalresectionin14patients(7.8%),incompleteresectionin13patients(7.3%),andbiopsyin69patients(38.5%).For8patientsnoimagingreportswereavailableandextentofresectionwasbasedonthecasereportformsofthetrialonly.Duringtreatment,77patientshadatleastonemoresurgicalresectionofprimarytumorsite.Afterbestsurgery,68.7%ofpatientsachievedcompleteresectionoftheprimarytumor,16.8%grosstotalresection,14.0%incompletesurgery,and0.5%biopsyonly.Themostradicalresectionoftheprimarytumorwasachievedduringfirstoperationin106patients(59.2%)andduringdelayedsurgeryin73patients(40.8%).Accordingtotheprotocolguidelines,3.9%ofallpatientsunderwentexternal-beamradiationtherapyofunresectableresidualsoftheprimarytumor,inwhichcaseamediandoseof36 Gywasapplied.ComplicationsduringfirstandbestoperationAtotalof56patientsexperiencedcomplicationsduring276surgicalinterventions(20.3%)whenundergoingfirst-linetreatmentforneuroblastoma.Duringfirstoperation(n = 179)horner’ssyndrome(3.9%),organinjury(3.4%)andintraoperativebleeding(2.8%)werethemostfrequentcomplications.Nosurgicalrelateddeathsoccurredandthetotalcomplicationratewas19.6%.Allothercomplications(infection,ileus,vesselornerveinjury)occurredin<1.7%ofpatients,respectively.Atbestoperation(n = 179)50complicationsin40patientsoccurredincludinghorner’ssyndromewith5.6%,whileorganinjuryandmajorbleeding/vesselinjuryaccountupto4.4%and3.9%,respectively.Twopatientsdiedduetosurgery(1.1%).Thecomplicationrateatbestsurgerywas27.9%.Twenty-onepatients(52.5%)outof40patientswhoexperiencedoneormorecomplicationshadmorethanoneoperation.Thecomplicationratewasnotsignificantlydifferentbetweenpatientswithcompleteresectionafterbestsurgery(22.4%),patientswithgrosstotalresection(13.3%)andincompleteresection(32%;p = 0.395).OutcomeafterfirstoperationCompleteresectioncouldbeachievedin83/179patients(46.4%).The5-yearEFSrateofallpatientswithcompleteresectionwas87.8% ± 3.6%,the5-yearLPFSratewas93.6% ± 2.7%,andthe5-yearOSratewas92.3% ± 3.0%.Forpatientswithgrosstotalresection,5-yearEFSandLPFSratewere78.6% ± 11.0%,andthe5-yearOSratewas92.9% ± 6.9%.Afterincompleteresection,5-yearEFSandLPFSratewere66.7% ± 13.6%,andthe5-yearOSratewas83.3% ± 10.8%.Patientswithbiopsyonlyhada5-yearEFSrateof61.5% ± 5.9%,a5-yearLPFSrateof66.7% ± 6.0%,anda5-yearOSrateof75.8% ± 5.3%afterfirstoperation.TheextentoffirstoperationhadanimpactonEFS(p = 0.000),LPFS(p = 0.000),andOS(p = 0.018;Fig.2;Table2).Ofnote,anysurgicalresectioncomparedtobiopsyimprovedpatient’soutcomeinEFSandLPFS(p = 0.001)andOS(p = 0.002).Fig.2Kaplan-Meier-curvesforallpatientswithlocalizedNB(n = 179)afterfirstoperationFullsizeimage Table2Resultsofunivariateoutcomeanalysisof179patientswithlocalizedNB>18 monthsFullsizetable OutcomeafterbestoperationCompleteresectioncouldbeachievedin123/179patients(68.7%).TheextentofresectionatthebestoperationwasassociatedwithbetterEFS(p = 0.001),betterLPFS(p = 0.001),andbetterOS(p = 0.020).The5-yearEFSrateofpatientswithcompleteresectionwas82.8.0% ± 3.4%,the5-yearLPFSratewas87.1% ± 3.1%,andthe5-yearOSratewas90.8% ± 2.7%.Forpatientswithgrosstotalresection,5-yearEFSratewas59.8% ± 9.0%,5-yearLPFSratewas62.7% ± 9.0%,andthe5-yearOSratewas75.4% ± 8.1%.Afterincompleteresection,5-yearEFSratewas58.0% ± 10.2%,5-yearLPFSratewas66.2% ± 10.5%,andthe5-yearOSratewas70.5% ± 