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0I-.043-TM DoVariationsinTreatmentofDuctalCarcinomainSituAffectOutcomes? by HeatherTaffetGold SubmittedinPartialFulfillment ofthe RequirementsfortheDegree DoctorofPhilosophy Supervisedby ProfessorJackZwanziger DepartmentofCommunityandPreventiveMedicine TheSchoolofMedicineandDentistry UniversityofRochester Rochester,NewYork 2002 11 CurriculumVitae HeatherTaffetGoldwasborninLosAngeles,CaliforniaonMay27,1970. SheattendedtheUniversityofCaliforniaatSanDiegofrom1988to1992and graduatedwithaBachelorofSciencedegreeinBiologyin1992.Shethenattended theUniversityofChicagofrom1992to1994andgraduatedwithaMasterofArts degreeinpublicpolicystudiesin1994.Ms.GoldcametotheUniversityof Rochesterinthefallof1998andbegangraduatestudiesinhealthservicesresearch andpolicy.ShereceivedaNationalResearchServiceAwardTraineeFellowshipin 1998and1999andaHealthCareFinancingAdministrationDissertationFellowship in2001.Shepursuedherresearchinhealthservicesresearchandpolicyunderthe directionofProfessorJackZwanzigerandwiththeguidanceofhercommittee members,ProfessorsAndrewDick,CharlesPhelps,andJenniferGriggs. Ill Acknowledgements Thisthesiswouldhavebeenmuchhardertofinishifitweren'tforsome incrediblepeople.Firstly,mydissertationadvisor,JackZwanziger,PhD,hasbeena greatmentorandprovidedmuchguidanceforthiswork.Hekeptmeontrackand well-focused.Mycommitteemembershavealsobeenterrific,andIamgratefulfor theirguidance.AndrewDick,PhD,spenthoursteachingmetheeconometric modelingandStataprogrammingrequiredfortheanalysesandhelpedmehavea senseofhumoraboutthedissertationprocess.JenniferGriggs,MD,MPH,offered herclinicalexpertiseandprovidedmewith"real-life"experiencessoIcouldsee whatpatientsactuallyfacedbecauseoftheirdisease.Andfinally,CharlesPhelps, PhD,hasseenthe"bigpicture"allalongandprovidedtimelyfeedbackandgreat adviceduringthischallengingendeavor.Iamindebtedtomycommitteeforallthe timetheygaveme. IamsoappreciativeofthedissertationfellowshipgrantIreceivedfromthe HealthCareFinancingAdministration(HCFA),nowtheCenterforMedicareand MedicaidServices(CMS),oftheUSDepartmentofHealthandHumanServices. IacknowledgetheeffortsrequiredtolinktheSEERdatabasewiththe Medicareclaimsdata,includingtheworkoftheAppliedResearchBranch,Division ofCancerPreventionandControl,NationalCancerInstitute;theOfficeofResearch andDemonstrationsatHCFA;andInformationManagementServices,Inc.. Finally,Iamgratefulforthesupportofmydearhusband,JeffreyTaffet,who helpedmekeepabalanceinlifeespeciallythroughroughspots. IV Abstract Ductalcarcinomainsitu(DCIS)isanoninvasiveformofbreastcancerwitha distinctdiseasepathologyandnaturalhistorycomparedtoinvasivebreastcancer.Its incidencehasincreasedsincethewidespreaduseofscreeningmammography. Earlierdetectionofthediseaseandchangingtreatmentpatternsforearlyinvasive breastcancerhaveledtotreatmentchangesforDCISwithoutanunderstandingof thenaturalhistoryofDCIS.ThelackofinformationonthenaturalhistoryofDCIS hasledtodoubtsaboutthebestwaytotreatitandhasgivenrisetosubstantial variationsintreatmentpatternsforthedisease. Theoverallobjectiveofthisprojectistoexaminetheeffectsofgeographic