A population-based study of lung cancer in Norway – the importance of resection rate and factors associated with treatment and survival

ApopulationͲbasedstudyoflungcancerinNorway–

theimportanceofresectionrateandfactorsassociated withtreatmentandsurvival

YngvarNilssen,MSc PhDthesis

FacultyofMedicine UniversityofOslo

© Yngvar Nilssen, 2016

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-8333-258-2

All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard

Printed in Norway: 07 Media AS – www.07.no

Contents

Acknowledgements... ..4

Listofpapers... ...6

Abbreviations... ...7

Introduction... ...9

Background... ...9

Incidence,prevalenceandmortality...9

Aetiology... ...11

Anatomyandhistology...13

Treatment... ...14

Prognosticfactors...16

Survival... ...23

Aimsofthestudy... ....25

Materialandmethods...26

Datasources... ...26

Datalinkage... ...28

Classificationofvariables...29

Statisticalmethods...33

Mainresults... ...40

LungcancersurvivalinNorway(PaperI)...40

Lungcancertreatment(PaperII)...41

Resectioninrelationtosurvival(PaperIII)...41

Discussion... ...42

Overviewofresults...42

Methodologicalconsiderations...42

Discussionoftheresults...50

Conclusion... ...58

Futureperspectives...59

Errorsinpublishedpapers...61

References... ...62

PapersIͲIII... ...76

Acknowledgements

ThisprojectwasconductedattheCancerRegistryofNorway,InstituteofPopulationͲbasedCancer Research,inOslofrom2013to2016.Iamgratefultoeveryonewhohascontributedinanywayto myPhDthesis,butsomedeserveextraacknowledgement.

First,IwouldliketothanktheCancerRegistryofNorway,ledbyDirectorGiskeUrsin,forgivingme theopportunitytowritethisthesis.Theworkingfacilitieshavebeenexcellent.Iwouldalsoliketo thanktheSouthͲEasternNorwayRegionalHealthAuthorityforunderstandingtheimportanceofthis workthroughtheirgenerousfinancialgrant.

Iwouldliketothankmymainsupervisorandinitiatorofthisproject,BjørnMøller,forhis

outstandingsupervisionoverthelastthreeyears.Throughhisunderstanding,patienceandabilityto challengeme,aswellas,hiswillingnesstosharehissuperbexpertiseinthefieldofstatisticsand cancerepidemiology,BjørnhasbeenabletoguidemethroughthisperiodinawayIhavefoundto benothinglessthanperfect.Further,myquestionsandsuggestionshavealwaysbeenreceivedwith apositiveattitude,somethingIhaveappreciated.Icouldnothaveaskedforabettersupervisor.

ThankyoutomyprojectgroupthatconsistedofBjørnMøller,TrondͲEirikStrand,LarsFjellbirkeland, KristianBartnes,OddͲTerjeBrustugun(coͲauthoronPaperII),XueQinYuandDianneL.O’Connell.

ThiswellͲorganised,multiͲdisciplinarygroupconsistedofseniorepidemiologists,cliniciansand statisticianswhoallcontributedtothecontentofthisthesisbyprovidingconstructivefeedback,all withinreasonabletimeframes.

IwouldalsoliketothankCancerCouncilNewSouthWales,Australia,forhostingmefromOctober 2014toSeptember2015,andparticularlyProfessorDianneL.O’Connellforgrantingmywishtowork abroadasapartofmyproject.IamgratefulthatIcoulddiscussprojectchallengesandlearnfrom theexpertiseandknowledgesheandQinpossess.AnextrathankstoeveryoneintheHealthServices Researchgroup.Theyallwelcomedandincludedmeinawaythatwasoverwhelming,warm,and beyondeveryexpectationIhadformystay.

IwanttothankallmyfellowPhDstudentsattheCRNforalltheircontributionsthroughoutthe differentphasesofmyproject,forprovidingagoodworkingenvironmentinourteamͲoffice,andfor therelaxingchatsandbreaks.

ThankstothehousestatisticianTorÅgeMyklebustandtheStataͲexpertBjarteAagnesfor outstandingassistancetoanyandallstatisticalͲandStataͲrelatedchallenges.Theirhelphasbeen invaluable.

Finally,Iwouldliketothanktomydearestfamilyandfriendsforalwaysbelieving,motivatingand supportingme,evenattimeswhenIstruggledtoseethelightattheendofthetunnel.

Listofpapers

PaperI:

Y.Nilssen,T.E.Strand,L.Fjellbirkeland,K.Bartnes,B.Møller.LungcancersurvivalinNorway,1997–

2011:fromnihilismtooptimism.EuropeanRespiratoryJournal2016Jan;47(1):275Ͳ87.

PaperII:

YngvarNilssen,TrondͲEirikStrand,LarsFjellbirkeland,KristianBartnes,OddTerjeBrustugun,Dianne LO’Connell,XueQinYu,BjørnMøller.Lungcancertreatmentisinfluencedbyincome,education,age andplaceofresidenceinacountrywithuniversalhealthcoverage.InternationalJournalofCancer 2016Mar15;138(6):1350Ͳ60.

PaperIII:

YngvarNilssen,TrondͲEirikStrand,LarsFjellbirkeland,KristianBartnes,DianneLO’Connell,XueQin Yu,BjørnMøller.Resectionratesandregionaldifferencesinsurvival:anationalpopulationͲbased studyofnonͲsmallcelllungcancerinNorway.[Submitted]

Abbreviations

ALK–Anaplasticlymphomakinase

CCI–Charlsoncomorbidityindex

CI–Confidenceinterval

CRN–CancerRegistryofNorway

cTNM–Clinicaltumour,node,metastasis

EGFR–Epidermalgrowthfactorreceptor

EOD–Extentofdisease

Gy–Gray

HR–Hazardratio

ICDͲOͲ3–InternationalClassificationofDiseaseforOncology,3^rdEdition ICDͲ10–InternationalClassificationofDisease,10^thEdition

MAR–Missingatrandom

MCAR–Missingcompletelyatrandom

MNAR–Missingnotatrandom

NPR–NorwegianPatientRegister

NSCLC–NonͲsmallcelllungcancer

PET–Positronemissiontomography

pTNM–Pathologicaltumour,node,metastasis

SBRT–Stereotacticbodyradiationtherapy

SCC–Squamouscellcarcinoma

SCLC–SmallͲcelllungcancer

SES–Socioeconomicstatus

SSB–StatisticsNorway

TNM–Tumour,node,metastasis

Introduction

Background

Lungcanceristhemostcommoncancerintheworldwith1.8millionnewcasesin2013,which accountsfor13%ofallnewcancerdiagnoses(1).Therehasbeenalotofstigmatisationrelatedto lungcancer,andanihilisticattitudecharacterisedthefieldforyears(2Ͳ5).However,anindicationof anupwardtrendinsurvivalhasbeenobservedinNorway(6).Therelationshipsbetweenprognostic factorsandsurvival,aswellas,predictorsandtreatment,havepreviouslybeenreportedbystudies thathaveusedselectedgroupsoflungcancerpatients,orhospitalmaterials(7Ͳ10).Therefore,the presentprojectwasinitiatedbytheCancerRegistryofNorway(CRN),withfundingfromtheSouthͲ EasternNorwayRegionalHealthAuthority,touseanationalpopulationͲbasedmaterialto(i)study prognosticfactorsandtheimprovementinlungcancersurvivalinNorway,(ii)describepredictorsfor treatmentforlungcancerand(iii)exploretherelationshipbetweenresectionratesandsurvival, whilestudyinggeographicalvariation.

Incidence,prevalenceandmortality

InNorway,3019newlungcancercases(9.5%ofallnewcancers)werediagnosedin2014,making lungcancerthethirdmostcommoncancertype,afterprostateandbreast(6).Lungcanceristhe mostcommoncauseofdeathfromcancerworldwide,responsibleforapproximately1.6million deathsin2013(1).InNorway,lungcancerwasresponsiblefor2158deathsin2014,whichismore thanprostatecancerandbreastcancerdeathscombined,anditwasalsoresponsibleforalmostas manyyearsoflifelostascolon,breastandprostatecancerscombined(6,11).

Figure1:AgeͲstandardisedlungcancerincidence(C33Ͳ34)intheNordiccountries(excl.Iceland) amongmenandwomen.

Footnote:SwedishratesarenotdirectlycomparabletothosefromtheotherNordiccountries,since theCancerRegistryofSwedendoesnotincludeinformationaboutcancerpatientsdiagnosedbased ondeathcertificateonly.Source:NordCan(12,13).

Historically,theageͲstandardisedincidenceratesamongmenwithlungcancerinNorwayreacheda plateauinthe1990s,whichwas10yearsand20yearsaftertheobservedpeaksinDenmarkand Finland,respectively(Figure1).Forwomen,theoverallincidenceisstillincreasingandthetrendin NorwayissimilartothatinDenmark,butsteeperthanthoseobservedinSwedenandFinland.When comparingNordiclungcancerincidencetrendsstratifiedbyageͲgroups,adecreasingtrendwas observedinwomenunder65,andmenunder80,whiletheincidencecontinuedtoincreaseamong olderfemalepatients(12,13).ArecentstudyalsoshowedthatlargedifferencesinageͲspecificlung

0 10 20 30 40 50 60 70 80 90

rate per 100 000

194 3

1953 196

3 197

3 1983

1993 200

3 201

3 Year of diagnosis

Men

0 10 20 30 40 50 60 70 80 90

rate per 100 000

1943 195

3 196

3 1973

198 3

199 3

2003 2013 Year of diagnosis

Women

Sweden Norway Finland Denmark

cancerincidencedoesexistbetweencountiesinNorway(14).Sincelungcancerisalethaldisease, themortalityratefollowstheincidencerateclosely,withanoverallestimatedmortalityͲtoͲincidence ratioof0.91and0.85amongNorwegianmenandwomen,respectively(15).Attheendof2014, therewere6619peoplealiveafteralungcancerdiagnosisinNorway,andoutofthese,lessthan 20%(1197)werediagnosedmorethanfiveyearsago(6).