9.4%.Onepatienthadabiopsyonlyanddidnotundergoasecondoperation,becausehediedeightmonthsafterdiagnosiswhileundergoingASCT.The5-yearsurvivalratesarelistedinTable2,andlife-tablesareshowninFig.3.Multivariableanalysisrevealedresection(completevs.other),andMYCN(non-amplifiedvs.amplified)asindependentprognosticfactorsforEFSandOS.Fig.3Kaplan-Meier-curvesforallpatientswithlocalizedNB(n = 179)afterbestoperationFullsizeimage INSSstageandMYCNamplificationSubgroupanalysisaccordingtoINSSstageafterbestoperationconfirmedallpatientswithstage1diseaseunderwentcompletesurgicalresection.InpatientswithINSSstage2,therewasnosignificantdifferencebetweenincompleteresection,grosstotalresectionandcompleteresectioninEFS(p = 0.901),LPFS(p = 0.520)andOS(p = 0.446).ButpatientswithINSSstage3diseaseshowedastatisticalsignificanceaccordingtotheextentofresectioninEFS(p = 0.032)andLPFS(p = 0.034),butnotinOS(p = 0.053).Analyzingstage3patientswithMYCNamplification(n = 29)andwithoutMYCNamplification(n = 35)separately,MYCN-amplifiedpatientsshowedabetteroutcomecorrelatedtotheextentofresectionatbestoperation(EFSp = 0.001;LPFSp = 0.001;OSp = 0.002)whereasnon-MYCN-amplifiedpatientsdidnot(EFSp = 0.411;LPFSp = 0.177;OSp = 0.905).INRGAccordingtoINRGpretreatmentriskclassification151patientscouldbeanalyzedretrospectively.AllpatientswithMYCNamplificationbelongtothehigh-riskgroup,resultingin36patients(20.1%).PatientswithahistologicalcategoryofGNBintermixedwithoutMYCNamplificationorIDRF(L1)arecategorizedasverylow-risk(n = 88,49.2%).AnypatientswithNBornodularGNBharboringmorethanoneIDRF(L2)maybelongtolow-(n = 4,2.2%)orintermediate-risk(n = 23,12.8%)dependingongradeoftumordifferentiationand11qaberration.High-riskpatients(n = 36)showabetterEFS(p = 0.001),LPFS(p = 0.001)andOS(p = 0.001)afterbestsurgerywhentumorresectionwascomplete(Fig.4).Patientsbelongingtointermediate-riskdidnotbenefitfromcompletesurgery(EFSp = 0.411;LPFSp = 0.177;OSp = 0.905).Fig.4Kaplan-Meier-curvesforINRGhigh-riskpatientsafterbestoperationFullsizeimage DiscussionInourcohort,extendedsurgeryoftheprimarytumorsiteimprovedlocalcontrolrateandoutcomeinpatientsolderthan18 monthswithlocalizedneuroblastoma.Aftercompleteresectionduringtreatmentthepatientshadabetterlocal-progression-freesurvival(LPFS),event-freesurvival(EFS)andOSthantheothergroups.Thewiderangeofclinicalmanifestationsofneuroblastomas,theirlocalizationandtheirresectabilityleadstoahighheterogeneityofourcohort.TheNB97protocolclearlyrecommendedlessaggressivesurgicalapproachparticularlyduringfirstoperationinanefforttoavoidsurgicalcomplications.Mostsurgeonschoosealessaggressiveapproachwhenthediseasewasconsideredtobeunresectableduringoperation.Thus,thequestionwhetherpatientsdidnotundergocompleteresectionbecauseoflessaggressivesurgicalapproaches,orsimplyduetounresectablediseasecannotbeansweredretrospectively.Moreover,lessaggressivesurgeonsaremorelikelytoclassifypatientsasunresectableandviceversa.Prospectivestudieswithastatementofthesurgeon’sdecisioninhis/hersoperationnotesareneededtoaddressdifferentapproaches.However,subgroupanalysesshowedbetterEFSandOSforpatientswithcompleteresectioninINSSstage3andMYCNamplification.PatientswithMYCNamplificationbelongtotheINRGhigh-riskstratificationandarethereforeofspecialinterestsincetheroleofsurgeryinhigh-riskpatientsremainscontroversial.Otherstudiesofhigh-riskpatientsespeciallyevaluatingstage4patientsshownoadvantageofcompleteresectiononpatient’soutcome[11,16],whilelowerlocalrecurrenceratesandbetterOSarereportedafterextendedsurgerybyLaQuagliaetal.