Proefschrift Timmermans

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U I T N O D I G I N G

voor het bijwonen van deopenbare verdediging van

mijn proefschrift

Advanced larynx cancer trends and treatment

outcomes

door

Jacqueline Timmermans

op donderdag 8 oktober2015 om 12.00 uur in deAgnietenkapel van de

universiteit van Amsterdam,oudezijds voorburgwal 231

te Amsterdam

Aansluitend bent uuitgenodigd voor eenreceptie ter plaatse

PArAnImFen

Liset [email protected]

Fleur [email protected]

Jacqueline TimmermansJohannes verhulststraat 78-2

1071 nJ [email protected]

+31 652 307 154

A . J . T i m m e r m a n s

A d vA n c e d l A r y n x c A n c e r T r e n d s A n d T r e A T m e n T o u T c o m e s

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mijn proefschrift


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te Amsterdam


PArAnImFen





+31 652 307 154



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te Amsterdam


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+31 652 307 154



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te Amsterdam


PArAnImFen





+31 652 307 154



ADVANCED LARYNX CANCERTRENDS AND TREATMENT OUTCOMES

COLOFON

Cover by Sophie van Bentum Patternofthecoverdesignedbyzilverblauw.nl

Layout NicoleNijhuis-Gildeprint

Printedby Gildeprint,Enschede

ISBN ISBN/EAN9789462330337

Online http://dare.uva.nl

TheresearchdescribedinthisthesiswasperformedattheNetherlandsCancer Institute,

Amsterdam,theNetherlands.

TheNetherlands Cancer Institute receives a ResearchGrant fromAtosMedical Sweden,

whichcontributestotheexistinginfrastructureforhealth-relatedqualityofliferesearchof

thedepartmentofHeadandNeckOncologyandSurgery.

Printingofthisthesiswasfinanciallysupportedby:

ATOSMedicalA.B.,ACTA,Boottekstentaal,ChipSoftB.V.,DalecoPharmaB.V.,DOSMedical

B.V./KNO-winkel.nl, Laservision Instruments B.V., Nederlandse KNO vereniging, NSvG

Patintenvereniging voor stembandlozen,OlympusNederland B.V., Specsavers Hearcare,

SpringMedicalB.V.

Copyright2015byA.J.Timmermans.Allrightsreserved.

ADVANCED LARYNX CANCER TRENDS AND TREATMENT OUTCOMES

ACADEMISCHPROEFSCHRIFT

terverkrijgingvandegraadvandoctor

aandeUniversiteitvanAmsterdam

opgezagvandeRectorMagnificus

prof.dr.D.C.vandenBoom

tenoverstaanvaneendoorhetCollegevoorPromotiesingesteldecommissie,

inhetopenbaarteverdedigenindeAgnietenkapel

opdonderdag8oktober2015,te12:00uur

door

Adriana Jacquelina Timmermans geborenteSanktGallen,Zwitserland

PROMOTIECOMMISSIE

Promotores:

Prof.dr.M.W.M.vandenBrekel,UniversiteitvanAmsterdam

Prof.dr.F.J.M.Hilgers,UniversiteitvanAmsterdam

Overigeleden:

Prof.dr.L.E.Smeele,UniversiteitvanAmsterdam

Prof.dr.M.J.vandeVijver,UniversiteitvanAmsterdam

Prof.dr.C.R.N.Rasch,UniversiteitvanAmsterdam

Prof.dr.ir.F.E.vanLeeuwen,VrijeUniversiteit

Prof.dr.C.R.Leemans,VrijeUniversiteit

FaculteitderTandheelkunde

Lieve opa van Bezooijen,

waar u het niet kon afmaken, ben ik verder gegaan.

CONTENTS

Chapter1 Generalintroduction(In part based on a publication in Dutch: 9

[New developments in the treatment and rehabilitation of head

and neck cancer in the Netherlands]). Ned Tijdschr Geneeskd. 2012; 156(40): A5059

PART I TREATMENT AND SURVIVAL TRENDS Chapter2 T3-T4larynxcancerintheNetherlandsCancerInstitute;10-year 25

resultsoftheconsistentapplicationofanorgan-preserving/-

sacrificingprotocol.

Head Neck, online October 10, 2014 Chapter3 Tumorvolumeasprognosticfactorforlocalcontrolandoverall 45

survivalinadvancedlarynxcancer?

Accepted, Laryngoscope 2015

Chapter4 Trendsintreatmentandsurvivalofadvancedlarynxcancer: 61

a20-yearpopulation-basedstudyintheNetherlands.

Accepted, Head Neck 2015

PART II ADVERSE EVENTS AND TREATMENT FACETS

Chapter5 Totallaryngectomyforadysfunctionallarynxafter 83

(chemo)radiotherapy.

Arch Otolaryngol Head Neck Surg. 2012; 138: 548-555 Chapter6 Predictivefactorsforpharyngocutaneousfistulizationafter 101

totallaryngectomy.

Ann Otol Rhinol Laryngol. 2014; 123: 153-161

Chapter7 Earlyoralintakeaftertotallaryngectomydoesnotresultin 119

increasedpharyngocutaneousfistulization.

Eur Arch Otorhinolaryngol. 2014; 271: 353-358

PART III POSTLARYNGECTOMY REHABILITATION FACETS Chapter8 Anintroductiontospeechrehabilitationfollowingtotal 133

laryngectomy.

Ned Tijdschr Tandheelkd. 2012; 119: 357-361 (English translation)

Chapter9 Voicequalityandsurgicaldetailinpost-laryngectomy 145

tracheoesophagealspeakers.

Submitted

Chapter10 BiofilmformationontheProvoxActiValve:compositionand 167

ingrowthanalyzedbyIlluminapaired-endRNAsequencing,

fluorescenceinsituhybridizationandconfocallaserscanning

microscopy.

Head Neck. Online Jan 12, 2015 Chapter11 Generaldiscussion 185

Summary 207

Samenvatting 211

Authorcontributions 217

Authorsandaffiliations 221

PhDPortfolio 225

Dankwoord 229

Abouttheauthor 233

CHAPTER 1General Introduction

InpartbasedonapublicationinDutch.

A.J.Timmermans

M.W.M.vandenBrekel

L.vanderMolen

A.Navran

T.F.Nijssen

F.J.M.Hilgers

[New developments in the treatment and rehabilitation of head and neck cancer in the Netherlands].

NedTijdschrGeneeskd.2012;156(40):A505

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EPIDEMIOLOGYOFLARYNXCANCER

In theNetherlands,headandneck cancer isdiagnosed inabout3000patientsannually,

ofwhom700sufferfromlarynxcancer(1).Themostimportantriskfactorsfordeveloping

larynx cancer are alcohol and smoking (2). For glottic tumors smoking behavior is

determinative whereas in supraglottic cancers the combination of smoking and alcohol

abuseisriskenhancing.Morementhanwomendeveloplarynxcancer.However,incidence

ofsupraglotticandglotticcancer inmenisslightlydecreasing,whereastheincidencefor

womenstaysstableovertheyears(period1989-2010).Theincidence-curvesofmenand

womenareconverging,duetosmokinganddrinkingbehaviorofmenandwomen,which

aremoresimilarnowadays.In65-70%ofthepatientsthetumorisoriginatingfromthevocal

cords(glottic)andin30%atsupraglotticlevel.Tumorsarerarelyfoundatthesubglotticlevel

(Figure1).

Figure 1. Anatomyofthelarynx,(A)anteriorviewofthelarynxand(B)topviewofthelarynx.

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STAGINGANDTREATMENTOFADVANCEDLARYNXCANCER

Decisionsabouttreatmentof larynxcancerarebasedontumorstagingaccordingtothe

Union InternationaleContre leCancer(InternationalUnionAgainstCancer) (UICC)orthe

American Joint Committee on Cancer (AJCC) TNM classification (3), functionality of the

larynx,thegeneralconditionofthepatientandpatientaswellasdoctorpreferences.To

determine T and N classification, physicians rely on clinical examination, laryngoscopy,

imaging,ultrasound-guidedfine-needleaspirationcytology,andbiopsy.T1andT2 larynx

cancers are generally considered early tumors and T3 and T4 larynx cancer advanced

tumors.ThedistinctionbetweenT3andT4ismainlybasedonthyroidcartilagedestruction

andextralaryngealspread(3).Primarytreatmentoptionsforadvanced(T3-T4)larynxcancer

are radiotherapy (RT), concurrent chemoradiotherapyor total laryngectomy (TL)withor

withoutadjuvantRT.IntheNetherlandsCancerInstitute,T3larynxcancerisusuallytreated

withacceleratedRTandT4larynxcancerwithTLandadjuvantRT.Incaseofextensivenodal

disease (for both T3 and T4 tumors), chemotherapy is given concurrently toRT. Thus, T

classificationplaysamajorroleinthetreatmentdecisionandshouldbeofpredictivevalue.