Aetiology

Lungcancerisoneofthefewcancertypeswheretheaetiologyisknownforthemajorityofthe cases.ThestudybyDollandHillin1950establishedtheassociationbetweenlungcancerand smoking(16).Itisestimatedthatapproximately90%ofalllungcancercasesarerelatedtosmoking (17).OtherwellͲknowncausesforlungcancerareradon,asbestosandoccupationalexposures,as wellas,bothindoor(e.g.solidfuelcombustion,environmentaltobaccosmoking)andoutdoorair pollution(18).

Theriskforlungcancerincreaseswiththenumberofcigarettessmoked,numberofyearssmoking andifapersonstartedsmokingatanearlyage(19).Thecloserelationbetweensmokingandlung cancercanbeobservedinhowthehistoricalincidenceoflungcancerfollowsasimilarshapedcurve asthesmokingprevalence,withatimelag.Whiletheprevalenceofdailysmokersamongmenaged 16–74inNorwayhassteadilydecreasedfrom42%in1973to16%in2012,thedecreaseamong womendidnotstartuntiltheendofthe1990s(20).Thesamereportshowedthatthedecreasein smokingprevalencehasbeenlargestamongpeopleagedbetween16–24,regardlessofgender(20).

SmokinghabitshavebeenshowntovarybyregioninNorway.Thenationalaverageofdailysmokers from2008to2012inNorwaywas19%,withtheprevalencevaryingfrom14%intheregionofOsloto

28%inFinnmark(21).Itisalsowellknownthatsmokinghabitsarestronglyrelatedtosocioeconomic status(SES)inthepopulation.Smokingprevalenceamongpeoplewithanelementaryschool education(34%)isfourtimeshigherthanthosewithauniversitydegreeorsimilar(8%)inNorway (Figure2)(20).

Figure2:TheproportionofNorwegianpopulationaged16–74thatarecurrentsmokers,stratifiedby levelofeducation,1976Ͳ2015.

0 10 20 30 40 50

Proportion current smoking (%)

1975 1980 1985 1990 1995 2000 2005 2010 2015 Year

Low Intermediate High

Level of education

Figure3:Anatomyoftherespiratorysystem,showingthetracheaandbothlungswiththeirlobes andairways.Lymphnodesarealsoillustrated.

Footnote:FortheNationalCancerInstitute©2006TereseWinslow,U.S.Govt.hascertainrights

Anatomyandhistology

Thelungisanatomicallydividedintolobes,threeontherightandtwoontheleftside(Figure3).

Fromthetrachea,thereisamainbronchusgoingintoeachofthelungs.Lungcancerischaracterised byuncontrolledgrowthofabnormalcells,whichdonotdevelopnewhealthylungtissue.According tohistologicaltype,lungcancerisbroadlydividedintotwomaingroups:nonͲsmallcelllungcancer (NSCLC)andsmallͲcelllungcancer(SCLC).BothinternationalandNorwegiandatareportthatNSCLC, withthemostcommontypesbeingadenocarcinomas,squamouscellcarcinomas(SCC)andlargecell

carcinomas,represents80–85%ofalllungcancerdiagnoses(22,23).Largedifferencesinhistological typebetweengendershavealsobeenobserved,as28%and42%ofalllungcancersare

adenocarcinomasinmenandwomen,respectivelyand44%ofmenand25%ofwomenwithlung cancerhaveSCC(24,25).Thesedifferencesarelikelytobecausedbyanearlierhistorical

introductiontosmokingamongmencomparedwithwomen(26).SCLCisnamedafterthesizeofthe tumourcells.Thesetumoursareoftenlocatedatthecentreofthelung,andtendtogrowandspread quickly.

Treatment

Possibletreatmentmodalitiesforlungcancerpatientsaresurgicalresection,radiotherapy,and chemotherapy.Chemotherapyhasbecomemorepersonalisedinrecentyears(27).Combinationsof thesemodalitiesarealsopossible.Thetreatmentdecisionisbasedonthehistopathological

diagnosis,whichmaybesupplementedbyanimmunohistochemicalandcancergenome(mutational) examinationtoobtainamorespecificsubgroupofhistology.Inaddition,thelocalisationandspread ofthetumour(usingtheInternationalClassificationofDiseaseforOncology[ICDͲOͲ3]andclinical stageI–IV^a),thepatient’sperformancestatus,presenceofcomorbidities,aswellas,thepatient’s ownpreferencesareconsideredimportantwhendecidingthetreatment(27).

Amongpatientsdiagnosedbetween2010and2014inNorway,44%werediagnosedwithdistant spread(6).Anadvancedstageofdiseasereducesthepossibilityforcurativetreatmentandthe probabilityofachievingcure.PatientsdiagnosedwithNSCLCinstageIorIIarecandidatesforsurgery withcurativeintent.Itisknownthatapproximately20%oflungcancerpatientsinNorwayare resectedeveryyear(23,29).AdjuvantplatinumͲbasedchemotherapyisofferedforpatientsinstage

aClassifiedaccordingtoStagingManualinThoracicOncologyintostageI:(T1,N0,M0),stageII:(T2,N0,M0), stageIII:(T1,T2,N1,M0)or(T1,T2,N2,M0)or(T3,N0,N1,N2,M0),andstageIV:(T4,anyN,M0)or(anyT, N3,M0)or(anyT,anyN,M1)(28).

II.Themajorityofresectionsperformedare(biͲ)lobectomies,whereoneortwoofthelobesare surgicallyremoved.OtherresectionalternativesincludepneumonectomyandsubͲlobarresection.

Neoadjuvantoradjuvantradiotherapy,i.e.radiotherapygivenbeforeoraftersurgery,respectively, canalsobeused,ifrequired.Ifthepatientisnotconsideredasurgicalcandidateduetotechnicalor medicalinoperability,eithertraditionalradiotherapyorstereotacticbodyradiationtherapy(SBRT), canbeoffered.DuringSBRT,highͲdoseradiationisdirectlyaimedatthetumourfrommultiple angles.Comparedtotraditionalradiotherapy,thebenefitsofSBRTincludebetterpreservationofthe normaltissuesurroundingthetumourandimprovedsurvival.However,thistechniqueisonly possibleinN0Ͳsituations,i.e.nolymphnodemetastases.Duetotheheterogeneityofpatients diagnosedinstageIII,thedifferentiationbetweentreatmentdecisionsisbasedonTͲandNͲstage.

WhilethedebatecontinuesastowhetherornotpatientswithstageIIIdiseaseandlimitedN2Ͳ metastasesshouldundergosurgicalresection,Norwegiannationalguidelinesrecommendthatthis groupofpatientsreceiveradiotherapyinconcomitantcombinationwithchemotherapy.

ForstageIVpatients,treatmentshouldbegivenwithlifeͲprolongingorpalliativeintent,i.e.

chemotherapy,palliativeradiotherapy,oracombinationofthetwo.Cytostatictreatmentwith cisplatinorcarboplatin,incombinationwithvinorelbine,gemcitabine,docetaxel,paclitaxelor pemetrexed,isconsideredstandardfirstͲlinetherapyinpatientswithnogeneticaberrations amenablefortargetedtherapy.Approximately10%ofpatientsharbourmutationsintheepidermal growthfactorreceptor(EGFR)geneandshouldbetreatedwithfirstͲlineerlotinib,gefitinibor afatanib.Crizotinibisthetreatmentofchoiceintheapproximately5%ofpatientswithchangesin theanaplasticlymphomakinase(ALK)Ͳgene.Thesetargetedtherapiesarealloraldrugs,containinga kinaseinhibitor,andaretakendailyaslongastheyprovidebenefittothepatient.Allpatientswill inevitablyrelapse,andapprovedsecondlinetherapiesincludedocetaxelorpemetrexedfornonͲ mutatedpatients.Novelkinaseinhibitorsarepreferableforpatientswithknownmutations.

MainlySCLCpatientswithstageI(<10%)areconsideredcandidatesforsurgerywithadjuvant chemotherapy,givenaswithfourcoursesofcisplatinincombinationwithetoposide.Allresected SCLCpatientsshouldalsoundergoprophylacticbrainirradiation.ForallotherSCLCpatients(>90%), surgeryisconsideredfutile.FornonͲresectablepatientswithlimitedspreadofdisease,fourcourses ofcisplatinandetoposideshouldbegiven,with3weeksofradiotherapyintercalatedbetween coursestwoandthree.ForSCLCpatientswithextendeddiseaseandgoodgeneralhealth,four coursesofplatinumandetoposidearerecommended,whileforpatientswithreducedgeneral health,fourcoursesofdoxorubicin,cyclophosphamideandvincristinearerecommended.

Prognosticfactors

Prognosticfactors(orpredictors)aredefinedasvariablesthatcanaccountforsomeofthe heterogeneityinthecourseofthediseaseandtheultimateoutcomeforthepatients(30,31).

Understandingthesefactorsmayhelpanswerawiderangeofimportantquestions,suchas

predictingtheoutcomeorprognosisforindividualpatients,andprovidinginformationaboutpossible differencesinthequalityandhealthcareservicesprovidedbetweensubͲgroupsofpatients(32).For thepurposeofthisthesis,prognosticfactorsaredividedintothreedifferentgroups:tumourͲ, patientͲandtreatmentͲrelatedfactors.TumourͲrelatedfactorsarethosedirectlyrelatedtothe biologicalaspectsofthetumour,suchasextentofdisease(EOD)andhistology.PatientͲrelated factorsarenotdirectlyrelatedtothecancer,butmorespecifictotheindividual,suchasgender,SES, comorbidity,smokingstatusandareaofresidence.TreatmentͲrelatedfactorsincludethetreatment modality,procedureandtheexpertiseoftheclinician(33).WhileitispossibletoquantifytumourͲ andpatientͲrelatedfactorsandwhetherornotpatientsreceivesurgery,otherfactorsthatare associatedwithqualityoftreatmentandpersonalexperiences,cannotaseasilybemeasured.

