ManagementofDesmoidsValeriePGrignolRaphaelPollockMDPhDJohnHarriso - PDF document

ManagementofDesmoidsValerieP.Grignol,,RaphaelPollock,MD,PhDJohnHarrisonHoward,Desmoidtumors(alsoknownasaggressivefibromatosis)arerare,withanincidenceof0.03%ofallneoplasmsand3.0%ofsofttissuetumors.Theyareseenmorecommonlyinwomenthanmenwitha2:1predilectionforwomen.Youngadults Disclosures:none.DivisionofSurgicalOncology,DepartmentofSurgery,TheOhioStateUniversity,N924DoanHall,410West10thAvenue,Columbus,OH43210,USA*Correspondingauthor.E-mailaddress: DesmoidfibromatosisKEYPOINTSDesmoidfibromatosisisaninfiltrativetumorthatcanbeaggressiveinnaturebecauseofitsabilitytolocallyinvadeadjacentstructures.Mutationsin-cateninandAPCgenesareresponsibleforthedevelopmentofmostdes-moidtumors. pregnancy,hormonalexposure,andphysicalfactors,suchastraumaand/orsur-Althoughdesmoidtumorscannotbeconsideredatruemalignancybecauseoftheirinabilitytometastasize,theyareaggressiveintheirabilitytolocallyinvadeadjacentstructures.Surgicalresectionhasbeenthemainstayoftreatment;however,recurrenceratesrangefrom20%to45%.Becauseofthepropensityforrecur-rence,multimodaltherapieshavebeenused,includinghormonaltherapy,nonste-roidalantiinflammatorydrugs(NSAIDs),chemotherapy,andradiation.Recentlythesurgery-firstapproachhasbeguntoevolveintoamovementofwatchfulwaiting,asobservationalstudieshaveshownlong-termstabilityofsometumorswithouttreat-mentandevenspontaneousregressionin5%to10%ofcases.AlterationsintheWntsignalingpathwayseemtobethemechanismoftumorigenesisinthedevelopmentofdesmoidfibromatosis.Geneticmutationsthatalterthispathwayandareassociatedwiththedevelopmentofdesmoidtumorshavebeenidentifiedinthe-cateninandAPCgenes.Both-cateninandAPCarepartoftheWntpathwaysuggestingthat2separatemutationsaffectingthesameendpointareinvolvedwiththedevelopmentofdesmoidfibromatosis.Thesemutationsresultinthedevelopmentofintranuclearaccumulationof-catenin,whichstimulatesDNAtranscriptionandcellproliferation.Eighty-fivepercentofsporadicdesmoidtumorshaveanactivatingmutationintheCTNNB1genecodingfor-catenin,whereasthegermlinemutationoftheAPCgeneleadstothedevelopmentofdesmoidtumorsforpatientswithFAP.Morerecentlyageneticanalysislookingatwild-typedesmoidsorthosewithouttheaforementionedknownmutationsfoundthatwithdeepsequencing95%ofdesmoidsmayhavemutationsthataffecttheWnt/pathwaysuggestinganear-universalrelationshipbetweendesmoidtumorsandtheWntsignaling.Insporadicdesmoidtumors,mutationsinthegenecodingfor-catenin,CTNNB1,occurin71%to91%oftumors.Thehighestrateofmutationisfoundinin

tra-abdominaltumors.ThemostcommonmutationsareT41AandS45F.Thediscoveryofgeneticmutationsinthedevelopmentofdesmoidtumorshasbeenanimportantadvancementastheyhavealsobeenassociatedwithprognosis,providingtheopportunitytoimprovetheabilitytoriskstratifypatients.Severalstudieshaveshownasignificantlyhigherchanceofdiseaserecurrenceat5yearsdespitecompleteresectionforpatientsharboringaS45Fmutation,whichislikelyexclusivetoextra-abdominaldesmoids.Thegrowingamountofdatasuggeststhatspecificmutationswithinthisgenedoplayaroleindiseaserecurrenceandprovidetheopportunitytoinfluenceclinicalcareinthefuture.Forthosewithouta-cateningenemutation,APCgenemutationsaresuspectedtobethesourceofdevelopmentofdesmoidtumors.APCmutationsaremostcommonamongpatientswithFAP.Approximately10%to15%ofpatientwithFAPdevelopdesmoids,andintra-abdominaltumorshavebecometheprimarycauseofdeathinpatientswithFAPwhohavepreviouslyhadaprophylacticcolectomy.DespiteasimilarmolecularendpointforAPCand-cateninmutations,thephenotypebetweenthetwoisdifferent,asmosttumorsinFAPareintra-abdominalwithinvolvementofthesmallbowelmesentery.Desmoidtumorscanoccuranywhereinthebody.Theyaredividedinto3generalanatomiclocations:extra-abdominal,intra-abdominal,andabdominalwall.ThereGrignoletal