However, some studies suggest that T classification is not sufficient to predict outcome

and several authors identified tumorvolumeasa substitute/additionalprognostic factor

for localandloco-regionalcontrolandforsurvival(4-7).Otherauthors,however,didnot

identifytumorvolumeasausefulprognosticfactorinadvancedlarynxcancer(8,9).

Oftheprimarytreatmentmodalitiesforadvancedlarynxcancer,TLwithadjuvantRThas

longbeenconsideredthegoldstandard.However,sincethisorgan-sacrificingsurgeryoften

results in significant morbidity leading to psychosocial, vocal, pulmonary and olfactory

problems, other options for treatment, e.g. partial laryngectomyandRT, have gained in

popularity. After the publication of two randomized studies, organ-preserving (chemo-)

RTtreatmentprotocolsare increasinglybeingusedasalternativetoTL(10,11).Thefirst

randomized study, conducted by theDepartment of VeteransAffairs (VA) Larynx Cancer

StudyGroup (1991) showed that 2-year survival rates inpatients treatedwith induction

chemotherapy(cisplatinumandfluorouracil)followedbyRTweresimilartothosetreated

with TL, except for T4N0 disease,which showed a significantly better survival in the TL

arm.Moreover,thelarynxwaspreservedin64%ofpatientsreceivingorganpreservation

treatment,incontrasttotheobvious0%intheTLarmofthestudy(10).Thesecond,purely

RT-basedorganpreservationstudywastheRadiationTherapyOncologyGroup(RTOG)91-

11trial,whichassessedinathree-armdesigntheeffectsoftheadditionofchemotherapyto

RT,eitherinductionwithcisplatinumandfluorouracil,orconcurrentwithcisplatinumonly.

At2-yearsposttreatment,larynxpreservationandloco-regionalcontrolratesinthisstudy

weresignificantlyhigherintheconcurrentchemoradiotherapyarmthanintheothertwo

arms.Overallsurvivalinthethreearms,however,didnotdiffersignificantly(11).

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Recently,the10-yearresultsofthisRTOG91-11trialwerepublished.Similarasinthe2-year

report, loco-regional control and larynxpreservation stillwerehighest in the concurrent

chemoradiotherapyarm.However,alsoat10-years theadditionofchemotherapy to the

radiationtreatmentdidnotprovideanyoverallsurvivalbenefit(12).

In2005Carvalhoetal.publishedtheresultsofapopulation-basedstudybasedontheSEER

(Surveillance,Epidemiology,andEndResults)databaseoftheNationalCancerInstituteand

reportedimprovedsurvivalformostheadandneckcancersites,exceptforlarynxcancer

(13). In 2006, Hoffman et al. studied changes in demographics, treatment patterns and

survivalbasedontheNCDB(ahospital-basedoncologydataset)andreporteddecreasing

survival for larynxcancerpatients fromthemid-80s to themid-90s in theUS (14).They

foundanincreaseintheuseoforgan-preservingtreatmentmodalitiesandadecreaseinthe

useofsurgeryinthesameperiod.Theshifttowardsorgan-preservingtreatmentprotocols

hasbeenpostulatedasapossiblecauseof the lackofgradual survival improvement for

larynxcancer,whencomparedtootherheadandnecksites(13,14).In2007,Chenetal.

aimedtodeterminefactorspredictiveforsurvivalinpatientswithadvancedlarynxcancer.

Theauthorsreportedahazardratiofordeathof1.6forRTand1.3forRTcombinedwith

chemotherapywhen compared to treatmentwith TL (15). Since then, there has been a

debateonwhetherornotTLshouldbeperformedmoreoftenin(aselectionof)patients

withadvancedlarynxcancer(16).

The above-mentioned studies were based on patients from the United States. In the

Netherlands, the Dutch Head and Neck Society (former Dutch Cooperative Head and

NeckOncologyGroup)publishedaconsensusdocumentonlarynxcancerdiagnosticsand

treatmentin1999(17).Thisdocumentcontainedevidence-basedprotocolsonallstagesof

larynxcancerandwasinpartbasedontheresultsofearliernationalstudiesontreatment

modalitiesandresults inallparticipatingcenters (18).Whereasbefore,T3andT4 larynx

cancersinmostcenterspreferablywouldbetreatedwithTL,fromthenonpatientswithT3

larynxcancerreceivedRT,inlinewiththeconsensusprotocolthendrafted.ForT4larynx

cancer,TLplusadjuvantRTremainedthepreferredtreatmentmodality.VanDijketal.(2013)

recentlypublishedastudyreportingadecliningincidenceandastablerelativesurvivalof

around70%foralllarynxcancercasesfrom1989to2010(19).Thus,althoughnodecreasing

survivalwasseenasintheUS,survivalratesdidnotincreaseeither.

Goals of this thesis are to study the changing treatment landscape in the Netherlands and its consequences for treatment outcomes in terms of survival, surgical sequels, and some of the voice rehabilitation aspects.

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In the 1st part of this thesis, oncological outcome after treatment for advanced larynx cancer was assessed in a retrospective cohort study in the Netherlands Cancer Institute.

Subsequently, the prognostic role of tumor volume in this cohort was evaluated. In a

population-based cohort study in the Netherlands, primary treatment trends and survival

were determined.

OUTCOMEAFTERTOTALLARYNGECTOMYINACHANGINGTREATMENTLANDSCAPE

Since the introductionofRTandRTcombinedwithchemotherapyasprimary treatment

modalitiesforpatientswithadvancedlarynxcancer,TL(plusadjuvantRTincaseofT4)isthus

nolongerconsideredtheonlycurativeoption.However,recurrentorresidualdiseaseisnot

uncommon(e.g.23-36%aftertreatmentwithRTforT3-T4larynxcancer(4,20))requiring

salvageTLwithanaccompanyinghigher riskofcomplications (21,22).Furthermore, the

function of the larynx, especially its vital role in swallowing/aspiration prevention, can

becomeimpairedtosuchanextentthatsomepatientsrequireTLbecauseofadysfunctional

larynxafterpriorRTorRTcombinedwithchemotherapy.Inthesecases,TLseemstheonly

resolutionforrestoringsomefunctionandthusqualityoflifeforpatients.

Pharyngocutaneous fistulization (PCF) is the most frequent complication in the early

postoperative period after TL. The reported incidences vary widely, ranging from 2.6%

to 65.5% (23). PCF increases morbidity, prolongs hospitalization, raises costs, possibly

necessitatesadditionalsurgery,anddelaysoralfeeding(23-25).Variouspredictivefactors

forPCFhavebeenidentifiedmostprominently,preoperativeRT(26,27).Inanerawithan

increaseintheuseoforgan-preservingtreatments,theadditionofchemotherapytoRThas

furtherincreasedtheincidenceofPCF(21).OtherpredictivefactorsforPCFaretheextent

of the pharyngeal resection, comorbidities such as hypothyroidism and diabetes, poor

nutritionalstatus,andanindextumorthatoriginatedinthehypopharynx(25,26,28-31).

Besidesthesefactors,thepostoperativedayofinitiatingoralfeedingisatopicofdiscussion,

andthereisnoconsensusconcerningthetimingoforalintake.Mostheadandnecksurgeons,

however,tendtodelayoralintakeuntil10-12dayspostoperativelyinordertopreventor

limitthechanceofPCF(32,33).However,evidencethatlateoralintake(LOI)reducesthe

incidenceofPCFisquiteweak,whereasthereareseveralargumentssupportingEOIasa

preferableandbeneficialapproach.First,EOIcouldhaveapositivepsychologicaleffectby

increasingthepatientsfeelingofearlierreturntonormalcy(34).Also,thepresenceofa

nasogastric feeding tubemovingacross thepharyngealsuture line,whichcanbepainful

orirritatingandmightpromotePCFmorethanLOIdoes.Furthermore,earlyreturntooral

feedingsavescostsandmayfacilitateearlierhospitaldischarge.Finally,quitesomestudies

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suggestthatEOIisasafeapproachinclinicalpractice(32,33,35,36).Inthisrespect,itcould

beinterestingtoconsiderdevelopmentsinotherareasofalimentarytractsurgery,wherea

worldwidetrendcanbeseentowardsEOIinpatientsundergoinggastro-intestinalsurgery

(37-39).