TumourͲrelated

Extentofdisease

Tumourstageisanimportantprognosticfactor,asthe5Ͳyearsurvivalratesrangefrom50%(stage IA)to2%(stageIV),andfrom73%(stageIA)to13%(stageIV),accordingtoclinicaltumour,node, metastasis(cTNM)andpathologicaltumour,node,metastasis(pTNM),respectively(34).Astudy from2012includinglungcancerpatientsfromAustralia,Canada,Denmark,Norway,Swedenandthe UK,showedsignificantdifferencesinstagedistributionbetweenthecountries,aswellas,significant survivaldifferencesbetweenthedifferentstages(35).

Histology

Anumberofstudieshaveexaminedtheassociationbetweenhistologicalgroupandsurvival.Astudy from2012showedthathistologymaybeanindependentprognosticfactor(36).WhileaNorwegian studyconsideringalllungcancerpatientsfoundnodifferencebetweenSCCandadenocarcinoma, theyfounda12%increasedrelativeriskofdeathwhencomparinglargeͲcellcarcinomawith adenocarcinoma(37).AnotherNorwegianstudy,onlyincludingresectedpatients,founda44%and 33%increasedmortalitywhencomparingadenocarcinomaandlargeͲcellcarcinoma,respectively, withSCC(38).ResultsfromtheInternationalAssociationfortheStudyofLungCancer(IASLC) identifiedhistologytobeanindependentprognosticfactoramongresectedpatients(39).While largeͲcellcarcinomawasassociatedwitha19%increasedmortalitycomparedtoSCC,adifference onlyobservedamongmen,theresultsslightlyfavouredSCCcomparedtoadenocarcinoma(hazard ratio[HR]=0.86,p<0.0001).AstudyusingpopulationͲbaseddatafromsevenregionsinSpain, reportedvarying5Ͳyearrelativesurvivalestimateswithhistologicaltype,favouringSCCand adenocarcinoma,whileSCLCpatientshadtheworstprognosis(40).Therefore,histologicalsubgroup shouldbeconsideredapotentialprognosticfactorwhenstudyingsurvival.

PatientͲrelated

Socioeconomicstatus

OneofthepatientͲrelatedprognosticfactors,SES,isintendedtomeasureaperson’ssocialposition (41).SESisdifficulttomeasureandtherefore,income,education,maritalstatusand/orareaof residencearecommonlyusedasproxies.InNorway,individualͲlevelinformationregardingboth incomeandeducationisavailablefromStatisticsNorway,however,theremaybesituationswhere agreementbetweenthesemeasuresandaperson’sSESispoor.Forexample,patientswhoarenot workingwouldberegisteredwithalowincomeandhencecategorisedwithalowSES.However, thesepatientsmayhavepartnerswhoareworkingandwhocanfinanciallysupportboth.Hence,the patient’spersonalincomeasaproxyforSESwouldcauseamisclassification,whileincluding informationaboutthetotalhouseholdincomewouldbemoreappropriate.

ArecentsystematicreviewandmetaͲanalysisshowedthatlungcancerpatientswithhighSESare morelikelytoreceivebothsurgeryandchemotherapy,whiletheinfluenceofSESonwhetherthe patientreceivesradiotherapyremainsinconclusive(42).TheseresultswerefoundbothinSCLCand NSCLCpatients(42Ͳ52).WhenreviewingliteratureontherelationshipbetweenSESandsurvival,it wasreportedthatthesesurvivalestimateswereambiguous(53).However,studiesfromSweden, DenmarkandEnglandhavereportedthatthesurvivaloflungcancerpatientsisaffectedbythe patients’SES(43Ͳ45,49,54,55).Differencesinlifestyle,cultureandbehaviour(e.g.smokinghabits), mayalsoberelatedtoSES,andthesemayfurtherinfluencethepatients’health.Similartocountries likeSweden,DenmarkandEngland,Norwayhasauniversalhealthcaresystemwherehealthcareis equallyavailabletoeveryoneindependentofsocialfactorsandareaofresidence.Thiscontrastswith theinsuranceͲbasedsystemintheUS,andtherefore,careshouldbetakenwhencomparingtheSES estimatesofNorway,withthosefromnonͲuniversalhealthcaresystems,wherethedifferences betweenSESgroupsareexpectedtobelarger.

Smokingstatus

Inadditiontobeingthedominatingaetiologicalfactor,smokinghasbeenstudiedinrelationto cancerrecurrenceandsurvival.Areviewarticlefrom2013showedthatpatientswhocontinueto smokeafteralungcancerdiagnosisare1.9timesmorelikelytogetarecurrenttumour,2.3times morelikelytogetasecondtumour,andhave2.9timeshigheroverallmortalitythanpatientswho quitsmokingatthedateofdiagnosis(56).Thisreviewalsofoundthatforpatientsreceivingpalliative treatment,smokingcessationattimeofdiagnosiswasassociatedwithimprovedpulmonaryfunction, weightgainandbetteroverallqualityoflife.Whiletherearesomeinconsistenciesinreported results,asystematicreviewandmetaͲanalysisshowedthatamongearlystageNSCLCpatients, continuingsmokingcomparedwithsmokingcessationwasassociatedwithalmosta3Ͳfoldincreasein allͲcausemortality,whilethecomparableincreaseforlimitedSCLCwasalmost2Ͳfold(57Ͳ60).Other studieshaveshownthatthereisasignificantpositiveeffectonsurvivalofbeinganeversmoker comparedtoaneversmoker,withestimatesvaryingfroma5–50%reductioninriskofdeath(61, 62).However,amongpatientswithstageIIandIII,theresultsareinconclusive(63,64).

Comorbidity

Asalargeproportionofthelungcancerpatientsarecurrentorformersmokers,theyaremorelikely tohavereducedlungfunction,inadditiontoanumberofotherconditions(65).Theseother conditionsarecalledcomorbidities,andareoftensummarisedintoascoreorindexusedin epidemiologicalstudies.ThemostcommonlyusedcomorbidityindexiscalledtheCharlson comorbidityindex(CCI),whichgivesascoreto17differentchronicdiseasesbasedontheirseverity (66).Thisscoreincludeschronicobstructivepulmonarydisease,themostcommoncomorbidityfor lungcancer,aswellas,myocardialinfarction,congestiveheartfailure,peripheralvasculardisease, cerebrovasculardisease,dementia,rheumaticdisease,pepticulcerdisease,mildliverdisease,

diabeteswithandwithoutchroniccomplications,hemiplegiaorparaplegia,renaldisease,cancer, moderateorsevereliverdisease,metastaticcancerandAIDS/HIV(66,67).Fromnationaland internationalguidelines,itisknownthatinformationaboutthepatient’sgeneralhealth,lung functionandcomorbiditiesareimportantwhenmakingatreatmentdecision.Whileitwouldbe optimaltohaveinformationonallthreefactors,comorbidityinformationwhichoftenservesasa proxyofgeneralhealth,ismostaccessibleinlargenationalpopulationͲbasedmaterials.Onestudy showedthatcomparedwithpatientswhohavealowlevelofcomorbidity,patientswithahighlevel hada35%increased1Ͳyearmortalityanda26%increased5Ͳyearmortality(68).Aliteraturereview ontheassociationbetweencomorbidityandlungcancersurvivalfoundthathavingmore

comorbiditieswasassociatedwitha10Ͳ50%increasedmortality(69).However,astheprognosisfor lungcancerisconsideredpoor,ithasbeenshownthathavingcomorbiditiesisofrelativelylow prognosticimportance.(70,71).

Symptoms

Themostcommonsymptomsthatlungcancerpatientsdisplayareprogressiveshortnessofbreath, coughing(blood),chestpain/oppression,hoarsenessorlossofvoiceandpneumonia(72).

Unfortunately,thesesymptomsaremostlikelynottobepresentuntilthetumourhasmetastasised beyondtheprimarysite.Vaguesymptomscanleadtolaterpatientcontactwithadoctor,andhence laterdiagnosis.Therehavebeenstudiesexaminingthepresenceanddurationofsymptomsin relationtosurvival.AKoreanstudyshowedthatamongNSCLCpatientstherewasasignificant reductionintheriskofdeath(oddsratio[OR]:0.2395%confidenceinterval[CI]0.22–0.52)for asymptomaticcomparedtosymptomaticpatientsatthetimeofdiagnosis,whilenoeffectwas observedamongSCLCpatients(73).InalocalcentrestudyfromEnglandwheretheyconsidered5Ͳ yearsurvivalamongallresectedNSCLCpatientsbetween2000and2009,therewasnosignificant differencebetweenasymptomaticandsymptomaticpatients(74).InIndiatheyfoundthatpatients whohadsymptomsforlessthanonemonthbeforediagnosishadagreaterthan50%reductionin

theriskofdeath(HR=0.4495%CI0.26–0.74)duringthenext30months(75).Asystematicreview from2009andareviewarticlefrom2014identifiedthepresenceofsymptomstobeasignificant negativeprognosticfactorforlungcanceroutcome(76,77).However,othershaveshownthat personslivingwithsymptomsforashortperiodoftimehadworseprognosiscomparedtothose livinglongerwithsymptoms.Hence,itisnotonlythepresenceofsymptomsthatisimportantto consider,butalsoitsduration.