areimportantbehavioraldifferencesrelatedtolocationthatmayaffectspecifictreatmentalgorithms.Extra-abdominaldesmoidtumorsarecomposedoftumorsinthepelvicandshouldergirdles,head,neck,andextremities(Fig.1A).Theyarisefromdeepfasciaorwithinmuscle,haveaninfiltrativegrowthpattern,andareoftenpoorlycircum-Thislocationhasbeenassociatedwitha2-to3-foldincreasedrateofrecurrenceand20%decreaseinrecurrence-freesurvivalwhencomparedwithintra-abdominalorabdominalwall/trunklesions.Intra-abdominaldesmoidsoftenariseinthemesenteryofthesmallbowelorarelocatedinthepelvis(seeFig.1B).ThislocationismorecommonlyassociatedwithFAPbutcanalsooccursporadically.Inpatientslessthan40yearsoldfoundtohaveanintra-abdominalorabdominalwalldesmoid,acolonoscopyshouldbeperformedtoruleoutpolyposis.Overall,FAP-associateddesmoidtumorsrepresentasmallproportion(2%–15%)ofallpatientswithdesmoidtumors.Themanage-mentofintra-abdominaldesmoidscanbequitedifficultbecauseofsizeandlocationandfrequentlyrequireresectionoflargeamountsofsmallbowelforcompleteremoval.InastudyofpatientswithFAPandmesentericdesmoidsthatweretreatedsurgically,smallbowelresectionswerenecessaryin87.5%ofcaseswithanaverageof45.6cmofbowelremoved.Inextremecasesthiscanleadtointestina

lfailure,chronictotalparenteralnutrition,andpossibleneedforsmallboweltransplantation.Thislocationinparticularmaybeoptimalfornonsurgicalapproachesfirstinasymp-tomaticpatients,astheconsequencesofextendedresectionscanbedevastating.Lesionsoftheabdominalwallortrunkseemtohavethemostfavorableprognosisofthe3groups(seeFig.1C).Theyhavebeenassociatedwiththelowestrecurrenceratesof6%to20%andthehighestlikelihoodofspontaneousregression.10,26 Fig.1.Desmoidtumorscanbedividedinto3anatomiclocations:()extra-abdominal,(abdominalwall()intra-abdominal.Arrowsdepicttumor.ManagementofDesmoids Thislocationisalsothemostcommonforpregnancy-relateddesmoidtumors.Therehasbeenareportedassociationbetweenpregnancyandthedevelopmentorprogres-sionofdesmoids.Itisthoughtthatthisisrelatedtotheobservationthatthesetumorsstainstronglypositiveforestrogen-receptoronimmunohistochemistry.Inarecentstudythatevaluateddesmoidfibromatosisandpregnancy,theinvestigatorsfoundthat,althoughtherewasanincreasedriskofprogressionduringpregnancy,patientscouldstillbemanagedwithstandardtherapieswithminimalrisktothemotherorchild.Theriskofprogressionwasmoreprominentinpatientswhowerediagnosedwithdesmoidfibromatosisbeforepregnancy(42%)versusthepatientswhosediseasepresentedduringpregnancy(13%).Therateofspontaneousregressioninthispopu-lationwas14%,whichishigherthanwhatisseeninotherpatientpopulations.Theyconcludedthatdesmoidtumorsduringpregnancyhaveanindolentcourse,donotincreaseriskofobstetriccomplications,andshouldnotbeacontraindicationforsubsequentpregnancies.EVALUATIONRadiologicEvaluationImagingmodalitiesusefulinthediagnosisandsurveillanceofdesmoidtumorsincludeultrasound,computedtomography(CT)scan,andMRI.Forinitialevaluation,cross-sectionalimagingismostappropriatetoevaluatetumorsizeandlocalinvasionofadjacentanatomicstructures.Contrast-enhancedCTscanisthepreferenceforintra-abdominaltumorstoevaluateproximitytoadjacentintra-abdominalvasculatureandorgans.CTscanofintra-abdominallesionsrevealsasoft-tissuedensitywithradi-atingstrandstypicallylocatedinthemesentericfat.MRIisthemodalityofchoiceforevaluatingextremityandsoft-tissuetumorsoftendemonstratingaheterogeneouspatternduetothemixedfibrousandcellularcomponents.Tumorsappearaslowin-tensitysignalsonT2-weightedimages.Linearextensionalongfascialplanesknownasthefascialtailsigniscommon.Ultrasoundcanbeusedtosurveyforrecurrenceortofollowlesionsintheextremitiesandabdominalwall.Appearanceonultrasoundisthatofahypoechoiclesionwithp

osterioracousticshadowing.Theyareoftenvascular,andafascialtailsignmayalsobeseenwiththismodality.Biopsyismandatorytoconfirmthediagnosisbeforetreatmentisdiscussed.Image-guidedcorebiopsiesaretherecommendedapproachwithultrasoundbeingusefulinperformingbiopsyofsoft-tissuelesionsandCT-guidedbiopsyforintra-abdominaldisease.Pathologicallydesmoidfibromatosisappearsasalowcellularityproliferationoffibroblastsandmyofibroblaststhatareinfiltrativeintosurroundingtis-sues.Thedifferentialdiagnosisofdesmoidtumorsincludesscartissue,low-gradefibromyxoidsarcoma,nodularfasciitis,andotherbenignfibroblastproliferations.Immunohistochemicalstainsaidinconfirmingthediagnosis.Inparticularintranuclearstainingof-cateninhasbeenshowntobepositivein67%to80%ofcases.Aspre-viouslymentioned,thesetumorsalsostainstronglypositiveforestrogenreceptorCyclooxygenase-2expressionmayalsobepresentandcanbeusefultodeterminedesmoidfromhealingscar.TREATMENTThemanagementofdesmoidtumorshastraditionallybeenasurgery-firstapproach.Forpatientswherebysurgicalremovalwouldleadtosignificantmorbidityorlesionsthatareunresectableoninitialpresentation,thereareseveralnonoperativestrategies.Grignoletal Arecentdevelopmentinmanagementincludeswatchfulwaitingasaninitialapproach,asstudieshaveshown50%progression-freesurvival(PFS)aswellasspontaneousregressionoftumorswithnotreatment.Becauseofthecomplexityofmanagementandthevarietyoftreatmentoptionsasoutlinedlater,treatmentrecommendationsarebestdeterminedinamultidisciplinarysetting.Widelocalexcisionwithnegativemarginshasbeenthestandardtreatmentofdes-moidtumors.Thistreatmentcanprovetobechallengingbecauseoftheinfiltrativena-tureofthesetumors.Retrospectivestudieshaveshownrecurrenceratesformarginnegative(R0)resectionrangingfrom16%to22%and19%to48%formicroscopicallypositivemargin(R1)resection.22,23,33–35Thefrequencyofrecurrencesaftersurgicalresectionhasledtomultiplestudiesthathaveevaluatedmarginstatusasaprognosticindicatorofrecurrence.Whenexaminingtheprognosticsignificanceofmicroscopicmarginstatus,thedataaremixed;somehavefoundittobesignificantlyassociatedwithrecurrence-freesurvival,whereasothershaveshownnoprognosticsignificancewhencomparingR0versusR1resectionsindesmoidtumors(Table19,33,36–38studyfromtheMDAndersonCancerCentercompareddesmoidoutcomesfrom2 Table1SelectedstudiesevaluatingR0versusR1asprognosticfactorforrecurrenceindesmoidtumorAuthorNo.PatientsTumorTypesUnivariateMultivariateMullenetal177Intra-abdominalandExtra-abdomin