In the 2nd part of this thesis, functional outcomes after TL for a dysfunctional larynx are evaluated. Moreover, incidence of PCF, predictive factors and the influence of timing of

oral intake after a TL on the development of PCF are described.

VOICEREHABILITATIONAFTERTOTALLARYNGECTOMY

AnotherimportantaspectinthischanginglandscapeconcernspostTLvoicerehabilitation.

Prostheticvoicerehabilitationisconsideredthepresentgoldstandard.Wewereinterested

inwhichclinicalandsurgicalcharacteristicswererelatedtospeechandvoiceoutcomesin

thesepatients. Further, the question arosewhether technological improvements canbe

helpfulinmaintainingtheadvancesofprosthetictracheoesophagealvoice.

Voice quality and surgical characteristics

After TL, the vocal tract and upper digestive tract are separated and the trachea is

attached to the base of the neck, forming a permanent stoma (Figure 2). Because the

voiceboxisremoved,analternativesoundsourcehastobefoundinordertorestoreoral

communication.Optionsareanexternalsoundsource intheformofanelectrolarynxor

usingthereconstructedpharynxasthenewsoundsource(calledpharyngoesophageal(PE)

segment,alsocalledneoglottis),eitherenablingesophagealspeechwithairinjectedintoand

thenexpelledfromtheesophagus,ortracheoesophagealspeechusingair inhaledduring

breathing. Inthelattercase,avoiceprosthesiscontainingaone-wayvalvemechanismis

implantedintoatracheoesophagealpuncturetracttoallowpulmonaryairtobediverted

intotheesophagus.Previousresearchhasdemonstratedthattracheoesophagealspeech,

utilisingaprosthesisactingasavalve,issuperiorintermsofqualityandintelligibility.Opde

Couletal.(2000),forinstance,reportedfairtoexcellentvoicequalityin88%ofthepatients

(40).Becauseofitshighsuccessrateandeaseofacquisition,tracheoesophagealprosthetic

voicehasbecomethemethodofchoiceforrestoringoralcommunicationafterTL.

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Figure 2.Thenormalanatomy(A)andtheanatomyafteratotallaryngectomyandspeechrehabilitationwithavoiceprosthesis(B).

Nevertheless,TLstillhasamajorimpactonspeech,swallowing,andpsychosocialwellbeing

(41-43).ForTEspeech,significantcorrelationswerefoundbetweenvoicequalityandquality

oflifemeasures,fatigue,sentenceduration,anxietytospeak,andthefrequencyofmaking

telephone calls. Femalepatientsexhibit a greater voicehandicapand significantly lower

qualityoflifescoresthanmales(43-45).

VoicequalityandspeakingeffortdifferwidelywithintheTEpopulation(44,46,47).The

tonicityof thePE segment, and therewith voicequality, is basedon theadaptationand

vibrationdynamicsofthepharyngealmucosa(48).Dependentontheindividualanatomy,

thesurgicalproceduresperformedandpossiblyradiotherapy,variationoccursinmuscular

control, position and length of the vibrating segment, andmass and stiffness of the PE

segment.Eachofthesecharacteristicscanaffectvoice(andswallowing)function.

In comparison to the quasi-symmetric vocal folds, the vibrating neoglottis consists of

amorphicvibratingelementsinthewallofthePEsegment.Thewholevibratingsegment

is in general larger (moremass) andneurologically less controllable than thevocal folds

are. Furthermore, in view of the fact that air pressure control is needed to initiate and

extendvibration, itseemsa drawbackthatthePEsegmentbelowandattheneoglottic

regionisexpandable,whilethe(sub)glotticlarynxandtracheaarestabilizedthroughtheir

cartilageframework.AfterTL,thelaryngealdifferencesbetweenthesexesarelostandthe

limited neurological control, themyo-elastic properties,mass, size, and diameter of the

neoglottisand its surroundingtissuesbringabouta lower frequencyandmore irregular

voice,decreaseddynamicrange,andlessaerodynamicvoiceandf0control(49-52).

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Although post-TL voice quality and control are known to differ substantially between

patients, studies discussing themorpho-physiology and surgical characteristics and their

(interacting)effectsonpost-TLfunctioningarestillsparse.Intheliteraturevariousvariables

werefoundtoaffectfunctionaloutcomes.Amongthese,besidestheextentoftheresection,

arethesurgicalmethodofpharynxclosureandreconstruction(muscleclosingtechniques,

donorsitetissueproperties),theconservationoftheposteriorpharyngealwall,thedegree

andlevelofneoglotticclosureduringphonation(presenceandplaceoftheneoglotticbar

anddistanceand intensityofcontactbetweenposteriorandanteriorwall), thepressure

builtupbelowtheneoglotticbarduringphonation(intraluminalpressure),thediameterof

thepharynx(pharyngealandesophagealvolumeandextension),previousorpost-operative

(chemo-)radiotherapy,and(theextentof)neckdissections(50,52-64).Althoughtheextent

of the surgical resection is primarily dictatedby tumor extent, surgical techniques, such

as neurectomy and upper esophagealmyotomy, and the technique of pharynx (muscle)

closureandtypeofreconstructionthusseemimportantphonosurgicalaspectsofTL.

Biofilm formation on voice prostheses

As already mentioned, prosthetic tracheoesophageal voice rehabilitation has become

thegoldstandard intheNetherlands.The lifespanofvoiceprosthesesvaries fromafew

weeks to several years. Inmost cases, voiceprostheses have to be replacedbecauseof

transprostheticleakage(40).Themainreasonforthisleakageismicrobialbiofilmformation

on thevalve causing failureof thevalvemechanism,and sometimesalsoblockageand/

oran increasedairflowresistance (65).Thebiofilmconsistsofamixtureofbacteriaand

fungi and starts todevelop from themoment thevoiceprosthesis is implanted into the

tracheoesophageal puncture. In particular, Candida species grow into and subsequently

builduponthesiliconerubber(66).

Tosolvethisprobleminamaterial-technicalway,aspecialvoiceprosthesiswasdeveloped:

theProvoxActiValve (AtosMedicalAB,Horby,Sweden) (67).Thevalveandvalveseatof

thisvoiceprosthesisaresolelymadeoutoffluoroplastic,which isdeemed insusceptible

toingrowthofCandidaspecies.ThelackofadestructiveeffectofCandidaspeciesonthe

fluoroplasticmaterialhassofarnotbeenvisualized inappropriatestudies.Furthermore,

thecompositionanddiversityofthebiofilmonfluoroplasticvalveshavenotbeendescribed

before.Buijssenetalalreadyshowedthatthebiofilmonsiliconerubbervoiceprostheses

is composedof lactobacilli as thepredominantbacterialgenusandCandidaas themain

fungalcomponent(66).Thecompositionanddiversityofthebiofilmonthefluoroplastic

valveoftheProvoxActiValve,however,havenotyetbeenstudied,andincreasinginsightin

thebehaviorofCandidaspeciesandthecompositionofthebiofilmonfluoroplasticmaterial

couldbehelpful to further improvedurabilityofvoiceprostheses inamaterial-technical

way.

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In the 3rd part of this thesis, voice and speech outcome of TL speakers will be related to surgical and medical details. Moreover, we aim to determine the composition and

diversity of the biofilm of both the silicone and the fluoroplastic material of the Provox

ActiValve and to confirm the hypothesis that the fluoroplastic material is not susceptible

to destruction by Candida-species.

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OUTLINEOFTHISTHESIS

Part Iofthisthesisdescribestreatmentandsurvivaltrendsinpatientswithadvancedlarynxcancer.Inchapter 2the10-yeartreatmentresultsforT3-T4larynxcancerintheNetherlandsCancer Institute are presented. In chapter 3 the prognostic value of CT- andMRI-basedtumorvolumeinthesamecohortasinChapter2isreported.Chapter 4willaddresstrendsintreatmentandsurvivalofadvancedlarynxcancerina20-yearpopulation-basedstudyin

theNetherlands.

