肛門(mén)癌2022.v1（英文）-NCCN腫瘤臨床實(shí)踐指南

NCCNClinicalPracticeGuidelinesinOncologyNCCNGuidelines?)AnalCarcinomarsionMarchVersion1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.AnalCarcinomadex*AlB.Benson,III,MD/Chair?RobertH.LurieComprehensiveCancerCenterofNorthwesternUniversity*AlanP.Venook,MD/Vice-Chair??UCSFHelenDillerFamilyComprehensiveCancerCenteryofMichiganRogelCancerCenteryofMichiganRogelCancerCenterNiloferAzad,MD?TheSidneyKimmelComprehensiveCancerCenteratJohnsHopkinsYi-JenChen,MD,PhD§CityofHopeNationalMedicalCenterngramCancerCenterngramCancerCenterStaceyCohen,MD?FredHutchinsonCancerResearchCenter/SeattleCancerCareAllianceHarryS.Cooper,MD≠FoxChaseCancerCenteryofWisconsinCarboneCanceryofWisconsinCarboneCancerCenterLindaFarkas,MD?UTSouthwesternSimmonsComprehensiveCancerCenterIgnacioGarrido-Laguna,MD,PhD?HuntsmanCancerInstituteattheUniversityofUtahfettCancerfettCancerCenterAndrewGunn,MDфONealComprehensiveCancerCenteratUABJ.RandolphHecht,MD?UCLAJonssonComprehensiveCancerCenternterSarahHoffenteresPanelDisclosuresJoleenHubbard,MD??MayoClinicCancerCenternCancerCenteratBarnesnCancerCenteratBarnesJewishHospitalandWashingtonUniversitySchoolofMedicineWilliamJeck,MD≠DukeCancerInstitutenterSmilowCancerHospitalimberlyLnterSmilowCancerHospitalNatalieKirilcuk,MD?StanfordCancerInstituteSmithaKrishnamurthi,MD?TCaseComprehensiveCancerCenter/UniversityHospitalsSeidmanCancerCenterandClevelandClinicTaussigCancerInstituteofColoradoCancerCenterWellsAofColoradoCancerCenterandWomensJeffreyandWomensenterEricD.Miller,MD,PhD§TheOhioStateUniversityComprehensiveCancerCenter-JamesCancerHospitalandSoloveResearchInstituteMaryF.Mulcahy,MD??RobertH.LurieComprehensiveCancerCenterofNorthwesternUniversityStevenNurkin,MD,MS?RoswellParkComprehensiveCancerCenterTheUniversityofTexasMDAndersonCancerCenterTheUniversityofTexasMDAndersonCancerCentertalandWashingtontalandWashingtonoolofMedicineMassachusettsGeneralHospitalCancerCenterHitendraPatel,MD?UCSanDiegoMooresCancerCenternCancerCenteratBarnesrinanCancerCenteratBarnesElizabethRaskin,MD?UCDavisComprehensiveCancerCenterLeonardSaltz,MD??TMemorialSloanKetteringCancerCenterCharlesSchneider,MD?AbramsonCancerCenterattheUniversityofPennsylvaniaTheUniversityofTennesseeHealthScienceTheUniversityofTennesseeHealthScienceCenterTheUniversityofTexasMDAndersonCancerTheUniversityofTexasMDAndersonCancerCenterConstantinosT.Sofocleous,MD,PhDфMemorialSloanKetteringCancerCenterElenaM.Stoffel,MD,MPH¤UniversityofMichiganRogelCancerCenterEdenStotsky-Himelfarb,BSN,RN??￥rCenteratJohnsrCenteratJohnsHopkinsChristopherG.Willett,MD§DukeCancerInstituteiPhD¤Gastroenterology?Hematology/HematologyoncologyTInternalmedicine?Medicaloncology≠Pathology￥Patientadvocate§Radiotherapy/Radiationoncology?Surgery/Surgicaloncology*DiscussionSectionWritingCommitteeVersion1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.AnalCarcinomadexedNCCNCategoriesofPreference:Allrecommendationsareconsideredappropriate.SeeNCCNCategoriesofPreference.oftheGuidelinesUpdateserANALntPerianalCancerANALeillanceANALyANALAtemicTherapyANALBherapyANALCorshipANALDTheNCCNGuidelinesareastatementofevidenceandconsensusoftheauthorsregardingtheirviewsofcurrentlyacceptedapproachestotreatmentAnyclinicianseekingtoapplyorconsulttheNCCNGuidelinesisexpectedtouseindependentmedicaljudgmentinthecontextofindividualstancestodetermineanypatientscareortreatmentTheNationalComprehensiveCancerNetworkNCCNmakesnorepresentationsorwarrantiesofanykindregardingtheircontentuseorapplicationanddisclaimsanyresponsibilityfortheirapplicationoruseinanywayTheNCCNationalComprehensiveCancerNetworkAllrightsreservedTheNCCNGuidelinesandtheillustrationshereinmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.?2022.Version1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.UPDATESVersion1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.AnalCarcinomadex?ClinicalStagepLocoregionaldiseasemodifiedwiththeadditionof“±positivepara-aorticlymphnodes”(alsoappliestoANAL-2[T1,N0poorlydifferentiatedorT2-4,N0orAnyT,N+])pFootnotefadded:Para-aorticnodesthatcanbeincludedinaradiationfield.(alsoappliestoANAL-2)?PrimaryTreatmentpRTremoved(alsoappliestoANAL-2)pThefollowingrecommendationadded:Re-evaluateandconsiderchemoradiationwith5-FUorCapecitabine(alsoappliestoANAL-2)?SuperficiallyInvasiveSquamousCellCarcinoma(SISCCA)pSub-bulletremoved:Forcompletelyexcisedanalcancer(removedattimeofbiopsy)with≤3-mmbasementmembraneinvasionandamaximalhorizontalspreadof≤7mm,localsurgicalresectionwithnegativemarginsmaybeadequatetreatment.pSub-bullet1added:SISCCAareanalcancersthataregenerallyfoundincidentallyinthesettingofabiopsyorexcisionofwhatisthoughttobeabenignlesionsuchasacondyloma,hemorrhoid,oranalskintag.pSub-bullet2added:Forsuchlesionsthatarenotedtohavehistologicallynegativemarginsincarefullyselectedpatientsfollowedbyanexperiencedproviderand/orteam,localexcisionalonewithastructuredsurveillanceplanmayrepresentadequatetreatment.?Perianal(AnalMargin)CancerpDiamond1modified:Localsurgicalexcisionofselect,smallerT2earlylesionsmaybeconsideredANAL-B1of2?Chemoradiationdosingadded:p5-FU225mg/m2IVover24hours(continuousinfusion)5or7days/weekduringXRT(referenceaddedtoANAL-B2of2)pCapecitabine825mg/m2POtwicedaily5days/week+XRTx5weeks(referencesaddedtoANAL-B2of2)ANAL-C1of5?Footnote*added:NCCNrecommendationshavebeendevelopedtobeinclusiveofindividualsofallsexualandgenderidentitiestothegreatestextentpossible.Onthispage,thetermsmalesandfemalesrefertosexassignedatbirth.ANAL-C3of5?DosePrescription;thefollowingstatementremoved:pUtilizationofSIBdosepaintingisarelativelynewapproachinthetreatmentofanalcancerandtheimplicationsof1.5Gyperfractiontotheelectivenodalregionarenotwellstudiedinthisdisease.ANAL-C4of5?Table1DoseSpecificationofPrimaryandNodalPlanningTargetVolumespT1,N0addedpInvolvedNodalPTVDosecolumnaddedANAL-C5of5?Table2DP-IMRTDoseConstraintsforNormalTissuespFootnoteremoved:Assignedcriteriaformajorandminorviolationswereconsideredaspartofthefeasibilitysecondaryendpoint.?SupportiveCarepTerminologiesmodifiedtobemoreinclusiveofallsexualandgenderidentities.pSub-bullet2added:Patientsofchildbearingpotentialshouldbecounseledabouttheeffectsofprematuremenopauseandconsiderationshouldbegiventoreferralfordiscussionofhormonereplacementstrategies.pSub-bullet3added:Patientsofchildbearingpotentialshouldbecounseledthatanirradiateduteruscannotcarryafetustoterm.pSub-bullet4modified:Patientsshouldbecounseledonsexualdysfunction,potentialforfuturelowtestosteronelevels,andinfertilityrisksandgiveninformationregardingspermbankingoroocyte,egg,orovariantissuebanking,asappropriate,priortotreatment.ANAL-D1of2?ManagementofLate/Long-termSequalaeofDiseaseorTreatmentpBullet3;sub-bullet1modified:Screenforsexualdysfunction,erectiledysfunction,dyspareunia,vaginalstenosis,andvaginaldryness.PrintedbyMinTangon3/14/20227:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.AnalCarcinomadexCLINICALPRESENTATIONAnalBiopsy:squamouscarcinomacarcinomabWORKUP?Digitalrectalexamination(DRE)?Inguinallymphnodeevaluation?Chest/abdominalCTc+?Chest/abdominalCTc+MRI?ConsiderPET/CTdorPET/MRI(ifavailable)?Anoscopy?HIVtesting(ifHIVstatusunknown)?Gynecologicexamforfemales,includingscreeningforcervicalcancer?Fertilityriskdiscussion/counselinginappropriatepatientsCLINICALPRIMARYTREATMENTgeeMetastaticwith5-FUorCapecitabinenfluorouracilwith5-FUorCapecitabinenfluorouracil(DCF)h(category2B)Mitomycin/5-FUh+RTiitomycinitomycincapecitabinehRTi5-FU/cisplatinh+RTi(category2B)Follow-upTherapyandSurveillancembrolizumabmbrolizumabh,kadiationhadiationhiyBaxelmbrolizumabh,kaThesuperiorborderofthefunctionalanalcanal,separatingitfromtherectum,hasbeendefinedasthepalpableupperborderoftheanalsphincterandpuborectalismusclesoftheanorectalring.Itisapproximately3to5cminlength,anditsinferiorborderstartsattheanalverge,thelowermostedgeofthesphinctermuscles,correspondingtotheintroitusoftheanalorifice.bFormelanomahistology,seetheNCCNGuidelinesforMelanoma:Cutaneous;foradenocarcinoma,seetheNCCNGuidelinesforRectalCancer.cCTshouldbewithIVandoralcontrast.PelvicMRIwithcontrast.Ifintravenousiodinatedcontrastmaterialiscontraindicatedduetosignificantcontrastallergyorrenalfailure,thenMRIexaminationoftheabdomenandpelviswithIVgadolinium-basedcontrastagent(GBCA)canbeobtainedinselectpatients(seeAmericanCollegeofRadiologycontrastmanual:/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf).IntravenouscontrastisnotrequiredforthechestCT.dPET/CTscandoesnotreplaceadiagnosticCT.PET/CTperformedskullbasetomid-thigh.ePrinciplesofSurgery(ANAL-A).fPara-aorticnodesthatcanbeincludedinaradiationfield.gModificationstocancertreatmentshouldnotbemadesolelybasedonHIVstatus.SeeNCCNGuidelinesforCancerinPeoplewithHIV.hPrinciplesofSystemicTherapy(ANAL-B).iPrinciplesofRadiationTherapy(ANAL-C).jCarboplatin/paclitaxelistheonlyregimensupportedbyrandomizeddataandmaybepreferredover5-FU/cisplatinduetotoxicityprofiles.kNCCNGuidelinesfortheManagementofImmunotherapy-RelatedToxicities.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.ANAL-1Version1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.screeningforcervicalFOLFOXhandconsiderNivolumabh,k?erfertilityriskMetastaticLFCIShionh,imbrolizumabh,kforfemales,includingorRe-evaluateomahistologyseescreeningforcervicalFOLFOXhandconsiderNivolumabh,k?erfertilityriskMetastaticLFCIShionh,imbrolizumabh,kforfemales,includingorRe-evaluateomahistologyseetheNCCNGuidelinesforMelanomaCutaneousforuspicioussphincteranAnalCarcinomadexCLINICALWORKUPCLINICALSTAGEPRIMARYTREATMENTgPRESENTATIONT1,N0WellorWellorAdequateObservepConsiderbiopsyornotinvolvemargins±5-FU/mitomycinhorFollow-upiunamphnodepConsiderbiopsyornotinvolvemargins±5-FU/mitomycinhorFollow-up?Chest/abdominalCTcT1,N0Poorly(ANAL-3)?Gynecologicexampaclitaxelh,j?Chest/abdominalCTcT1,N0Poorly(ANAL-3)?Gynecologicexampaclitaxelh,j