andtemporalvariationinthetreatmentofwomendiagnosedwithunilateralDCIS. Thestudywilltesttwomajorhypotheses:(1)thereisstatisticallysignificant geographicandtemporalvariationinthetreatmentofwomenwithDCIS,bothin typeofsurgery(mastectomyorbreast-conservingsurgery)anduseofradiotherapy; and(2)variationintreatmentofDCIShasconsequencesforratesofrecurrenceof DCISanddevelopmentofsubsequentinvasivebreastcancer. ThisresearchisbasedondatafromtheSurveillance,EpidemiologyandEnd Results(SEER)programlinkedwithMedicareclaimsdatafrom1991-1998,the DartmouthAtlasofHealthCareintheUnitedStates,andUSCensusdata.The longitudinal,observationalstudyuseseconometricmethodstoadvancethefieldof measuringgeographicvariationandtoanalyzetheimpactoftreatmentchoice,region effects,andsocioeconomicfactorsonpatientoutcomesforwomenages65and older. Geographiclocationandyearofdiagnosisaresignificantpredictorsof treatmentchoiceforDCIS,indicatinggeographicandtemporalvariationintreatment patterns.Theresultsoftheoutcomesanalysisstronglysuggestthattreatmentof DCISwithmastectomyorbreast-conservingsurgery(BCS)withradiotherapyare muchbetterthanwithBCSalone.Disease-freesurvival6yearsafterdiagnosisand treatmentbymastectomyorBCSwithradiotherapyis96%comparedto86%for BCSalone.TreatmentwithmastectomyorBCSwithradiotherapyproducessuperior outcomescomparedtoBCSalonewhichistheworstintermsofdisease-free survival. VI TableofContents page ListofTables vii ListofFigures ix Chapter1 Background 1 Introduction 1 BackgroundandSignificance 2 Summary 18 Chapter2 DataandMethods 19 Data 19 Methods 32 Software 48 Chapter3 Results 49 GeographicVariationsResults 49 OutcomesAnalysisComparingBCS,BCSwith 62 Radiotherapy,andMastectomy Chapter4 Discussion 78 TreatmentOutcomes 78 VariationsinTreatmentChoice 82 DataLimitations 86 ModelLimitations 90 AreasforFutureWork 91 Conclusion 92 References 94 AppendixA ComorbidityIndices 107 AppendixB OutcomesAnalysisofMastectomyOnly 110 . Vll ListofTables page Table2-1. DataandExclusionsforInitialSampleofCasesandfor 21 AnalyticSamplesofLinkedSEER-MedicareData,1986- 1998. Table2-2. MedicareClaimsandSEERCodesUsedtoDetermine 25 InitialTreatment. Table2-3. MedicareClaimsCodesUsedtoDetermineSubsequent 28 BreastEvents. Table2-4. HypothesizedEffectsofVariablesonProbabilityof 38 ChoosingBCS,BCSwithRadiotherapy,orMastectomy, 1991-1996. Table2-5. HypothesizedEffectsofVariablesonDCISTreatment 47 Outcomes,1991-1998. Table3-1 InitialTreatmentTypeandComparisonofMeansof 55 DemographicFactorsforGeographicVariationsAnalysis BasedonLinkedSEER-MedicareDatabase,1991-1996. Table3-2. MultinomialLogitModelCoefficientEstimatesfor 57 ProbabilityofTreatmentChoiceComparedtoBreast- conservingSurgeryAlone,1991-1996. Table3-3. PredictedPercentageUseofInitialTreatmentforDuctal 59 Carcinomainsitu,basedonLinkedSEER-Medicare Database,1991-1996. Table3-4. ObservedSampleStandardErrorsandConfidenceIntervals 60 forProbabilityofChoosingTreatmentOptionObtainedby Bootstrapping400Times. Table3-5. InitialTreatmentTypeandSubsequentBreastEventsfor 64 WomenDiagnosedwithDCISinFinalOutcomes-Analysis SamplefromLinkedSEER-MedicareDatabase,1991-1996. Table3-6. InitialTreatmentTypeandComparisonofDemographic 