alHR0.42(95%CI0.22–0.79)HR0.39(95%CI0.19,0.82)Gronchietal203Extra-abdominal—PrimarytumorsHR0.76(95%CI0.31,1.88),recurrenttumorsHR1.92(95%CI0.80,4.64)Bertanietal62Intra-abdominalandExtra-abdominal—HR2.94(95%CI0.47,18.20)Huangetal198Extra-abdominalandabdominal—HR3.11(95%CI1.40,6.93)Pengetal,211Intra-abdominalandExtra-abdominalHR2.16(95%CI1.17,4.01)HR1.51(95%CI0.85,2.66)Cragoetal495Intra-abdominalandExtra-abdominalHR1.18(95%CI0.78,1.80)HR0.99(95%CI0.65,1.52)vanBroekhovenetal132Extra-abdominalHR1.22(95%CI0.38,3.90)Spearetal,107Extra-abdominalNSHR3.00CI,confidenceinterval;HR,hazardratio.ManagementofDesmoids distincttimeframes:thefirstis1965to1994andamoremoderncohortfrom1995to2005.Interestingly,marginstatuswasasignificantpredictorofdiseaserecurrenceintheoldercohortbutthatsignificancewaslostinthemoderncohortdespitesimilarratesofmarginpositiveresectionsbetweenthetwogroups(46%vs47%).atingthecurrentdata,itisnotclearthatrecurrenceratesaresignificantlydifferentwithmicroscopicallypositivemargins.TheinabilitytoclearlydefinemarginstatusasaprognosticfactorhasledtotherecommendationthateffortshouldbemadetoperformanR0resectionbutnotattheexpenseoforganorlimbfunction.Re-resectionforrecurrentdiseasehassimilarcureratesasthoseachievedforprimaryresection,eveninmultiplyrecurrentpatients.Thus,forrecurrentdiseasethatistechnicallyresectablewithoutunreasonablemorbidity,surgeryshouldstillbeofferedasaviableoptionforcure.Frozen-sectionanalysishasbeenusedtohelpimprovemarginclearance.39,41ItisnotclearwhetherthistechniquehasledtoimprovedR0resectionrates.Incasesofrecurrenceitisdifficulttodistinguishdesmoidfibromatosisfromscaronfrozensec-tion.Basedonthesefindings,theuseofintraoperativefrozen-sectionanalysisisnotrecommendedforconfirmationofmarginnegativeresection,asitisunreliable.Thesurgicalchallengesofdesmoidtumorsextendbeyondtheirinfiltrativenatureandabilitytoadequatelyobtainclearmargins.Removalofthesetumorsintheabdom-inalwallorextremitylocationscanleavelargeanatomicdefects.Thegoalintheselo-cationsistorestoreskinandmusculofascialintegrity.Thisrestorationoftenrequiresmyocutaneousflapsand/ormeshfortheabdominalwall.Thesafetyofmeshclosurewasdemonstratedinastudyof50patientswithabdominaldesmoidtumor.AlthoughmorethanhalfhadanR1resection,therecurrenceratewaslowat8%andrepairsweredurable.Forthosetumorsthatextendintotheintra-abdominalspace,caremustbetakentoclosetheperitoneumtopreventfistulas;alternativelystagedrecon-structionwithbioprosthet

icmeshmaybeappropriate.Forextremitytumorslimb-salvageisthestandard.Inareviewof15patientswhowouldrequireamputationforresectionoflimbrecurrence,patientsweretreatedwithavarietyofadjuvanttherapiesaswellasobservationalone.Noonedevelopedsignificantdiseaseprogressionrequiringamputationsupportingtherecommendationthatfunction-preservingman-agementissafe.TumorsoftheextremitynotamenabletoR0resectionduetoneu-rovascularinvolvementcanoftenberesectedinanR1fashionusingadjuvantsystemictherapyorradiationtohelpachievelocalcontrolandavoidamputation.Multidisciplinarysurgicalapproaches,includingplasticandreconstructivesurgery,areimportantinpreoperativeplanning.Regionaltherapywithisolatedlimbinfusionorperfusionhasbeenusedinavarietyofskinandsoft-tissueextremitytumorstocon-troldiseasewhileavoidingamputationwhenothermoreconservativeapproacheshavefailed.Theuseoflimbperfusionwithtumornecrosisfactoralphaandmelphalanindesmoidtumorshasbeendescribedandledtoaresponsein19of28treatmentsinacohortof25patients.Limbpreservationwasachievedinallbut3patients.techniqueseemstobeaviableapproachforsymptomatic,progressivetumorsoftheextremity.Givenalloftheaforementionedinformation,amputationisstillappro-priateinaselectgroupofpatients