[17,18].Butanalyzinglocalizedneuroblastomainpatients>1 year,radicalsurgeryisrecommendedwhichisinlinewithourfindings[2].Ameta-analysisof2599patientswithstage3and4neuroblastomasfrom33studiesdemonstratedthatrelativeriskofmortalitywasdecreasedinpatientswhounderwent>90%resection[19].OurstudyindicatesthatcompletesurgicalresectionoftheprimarytumorsiteshouldbeattemptedinINRGhigh-riskpatients.Riskofcomplicationsatfirstandbestoperationiscomparabletopreviouslypublisheddata[2].SincethepresenceofIDRFpredictstheriskofcomplicationsandtheextentofsurgery,theimpactofIDRFshouldbecomeanintegratedpartoftherapyplanningasshownbefore[20,21,22],butcannotbesafelyusedasanindependentriskfactorforoutcome.Therefore,INRGclassificationconsideringIDRF,histologicalcategory,MYCNamplification,gradeoftumordifferentiationandchromosomalaberrations,wasappliedinourstudyandshowedasignificantdifferenceinhigh-riskpatientswithcompletesurgicalresectionofthetumor.FuturetrialsshouldencourageacompleteresectionoftheprimarytumorinINRGhigh-riskpatientswithamoreaggressiveapproachtoimproveoutcomewithanacceptableriskofcomplication,butprobablelife-threateningcomplicationsshouldstillbeavoided.Inthisstudypostoperativestagingtoassessthepresenceandextentofpossibleresidualtumorswascarriedoutbycomputedtomography,magneticresonanceimagingorultrasound,butMRIwasrecommendedasgoldstandardforfollow-up.Theintervalbetweensurgeryandimagingvariedbetweenoneandthreemonthspostoperatively,whichcanresultindifferencesoftheextentofresectiondescribedbyimagingstudiesandbyoperationnotes.Whenevertherewasinconsistency(26.7%ofallcases),jointreviewwitharadiologistwasperformed.Eveninpatientswithlocalizedneuroblastomaolderthan18 months,spontaneousregressionordifferentiationcanoccuratanytimethroughouttherapy.Thisshouldbeconsideredinpatientswithincompleteresectionorgrosstotalresectionachievedatfirstoperation.Inthisstudy,onlyfewpatientswithincomplete/grosstotalresectionafterfirstoperationunderwentsecondoperationstoachievecompleteresection,whereasmostpatientsdidnot(9vs.18).Duetothesmallnumberofpatients,abenefitoffurthersurgeryinthesecasesremainsunclear.Possibly,molecularcharacterizationoftheprimarytumorswillbeabletoanswerthesequestionsinthefuture.ConclusionInpatientswithlocalizedneuroblastoma>18 months,especiallywithINRGhigh-riskclassification,extendedsurgeryimprovesEFS,LPFSandOSandshouldthereforebeattempted. AbbreviationsASCT: autologousstemcelltransplantation EFS: event-freesurvival GNB: Ganglioneuroblastoma Gy: Gray IDRF: imagedefinedriskfactor INPC: InternationalNeuroblastomaPathologyClassification INRG: InternationalNeuroblastomaRiskGroup INSS: InternationalNeuroblastomaStagingSystem LPFS: local-progression-freesurvival MIBG: metaiodobenzylguanidinescintigraphy MRI: magneticresonanceimaging MYCN: oncogene NB: neuroblastoma OS: overallsurvival RT: radiotherapy vs.: versus ReferencesParkJR,EggertA,CaronH.Neuroblastoma:biology,prognosis,andtreatment.HematolOncolClinNorthAm.2010;24(1):65–86.Article  PubMed  GoogleScholar  vonSchweinitzD,HeroB,BertholdF.Theimpactofsurgicalradicalityonoutcomeinchildhoodneuroblastoma.EurJPediatrSurg.2002;12(6):402–9.Article  GoogleScholar  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GoogleScholar  YonedaA,NishikawaM,UeharaS,OueT,UsuiN,InoueM,FukuzawaM,OkuyamaH.Canimage-definedriskfactorspredictsurgicalcomplicationsinlocalizedneuroblastoma?EurJPediatrSurg.2016;26(1):117–22.PubMed  GoogleScholar  