65 FactorsforOutcomesAnalysisbasedonLinkedSEER- MedicareDatabase,1991-1996. Vlll Table3-7. CoefficientEstimatesfromSemiparametricOutcomes 69 ModelwithIndicatorsforEachTimePeriod. Table3-8. CoefficientEstimatesfromSemiparametricOutcomes 71 ModelwithParametricDuration. Table3-9. PredictedProportionofSubsequentBreastEventsandof 72 Disease-freeSurvivalfromPeriod-to-Period,Conditionalon HavingNoSubsequentBreastEventinPriorPeriodand BasedonMeanValuesofCovariates. Table3-10. DifferencesinSurvivalCurves,BasedonOutcomesModel 77 withParametricDurationandaStandardizedPopulation, Bootstrapped100Times. TableA-l. ConditionCoefficientsforComorbiditiesDerivedfrom 109 MedicareClaimsDatafortheBreastCohort. TableB-l. DescriptiveStatisticsofDemographicFactorsforOutcomes Ill AnalysisforMastectomyOnlybasedonLinkedSEER- MedicareDatabase,1986-1996. TableB-2. CoefficientsforSemiparametricMastectomy-OnlyModel 113 withIndicatorsforEachTimePeriod,1986-1998. TableB-3. CoefficientsforSemiparametricMastectomy-OnlyModel 114 withParametricDuration,1986-1998. TableB-4. HazardRatesandDisease-freeSurvivalafterMastectomy 116 Only,SemiparametricModels,1986-1998. .. IX ListofFigures page Figure3-1 StandardDeviationofTreatmentProbabilityAcross 61 Registries,byTreatmentStrategyandYear. Figure3-2. ProbabilityofSubsequentBreastEvent, 73 SemiparametricModelwithDurationIndicator Variables. Figure3-3. Disease-freeSurvival,SemiparametricModelwith 74 DurationIndicatorVariables. Figure3-4. ProbabilityofSubsequentBreastEvent, 75 SemiparametricModelwithSingleDurationVariable. Figure3-5. Disease-freeSurvival,SemiparametricModelwith 76 SingleDurationVariable. FigureB-1 ProbabilityofSubsequentBreastEventafter 117 MastectomyforDCIS,1986-1998. FigureB-2. Disease-freeSurvivalafterMastectomyforDCIS, 118 1986-1998. Chapter1 Background Introduction Ductalcarcinomainsitu(DCIS)isanoninvasiveformofbreastcancerwitha distinctdiseasepathologyandnaturalhistorycomparedtoinvasivebreastcancer. DCIStypicallypresentsasasymptomaticcalcificationsoflessthan10mmon mammography,andthepresumablymalignantcellsremainatthesiteoforigininthe ducts(1,2).Unlikeinvasivebreastcancer,DCISisnotassociatedwiththeriskof metastaticdisease.DCIS,bydefinition,doesnotinvadethebasementmembraneor metastasize.Thediseasecandevelopintoalocalinvasiverecurrenceinthebreast, however,thatcouldleadtobreastcancermetastasisandmortality(3). Approximately50%oflocalrecurrencesfollowingDCISdiagnosisandtreatmentare invasive(1),butthe10-yearriskofbreastcancerdeathislowatunder2%(4). ThetreatmentoptionsforDCISaresimilartothoseforearlybreastcancer: mastectomyorbreast-conservingsurgery(BCS)withorwithoutradiotherapyand morerecently,withorwithouttheadditionofhormonaltherapysuchastamoxifen. ThecontroversiesovertreatmentforDCISexistbecauseitisunclearwhichwomen mightdobetterafteratotalmastectomyormightbenefitfromradiotherapyin additiontoBCS.DCISisinterestingtostudybecauseofthedownstreammortality risksassociatedwithasubsequentbreastevent-thatis,arecurrenceofDCISor developmentofinvasivebreastcancer-andtheincreasingincidenceofthedisease (1),aswellasthequality-of-lifetrade-offsassociatedwiththedifferenttreatment