Gender

Genderdifferencesinregardtosurvivalhavebeenstudiedextensively,andtheresultsconsistently showthatwomenhaveabetterprognosisthanmen(78).PreviousstudiesfromNorwayshowedthat womenhada14%and41%improvedsurvivalcomparedtomen,whenanalysingalllungcancer patientsandresectedpatients,respectively(38,79).Thelatterresultiscomparabletoastudyfrom theUnitedStates(US)thatreporteda50%lower30ͲdaypostͲoperativemortalityamongwomen comparedwithmen(80).OtherstudiesexaminedthegenderdifferencesamongNSCLCandSCLC patients,separately,andfounda15–20%highersurvivalamongwomeninbothgroups(81Ͳ83).A Polishstudyfoundthatmenhada15%increasedriskofdeathcomparedtowomen(84).Another studyofNSCLCpatientsfoundbetteroverallsurvivalaswellasstageͲspecificsurvivalamongwomen (85).Unlesstheseresultsare(residually)confoundedbyfactorsthatcouldnotbeadjusted

(sufficiently)for,itisimportanttoadjustforgenderasaprognosticfactor.Anexampleofapossible confounderissmoking,asitiswellknownthatsmokinghabitsdifferbetweenmenandwomen.

Therefore,itisimportanttointerpretthepreviousresultswithcare,andkeepinmindthatthere maybeotherassociationsdisguisedasagenderdifference.

Areaofresidence

AnotherpatientͲrelatedprognosticfactorisareaofresidence.TheresultsofanumberofEuropean studieshaveshownthattheprobabilityofgettingtreatmentdifferswithincountries(29,43,86Ͳ88).

Theproportionofpatientsbeingresectedvariedbetween15–31%inNorway,3–18%inEngland,13–

24%inDenmarkand8–16%inIreland.MarkedsurvivaldifferencesbetweenregionsinNorway, SwedenandEnglandhavebeenreported(43,88Ͳ90).FromEngland,itisknownthattheregional differencesinsurvivaldecreasedbetweentheperiods1991to1995and2001to2006,bothamong menandwomen(91).Eventhoughthegeographicaldifferencesinoverallsurvivalgotsmaller,two studiesshowedthatamongNSCLCpatientsthereisstillsignificantvariationinsurvival(43,92).

Hence,areaofresidenceseemstobeanimportantprognosticfactorforsurvival.

TreatmentͲrelated

The5Ͳyearoverallsurvivalamongalllungcancerpatientsisapproximately15%,however,resected patientsexperiencea5Ͳyearsurvivalrangingfrom20%to80%dependingontheirstage(93).A NorwegianpopulationͲbasedstudy,examiningprognosticfactorsamongresectedpatients,showed thathavingamoreextensiveprocedurethanlobectomywasassociatedwithaworseprognosis(38).

Eventhoughstudiesshowedsignificantassociationbetweenresectionratesandsurvival,theoptimal proportionofpatientswhoshouldberesectedhasnotbeenfound.Inaddition,thevarying

definitionsofaresectionratebetweencountriesmakeitdifficulttocompareresults(94Ͳ96).For patientsreceivingradicalradiotherapyinstagesIandII,the5Ͳyearsurvivalwas17%accordingtoa publishedCochranereport(97).Ifleftuntreated,barelyanyoftheselungcancerpatientswouldbe aliveafterthreeyears(98).

Further,astrongassociationbetweenoverallsurvivalandregionalvariationinresectionrateshas beenreported(43,92).ResultsfromtheLungCancerRegisterofCentralSweden,observedthatthe

riskofdeathwas20–40%higherinothercountycentresthanthereferencecentre(88).However, afteradjustingfortreatment(surgery,radiotherapy,chemotherapy),countyofresidencewasno longerconsideredaprognosticfactor.

Survival

Worldwide,whilesurvivalafteralungcancerdiagnosishasbeenconsideredpoorfordecades,there havebeenrecentindicationsofapromisingpositivetrendinsurvival(99Ͳ101).Inaddition,variation insurvivalestimatesbetweencountrieshasbeenobserved(15,99,100,102Ͳ107).In2013in Norway,themediansurvivaltimewas8.2and12.3monthsformenandwomen,respectively(27).

ExcludingIcelandduetoitssmallpopulationwhichwouldaffecttherelativesurvivalestimatesby randomvariationfromyeartoyear,therehavehistoricallybeendifferencesbetweentheNordic countriesinsurvivalestimatesamongmenandwomen.TheNordCandatabaseshowsthatforthe periodfrom2009to2013,the5Ͳyearrelativesurvivalestimatesvariedfrom10to15%andfrom16 to19%amongmenandwomen,respectively(Figure4)(12,13).Thesurvivalestimateswere15%for menand19%forwomeninNorwayduringthisperiod.NorwayandSwedenhadthehighestsurvival estimates,whileDenmarkandFinlandhadthelowest,accordingtotheNordCandatabase(12,13).

Varying5Ͳyearrelativesurvivalhasbeenobservedinregionswithsimilaruniversalhealthcare systems,rangingfrom8.7%inEnglandto20.1%inManitoba,Canada,fortheperiodfrom1995to 2007(103).ItwasarguedthatthelowsurvivalinEnglandcanbeattributedtothefactthatcancer patientsseekcontactwiththeirdoctorsatalaterstageofdisease(104).TheEUROCAREͲ5study estimatedthe5ͲyearEuropeanmeanrelativesurvivaloflungcancertobe13.0%,whichwasthe poorestofthetenindexcancersites.TheCONCORDͲ2study,whichincorporatesworldwide informationfrom279populationͲbasedregistriesin67differentcountriesincludingover25million cancerpatients,reporteda5Ͳyearrelativelungcancersurvivalof<20%alloverEurope,15–19%in NorthAmericaand7–9%insomepartsofAsia,intheperiodfrom1995to2009(100).

Figure4:Showingtheimprovementin5Ͳyearrelativesurvivalfrom1999–2003to2004–2008,aswell as,from2004–2008to2009–2013intheNordiccountries(excl.Iceland)amongmenandwomen.

Source:NordCan(12,13).

Sweden

Norway

Finland

Denmark

0 5 10 15 20

5−year relative survival (%)

Men

Sweden

Norway

Finland

Denmark

0 5 10 15 20

5−year relative survival (%)

1999−2003 to 2004−2008 2004−2008 to 2009−2013

Women

Aimsofthestudy

Theaimsofthepresentstudywereto:

x examinechangesinsurvival,andpatientͲ,tumourͲandtreatmentͲrelatedfactorsaffecting survival,amongresectedandnonͲresectedlungcancerpatients(PaperI).

x identifysubgroupsofage,gender,SES,histologyandtreatmentinrelationtoimprovement insurvivaloverthelastdecade(PaperI).

x examineandquantifytheassociationbetweenpossiblepredictorsandsurgicaltreatment, radicalradiotherapyorpalliativeradiotherapyforlungcancerpatients(PaperII).

x examineifregionalvariationinsurvivalexistsamonglungcancerpatientsinNorwayand,ifit does,canthevariationbeexplainedbyvaryingresectionrates(PaperIII).

x exploretherelationshipbetweensurvivalandresectionrate,andinvestigatewhetheran optimalresectionratecanbeidentified(PaperIII).

Materialandmethods

Datasources

Thisnational,populationͲbasedstudyinvolvesthreesourcesofinformation:CancerRegistryof Norway(CRN),StatisticsNorway(SSB),andNorwegianPatientRegister(NPR).Auniquepersonal identificationnumberhasbeenassignedtoeveryNorwegiancitizensince1964.Thispersonal identificationnumberallowslinkageofinformationonallNorwegiancitizensacrossinstitutionsand nationalhealthregistries.

CancerRegistryofNorway

Itismandatoryforallhospitals,pathologylaboratoriesandgeneralpractitionersinNorwaytoreport allnewlydiagnosedmalignantneoplasmstotheCRN.TheCRNhasdataoncancersinNorwaydating backto1953.TheCRNalsoreceivesdeathcertificatesforallpatientswithacancerdiagnosisfrom theCauseofDeathRegistry,whichisoperatedbytheNorwegianInstituteofPublicHealth.Usingthe personalidentificationnumber,theCRNislinkedmonthlytotheNationalPopulationRegisterto updatevitalstatus(deathoremigration),andthreetimesperyearwiththeNPRtoensure completenessofcancercases(6).Thequality(i.e.comparability,completeness,validityand timeliness)ofthedataintheCRNhasbeenevaluatedtobehigh(108).

StatisticsNorway

StatisticsNorwaywasestablishedin1876andisagovernmentalentitythatfallsundertheMinistry ofFinance(109).Itisconsideredtobeanindependentscientificinstitutionasitdecideswhenand whattopublish.ItsmainobjectiveistopublishstatisticsaboutNorwegiansocietyregardingmany differentareas,suchaspopulation,health,financeandeducation.StatisticsNorwaydoesnotdirectly collectdatafromthepopulationregardingeducationandincome,butreceivesthatinformationfrom otherrelevantadministrativeregisters.Theerrorsinthesedataareconsideredtobenegligible(110).

EveryNorwegiancitizenhastodeclarehisincomeandwealthannuallytothetaxauthorities,who alsocollectthesedatafromemployers,banksetc.ThesedataarethentransferredtoStatistics Norway.Inadditiontotaxfiles,StatisticsNorwayalsocollectvarioustaxͲfreetransfersfromother administrativeregisters,primarilyfromTheLabourandWelfareAdministration(110,111).When StatisticsNorwaypublishesinformationabouteducation,itusesinformationfrom“Nasjonal utdanningsdatabase”,“Nasjonalvitnemålsdatabase”,“Helsepersonellregisteret”and

“Utlendingsdatabasen”.Forimmigrantswithunknowneducation,asmallproportionofpersonsare directlycontactedtocollectthisinformation(112).ThenSSBclassifiestheeducationlevelbasedon theNorwegianStandardClassificationofEducation(113).