DownloadreferencesAcknowledgementsWethankallpatientsandtheirparentsforconsentandparticipation.WethankallstaffoftheNB97study,especiallyMonikaSchmitzandMartinaBreuerfortheirhelpwithdatacollection. Funding ThestudyNB97wasfundedbytheGermanCancerAid(grantno.70–2290-Be)toFB.Thefundingbodywasneitherinvolvedinthedesignofthestudynorcollection,analysis,interpretationofdataorinwritingthemanuscript. Availabilityofdataandmaterials Thedatasetsanalyzedduringthecurrentstudyareavailablefromthecorrespondingauthoronreasonablerequest. AuthorinformationAuthorsandAffiliationsDepartmentofPediatricOncologyandHematology,UniversityChildren’sHospitalofCologne,KerpenerStr.62,50924,Cologne,GermanyJaninaFischer, RuthVolland, BarbaraHero, FrankBerthold & ThorstenSimonDepartmentofPediatricSurgery,Dr.vonHaunerschesChildren‘sHospital,Munich,GermanyAlexandraPohl & DietrichvonSchweinitzDivisionofPediatricSurgery,UniversityChildren‘sHospitalofCologne,Cologne,GermanyMartinDübbers & GrigoreCernaianuAuthorsJaninaFischerViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAlexandraPohlViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarRuthVollandViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarBarbaraHeroViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMartinDübbersViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGrigoreCernaianuViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarFrankBertholdViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarDietrichvonSchweinitzViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarThorstenSimonViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsConceptionanddesign:JF,TS,BH,FB,DS.Administrativesupport:FB,DS.Collectionandassemblyofdata:JF,AP,GC,MD,Dataanalysisandinterpretation:JF,AP,RV,TS,BH.Manuscriptwriting:Allauthors.Allauthorshavereadandapprovedthefinalversionofthemanuscript.CorrespondingauthorCorrespondenceto JaninaFischer.Ethicsdeclarations Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Ethicsapprovalandconsenttoparticipate ThetrialwasapprovedbyEthicsCommitteeoftheUniversityHospitalofCologne(no.9764).Writteninformedconsentwasobtainedfrompatientsortheirguardiansforparticipationinthestudydesign,datacollectionandtreatment(Registrationnumber:NCT00017225,ClinicalTrials.gov). Consentforpublication Notapplicable. Publisher’sNote SpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations. Rightsandpermissions OpenAccessThisarticleisdistributedunderthetermsoftheCreativeCommonsAttribution4.0InternationalLicense(http://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedyougiveappropriatecredittotheoriginalauthor(s)andthesource,providealinktotheCreativeCommonslicense,andindicateifchangesweremade.TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated. ReprintsandPermissionsAboutthisarticleCitethisarticleFischer,J.,Pohl,A.,Volland,R.etal.CompletesurgicalresectionimprovesoutcomeinINRGhigh-riskpatientswithlocalizedneuroblastomaolderthan18 months. BMCCancer17,520(2017).https://doi.org/10.1186/s12885-017-3493-0DownloadcitationReceived:15May2017Accepted:20July2017Published:04August2017DOI:https://doi.org/10.1186/s12885-017-3493-0SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsSurgicaloncologyHigh-riskneuroblastomaLocalizedneuroblastomaNeuroblastomasurgery DownloadPDF Advertisement BMCCancer ISSN:1471-2407 Contactus Submissionenquiries:[email protected] Generalenquiries:[email protected]