In part IIoutcomesaftertotallaryngectomyinachangingtreatmentlandscapearedescribed.In chapter 5 the results of a retrospective analysis of all relevant clinical and functionalcharacteristicsof25patientswhounderwentTLforadysfunctionallarynxarereported.In

chapter 6 theincidenceofPCFandpredictivefactorsforthedevelopmentofPCFaftertotallaryngectomyareassessed.Inchapter 7thetimingoforalintakeaftertotallaryngectomyanditsinfluenceonPCFispresented.

In part III, postlaryngectomy rehabilitation facets are presented.Chapter 8 provides anintroduction to voice and speech rehabilitation following total laryngectomy. In chapter 9 voice and speech outcomes in laryngectomized speakers will be related to surgicalandmedical details. In chapter 10wewill address the composition anddiversity of thebiofilmofboththesiliconeandthefluoroplasticmaterialoftheProvoxActiValveandtest

thehypothesisthatthefluoroplasticmaterialisnotsusceptibletodestructionbyCandida

species.

Finally,inchapter 11,theresultsobtainedinthisthesisarediscussedandsuggestionsforfutureresearchprojectsaregiven.

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nutrition.2011;35(4):473-87.

40. OpdeCoulBM,HilgersFJ,BalmAJ,TanIB,vandenHoogenFJ,vanTinterenH.Adecadeofpostlaryngectomy

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indwellingvoiceprostheses.Archivesofotolaryngology--head&necksurgery.2000;126(11):1320-8.

41. OozeerNB,OwenS,PerezBZ, JonesG,WelchAR,PaleriV.Functional statusafter total laryngectomy:

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laryngectomy].DerRadiologe.1991;31(7):324-31.

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50. Reis N, Aguiar-Ricz L, Dantas RO, Ricz HM. Correlation of intraluminal esophageal pressure with the

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55. Brok HA, Stroeve RJ, CopperMP, Schouwenburg PF. The treatment of hypertonicity of the pharyngo-

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56. AlbirmawyOA, ElsheikhMN, Silver CE, Rinaldo A, Ferlito A. Contemporary review: Impact of primary

neopharyngoplasty on acoustic characteristics of alaryngeal tracheoesophageal voice. Laryngoscope.

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57. McIvorJ,EvansPF,PerryA,CheesmanAD.Radiologicalassessmentofpostlaryngectomyspeech.Clinical

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58. BlomED,SingerMI,HamakerRC.Aprospective studyof tracheoesophageal speech.ArchOtolaryngol

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59. deCassoC,SlevinNJ,HomerJJ.Theimpactofradiotherapyonswallowingandspeechinpatientswho

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60. FouquetML,GoncalvesAJ,BehlauM.Relationbetweenvideofluoroscopyoftheesophagusandthequality

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61. GadepalliC,deCassoC,SilvaS,LoughranS,HomerJJ.Functionalresultsofpharyngo-laryngectomyand

totallaryngectomy:acomparison.TheJournaloflaryngologyandotology.2012;126(1):52-7.

62. KaziR,SinghA,MullanGP,VenkitaramanR,NuttingCM,ClarkeP,etal.Canobjectiveparametersderived

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65. Mahieu HF, van SaeneHK, Rosingh HJ, SchutteHK. Candida vegetations on silicone voice prostheses.

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66. Buijssen KJ, van der Laan BF, van derMei HC, Atema-Smit J, van den Huijssen P, Busscher HJ, et al.

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67. HilgersFJ,AckerstaffAH,BalmAJ,VandenBrekelMW,BingTan I,Persson JO.Anewproblem-solving

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PART ITREATMENT AND SURVIVAL TRENDS

CHAPTER 2T3-T4 larynx cancer in the Netherlands Cancer Institute;

10-year results of the consistent application of an organ-

preserving/-sacrificing protocol

A.J.Timmermans C.J.deGooijer

O.Hamming-Vrieze

F.J.M.Hilgers

M.W.M.vandenBrekel

HeadNeck,onlineOctober10,2014

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ABSTRACT

Background: Both organ-preserving (concurrent chemo)radiotherapy ((CC)RT) and organ

sacrificing surgery (total laryngectomy; TL) are used for treatment of advanced larynx

cancer.Thepurposeofthisstudywastopresenttheassessmentofourtreatmentprotocol

forT3((CC)RT)andT4disease(TL+postoperativeRT).

Methods:Weconductedaretrospectivecohortstudy in182consecutivepatients (1999-

2008).Theprimaryoutcomewasoverallsurvival(OS)inrelationtostageandtreatment.

Results:OnehundredtwopatientsreceivedRT(82.4%T3),20patientsCCRT(60.0%T3),

and60patientsTL+RT(91.7%T4).Five-yearOS:T352%,T448%,forRT50%,forCCRT43%

andforTL+RT52%.Five-yearlaryngectomy-freeintervalwas72%afterRT,83%afterCCRT.

Conclusions:TherewerenodifferencesinsurvivalaccordingtoTclassificationortreatment

modality. Because the majority of T3 larynx cancers were treated with (CC)RT and the

majorityofT4withTL+RT,thisgivesfoodforthoughtonwhetherthepresentprotocolfor

T3larynxcancerisoptimal.

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INTRODUCTION

Over the last twodecades, several studieshave shownanoverall increaseof survival in

headandneckcancer.Unfortunately,however,thisdoesnotseemtoapplytoallsubsites

andespeciallysurvivaloflarynxcancerseemstohavedecreasedintheUnitedStatesandto

haveremainedstableinothercountries,e.g.theNetherlandsandCanada(1-4).

Historically,theadvancedstagesoflarynxcancerhavebeentreatedwithtotallaryngectomy

(TL)withorwithoutpostoperativeradiotherapy(RT).However,inanattempttopreserve

the larynx, organ preservation (chemo)radiotherapy ((CC)RT) protocols increasingly are

beingapplied.Thisismainlybasedontheresultsoftwolandmarkstudies.Thefirstwas

theDepartmentofVeteransAffairs (VA)LarynxCancerStudyGroup(1991)showingthat

2-year survival rates in patients treated with induction chemotherapy (cisplatinum and

fluorouracil)followedbyRTweresimilartothosetreatedwithTL,exceptforT4N0disease,

whichshowedasignificantlybettersurvivalintheTLarm.Thelarynxwaspreservedin64%

ofpatients receivingorganpreservation treatment, in contrast to theobvious0% in the

TLarmofthestudy(5-7).Thesecond,purelyRT-basedorganpreservationstudywasthe

RadiationTherapyOncologyGroup(RTOG)91-11trial,whichassessedinathree-armdesign

theeffectsof theadditionofchemotherapytoRT,either inductionwithcisplatinumand

fluorouracil,orconcurrentwithcisplatinum(CCRT)only.At2-yearsposttreatment, larynx

preservationand loco-regional control rates in this studyweresignificantlyhigher in the

CCRTarm than in theother twoarms.Overall survival (OS) in the threearms,however,

didnotdiffersignificantly (8).Recently, the10-yearresultsofthisRTOG91-11trialwere

published.Similarasinthe2-yearreport,loco-regionalcontrolandlarynxpreservationstill

werehighestintheCCRTarm.However,alsoat10-yearstheadditionofchemotherapyto

theradiationtreatmentdidnotprovideanyOSbenefit(9).

BasedontheresultsoftheVAstudy,patientswithlarge-volumeT4lesionswithcartilage

invasionorextendingmorethan1cmintothetonguebasewereexcludedfromtheRTOG

91-11study.Thismeansthatonlyselectedcasesofadvancedlarynxcancerwerestudied

andthattheoutcomesofthisstudycannotbegeneralizedforalladvancedlarynxcancers,

asoftenhasbeensuggested(8).Hoffmannetal.,asalreadymentioned,suggestedthatthe

decreasedsurvivalintheUnitedStateswasinparallelwiththedeclininguseofsurgeryin

favoroforgan-preservingtreatmentmodalities.Sincethen,thereisagrowingconcernabout

thedecreasingsurvival inadvancedlarynxcancerbecauseofthisshiftinthetherapeutic

approach.