NorwegianPatientRegister

TheNorwegianPatientRegister(NPR)fallsundertheNorwegianDirectorateofHealthandisa nationalhealthregistrycoveringallsectorsofspecialisedhealthcareservices.ReportingtoNPRis mandatory,andtheregisterincludesdataonallpatientstreatedinNorwegiangovernmentͲfunded institutions.PersonalidentificationnumbershaveonlybeenreportedtotheNPRfrom2008 onwards.Thisenablesresearchersandhealthplannerstofollowthediseasetrajectoryofpatients betweensectorsandhospitals.Inaddition,alignmentofdataandvalidationwithothernational healthregistriesaremadefeasible.TheNPRdataconsistofthreemainsourcesforstatistics:visitsfor medicaltreatmentforinͲandoutpatientsatpubliclyfinancedhospitals,privatehospitalsandprivate specialistpractices.Itisimportanttohavedatafromallthesesources,asthegovernmentpurchases medicaltreatmentfromprivatehospitalsandprivatespecialistpracticesasasupplementtoservices atthepublichospitals.TheNPRdoesnotincludedataonprivatelyfinancedhospitaltreatments, however,in2008onlyaround0.5%ofallhealthcareserviceswereprovidedbythesehospitals(114).

ThebasicdataunitintheNPRishospitalvisits.However,whenapatientistransferredbetween wardsatthesamehospital,theindividualdatarecordsareaggregated.Eachepisodeofnational

hospitaldatacontainsoneormorediagnoses,codedaccordingtotheInternationalClassificationof Diseases,10^thEdition(ICDͲ10)classification.

Datalinkage

Inthisstudy,thenational,populationͲbaseddataregisteredintheCRNwereusedtoidentifyall patientsdiagnosedwithmalignantneoplasmofbronchusandlung(ICDͲ10codeC34)between1 January1997and31December2011inNorway(n=34157).Inordertohaveahomogeneousgroup oflungcancerpatients,thosewithtrachealcancer(C33)wereexcluded(n=49).Ifapatientwas registeredwithmultipletumours,onlythefirstcasewithinICDͲ10groupC34wasincluded.For example,ifapatientwasdiagnosedwithatumourinonelobeandlaterdiagnosedwithanother independenttumourinadifferentlobe,onlythefirstdiagnosiswouldbeincludedinthisstudy.

Patientsregisteredasdeadbeforediagnosis,andpatientswhosediagnosiswassolelybasedon deathcertificateandautopsy,wereexcludedfromthestudy(n=886).InformationfromStatistics NorwaywaslinkedwithindicatorsforSES,i.e.education,personalandhouseholdincomes.

Educationwasmeasuredbythehighestachievededucationattheyearofdiagnosis,whilepersonal andhouseholdincomesweremeasuredtheyearpriortolungcancerdiagnosis.Educationand personalincomewereavailableforthewholestudyperiod,whilehouseholdincomewasonly availableafter2003.Finally,informationaboutcoͲexistingdiseases(i.e.comorbidities)duringoneͲ yearpriortodiagnosiswasobtainedfromtheNPR,butthiswasonlyavailableforpatientsdiagnosed after1January2009.

InPaperI,dataonalllungcancerpatientsregisteredintheCRNfrom1997to2011wereused.The rationalebehindstartingthestudyperiodin1997wasthatthiswasthefirstyearradiotherapydata onanationallevelwereavailable.InPaperII,alllungcancerpatientsidentifiedintheCRNfrom2002 to2011wereincluded,ashealthtrustsweredefinedandcameintoeffectinNorwayfromJanuary1

2002,andsinceregionalvariationwasanaimofthestudy(115).ForPaperIII,onlyNSCLCpatients whowerediagnosedfrom2002to2011wereincluded.PatientswithSCLCrarelyundergosurgery,so theywereexcludedinthisstudy(27).Figure5showsthelinkageofthedifferentdatasourcesand showswhichpatientswereincludedinthedifferentpapers.

Figure5:FlowchartshowingthedatalinkageandstudypopulationsforpapersI–III.

Classificationofvariables

Thefollowinginformationwasavailableforthelungcancerpatientsinthestudy:dateofdiagnosis, dateofdeathorlastobservation,age,gender,EOD,education,personalincome,householdincome (after2004),histology,topography,dateandtypeoftreatment(surgeryandradicalorpalliative radiotherapy),laterality,comorbidity(after2008),symptomdurationandsmokingstatus(2004–

2010).Inaddition,duetotheextensivequalitycontrolworkdonebyH.RostadandT.E.Strand internallyattheCRN,surgicalprocedure,pTNM,tumoursizeandresectionmargininformationwere alsoavailableforresectedpatients.

Radiotherapy

TheCRNreceiveselectronicrecordsfromallradiotherapycentresannually,withinformationabout ICDͲ10group,dateoftreatment,treatmentintention,totalradiationdoseandthenumberof fractions.Thepossibletreatmentintentionsarecurative,localcontrol,prophylacticorpalliative,and forthepurposeofthisthesisthefirstthreeintentionsweregroupedtogetherasradical(116).For 95%ofthelungcancercohort,theintentionwasknown,whileforthelast5%ofpatients,total radiationdosegivenwasusedtocategorisethemaseitherradicalorpalliative.ForNSCLCpatients whodidnotundergosurgery,atotalradiationdoseover60Gray(Gy)wasconsideredasradical,and thecomparablelimitforresectedpatientswas50Gy.ForSCLCpatients,radiationdosesof42Gyor higherwereclassifiedasradical.Anyradiationdoselowerthanthosedescribedabove,wasclassified aspalliative.

Histology

ForPapersIandIII,informationabouthistologywasobtainedusingallinformationregisteredinthe CRNandbychoosingthemostinformativeandspecificsubgroup.ForPaperII,informationaboutthe mostspecifichistologicalsubgroupregisteredintheCRNbeforethetimeofresectionwasusedfor theresectedpatients.However,ifthepatientswerenotresected,theapproachforclassifying histologywasthesameinPaperIIasitwasinPapersIandIII.

Histologywasclassifiedbasedonthe2004versionoftheWorldHealthOrganizationclassificationas SCC,adenocarcinoma,smallͲcellcarcinoma,largeͲcellcarcinoma,otherspecifiedcarcinomas, carcinomanotspecifiedandunknownhistology(72).Table1showswhichICDͲOͲ3codesthatwere includedinthedifferenthistologygroups.Sincesarcomasarebiologicallydifferentfromtheother tumours,andbecausethenumberofsarcomapatientsisverylow(0.2%),thesetumourswerenot includedinthisstudy.

Table1:Showswhichmorphologycodes(ICDͲOͲ3)areincludedinthedifferenthistologicalgroups.

Histologicalgroup: ICDͲOͲ3Codes:

Squamouscellcarcinoma 8050–8076

Adenocarcinoma 8140,8211,8230–8231,8250–8260,8333,8341,8480–8490, 8550,8560,8570,8574

Smallcellcarcinoma 8040–8045 Largecellcarcinoma 8012–8031,8310

Otherspecifiedcarcinoma 8046,8082,8123,8200,8240,8244,8246,8249,8430 Carcinoma,notspecified 8010,8032,8033

Unknown 6900,6999,8000,8001

Extentofdisease

ItisimportanttoincludeinformationaboutEODbothforanalysingprognosisandlikelihoodof treatmentforlungcancerpatients.IntheCRN,thevariabledescribingEODatthetimeofdiagnosisis groupedintolocalised,regional,metastaticorunknownaccordingtothecondensedtumour,node, metastasis(TNM)status(117).Localisedtumoursaredefinedastumourswithnodirectgrowthinto neighbouringtissue,lymphnodesororgans,however,therecanbemicroͲinvasivegrowthor carcinomawiththebeginningofamicroscopicallyinfiltratingtumour.Regionaltumoursaredefined astumourswithmetastasistoregionallymphnodesormicroscopic/macroscopicgrowthinto neighbouringtissue.Metastaticdiseaseinvolvesmetastasistodistantlymphnodesormetastasisto organsinthesame/differentpartofthebodyastheprimarytumour.TheEODiscodedasunknown ifametastasisisfoundbutthelocationoftheprimarytumourisuncertain.

Before2008,EODwascodedasunknownifthecodingwassolelybasedonapathologyreport,i.e.no validclinicalnotification,andtherewasnoinformationaboutmetastasisatthetimeofdiagnosis.

After2008,thesecaseswerecodedaslocalisediftheyreceivedcurativesurgery.Toobtain consistencyinthedataandtoavoidbiasintheanalyses,allstageinformationpostͲ2008were consideredunknown.Thisapproachledtosomemethodologicalchallengeswhenitcameto

analysingchangesineithersurvival(PapersI,III)andtreatmentovertime(PaperII),whichwillbe addressedlater.

Socioeconomicstatus

Alltheanalysesincludededucationandincome,bothservingasproxiesforSES.InPapersIandIII, personalincomewasusedasaproxyforSES,whileinPaperII,householdincomewasused.While bothpersonalandhouseholdincomeswereexploredaspredictorsinPaperII,itwasconcludedthat householdincomewasabetterpredictoroftreatment.Thiswasespeciallynotedforwomen;while formenusingpersonalorhouseholdincome,didnotchangetheresultsmarkedly.Educationwas categorisedbasedonthenumberofyearsofeducation:low(1–9years,lowersecondaryschool), intermediate(10–12years,uppersecondaryschool)andhigh(12+years,universityorsimilar).Data onbothpersonalandhouseholdincomesweredefinedbasedonthepercentiles.ThecutͲpoints weresetatthe33rd(low)and66th(high)percentiles,andwereredefinedeveryyeartoadjustfor theincreaseinincomeovertime.Inaddition,whenredefiningthesecutͲpointsforpersonalincome, genderwastakenintoaccount.