adenocarcinoma,seetheNCCNGuidelinesforRectalCancer.fPara-aorticnodesthatcanbeincludedinaradiationfield.cCTshouldbewithIVandoralcontrast.PelvicMRIwithcontrast.IfintravenousgModificationstocancertreatmentshouldnotbemadesolelybasedonHIVstatus.iodinatedcontrastmaterialiscontraindicatedduetosignificantcontrastallergyNCCNGuidelinesforCancerinPeoplewithHIV.orrenalfailure,thenMRIexaminationoftheabdomenandpelviswithIVGBCAhPrinciplesofSystemicTherapy(ANAL-B).canbeobtainedinselectpatients(seeAmericanCollegeofRadiologycontrastiPrinciplesofRadiationTherapy(ANAL-C).manual:/-/media/ACR/Files/Clinical-Resources/Contrast_jCarboplatin/paclitaxelistheonlyregimensupportedbyrandomizeddataandmayMedia.pdf).IntravenouscontrastisnotrequiredforthechestCT.bepreferredover5-FU/cisplatinduetotoxicityprofiles.dPET/CTscandoesnotreplaceadiagnosticCT.PET/CTperformedskullbasetokNCCNGuidelinesfortheManagementofImmunotherapy-RelatedToxicities.mid-thigh.lTheperianalregionstartsattheanalvergeandincludestheperianalskinoveraePrinciplesofSurgery(ANAL-A).5-cmradiusfromthesquamousmucocutaneousjunction.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.ANAL-2Version1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.?DREevery3–6mofor5y?Inguinalnodepalpationevery3–6mofor5y?Anoscopy?DREevery3–6mofor5y?Inguinalnodepalpationevery3–6mofor5y?Anoscopyevery6–12mox3yComplete?Chest/abdominal/remissionpelvicCTwithorchestoutcontrastominalMRIwithstannuallywkwithexam+DREPersistentdiseasemProgressivediseasemAnalCarcinomadexFOLLOW-UPSURVEILLANCEFOLLOW-UPSURVEILLANCEesectionAPRoLocalesectionAPRordiseasendiseaseninFUmitomycinhinFUmitomycinhycincapecitabinehCarboplatin/paclitaxelorUcisplatinhcategoryBRTModifiedDCFhcategory2B)TiTiifnopriorRTtoCarboplatin/paclitaxelh,jFOLFCIShFOLFCIShorUcisplatinhcategoryBNivolumabh,kmbrolizumabh,klowmBasedontheresultsoftheACT-IIstudy,itmaybeappropriatetofollowpatientswhohavenotachievedacompleteclinicalresponsewithpersistentanalcancerupto6monthsfollowingcompletionofradiationtherapyandlongasthereisnoevidenceofprogressivediseaseduringthisperiodoffollow-up.Persistentdiseasemaycontinuetoregressevenat26weeksfromthestartofePrinciplesofSurgery(ANAL-A).treatment.JamesRD,ePrinciplesofSurgery(ANAL-A).iplesofSystemicTherapyANALBiplesofRadiationTherapyANALCnPalliativeRTmaybeconsiderediniplesofSystemicTherapyANALBiplesofRadiationTherapyANALCjCarboplatin/paclitaxelistheonlyregimensupportedbyrandomizeddataandmaypreviouslyirradiatedjCarboplatin/paclitaxelistheonlyregimensupportedbyrandomizeddataandmaybepreferredover5-FU/cisplatinduetobepreferredover5-FU/cisplatinduetotoxicityprofiles.elinesfortheManagementofImmunotherapyRelatedelinesfortheManagementofImmunotherapyRelatedToxicitiesNote:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.ANAL-3Version1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.AnalCarcinomadexTREATMENTSURVEILLANCEpProgressivediseasemdiseasemPersistentdiseasemLocallyAPRo,r+groinLocallyAPRo,r+groinMetastaticdisMetastaticdiseasen5-FU/cisplatin5-FU/cisplatinh(category2B)ModifiedDCFhcategory2B)ssionorationandeasereevaluateqatCompletetervalsialexamsoralexams?Inguinalnodepalpationevery3–6mofor5y?Chest/abdominal/pelvicCTwithcontrastorchestCTwithoutcontrastandabdominal/pelvicMRIwithcontrastannuallyfor3ymbrolizumabh,keillanceANALlowhPrinciplesofSystemicTherapy(ANAL-B).jCarboplatin/paclitaxelistheonlyregimensupportedbyrandomizeddataandmaybepreferredover5-FU/cisplatinduetotoxicityprofiles.kNCCNGuidelinesfortheManagementofImmunotherapy-RelatedToxicities.mBasedontheresultsoftheACT-IIstudy,itmaybeappropriatetofollowpatientswhohavenotachievedacompleteclinicalresponsewithpersistentanalcancerupto6monthsfollowingcompletionofradiationtherapyandchemotherapyaslongasthereisnoevidenceofprogressivediseaseduringthisperiodoffollow-up.Persistentdiseasemaycontinuetoregressevenat26weeksfromthestartoftreatment.JamesRD,LancetOncol2013;14:516-524.nPalliativeRTmaybeconsideredinsymptomaticpatients.RecordsofpreviousRTshouldbecarefullyreviewedandconsideredpriortopotentialre-irradiationofpreviouslyirradiatedfields.PrinciplesofRadiationTherapy(ANAL-C).oConsidermuscleflapreconstruction.pPrinciplesofSurvivorship(ANAL-D).qUseimagingstudiesasperinitialworkup.rConsidertheuseofimmunotherapy(nivolumaborpembrolizumab)(category2B)beforeproceedingtoAPR.Institutionalexperiencehasdemonstratedsomepatientsreceiveagoodresponseandcanavoidsurgery.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.ANAL-4Version1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.AnalCarcinomadexPRINCIPLESOFSURGERY?SuperficiallyInvasiveSquamousCellCarcinoma(SISCCA)pSISCCAareanalcancersthataregenerallyfoundincidentallyinthesettingofabiopsyorexcisionofwhatisthoughttobeabenignlesionsuchasacondyloma,hemorrhoid,oranalskintag.pForsuchlesionsthatarenotedtohavehistologicallynegativemarginsincarefullyselectedpatientsfollowedbyanexperiencedproviderand/orteam,localexcisionalonewithastructuredsurveillanceplanmayrepresentadequatetreatment.?Perianal(AnalMargin)CancerpT1N0,moderatelytowell-differentiatedorselectT2N0squamouscellcarcinoma(SCC)oftheperianal(analmargin)regionmaybeadequatelytreatedbylocalexcisionwith1-cmmargins.?Localsurgicalexcisionofselect,earlylesionsmaybeconsidered–Wherethetumorformsadiscretelesionarisingfromtheperianalskinthatisclearlyseparatefromtheanalcanal–Wherenegativemarginexcisioncanbeaccomplishedwithoutcompromiseoftheadjacentsphinctermuscles–WherethereisnoevidenceofregionalnodalinvolvementalRecurrencePersistencepAPRistheprimarytreatment.pGeneralprinciplesforAPRaresimilartothosefordistalrectalcancerandincludetheincorporationoftotalmesorectalexcision(TME).pAPRforanalcancermayrequirewiderlateralperianalmargins.pDuetothenecessaryexposureoftheperineumtoradiation,patientsarepronetopoorperinealwoundhealingandmaybenefitfromtheuseofreconstructivetissueflapsfortheperineumsuchastheverticalrectusorlocalmyocutaneousflaps.?InguinalRecurrencepPatientswhohavealreadyreceivedgroinradiationshouldundergoaninguinalnodedissection.pGroindissectioncanbedonewithorwithoutAPRdependingonwhetherdiseaseisisolatedtothegroinorisinconjunctionwithrecurrence/persistenceattheprimarysite.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.ANAL-AVersion1.2022,03/02/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.AnalCarcinomaHYPERLINK"/professionals/physician_gls/def