In 1999 the Dutch Head and Neck Society (former Dutch Cooperative Head and Neck

Oncology Group) published a consensus document on larynx cancer diagnostics and

treatment(10).Thisdocumentcontainedevidence-basedprotocolsonallstagesoflarynx

cancerandwas,inpart,basedontheresultsofearliernationalstudiesonthetreatment

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modalitiesandresultsinallparticipatingcenters(11).Sincethen,thetherapeuticapproach

intheNetherlandsCancerInstitutefollowedthenationalconsensusprotocolsandremained

unchangedover the last 10 years. For advanced (T3 and T4) larynx cancer this protocol

consistedofacceleratedRTforT3disease,supplementedwithconcurrentchemotherapy

incaseofextensiveneckdisease,andofTLwithplannedpostoperativeRT incaseofT4

disease.Thisprotocol remainedunchangedalsoafter thepublicationof theRTOG91-11

resultsin2003.

Inviewoftheongoingdiscussionaboutthestatusofthe(CC)RT-basedlarynxpreservation

approach in both T3 and T4 cancer, and its possible impact on survival, a retrospective

analysis was conducted to assess whether the commonly found difference in survival

betweenT3andT4(12),obviouslyalsodependingonnecknodestatus,stillexistsdespite

thefactthatT3diseasewasnottreatedsurgicallyanylongerinourInstitute.

MATERIALSANDMETHODS

Atotalof635patientswithlarynxcancerweretreatedattheNetherlandsCancerInstitute

betweenJanuary1999andDecember2008.Ofthese,197patientswithT3andT4tumors

wereselectedforthisstudy.Intotal,182patientswereeligibleforfurtheranalysis,andthe

reasonsfortheexclusionof15patientsaregivenintheflowchartinFigure1.

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this study. In total, 182 patients were eligible for further analysis, and the reasons for the exclusion

of 15 patients are given in the flow chart in Figure 1.

Figure 1. Flowchart of patient inclusion and exclusion.

The following data were collected for each patient, if available: age and sex, American Society of

Anesthesiologists (ASA) classification, staging according to the 7th edition of the Union for

International Cancer Control (UICC) TNM staging manual (2009), primary tumor site, tracheotomy

and/or debulking before primary treatment (yes/no), treatment characteristics, recurrences,

outcome and last date of follow-up.

Tumors were clinically staged according to the 7th edition of the UICC TNM staging manual

(2009). As patients treated before 2002 were staged following the 5th edition, restaging was

necessary since the 5th edition differs from the 6th and 7th edition, especially for the delineation

between T3 and T4. For restaging, clinical records, computed tomography-scans and pathology

examinations were reviewed by 2 of the authors in consensus.

The primary endpoint was OS. Although we do provide information on recurrences, disease

free survival was not calculated, because information about the cause of death in our database was

deemed not to be reliable enough, since most patients died at home. OS was defined as the period of

time the patients were diagnosed with larynx cancer until the last follow-up or death. The last follow-

Figure 1. Flowchartofpatientinclusionandexclusion.

The following data were collected for each patient, if available: age and sex, American

Society of Anesthesiologists (ASA) classification, staging according to the 7th edition of

the Union for International Cancer Control (UICC) TNM stagingmanual (2009), primary

tumorsite, tracheotomyand/ordebulkingbeforeprimary treatment (yes/no), treatment

characteristics,recurrences,outcomeandlastdateoffollow-up.

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Tumorswereclinicallystagedaccordingtothe7theditionoftheUICCTNMstagingmanual

(2009). As patients treated before 2002were staged following the 5th edition, restaging

wasnecessarysince the5theditiondiffers fromthe6th and7thedition,especially for the

delineationbetweenT3andT4.Forrestaging,clinicalrecords,computedtomography-scans

andpathologyexaminationswerereviewedby2oftheauthorsinconsensus.

TheprimaryendpointwasOS.Althoughwedoprovideinformationonrecurrences,disease

free survival was not calculated, because information about the cause of death in our

databasewasdeemednottobereliableenough,sincemostpatientsdiedathome.OSwas

definedastheperiodoftimethepatientswerediagnosedwithlarynxcanceruntilthelast

follow-upordeath.Thelastfollow-updatewasdefinedbythelastvisittotheoutpatient

clinicofourinstitute.Thelastfollow-updateandsurvivalstatuswereupdatedonAugust

1,2012.

Statistical analysis

Descriptive statistics were performed. To find differences between the groups we used

the Pearson Chi-Square, one-way ANOVA and linear-by-linear. Univariate analysis was

performedbyCoxregressionanalysistorevealfactorsassociatedwithahigherlikelihood

ofmortalityinpatientswithT3orT4larynxcancer.Furthermore,formultivariableanalysis,

Coxregressionanalysiswasperformedusingbackwardeliminationwithasignificancelevel

of10%(2-sided) toeliminateparameters.Hazardratios (HRs)and95%confidence levels

(CIs)wereestimated.ForOS, loco-regionalcontrolandlaryngectomyfreeintervalKaplan

Meier curveswere plotted. To determine loco-regional control, local, regional and loco-

regionalrecurrenceswereincluded.Incaseofasecondprimaryordistantmetastasisonly,

thedateofdiagnosiswasusedasmomentofcensoring.Othercaseswerecensoredatdate

oflastfollow-upordatethepatientdeceased.Forlaryngectomyfreeinterval,patientsat

risk(treatedwithRTorCCRT)wereincluded.DateofTLwasthedateoftheevent.Other

caseswerecensoredatdateoflastfollow-uporatdatethepatientdeceased.Tocompare

groupsLog-Rank testswereperformed.Variableswithap-value80%ofthepatientsinbothcountrieswereirradiated.Itisthusnoteworthy

thatsuchdifferenceinsurvivalwasabsentinourcohort.

The treatmentprotocol consistentlyused in thispatient cohort isbasedona consensus

documentonlarynxcancerdiagnosticsandtreatmentoftheDutchHeadandNeckSociety

(formerNetherlands CooperativeHead andNeck TumorGroup) published in 1999 (10).

Thatdocument,inpart,wasbasedonanearliernationalstudyreportingonthetreatment

resultsofT3larynxcancer(11,16-17).Thatstudyshowedthatplannedcombinedtreatment

(consistingofsurgeryandRT)significantlyincreasedcorrectedsurvival.Primarysurgeryand

primaryRThadsimilareffects.WiththeimprovedRTprotocols(i.e.reductionoftheoverall

treatmenttimeintheDAHANCAprotocol)emergingatthattime,itwasexpectedthatloco-

regionalcontrolandsurvivalwouldimprove,andtheneedforTLwithorwithoutadjuvant

RT,atthattimethestandardtreatmentforT3larynxcancerinmostheadandneckservices

intheNetherlands,woulddecrease.

The respective roles of organ preservation ((chemo-)RT) treatment and organ sacrificing

surgical treatment for advanced larynx cancer have been extensively addressed in the

recent literature(2,7,18-22).Gourinetal (2009)foundthatpatientswithT4diseasehad

significantlybettersurvivalafterTL(55%)thanafterCCRT(25%)orRTalone(0%).Alsoafter

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controllingfornodalstatus,organ-preservingtreatmentwasstillasignificantpredictorof

worsesurvival(18).Furthermore,Hoffmanetal(2006)studiedpatternsofcareandsurvival

after larynxcancerbetween1985and2001 in theUnitedStates in158.426patients (2).

Theseauthorsreportedadecreasingtrendinsurvivalfromthemid-80stothemid-90sand,

inthesameperiod,anincreaseofchemoradiationasprimarytreatmentwithadecreasein

surgery.ForT3N0M0larynxcancerspecifically,asignificantbetter5-yearrelativesurvival

was found for those patients treatedwith surgery and irradiation compared to patients

treatedwithirradiation(withorwithoutchemotherapy;64.4%versus49.4%).Itshouldbe

notedhowever,thatspecificdataregardingRTandchemotherapywerenotavailable.Also,

surgerywas not further specified in TL, endoscopic surgery or other surgery. Recently,

Dziegielewskietal(2012)foundbettersurvivalforpatientswithT3andT4alarynxcancer

treatedwithTL(with(CC)RT)comparedtoRTandCCRTandsuggestreassessmentofcurrent

treatmentguidelines(20).Also,ChenandHalpern(2007)foundTLtobesuperiortoRTand

CCRTasprimarytreatmentinpatientswithstageIVlarynxcancerintermsofOS(21).For

stageIIIdiseaseTLhadbettersurvivalthanRTintheirseries.Thefindingsofadecreased

survivalfortheadvancedstagesoflarynxcancerareseriousandwarning.Severalauthors

alreadyhaveexpressedtheirconcernsaboutthisissue(7,22).