Healthtrust

In2011,Norwayconsistedof21healthtrusts,whichareresponsibleforgeneralhealthcareand managementofallpatientsresidinginitsgeographicalcatchmentarea.Ifahealthtrustdoesnot providecertainservices(e.g.lungcancerresection),thesepatientsarereferredtoanotherhealth trustthatoffertheappropriatetreatment.Thestudyvariabledenotinghealthserviceregion(health trust)waschoseninsteadofcounty,becauseitrepresentstheactualcatchmentareaofthedifferent treatmentinstitutions.Healthtrustisanexplanatoryvariablethatisbasedonthepatient’splaceof residenceatthetimeofdiagnosis,independentofwherethepatientwastreated.

Comorbidity

ComorbidityinformationwasmeasuredusingamodifiedversionoftheCCI,whichwasconstructed byusingdiagnosticcodes(ICDͲ10)fromhospitalisationswithinoneͲyearpriorto,andincluding,the dateofdiagnosisforalistof17chronicdiseases.Ascorewasdeterminedforeachofapatient’s recordedcomorbiddiseasebasedonitsseverity,andthecombinationofthesescoresresultedina modifiedCCI.Theindexwascategorisedinto:“nohospitaladmissionsbeforelungcancerdiagnosis"

(CCI=Ͳ1),low(CCI=0),intermediate(CCI=1,2)andhigh(CCIш3)(66,118).

Statisticalmethods

Inadditiontostandarddescriptivestatistics,anumberofdifferentstatisticalmethodswereapplied inthisstudy.

Coxproportionalhazardregression

InPaperI,Coxproportionalhazardregressionanalyseswereperformedtoidentifyandexaminethe effectsthatdifferentprognosticfactorshaveon1Ͳyearsurvivalamongthefollowingthreegroupsof lungcancerpatients:allpatientsdiagnosed,nonͲresectedpatients,andresectedpatients.Cox regressionwasalsousedinPaperItoidentifywhichsubͲgroupsofpatientshadthelargest improvementinsurvivalovertime.Theunderlyingassumption(i.e.theproportionalhazard assumption)ofthismodelisthattheexplanatorycovariatesaremultiplicativelyrelatedtothe baselinehazard,andthattheratioofthehazardscomparinggroupswithdifferentvaluesofthe explanatoryvariables,remainsconstantovertime.TheCoxregressionmodelcangenerallybe expressedash t( ) h t₀( )exp(

E

_{1 1}x ...

E

_{n n}x ),whereh t( )isthehazardfunction,h t₀( )isthe baselinehazardfunctionandx₁,...,x_narethecovariateswiththeircorrespondingparameters

1,..., _n

E E

(119).

Logisticregression

InPaperII,threeseparatemultivariablelogisticregressionmodelswereestimatedtoinvestigatehow differentcovariatesinfluencetheoddsofreceivingsurgicaltreatment,aswellas,curativeand palliativeradiotherapy,asapatient’sfirsttreatmentwithinoneͲyearofalungcancerdiagnosis.In eachofthethreemodels,thedichotomousoutcomewasdefinedaseitherreceivingtreatmentor

not.Thelogisticregressionmodelcanbeexpressedasln( ) _{0 1 1} ...

1 ^{n n}

p x x

p E E E

^,wherepis

thesuccessprobabilityoftheeventofinterest,inthiscase,thepatientreceivingtreatment,E₀isthe

interceptwhichistheestimateasallcovariatesarezero,x₁,...,x_narethecovariatesandE₁,...,E_nare thecorrespondingparameters(120).

Netsurvivalandexcessmortality

Netcancersurvivalistheprobabilityofsurvivinginahypotheticalworldwherecanceristheonly possiblecauseofdeath(121).Itprovidesameasureoftheexcessmortalityassociatedwithbeing diagnosedwithcancer.CauseͲspecificsurvivalandrelativesurvivalaretwowaysofestimatingnet survival.Themajoradvantageofusingarelativesurvivalframework,isthatitdoesnotrequireany causeofdeathinformation,asthisinformationcannotalwaysbetrusted,especiallyforolder

patients(t85years)(122).Netsurvivalcanbedescribedas

1

( ) ( ) 1

* ( )

n i

i i

NS t S t

n

¦

S t ^{,whereS ti( )isthe} allͲcausesurvivalforpatientiweightedusingtheinverseofthecumulativeexpectedsurvivalfora comparable,lungcancerͲfreeindividual(S_i*( )t ).Thiscomparableindividualisfoundbymatching thelungcancerpatientcohortwithanage,genderandcalendaryearstratifiedNorwegianlifetable obtainedfromStatisticsNorway.Thelifetableusedinthisthesiswasnotadjustedforsmokingstatus

inthegeneralpopulation,however,ithasbeenshownthatadditionaladjustmentsmayhavelittle effectonthenetsurvivalestimates(123).FiveͲyearnetsurvivalwasestimatedusingthemethod proposedbyPoharͲPermein2011,implementedintheStatacommandstrs,forbothresected andnonͲresectedlungcancerpatientsseparatelyinPaperI(124,125)^b.InPaperIII,therelative excessriskofdeathamongpatientswithlocalised,regionalandmetastaticdiseasebyhealthtrust wasmodelled.Theexcessriskofdeath,

O

( )t attimetcanbeexpressedas

O

( )t h t( )h t( *),where

( )

h t istheallͲcausemortalityrateexperiencedbythepatientsandh t( *)isthecorresponding

expectedmortalityrate.Comparingtheexcessriskofdeathforthedifferenthealthtruststothatof theentirecountryresultedinestimatesoftherelativeexcessriskofdeath.Inordertoaccountfor caseͲmixdifferencesbetweenhealthtruststhatmightaffectsurvival,aPoissonregressionmodel wasusedtoadjustforavailableexplanatoryvariables.ThePoissonregressionmodelestimatedthe expectednumberofdeathsduetocausesotherthanlungcancer.Thesewereestimatedusingthe generalpopulationmortalityrates(125,126).ThegeneralformofaPoissonregressionwitha logarithmiclinkfunctioncanbewrittenaslog(E( | ))Y x D E_{1 1}x ... E_{n n}x,whereYrepresents thenumberofcountsofanevent,Disascalingvariablecalledtheoffsettermwhichisusedtomake thedifferentgroupscomparableandx₁,...,x_narecovariateswiththeircorrespondingparameters

1,..., _n

E E .InPaperIII,thelinkfunctionproposedbyDickmanetal.in2004wasusedwhenmodelling

relativeexcessriskofdeath(125).

Competingrisk

Whilenetsurvivalaimstoestimatethehypotheticalsurvivalprobabilityinaworldwherecanceris theonlypossiblecauseofdeath,competingriskcanbeusedtoestimaterealͲworldsurvival probabilities,i.e.survivalprobabilitiesinasituationwhereothercausesofdeathalsoexists(127).In

bInPapersIandIIIthetermrelativesurvivalwasusedtodenotenetsurvival.

PaperII,thecumulativeincidenceusingtheAalenͲJohansenestimator,i.e.theprobabilityofpatients experiencingsurgeryandradicalorpalliativeradiotherapyastheirfirsttreatmentwithinoneͲyearof lungcancerdiagnosis,wasestimatedusingStata’sstcompetcommand,undertheassumptionthat anyoftheothertreatmentmodalities(competingrisks)couldhappen(128,129).

Joinpointregression

Ajoinpointisapointwheretwolinearlineswithdifferentslopesmeet.ByusingtheJoinpoint RegressionProgramavailablefromSurveillance,Epidemiology,andEndResultsProgram(SEER),itis possibletoanalyselineartrends,identifychangesinlineartrendsanddeterminethenumberof significantjoinpoints(130).Theprogramfitsthesimplestmodelasastraightline,i.e.zerojoinpoints, andthendeterminesifadditionaljoinpointsshouldbeaddedtothemodel.InPaperIIIwherethe relationshipbetweensurgeryandsurvivalwasstudied,therelativeexcessrisksofdeathwith standarderror,aswellas,theresectionrateswereestimatedforeachhealthtrustperyear.Using theseestimatesinthejoinpointprogramtoplottherelativeexcessriskofdeathagainstthe

resectionrates,anoptimalrateofresectedpatients,bothamongpatientswithlocalisedandregional diseases,wassought.Theprogramcalculatedtheannualpercentagechange,whichinthiscasewas interpretedastheaveragechangeinrelativeexcessriskofdeathastheresectionratecategory increasedbyoneunit.Hence,aninflectionpointintherelativeexcessriskofdeathwherethe survivalstabilisesordeclines,forincreasinglevelsofresection,wouldidentifyanoptimalresection rate.

Multipleimputation

Inmedicalandepidemiologicalresearchtherewillbemissinginformationinthedataforanumberof reasons.Thedegreeofmissinginformationvariesfromdatasettodatasetandfromstudytostudy.

Theremaybemanypossiblereasonsfordatatobemissing,butthreekindsofmissingmechanisms areidentifiedintheliterature:missingcompletelyatrandom(MCAR),missingatrandom(MAR)and missingnotatrandom(MNAR).FordatatobeMCAR,theinformationmissingshouldbecompletely independentfrombothobservedandunobserveddata.DataareconsideredMARiftheprobability ofmissingdatadoesnotdependonunobserveddata.Andfinally,dataareMNARiftheprobabilityof missingdatadoesdependonunobserveddata.

Historically,therehavebeendifferentwaystodealwithmissinginformation,e.g.completecase, meanimputation,lastobservationcarriedforwardandtreatingmissingdataasanewcategory(131).