,includingthosewithintractablepain,lossoffunc-tionoftheextremity,orcomplicatedwounds.Intra-abdominaltumorspresentaseparatesetofchallenges,particularlythoselocatedinthemesenteryofthebowel.Proximitytothesuperiormesentericarteryandveinmaylimitresectability.Effortstoobtainhistologicallynegativemarginscanleadtosignificantlossofbowellengthanddoesnotimproverecurrenceratesorover-allsurvival.Surgicalbypassmaybepreferableinsymptomaticpatientswithexten-sivevascularinvolvementinanefforttolimitmorbidityandmortality.Grignoletal Historicaldatahavesuggestedthatrecurrenceratesforintra-abdominaltumorsinpatientswithFAPwerehigherthanthosewithsporadicdisease;however,morerecentdatasuggestthatthereisnodifference.ThepropensityfortheFAPpopulationtodevelopmesenterictumorsthatarediffuseanddifficulttoresectmaybethereasonforpreviousfindings.Withmoremodernsurgicalandnonsurgicalstrategies,thealgo-rithmforpatientswithFAPisthesameasthosewithsporadicdisease.Treatmentde-cisionsshouldbemadeinthecontextofamultidisciplinaryreviewandusemultimodalitytherapywithsurgeryreservedforthosewithimpendinglossofcriticalstructuresorsymptoms.Surgicalresectionwithwidelocalexcisioncanachievecureorlocalcontrolofdis-easeformostdesmoidtumors.Thegoalofsurgicalresection

shouldbeamarginnegativeresectionwiththepreservationoffunctionofsurroundinginvolvedorgansandstructures.SystemicTherapyBecauseofthepropensityforrecurrenceandthemorbidityofrepeatresections,therehasbeenamultitudeoftherapiesusedtotreatdesmoidtumorseitherintheadjuvantsettingorasdefinitivetreatment.Traditionallytheuseofsystemictherapyhasbeenintheunresectable,recurrent,orprogressingdesmoidtumors;butthisischanging.HormonalandnonsteroidalantiinflammatorydrugsAntiestrogenagentsandNSAIDsareconsideredfirst-lineagentsbecauseoftheireffectivenessandrelativelylowside-effectprofile.2,38,46–48Basedontheobservationthatmanydesmoidtumorsstainstronglypositiveforestrogenreceptor,theuseofantiestrogentherapymayhaveabiologicalbasis.Themostcommonantiestrogenagentsaretamoxifenandraloxifene.Responseratestotheseagentsareapproxi-mately40%to51%.SulindacisthemostcommonlyusedNSAID.TheresponseratetothisNSAIDisapproximately28%.Toimproveresponserates,hormonaltherapiesandNSAIDsaretypicallyusedincombination.Areportof134patientstreatedwithbothanantiestrogenagentandsulindacachievedan85%responseratewhenusedaseitheradjuvantordefinitivetherapy.Inpatientswhohadpreviouslybeenresected,therapycouldeventuallybetaperedwithonlyonelong-termrecurrence.Thisgroupcontainedpatientswithspo-radicandFAP-relatedtumors.Thehighresponserateanddurabilityisencouragingfornonsurgicalmanagementofthesetumors.However,anobjectiveresponsemaytakeseveralmonthstoachievestabilityofdiseaseanddecreaseinassociated46,47,50Theresponserateofchemotherapyindesmoidtumorshasbeenreportedtobeashighas79%.SimilartohormonalandNSAIDtherapy,timetoresponsecanbevariable.Becauseoftheassociatedsideeffects,chemotherapyisgenerallyconsideredsecond-linesystemictherapy.Forthosewithrapidlyprogressivedisease,impendingdestructionofcriticalanatomicstructures,orsymptomatic,unresectabletumors,itshouldbeconsideredasafirst-linetherapy.20,47,51–53Combinationsusinganthracyclinesseemtobethemosteffective.Othercommonlyusedagentsincludemethotrexate,vinblastine,andcisplatin.Anthracycline-basedregimenshaveresultedinlongPFSandevencompletere-sponses.InaretrospectivestudybytheFrenchSarcomaGroupevaluatingtheroleofchemotherapyindesmoidtumors,responseratesfavoredanthracycline-basedregimenscomparedwithothersystemictherapies(54%vs12%.0011).TheManagementofDesmoids anthracyclinegroupcontainedonly13patients;allexperiencedstabledisease(46%)orapartialresponse(PR)(54%).OthershaveconfirmedtheseresultswithaPFSof74monthsinanthr