EspeciallyinT3larynxcancerthereisdiscussionaboutwhattreatmentmodalityisbestfor

whichpatient.Besides (CC)RTandTL,other treatmentoptions forT3diseasearepartial

openlaryngealsurgeryortransorallasermicrosurgery(TLM).E.g.withrespecttothelatter

approach,recentlyCanisetal(2013)publishedtheresultsofacohortof226patientswith

pT3larynxcancertreatedwithTLM.Sixteenpercentofpatientsalsounderwentselective

neckdissectionandpostoperativeRT,andpostoperativeRTonlywasgiveninanother2%

ofthepatients.Five-yearOSwas64.4%.Thefunctionalresultswerealsoquitefavorable,

6 patients (2.7%) required a temporary tracheotomy and 2 patients (0.9%) needed a

permanent tracheotomy. Percutaneous endoscopic gastrostomy tubes were temporarily

necessaryin6patients(2.7%)andpermanentlyin3patients(1.3%).Unfortunately,nodata

onthevoicequalitywereavailable.Theauthorsconcludedthattheresultsoftransorallaser

microsurgeryaresatisfactory,buttheyalsoaddressthatthedataareonlyof1institution

andthatfurtherprospectivestudiesshouldbedone(23).Forcarefullyselectedcases,itmay

beagoodalternative.

InthemultivariableanalysisinthepresentstudyNclassificationandASAscorewerefound

tobeassociatedwithmortality.Bothfindingsareinlinewiththeliterature.Variousstudies

reportedthatpatientswithpositivenecknodeshaveworseprognosis(18,24).Also,ASA

scoreshavebeenreportedtobepredictiveformorbidityandmortalityaswellaschancefor

successfulorganpreservation(25-27).

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Nexttosurvival,qualityoflife,toxicityandlarynxpreservationareimportantparametersin

thedecision-makingprocess.Bothorgansacrificingandpreservingtreatmentsforadvanced

larynxcancersignificantlyaffectqualityoflife.Finiziaetal(1998)studiedvoiceandquality

oflifeofpatientstreatedforlarynxcancerwithRTwithorwithoutTLassalvagesurgery.

They found that irradiated patients and listeners rated their voices higher than that of

laryngectomizedpatientsusingtracheoesophagealspeech.Inmoststudies,however,scores

forqualityoflifeweresimilarregardingmostfunctionsandsymptoms(28-30).Moreover,

onehastokeepinmindthatinthelasttwodecadesmajorprogresshasbeenmadewith

respect to vocal, pulmonary, and olfactory rehabilitation,making the functional deficits

of TL less debilitating than ever before (31). Toxicity after (CC)RT can be considerable,

resulting in swallowing problems, difficulties with speech and a dysfunctional larynx.

Fortunately,thereductionoftheradiationdosetothesurroundingtissuesachievablewith

IMRThasdecreasedRTsideeffects.Especiallythroughpreservationofthesalivaryglands,

the reductionof xerostomia leads to less severedysphagia.Nevertheless, in somecases

aTL is still deemed tobe theonly solution to resolve the sequelsof (CC)RT, as recently

publishedfromourinstitute,where11%oftheTLsoverthelastdecadewasindicatedfor

a dysfunctional larynx (32). It shouldbenoted that in that studyallpatientspreviously

treatedwithRTorCCRTforanyheadandneckcancersitewereincluded.Inthepresent

study, the 5-year laryngectomy-free interval was 72% after RT and 83% after CCRT. Of

thesepatients20underwentTLforrecurrentdiseaseand5foradysfunctionallarynx.This

however givesno complete informationonhow severe toxicitywas in our (CC)RT study

population.Unfortunatelywecouldnot retrieve reliabledataon theseaspects fromthe

medicalrecords.

An obvious shortcoming of this study is its retrospective character. Also, the relative

small sample sizeprecludesdrawing far-reachingconclusions.Anaspect to stress is that

retrospective(andthisobviouslyalsocountsforprospective)studiesliketheonepresented

hereshouldtobebasedonuniformstaging.Sincethelarynxcancersinthisstudyoriginally

werestagedaccordingtothe5th,6thand7theditionoftheUICCTNMstagingmanual,the

necessityofrestagingalltumorsaccordingtothe7theditionoftheUICCTNMstagingmanual

(2009)wasobvious.Adisadvantageofre-stagingisthatcomparisonwithliteraturebased

onearliereditionsoftheUICCTNMstagingbecomesdifficult.Inthe6theditionthecriterion

minorthyroidcartilageerosionwasaddedtotheT3classificationofsupraglotticandglottic

larynxcancer.ThismeansthattumorsstagedasaT4ineditionsbeforethe6thedition,will

beclassifiedasaT3now,resultinginahigherchanceoftreatmentwith(CC)RTforatumor

thatwouldhavebeentreatedsurgicallyyearsago.Themoveoftheminorcartilageerosion

casesfromT4toT3meansthattheT3categorynowmightbemoreunfavorablethanin

thepast,butontheotherhand,itislikelythattheT4categoryhaslostitsmostfavorable

subgroup,sothattheremainingT4saretherelativelymoreunfavorablecases,neutralizing

thepotentialeffectsonsurvivalthisrestaginghasforbothcategories.Anadditionalpoint

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tomakewithregardstothepresentstudyisthatwedidincludeallT3andT4tumors,also

thelarge-volumetumorsinvadingthelarynxandwithextralaryngealspread,whichmeans

thattherewasnoselectionbiasforthelargertumorsinthiscohort,somethingthathasnot

alwaysbeenthecaseinprospectivestudiesandisaconcernwithregardstogeneralizing

resultsforalllarynxcancers(8).

Inconclusion, inthiscohort,representingasingle institutionstreatmentoutcomebased

on a consistent application (91%)of treatmentprotocols over a 10-year period, survival

accordingtostaging(T3versusT4larynxcancer),andaccordingtotreatmentmodality(TL+

RTversus(CC)RT)showednodifferencesforeitherofthetwo.Consideringthatthemajority

ofT3larynxcancersweretreatedwithorgan-preservingmodalitiesandthemajorityofT4

larynxcancerswithTL+RTthisgives food for thoughtonwhether thepresent treatment

protocolforT3larynxcancerisoptimal.

ACKNOWLEDGMENT

The authors thank Harm van Tinteren, certified statistician at the Netherlands Cancer

Institute,forhisstatisticalsupport.

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REFERENCES

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cancerintheUnitedStates:asite-specificanalysisoftheSEERdatabase.IntJCancer2005;114(5):806-16.

2. HoffmanHT,PorterK,KarnellLH,etal.LaryngealcancerintheUnitedStates:changesindemographics,

patternsofcare,andsurvival.Laryngoscope2006;116(9Pt2Suppl111):1-13.

3. KachuriL,DeP,EllisonLF,SemenciwR.Cancerincidence,mortalityandsurvivaltrendsinCanada,1970-

2007.ChronicDisInjCan2013;33(2):69-80.

4. vanDijkBA,Karim-KosHE,CoeberghJW,MarresHA,deVriesE.Progressagainstlaryngealcancerinthe

Netherlandsbetween1989and2010.IntJCancer2013doi:10.1002/ijc.28388.

5. GourinCG,JohnsonJT.Acontemporaryreviewof indicationsforprimarysurgicalcareofpatientswith

squamouscellcarcinomaoftheheadandneck.TheLaryngoscope2009;119(11):2124-34.

6. Inductionchemotherapyplusradiationcomparedwithsurgeryplusradiationinpatientswithadvanced

laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med

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7. OlsenKD.Reexaminingthetreatmentofadvancedlaryngealcancer.HeadNeck2010;32(1):1-7.

8. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ

preservationinadvancedlaryngealcancer.NEnglJMed2003;349(22):2091-8.

9. Forastiere AA, Zhang Q,Weber RS, et al. Long-Term Results of RTOG 91-11: A Comparison of Three

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JClinOncol2013;31(7):845-52.

10. KaandersJH,HordijkGJ.Carcinomaofthelarynx:theDutchnationalguidelinefordiagnostics,treatment,

supportivecareandrehabilitation.RadiotherOncol2002;63(3):299-307.