Ifmissingdataarehandledinadequately,thestatisticalanalyseswillleadtobiasedand/orinefficient estimates.Treatingtheunknowndataasaseparatecategoryhasbeenshowntobeapooroption, evenwhenthedataareMCAR,sinceseverebiascanariseinparameterestimations(132,133).Using thecompletecaseapproach,whichisdeletingallobservationswithunknowninformation,willlead tocorrectandunbiasedestimates,butonlyifthemissingdataareMCAR.However,aspartofthe givendatawillbeexcluded,thestatisticalpoweroftheanalysiswilldecrease.

Imputationasanalternativeapproachtohandlemissingdataneedstobecarefullyconsidered.Using asingleimputationapproach,i.e.replacingthemissingobservationwithasinglevalue,willresultin standarderrorestimatesthataretoosmall.Incontrast,multipleimputationprocedureshave becomewidelyacceptedasastandardapproachtohandlingmissingdata.Inordertousethis methodologyandobtainunbiasedandefficientestimates,thenatureofthemissingdatais important.Toachieveasymptoticallyunbiasedestimates,itisimportantthatthedatameetatleast theMARassumption.MultipleimputationcanbeperformedevenonMNARdata,however,thenthe mechanismofmissingdataneedstobemodelledaswell.

Multipleimputationisgenerallyperformedinthreesteps:(i)generatingmultiple(m)imputeddata sets,(ii)analysingeachoftheimputeddatasetsand(iii)poolingtheestimatesfromthedifferent analysestogether.Multipleimputationbychainedequations(MICE)isanapproachtoconstructm imputeddatasets.Thesearebasedonasetofimputationmodels,i.e.onemodelforeachvariable withmissingvalues.Theinitialstepinvolvesfillingthemissingvaluesineachvariablewitharandom replacementfromtheobserveddata.Thenthemissingvaluesofavariable,sayy₁,willberegressed ontheothervariablesy₂,...,y_n,usingtheindividualswherey₁isobserved.Initialmissingvaluesof

y1isreplacedwithsimulateddrawsfromtheobtainedposteriorpredictivedistributionofy₁.The sameprocedurefollowsfory₂,whichisregressedony y₁, ,...,₃ y_nrestrictedtotheindividualswith observedy₂,usingtheimputedvaluesony₁.Valuesformissingy₂isreplacedbydrawsfromthe posteriorpredictivedistributionofy₂.Thisisrepeatedforallothervariablesandtheprocessisoften calledacycle.Inordertostabilisetheresults,severalcyclesareperformedresultinginoneimputed dataset.Thisprocedureisthenrepeatedmtimestogivemimputeddatasets.Thesecondstepis analysingthemdatasetsseparatelyandisusuallyeasyasstandardanalysistoolscanbeused.

Finally,usingRubin’srule,theestimatesandvarianceͲcovariancematrixfromthemdifferent imputeddatasetscanbepooledtogether.Thecombinedestimateoftheindividualobtained

estimates(T_j)canbefoundbytakingtheaverageoverallimputations,i.e.

1

ˆ 1 ^m

j

m j

T

¦

T ^.The

combinedvarianceͲcovariancematrixincludesthecomponentsdescribingbothwithinͲimputation variability(i.e.variationbetweenthedifferentimputeddataset)andbetweenͲimputation(i.e.

reflectionoftheuncertaintyduetomissinginformation).Thetotalvarianceobtainedcanbe

expressedasvar( )ˆ W (1 1)B

T m ,wherethewithinͲimputationvariance _j

1

1 ^m var( )

j

W m

¦

T ^and

thebetweenͲimputationvariance ²

1

1 ( ˆ)

1

m j j

B m T T

¦

.Tofindasufficientnumberofimputations, mshouldbechosentofulfilmt100*thepercentageofincompletecasesinthedata(134,135).

Itispossibletousemultipleimputationwithdifferentkindsofvariables,i.e.continuous,binaryand categoricalvariables.Categoricalvariablescanbemodelledusingamultinomiallogisticregression.

Whenchoosingwhichvariablestouseintheimputationmodel,itisimportantthatallvariables, explanatoryandoutcome,areincludedinthesameformastheyappearinthefinalanalysismodel.If theanalysisisbasedonasurvivalmodel,theoutcomevariablestoincludeareacensoringindicator andsomefunctionoffollowͲuptime.AnalternativetousingthefollowͲuptimeistousetheNelsonͲ Aalencumulatehazardestimate(136,137).

Inallpapers,multipleimputationwasusedtoimputemissingvaluesonthevariableseducation, income,EOD,histologyandsmokingstatus.Inaddition,laterality,tumoursizeandresection procedurewereimputedinPaperI,whilesymptomstatuswasimputedinPaperII.Allofthese variableswerecategoricalvariables,andtherefore,multinomiallogisticregressionswereperformed usingtheactualvariablesfromtheanalysesmodelasexplanatoryvariables.Unfortunately,thereis noformalwaytotesttheunderlyingassumptionofdatabeingMAR,andthebestapproachisto conditionthevariableswithmissingvaluesontheavailablevariableswithaknownorplausibly importantassociation(138).Inthedata,therewasnoreasontosuspectthattherewasany associationbetweenthemissingstructureofthevariablesandtheirtruevaluesorwithanyother

variablesthatwasnotadjustedforintheimputationmodel.

Mainresults

LungcancersurvivalinNorway(PaperI)

From1997to2011,the1Ͳand5Ͳyearrelativesurvivalforalllungcancerpatientsincreasedfrom 35.4%to47.7%and11.6%to17.5%,respectively.The1Ͳand5Ͳyearrelativesurvivalamongresected patientsincreasedfrom77.2%to93.3%and47.0%to62.2%,respectively.Thecorrespondingfigures fornonͲresectedpatientswere28.4%to37.0%and3.6%to6.3%,respectively.TheHRsfordeath amongresectedandnonͲresectedpatientsuptotwoyearsafterresection/diagnosisshowedthat thesewereconsistentlylowerin2004–2011comparedto1997–2003,varyingfrom0.50(95%CI 0.37–0.68)to0.71(95%CI0.62–0.82)forresectedpatientsand0.75(95%CI0.70–0.81)to0.88(95%

CI0.83–0.94)fornonͲresectedpatients.Thelargestimprovementsinsurvivaloccurredamong resected,aswellas,adenocarcinomapatients,whilepatientsaged80yearsorolderexperiencedthe smallestincrease.

Therewereseveralfactorsaffectingtheimprovementinsurvivalduringthestudyperiodfrom1997 to2011.Thewaitingtime(mediannumberofdays)fromdiagnosistoresectionincreasedfrom26to 34days.Diagnosticimprovementswerealsomadeduringthisperiod,whichcanbeseenbythefact thatmorepatientsreceivedtheirdiagnosisbasednotonlyonahistologicalexaminationbutalso withadditionalexaminations.Hence,theproportionofpatientsreceivingdiagnosisbasedonlyon histologicalexaminationdecreasedfrom68%in1997to30%in2011.Theproportionofmolecular geneticexaminations(includingEGFRtesting)increasedfrombeinglessthan1%upuntil2009to 26%in2011.

Lungcancertreatment(PaperII)

TheresectionrateamonglungcancerpatientsinNorwayremainedfairlyconstantaround18%while theproportionofradicalradiotherapyadministeredincreasedfrom8.6%to14.1%in2002–2011.The proportionofpatientsnotreceivingeithersurgeryorradiotherapydecreasedfrom50.0%to38.7%in thesameperiod.

Olderpatients(i.e.patientsaged80+),patientswithlowhouseholdincome,andpatientsfrom certainhealthtrusts,werelesslikelytoreceiveanytreatment.Comparedtopatientswithahigh levelofeducation,patientswithalowlevelwerefoundtohavealoweroddsofresection.Havinga lowlevelofeducationwasidentifiedasanegativepredictorforreceivingsurgery.Asmokinghistory waspositivelyassociatedwithbothradicalandpalliativeradiotherapy,whilecomorbidityand symptomspriortodiagnosiswereindependentlyassociatedwithreceivingpalliativeradiotherapy.

Resectioninrelationtosurvival(PaperIII)

TheexistenceofregionalvariationinsurvivalamongNSCLCpatientsinNorwaywasestablishedin thestudyperiod(2002–2011)bothamongpatientswithlocalisedandregionalspreadofdisease.

ThesedifferencesbetweenregionspersistedafteradjustingforcaseͲmixwhichincludedinformation aboutwhetherornotpatientsunderwentresection.

Forpatientswithlocaliseddiseaseanincreasingresectionratewasassociatedwithamonotone decreaseintherelativeexcessriskofdeath,whileamongpatientswithregionaldiseaseapointwas identifiedwhereafurtherincreaseinresectionwouldnotcontributetoanysurvivalbenefit.

Discussion

Overviewofresults

Theresultsconfirmedthatsurvivalafteralungcancerdiagnosisforallpatientshasimprovedover thelast15yearsinNorway,withalargerimprovementseenamongresectedthannonͲresected patients(PaperI).Wheninvestigatingthepredictorsforreceivingdifferentlungcancertreatments, SESvariablesandplaceofresidencewereidentifiedasindependentpredictivefactors(PaperII).

Differencesinsurvivalbetweengeographicalregionscouldnotbeexplainedbyregionaldifferences inresectionrate(PaperIII).

Methodologicalconsiderations

Allstudieshaveanalysedriskbyeitheranalysingsurvivalinrelationtosurgeryandotherprognostic factors,orthechanceofreceivingtreatment.