acycline-basedtherapy.Toxicityishigherwiththisregimenresultingingrade3to4hematologicaltoxicitiesinapproximately31%to43%ofpa-Cardiotoxicityisaconcernforthisregimenparticularlybecauseoftheyoungpatientpopulation.Apegylatedliposomalformulationofdoxorubicin,whichim-provesdrugdeliverywithdecreasedcardiotoxicity,hasbeenreported.AsmallserieshasshownsimilarefficacyasallpatientshadeitherPR(36%)orstabledisease(64%)withdecreasedtoxicity.Anothercommonlyusedregimenfordesmoidsistermedlow-dosechemotherapy,whichconsistsofmethotrexateandvinblastine.Thisregimenhasconsistentlyresultedinstableorrespondingdiseasein67%to100%ofpatientstreated.Low-dosechemotherapyhasbeenassociatedwithadurableresponseand5-yearPFSashighas67%.Similartoanthracycline-basedregimens,toxicityresultsinpa-tientintoleranceanda50%attritionrate.Neurotoxicityrelatedtovinblastineisthemostcommonsideeffectresultinginpatientintolerance.AnotherVinkaalkaloid,vinorelbine,hasbeendescribedasaneffectivealternativetovinblastinewithlesslong-termneurotoxicity.Thisalkaloidisalsogivenwithmethotrexateandmaybeausefulregimeninpatientswhodonottoleratevinblastine.TargetedtherapyThetyrosinekinaseinhibitors(TKI)havebeenusedforthetreatmentofdesmoidsresultinginstabilityofdisease,limitedtoxicity,butlowresponserates.AphaseIItrialusingimatinibreporteda1-yearPFSof66%butanobjectiveresponserateofonlyInaheavilypretreatedgroupofpatientsusinghigherdosesofimatinib,Heinrichandcolleaguessawa15.7%PRrate(50%tumorshrinkage).Thedurationofresponsewasgreaterthan1.5yearsforallpatients.InathirdphaseIItrialusingima-tinibpatientsexperiencedprogressionfreesurvivalof67%at1year.Toxicityforall3ofthesetrialswasacceptablewithveryfewgrade4toxicities,whichweretreatedeffectivelywithdosereduction.InadditiontothesephaseIItrials,othersmallretro-spectivereviewshaverevealedstableorPRin36%to80%ofpatientstreatedwithTKIandamedianPFSofnearly27monthsbyResponseEvaluationCriteriainSolidTumors(RECIST)criteria.Sunitinib,anotherTKIthatalsoblocksvascularendothelialgrowthfactorreceptors,hasalsobeeninvestigatedforuseinthetreatmentofdesmoidtumors.AphaseIIstudyshowedanoverallresponserateof26.3%anda2-yearPFSrateof74.7%.Importantly,3ofthe12patientswithmesentericdiseasedevelopedseriousadverseeventswiththefirstdoseoftreatment,whichpresentedastumorbleeding,bowelperforation,andentero-tumoralfistulaformation.Theinvestigatorspostulatethatalloftheseeventscouldbeexplainedbythedrugsantiangiogenicaffectwithresultanttumornecrosis.Alth

oughthisreportmaysignifysunitinibasapotenttreatmentofdesmoids,thesignificanceofadverseeventswiththistherapyshouldbenoted.OtherTKIandantiangiogenicdrugsthathavebeenevaluatedandshowntohaveefficacyintreatingdesmoidtumorsaresorafenibandpazopanib.Inaretrospec-tivereviewof26patientstreatedwithsorafenib,70%ofpatient-reportedimprovedsymptomsand95%ofpatientshadeitheraPRorstablediseaseat6months.Followingtheresponseseenfromsorafenib,theantiangiogenicdrugpazopanibhasalsoshownpromiseasapotentialoptionintreatingdesmoidtumors.Twocasere-portsshowthatpatientstreatedwithpazopanibhadimprovedsymptoms,tumorshrinkage,anddecreasedtumorcellularitysimilartoresultsseenwithsorafenib.Grignoletal