11. Tjho-HeslingaRE,TerhaardCH,SchouwenburgP,etal.T3 laryngealcancer,primarysurgeryvsplanned

combinedradiotherapyandsurgery.ClinOtolaryngolAlliedSci1993;18(6):536-40.

12. RobinPE,RockleyT,PowellDJ,ReidA.Survivalofcancerofthelarynxrelatedtotreatment.ClinOtolaryngol

AlliedSci.1991;16(2):193-7.

13. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional

radiotherapyofsquamous-cellcarcinomaofheadandneck:DAHANCA6and7randomisedcontrolled

trial.Lancet2003;362(9388):933-40.

14. NederlandseKankerregistratie.CijfersoverkankerinNederland.2012;Accessed2013,August/29.www.

cijfersoverkanker.nl.

15. GroomePA, SchulzeK,BoysenM,etal.A comparisonofpublishedheadandneck stagegroupings in

laryngealcancerusingdatafromtwocountries.JClinEpidemiol2002;55(6):533-44.

16. Manni JJ, TerhaardCH, deBoerMF, et al. Prognostic factors for survival in patientswith T3 laryngeal

carcinoma.AmJSurg1992;164(6):682-7.

17. TerhaardCH,HordijkGJ,vandenBroekP,etal.T3laryngealcancer:aretrospectivestudyoftheDutch

HeadandNeckOncologyCooperativeGroup:studydesignandgeneralresults.ClinOtolaryngolAlliedSci

1992;17(5):393-402.

18. Gourin CG, Conger BT, SheilsWC, Bilodeau PA, Coleman TA, Porubsky ES. The effect of treatment on

survivalinpatientswithadvancedlaryngealcarcinoma.Laryngoscope2009;119(7):1312-7.

19. ZhangH,TravisLB,ChenR,etal.Impactofradiotherapyonlaryngealcancersurvival:apopulation-based

studyof13,808USpatients.Cancer2012;118(5):1276-87.

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20. DziegielewskiPT,OConnellDA,KleinM,etal.Primarytotallaryngectomyversusorganpreservationfor

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Suppl1:S56-64.

21. ChenAY,HalpernM.Factorspredictiveofsurvivalinadvancedlaryngealcancer.ArchOtolaryngolHead

NeckSurg2007;133(12):1270-6.

22. Genden EM, Ferlito A, Rinaldo A, et al. Recent changes in the treatment of patients with advanced

laryngealcancer.HeadNeck.2008Jan;30(1):103-10.

23. CanisM, Ihler F,MartinA,WolffHA,MatthiasC, SteinerW.Resultsof 226patientswithT3 laryngeal

carcinomaaftertreatmentwithtransorallasermicrosurgery.HeadNeck.2013Apr18.

24. GanlyI,PatelSG,MatsuoJ,etal.Predictorsofoutcomeforadvanced-stagesupraglotticlaryngealcancer.

HeadNeck2009;31(11):1489-95.

25. ThomasM,GeorgeNA,GowriBP,GeorgePS,SebastianP.ComparativeevaluationofASAclassificationand

ACE-27indexasmorbidityscoringsystemsinoncosurgeries.IndJAnaesth2010;54(3):219-25.

26. FerrierMB, Spuesens EB, Le Cessie S, Baatenburg de Jong RJ. Comorbidity as amajor risk factor for

mortalityandcomplicationsinheadandnecksurgery.ArchOtolaryngolHeadNeckSurg2005;131(1):27-

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27. ShermanEJ,FisherSG,KrausDH,etal.TALKscore:Developmentandvalidationofaprognosticmodelfor

predictinglarynxpreservationoutcome.Laryngoscope2012;122(5):1043-50.

28. FiniziaC,HammerlidE,WestinT,LindstromJ.Qualityoflifeandvoiceinpatientswithlaryngealcarcinoma:

a posttreatment comparison of laryngectomy (salvage surgery) versus radiotherapy. Laryngoscope

1998;108(10):1566-73.

29. GuibertM, Lepage B,Woisard V, RivesM, Serrano E, Vergez S. Quality of life in patients treated for

advancedhypopharyngealorlaryngealcancer.EurAnnOtorhinolaryngolHeadNeckDis2011;128(5):218-

23.

30. HannaE,ShermanA,CashD,etal.Qualityoflifeforpatientsfollowingtotallaryngectomyvschemoradiation

forlaryngealpreservation.ArchOtolaryngolHeadNeckSurg2004;130(7):875-9.

31. vanderMolenL,KornmanAF,LatensteinMN,vandenBrekelMW,HilgersFJ.Practiceoflaryngectomy

rehabilitation interventions: a perspective from Europe/the Netherlands. Curr Opin Otolaryngol Head

NeckSurg2013;21(3):230-8.

32. TheunissenEA,TimmermansAJ,ZuurCL,etal.Totallaryngectomyforadysfunctionallarynxafter(chemo)

radiotherapy.ArchOtolaryngolHeadNeckSurg2012;138(6):548-55.

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CHAPTER 3Tumor volume as prognostic factor for local control and

overall survival in advanced larynx cancer?

A.J.Timmermans

C.A.H.Lange J.A.deBois

E.vanWerkhoven

O.Hamming-Vrieze

F.J.M.Hilgers

M.W.M.vandenBrekel

AcceptedforpublicationinLaryngoscope,2015

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ABSTRACT

Objective: Tumor volume has been postulated to be an important prognostic factor

for oncological outcome after radiotherapy or chemoradiotherapy. This postulate was

retrospectivelyinvestigatedinaconsecutivelytreatedcohortofT3-T4larynxcancerpatients.

Studydesign:Retrospectivecohortstudy.

Methods:For166withT3-4 larynxcancer (1999-2008),pre-treatmentCTandMRIscans

were available for tumor volume delineation. Patients were treated with radiotherapy,

chemoradiotherapyortotallaryngectomywithpostoperativeradiotherapy.Bothadedicated

headandneck radiologist and thefirst authordeterminedall tumor volumes. Statistical

analysis:Kaplan-meierplots,Coxproportionalhazardmodels.

Results:PatientswithT3larynxcancerhadsignificantlysmallertumorvolumesthanpatients

withT4larynxcancer(median:8.1ccrespectively15.8cc;p

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INTRODUCTION

Advanced larynxcancercanbetreatedwithradiotherapy(RT)alone,RTwithconcurrent

chemotherapy (CCRT) orwith total laryngectomy (TL) with orwithout postoperative RT

(PORT) (1-3).Decisionsabout treatmentarebasedupon tumor stagingaccording to the

Union InternationaleContre leCancer(InternationalUnionAgainstCancer) (UICC)orthe

American Joint Committee on Cancer (AJCC) TNM classification (4), functionality of the

larynx,thegeneralconditionofthepatientandpatientaswellasphysicianspreferences.

IntheNetherlandsCancerInstitute,patientswithT3larynxcancergenerallyreceiveorgan-

preservingtreatment(RT,orCCRTincaseofextensivenodaldisease),andtopatientswith

T4 larynxcancerTL+PORT isadvised,aprotocolbasedon theconsensusprotocolof the

DutchHeadandNeckSociety (5).TodetermineTandNclassification,physiciansrelyon

clinical examination, laryngoscopy, CT or MRI, ultrasound-guided fine-needle aspiration

(cytology), and biopsy. The distinction between T3 and T4 is mainly based on thyroid

cartilage destruction and extralaryngeal spread (4). Thus, T classification plays a major

role inthetreatmentdecision.However,somestudiessuggestthatTclassification isnot

sufficienttopredictoutcomeandseveralauthorsidentifiedtumorvolumeasasubstitute/

additionalprognosticfactorforlocalandloco-regionalcontrolandforsurvival(6-9).Other

authors,however,didnotidentifytumorvolumeasausefulprognosticfactorinadvanced

larynxcancer(10,11).