Studydesign

Withinepidemiologicalstudies,thetwomainbranchesofstudiesareobservationaland

experimental.Observationalstudiesexaminetheindividualsofinterestwithoutanyintervention, onlybasedonrecording,classifying,countingandperformingstatisticalanalyses(18).Thesestudies canfurtherbedividedintodescriptiveandanalytical,whereanalyticalstudiesusuallymeasurethe effectofdifferentriskfactorsinrelationtoaspecifiedoutcome.Further,therearetwotypesof analyticalstudies,i.e.caseͲcontrolandcohortstudies.Acohortisdefinedasa“groupofindividuals whoarefollowedortracedoveraperiodoftime”(139).Startingfromagiventime,therelationship betweendifferentfactorsandtheoutcomeofinterestareexploredforthecohort.Therearetwo typesofcohortstudies,whichdifferinwhenthedataarecollected,i.e.prospectivelyandhistorically (140).Allpaperscontributingtothisthesisarehistoricalcohortstudies.Thiskindofstudyis

importantinordertorevealpossibledifferencesinhealthservicesorincaregiven,andtheresults canbeusedtohelpdecisionmakerschangehealthpolicies.Forexample,theresultsofPaperII, identifiedgroupsofpatientswhowerelesslikelytoreceivetreatment,andtherefore,effortsshould bemadetoaddresstheinequity.AndinPaperIII,anoptimalresectionratewasfoundwhere performingadditionalsurgeryhasnofurthersurvivalbenefit,andthisresultmayaffectthe recommendedpatternsofsurgicalcare.

Validity

Thevalidityofanepidemiologicalstudyisusuallydividedintointernalandexternalvalidity(141).

Internalvaliditymeansthattheinferenceperformedinthestudyisvalidforthestudysubjects themselves.However,(mainly)threedifferenttypesofbiasescanimpairastudy’sinternalvalidity, namely,selectionbias,informationbiasandconfounding(discussedlater).Sinceanunselected populationͲbasedlungcancercohortwasused,theresultsfromthepapersareconsideredvalidand representativefortheNorwegianpopulation.Externalvalidityreferstotheapplicabilityoftheresults foundwithinthestudypopulationtootherpopulations,i.e.thegeneralisabilityoftheresults.

Externalvalidityassumesinternalvalidity,butalsoreliesoncomparabilityofcharacteristicsbetween thestudyandtargetgroups.Theresultsthatwereobtainedfromthesedataregardinglungcancer patientsinNorwaycanbeconsideredexternallyvalidandcomparabletootherpopulationsthathave similardemographicsandauniversalhealthcaresystem,wheretreatmentandcareareequally availableforeveryone,independentofsocialfactors.

Selectionbiasisasystematicerrorthatmaybearesultoftheprocedureofselectingparticipantsfor astudy.Thisbiaswilloccuriftheassociationbetweentheexposureandthediseasediffersamong patientsthatareandarenotincluded.Themandatoryreportingaboutallnewcancercasestothe CRNpreventsthedatafromsufferingfromselectionbias.Asalllungcancerpatientsregisteredinthe

CRNwereincludedinPapersIandII,thesestudiesareveryunlikelytobeaffectedbyselectionbias.

TheresultsfromthethirdpaperareonlyvalidforNSCLCpatients,however,withinthisgroupthere havenotbeenanyfurtherselections.Anothertypeofbiascalledinformationbiasisrelatedto measurementerrorsregisteredforthepatients.Thatis,thecovariatesoroutcomevariablesmaybe ofdifferentquality,andthusmisclassificationormeasurementerrorwillvarybetweenthe

comparisongroups.AsthequalityofthedataintheCRNisconsideredtobehigh,theriskof informationbiasisconsiderablyreduced.However,randomerrorscanstilloccurandarerelatedto typingerrorsanddataprocessing.Forexample,ifacoderattheCRNisindoubtofwhatiswrittenon theclinicalreportregardingstageorhistology,hewillmakeadecisionregardingtheclassificationof thispatient.However,itisunlikelythattherearesystematicerrors.Inallthepapers,stage

informationhasbeenadjustedforasapossibleconfounder.Duetothechangesinthecoding practice(describedearlier)after2008,ourresultsfortheperiod2002–2011wouldbeinfluencedby informationbias.However,allinformationregardingstagewasconsideredasunknownafter2008in ordertominimisethiskindofbias.

Thedefinitionofaconfounderisavariablethatiscorrelatedtothedependentvariableandcausally linkedtotheoutcome(18,142).Confoundingvariableseitherfalselycreateanassociationthatdo notreallyexist,orhideanalreadyexistingrelationbetweenthegroupsbeingcompared.Inthedata analysisprocesstherearetwowaysofdealingwithconfounders:bystratificationorbyadjustmentin astatisticalregressionmodel(139).Inthepapersbothtechniqueshavebeenused,e.g.inPaperI, theanalyseswerestratifiedbyresectionstatusandthenadjustedforpossibleconfounders,suchas ageandstage.

InPaperI,theeffectofeducationlevelonsurvivalforacohortoflungcancerpatientswasexamined.

Survivaldependsonthestageofthedisease,andtherefore,performingamultivariableregression

withoutstage,couldbeconfoundedifthosewithlowereducationlevelhavemoreadvancedstageat timeofdiagnosis.Therefore,inallthepapers,theinternalcodingpracticeattheCRNwhichdivides stageintolocalised,regional,andmetastatic,wasused.Astratifiedanalysismaystillbeaffectedby confoundingwithinthethreestrata,asitwillonlybeabletocontrolforconfoundingbetween,and notwithinthedifferentstrata.Thiswithinstrataconfoundingisalsoreferredtoasresidual confounding.Residualconfoundingmayappearinanyepidemiologicalstudywhenacertain confoundingvariableisnotsufficientlyadjustedfor.Awayoftestingifanobservedeffectisaffected byresidualconfoundingistofirstperformamultivariableregressionexcludingtheconfounding variableofinterest,andthentoexaminethechangeintheestimateswhentheconfoundingvariable isincluded.Iftheestimateforthevariableofinterestchangestowardsasmallereffect,itindicates thatconfoundingstillexistswithinthevariablethatwasadjustedfor.Forexample,stageinformation (condensedTNM)wasusedintheregressionmodelinPaperI.Ifinsteadinformationaboutthe patients’TNM,whichisamoredetailedgroupingofstage,wasavailable,theestimatesforeducation couldmovecloserto1.Thiswouldindicatethattheobservedeffectofeducation,whenadjustedfor stagecategorisedinbroadgroups,couldbearesultofresidualconfounding.However,whenstage wasincludedinthemultivariablemodel,theestimatesforintermediateandhigheducationwent from0.92(95%CI0.89–0.95)and0.87(95%CI0.83–0.92)to0.91(95%CI0.88–0.94)and0.85(95%

CI0.81–0.89),respectively,indicatingthattheestimateswerenotlikelytobearesultofresidual confounding.

Statisticalmethods

Multipleimputationwasusedinallthreepaperstohandlethedifficultiesrelatedtochangesin codingpracticeontumourstageintheCRN.Tumourstagewasconsideredasmissingfor100%ofthe patientsfrom2009to2011,astherewasnowaytoreͲcodethesepatientssimilartothosecoded before2009.Canonereallyusemultipleimputationswhenmissingawholeyearofinformation?To

validatethemethodusedinthepapers,sensitivityanalysesbasedonobserved,historicaldatafrom 2002to2008wereperformedcomparingtumourstagedistributionintwodifferentscenarios:1) imputationonthepatientsthatwereactuallymissingtumourstage,and2)imputationondatathat camefromsequentiallydeletingallinformationabouttumourstageforentireyearlycohorts.The firstscenariotookthedataasitisregisteredintheCRNandimputedtheunknownstageinformation basedontheotherknownvariablesofthepatients.ThesecondscenariowasperformedbyreͲcoding allstageinformationforpatientsdiagnosedin2002asmissing.Toobtaintheimputedstage

distributionforthiscohort,stageinformationregardingpatientsdiagnosedfrom2003to2008and otheravailablevariablesforthe2002Ͳcohortwereused.Thesameprocedurewasthenapplied sequentiallyforallcohortsinyears2003to2008.

Figure6:Comparing1Ͳyearsurvivalwhendealingwithmissingstageinformationintwodifferent

ways.First,multipleimputationisusedtoimputestagedatathewayithasbeenregisteredatthe CancerRegistryofNorway(method1).Second,multipleimputationwasusedtoimputestagewhen assumingthatallinformationaboutstagewasmissingforentireyears(method2).

SincetheoutcomeinPapersIandIIIwererelatedtosurvivalandprognosis,thesurvivalestimatesin thesetwoscenarioswerecompared.Thedistributionandsurvivalforthedifferenttumourstagesat differentyearsareshowninFigures6and7.

0 10 20 30 40 50 60 70 80 90 100

1-year survival (%)

2002

2003

2004

2005

2006

2007

2008 Year of diagnosis

Localised - method 1 Localised - method 2 Regional - method 1 Regional - method 2 Metastasis - method 1 Metastasis - method 2

Figure7:Comparingthestagedistributionwhendealingwithmissingstageinformationintwo

differentways.First,multipleimputationisusedtoimputestagedatathewayithasbeenregistered attheCancerRegistryofNorway(method1).Second,multipleimputationwasusedtoimputestage whenassumingthatallinformationaboutstagewasmissingforentireyears(method2).

Figures6and7showthatsurvivalandthedistributionforstageforthetwoscenariosweresimilar,

exceptforthemarginaldifferenceinthestageͲdistributionsin2002and2008.Thisindicatesthatthe imputedstageinformationisreliable,andthatusingmultipleimputationtechniquestodealwith wholeyearsofmissingdataseemsreasonable.

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Proportion (%)

2002

2003

2004

2005

2006

2007

2008 Year of diagnosis

Localised - method 1 Localised - method 2 Regional - method 1 Regional - method 2 Metastasis - method 1 Metastasis - method 2