Conclusionsregardingthesedrugs’efficacymustbeinterpretedwithcautionuntillargerprospectiveclinicaltrialsareperformedtovalidateinitialfindings.NoveltherapiesTherapiesareevolvingasnewinformationemergesonthepathophysiologyofdesmoidtumors.TheNOTCHpathwaydrivesseveralcancer-relatedprocessesinsolidtumorsandhasrecentlybeenrecognizedasapotentialtherapeutictargetindesmoidtumors.Itcanbeblockedby-secretaseinhibition.Desmoidtumorcelllinestreatedwithasecretaseinhibitorshoweddecreasedcellgrowth,migration,andinvasion.Inanopen-labelphaseIdose-escalationtrialofa-secretaseinhibitor,5of7patientswithdes-moidtumorsthatweretreatedshowedanobjectiveresponserateof71.4%withsomepatientsachievingdurableresponse.ThesepromisingearlydatahaveledtoanongoingphaseIItrial.Recentlyanothertarget,hyaluronan(HA),aglycosaminoglycaninthestro-malmicroenvironmentinvolvedwithnormalwoundhealing,hasalsobeenassociatedwithdesmoidtumorigenesis.HAlevelswereshowntobeoverexpressedindesmoidtu-morsurgicalspecimensaswellasinimmortalizedcelllines.ByusinganinhibitorofHA,tumorproliferationratesaswellasHAlevelsweredecreased,suggestinganovelthera-peutictargetintreatingdesmoidfibromatosis.Asthepathwaysindesmoidtumorigenesisareelucidated,noveltherapeutictargetswillcontinuetoemerge.RadiationTherapyTheuseofradiationtherapyindesmoidtumorshasbeenevaluatedinseveralsettings.Ithasbeenusedasadjuvanttherapyformarginpositiveresectionsandtodecreaserecurrenceofcompletelyresectedtumors.Radiationhasalsobeenusedsuccessfullyasadefinitivetreatmentofunresectabletumorsorfortumorswherebyresectionwouldbeassociatedwithunacceptablemorbidityorfunctionaldeficit.Inalargemeta-analysisof22studiesevaluatingpatientstreatedwithsurgery,surgeryplusradiation,orradiationalonerevealedasuperiorlocalcontrolratewithradiationorradi

ationplussurgery(78%and75%,respectively)thanpatientstreatedwithsurgeryalone(61%).Theinvestigatorssuggestedthatallpatientswithdesmoidbetreatedwithradiation.However,theradiationdosesinthisstudywerehighlyvariable;thisrecommendationdoesnottakeintoconsiderationthemorbidityassociatedwithradiation.Complicationratesrelatedtoradiationfordes-moidfibromatosisare17%to23%.21,69,70Radiation-inducedmalignanciesareparticularlyrelevantinadiseasethatoftenaffectsayoungercohortofpatients.Inamorerecentsingle-institutionretrospectivereviewof95patients,investigatorsfoundnodifferenceintherateofrecurrenceforsurgeryalone(14.8%),radiationalone(15.4%),andsurgeryplusradiation(32.1%)(.300).Therewasalsonoas-sociationbetweenlocalcontrolandradiationtherapyinthosepatientswithapos-itivemargin.Theydidfindthattheheadandnecklocationwasassociatedwithincreasedrecurrenceintheirpatientpopulation.Theinvestigatorsconcludedthatasubsetofpatientswithhighriskforlocalfailurecanbeidentifiedthatmaybenefitfromadjuvantradiation,includingthosewithheadandnecklocation,recurrentdis-easeaftersurgery,andpossiblythosewithpositivemargins.Althoughthereseemstobearealbenefitofradiationforsomepatients,thetrueutilityofradiationasanadjuvanttherapyindesmoidfibromatosishasnotbeenevaluatedinaprospective,randomizedtrial.Moststudiesaresmall,retrospective,anddonothavestandard-izationofpatientselection.Becauseofthelackofclearlydefinedindicationsforra-diation,itiscriticaltomakethesedecisionsinlarge-volumemultidisciplinarycenterstoproperlyselectpatientstooptimizebenefitandavoidunnecessaryexpo-sureandmorbidityfromthistreatment.ManagementofDesmoids