Recently,wepublishedtheresultson182patientswithT3orT4larynxcancertreatedin

theNetherlandsCancer InstitutewithTL+PORT,RTorCCRT(12).Nodifference inoverall

survival(OS)wasfoundbetweenT3andT4larynxcancers,orbetweenthethreetreatment

modalitiesapplied.ThiswasanunexpectedfindingsincegenerallyT3tumorsareconsidered

tohaveabetterprognosisthanT4disease,whencorrectedfornodalstatus.Thefactthat

themajorityofT3larynxcancersweretreatedwithRTorCCRTandthemajorityofT4with

TL(+/-PORT)wasapossibleexplanationforthisfinding(12). Inthatstudyallcaseswere

uniformlyrestaged(basedontheavailableradiologyreports)accordingtothelatest(7th)

UICCedition,becauseoftheclassificationhaschangedovertime.However,tumorvolume

wasnotavailableforinclusioninthatanalysis.Inviewofthelackofdiscriminatoryrolefor

Tclassificationforlocal,loco-regionalcontroland/orsurvival,thequestionarosewhether

tumorvolumecouldplaysucharoleinthispatientcohort.Therefore,theaimofthepresent

study was tomeasure tumor volume and to assess its prognostic value for local, loco-

regionalcontrolandOS.

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MATERIALSANDMETHODS

Patients

From a total of 635 larynx cancer patients treated at the Netherlands Cancer Institute

betweenJanuary1999andDecember2008,182patientshadbiopsy-provenT3orT4larynx

cancer and were treated with curative intent with RT, CCRT or TL+PORT, as extensively

described earlier (12). Patient and treatment specific data collected included age, sex,

AmericanSocietyofAnesthesiologistsscoreforcomorbidity(ASAscore),TNMclassification

(4), subsite, treatment, local and regional recurrences, distant metastases and survival

status.Inordertoachieveuniformstaginginthiscohort,becauseT3-T4classificationhad

undergone(mainlyimaging-based)changesduringthestudyperiod,tumorswerere-staged

accordingtothe7theditionoftheUICCTNMstagingmanual(2009)basedontheavailable

radiologyreports.Wewill furtherrefertothisre-stagedT-classificationastheoriginalor

Torgclassification(12).

Tumor volume assessment Sixteenpatientshadtobeexcludedfromtumorvolumeassessmentbecauseimagingwasof

insufficientqualityforadequatevolumemeasurements(n=9)orimagingcouldnotbetraced

(mostlyperformedinotherhospitals;n=7)leaving166patientsforthisassessment.In151

patientsadiagnosticCTscanwasused;in10patientsadiagnosticMRIscan.Atreatment

planningCTscanwasused in5patients,becausenodiagnosticscanwasavailable.Both

hard-copy scans and digital scans were used. Hard-copy scans were first digitized and

transferredtoadelineationsystemwhere3Dvolumeswere(re)created.Digitalscanswere

directlytransferred.Tumorsweremanuallydelineatedontheaxialslicesofthe3Dvolumes

usingdelineationtoolsandsoftwaredevelopedatourinstitute.Bothadedicatedheadand

neckradiologist(C.A.H.L.)andthefirstauthor(A.J.T.)evaluatedthescansanddelineated

all tumorvolumesseparatelyand inconsensus.Tumorvolumesweremeasured incubic

centimeter(cc).AllimageswereclassifiedfollowingtheUICCTNMstagingmanual(2009).

Wewill further refer to this revision radiological T classification as Tradrev

classification.

However,sincetheTorgclassificationwasbasedonclinicalexamination,laryngoscopyand

theoriginalimagingreportandtheTradrev

classificationwasbasedonrevisionoftheimaging

only,andalsotreatmentdecisionsobviouslywerebasedonTorg,onlytheT

orgclassificationwas

usedinthemultivariableanalysis.UsingtheoriginalTclassificationalsomakescomparison

withearlierpublishedresultspossible(12).Pathologicallymphnodeswerenotincludedin

thesevolumemeasurementsandrevisions.Instead,theoriginalmedicalrecords,imaging

andfine-needleaspirationwereusedtodeterminethepresence(N+)orabsence(N0)of

pathologiclymphnodes.

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Tumor volume as prognostic factor for local control and overall survival

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Outcome measuresOutcomemeasureswerelocalcontrol,loco-regionalcontrolandOS.Localorloco-regional

controlwasdefinedastimefromdateofdiagnosisuntil(histopathologic)confirmationof

localorloco-regionalfailure.Toassesslocalcontrol,thefirstlocalrecurrencewasrecorded.

Toassess loco-regional control, thefirst recurrence (local, regional or loco-regional)was

recorded.Incaseofresidualdisease,dateofprimarytreatmentwasusedasdateofevent.

Incaseofa secondprimary in theheadandneckarea,TL foradysfunctional larynx (or

regional)ordistantmetastasis, thedateofdiagnosiswasusedasmomentof censoring.

Othercaseswerecensoredatdateoflastfollow-upordatethepatientdeceased.OSwas

definedastimefromdateofdiagnosisuntillastfollow-upordeath.Thelastfollow-update

wasdefinedbythelastvisittotheoutpatientclinicinourinstitute.Thelastfollow-update

andsurvivalstatuswereupdatedonthe1stofApril2014.

Statistical analysis

Descriptive statistics were performed. To find differences between groups the Pearson

Chi-Square, Fishers exact test, independent t-test, one-way ANOVA, Mann-Whitney UandKruskalWalliswereused. The latter two testswereused in caseof non-parametric

distributionofdata.UnivariableanalysiswasperformedbyCoxregressionanalysistoreveal

factorsassociatedwithahigherlikelihoodoflocalfailure,loco-regionalfailure,andmortality.

Furthermore,formultivariableanalysis,Coxregressionanalysiswasusedandhazardratios

and95%confidencelevelswereestimated.Wealsotestedforapossibleinteractionbetween

primarytreatmentandtumorvolumeforlocalcontrol.Forlocalandloco-regionalcontrol

andoverallsurvivalKaplanMeiercurveswereplotted.Maximallyselectedlog-rankstatistics

wereusedtolookforpossiblecut-pointsofvolumeasprognosticfactor.Variableswitha

p-valueCCRT>RT).

In the literature studies are conflicting regarding these results. Recently, Janssens et al

(2014)prospectivelyinvestigatedtheimpactoftumorvolumeonoutcomein270patients

withcT2-4larynxcancertreatedwithacceleratedRTwithorwithoutcarbogenbreathing

andnicotinamide (ARCON). These authors foundno correlationbetweenprimary tumor

volumeandlocalcontrol.Theyalsoreportedthepresenceofacorrelationbetweenprimary

tumorvolumeandTclassification(10).Bernsteinetal(2014)concludedthatin114patients

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with advanced larynx or hypopharynx cancer treated by organ preservation strategies

tumorvolumewasnotanindependentprognosticfactorforloco-regionalcontrol.However,

theseauthorsdidfindthatahighertumorvolumewasanindependentprognosticfactorfor

disease-specificmortality(11).Ontheotherhand,thereareseveralstudiesthatidentified

tumorvolumeasaprognosticfactorforoncologicaloutcome.Hoebersetal(2013)reported

on117patientswithcT3-4larynxcancertreatedwithprimaryRTonlyandfoundthatgross

tumorvolumewasanindependentprognosticfactorforbothoverallsurvival(HR1.016(95%

CI1.006-1.026);p=0.001)and local relapse freesurvival (HR1.017 (95%CI1.007-1.027);

p=0.001),whereascTandcNclassificationwerenotsignificantprognosticfactorsforoverall

survival(6).AlsoPameijeretal(1997)foundin42patientswithT3larynxcancertreated

withRTalonethattumorvolumesignificantlyinfluencedlocalcontrol(13).Knegjensetal.

(2011)foundthatin361patientstreatedwithchemoradiationforadvancedheadandneck

cancertumorvolumewasmorepowerfulforpredictingoutcomeafterchemoradiationthan

theTNMclassification.However,inthatstudynopatientswithlarynxcancerwereincluded

(8). Finally, Yang (2013) found that in 182 patientswith larynx and hypopharynx cancer

treatedwitheithersurgeryororgan-preservingtreatmentprimarytumorvolumewasof

significantinfluenceonOSinunivariateanalysis.Becauseofmulti-colinearitybetweentotal

tumorvolume (also includingmetastaticneck lymphnodes),primary tumorvolumeand

othervariablesonlytotaltumorvolumewasincludedinmultivariateanalysis,wheretotal

tumorvolumeatacut-offvalueof8.38ccremainedasignificantpredictor(9).

It should be noted, however, that most studies focused on irradiated patients (with or

withoutchemotherapy)andthatstudiesfocusingonsurgeryarescarce(9,14).Galloetal

(2003)studied327T3N0larynxcancerpatientstreatedwithTLandreportedthatatumor

sizeofmorethan2cmresultedinahigherrisk

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Proefschrift Timmermans