Definitiveradiationseemstobeaseffectiveassurgeryforthosethatwouldother-wiseneedradicalanddisfiguringsurgery.Radiationastheprimarymodeoftherapyforunresectablediseaseoffersa70%to80%chanceoflocalcontrolinretrospective21,72,73TheEuropeanOrganizationforResearchandTreatmentofCancerconductedaphaseIIstudythatstandardizedtreatmentof44patientswithunresect-ablediseaseto56Gyreceivedin28fractions.At3years,localcontrolwas81.5%with13.6%ofpatientshavingacompleteresponse.Notably,radiationresponsewillcontinuebeyond3yearsinsomepatientspromotingthedurabilityofthistherapyforunresectabledisease.Forpatientstreatedunsuccessfullywithdefinitiveradia-tion,surgeryorsystemictherapymaybeanoptionassalvagetherapy.Theuseofradiationfordesmoidtumorsinaneoadjuvantsettinghasnotbeeninves-tigatedinatrialbuthasbeenreported.Theproposedbenefitwouldbeforthosepa-tients

whoareinitiallydeemedunresectableorwhenaresponsewouldallowpreservationofcriticalstructuresdecreasingthemorbidityofsurgicalresection.Becauseofthesmallnumbersofpatientstreatedwithneoadjuvantradiationfollowedbysurgery,itisdifficulttoevaluatethetruebenefitofthisapproach,althoughitseemstobesimilartoeithermodalityalone.Radiationhasalsobeenusedincombinationwithchemotherapyintheneoadjuvantsettinginsmallseriesandwasassociatedwithacontrolrateof85%to90%.WatchfulWaitingTheheterogeneousnatureofdesmoidshasledtoavarietyoftherapiesusedtotreatandcontrolthedisease.Inmanylargedatabases,therearepatientswhoreceivenotreatmentoftheirtumorsbuthaveshownnoprogressionandsometimesevenspon-taneousregression.Whileevaluatingthebestinitialtherapyforprimarydesmoidtu-mors,Bonvalotandcolleaguescomparedagroupofpatientswhoweretreatednonsurgicallywiththosewhounderwentsurgeryastheirinitialtherapy.Three-yearevent-freesurvivalwassimilarbetweenthegroups(68%nosurgeryvs65%surgery).Thenonsurgicalgroupincludedmedicallytreatedpatientsandpatientswhounder-wentobservationonly.Tounderstandthisobservationfurther,amulti-institutionalstudytoevaluatethewait-and-seeapproachwasundertaken.Patientswerestratifiedintoanobservationgrouporamedicaltherapygroupfromaprospectivedatabase.Inthe83patientstreatedwithobservation,the5-yearPFSwas49.9%,whichwasnotdifferentfromthe58.6%PFSinthe59medicallytreatedpatients.Significantprog-nosticfactorstoidentifyprogressionwerenotidentified.Whenprogressionoccurred,itwasinthefirst2yearsformostpatients(89%).Basedonthesefindings,theinves-tigatorshaveproposedclosediseasesurveillancefor24months.ThesedataledtoseveralnotableEuropeangroupsdevelopingproposalstostandardizedesmoidtumormanagementsuchthatawatchful-waitingstrategyisthefirststepforallnewtu-Patientswillbefollowedcloselybyamultidisciplinaryteam,withescalationofcareonlyifthetumordeclaresanaggressivephenotypeandsparepatientswithindolenttumorsthemorbidityofaggressivetherapy(Fig.2Thisapproachshouldnotbeconfusedwithdoingnothingandmaynotbeappro-priateforeverytumor.Itrequiresclosefollow-upandmonitoringofthediseasewithappropriateimagingbasedontumorlocation.Therecommendedimagingscheduleiseverymonthfor2months,every3monthsforthefirstyear,thenevery6monthsupto5years,andyearlythereafter.Itismostappropriateinpatientswithtumorsthatareasymptomaticandfreeofanatomicallycriticalstructures.Forthosewithtu-moradjacenttocriticallyimportantanatomy,frequentimagingiscriticalsoastonotloseanoperativew

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