Outcomes following total laryngectomy for squamous cell carcinoma: one centre experience

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ORIGINAL

ARTICLE

Outcomes

following

total

laryngectomy

for

squamous

cell

carcinoma:

One

centre

experience

S.C.

Leong

,

S.-S.

Kartha

,

C.

Kathan

,

J.

Sharp

,

S.

Mortimore

a_{DepartmentofOtolaryngology—Head&NeckSurgery,DerbyRoyalInfirmary,DerbyDE12QY,UnitedKingdom} b_{FacultyofEconomics,AdministrativeandSocialSciences,BilkentUniversity,06800Ankara,Turkey}

KEYWORDS Laryngectomy; Outcome; Cancer; Larynx; Hypopharynx Summary

Objectives: Toevaluatetheclinicaloutcomesoftotal laryngectomy(TL),complicationsand factorsaffectingsurvival.

Design:Retrospectivereviewofhospitalelectronicdatabaseforheadandnecksquamouscell carcinoma(SCCa).

Setting: LargedistrictgeneralhospitalinEngland,UnitedKingdom. Participants:PatientswhohadTLbetweenJanuary1994andJanuary2008.

Mainoutcomemeasures: 5-yeardiseasespecificsurvival(DSS)anddisease-freesurvival(DFS). Resultsandconclusions: Seventy-onepatients werereviewed,ofwhom38(54%) had laryn-gealSCCaand33(46%)hypopharyngealSCCa.TheoverallmeansurvivalperiodfollowingTL was42.4months.The5-yearDSSandDFSwasbetterforlaryngealSCCacomparedto hypopha-ryngealSCCa,althoughnotstatisticallysignificant (P=0.090,P=0.54respectively).Patients treatedforlaryngealSCCahadameansurvivalperiodof47.5monthscomparedto36.5months forhypopharyngealdisease.Thosewhohadlaryngealrecurrenceafterprimaryradiotherapy (RT)demonstrated statistically bettersurvival probabilitythan thosewho had hypopharyn-gealrecurrence(P=0.011).Patientswithoutcervicallymphadenopathyhadstatisticallybetter survival(P=0.049).Themostcommonearlycomplicationwasrelatedtothecardiorespiratory system.Onefatalcomplicationoferosionofthebrachiocephalicarteryduetothelaryngectomy tubewasnoted.Themostcommonlatecomplicationwasneopharyngealstenosis. The com-monestcauseofdeathwasduetolocoregionalrecurrence,followedbymedicalco-morbidities. Patientsreferredtospecialisedheadandneckclinichadabettersurvivalprobabilitythanthose referredtoageneralENTclinic(P=0.37).Whilethereisincreasingtendencytowardslaryngeal conservation,totallaryngectomyremainsarobusttreatmentoptioninselectedpatients. ©2012PublishedbyElsevierMassonSAS.

∗_{Correspondingauthor.}

E-mailaddress:sean.mortimore@derbyhospitals.nhs.uk (S.Mortimore).

Introduction

Laryngealcanceristhecommonestcarcinomaofthehead and neck region [1]. In 2005, 2190patients were diag-nosedintheUnitedKingdomandcaused800deathsin2006

[2].Despiteadvancesinchemo-radiotherapy(RT),surgery

1879-7296/$–seefrontmatter©2012PublishedbyElsevierMassonSAS. doi:10.1016/j.anorl.2011.10.012

continuestoplayanimportantroleinthemanagementof laryngeal cancer. Laryngeal preservation techniques such asendoscopic laser resection have been increasing popu-lar.However,totallaryngectomy(TL)remainsareasonable optionforadvanceddiseaseinselectedpatients.

Whilst therearenumerousstudiescomparingoutcomes ofdifferenttreatmentarmsforlaryngealcarcinoma,there are scarce data on patients who have undergone TL, especially with regards to long-term outcome and prog-nosis. Outcome datawould improveour abilityto council these patients regarding important therapeutic decisions and end-of-life issues. The aim of this paper was to retrospectivelyevaluatetheclinicaloutcomesofTL, post-operativecomplicationsandfactorsaffectingsurvivalrate. The impact of surgery on quality of life (QoL) was not included in thisreview asnotall patientshad QoL evalu-ation,especiallythosewhohadsurgeryatthebeginningof thereviewperiod.Furthermore,itwasnotpossibleto ret-rospectivelyevaluateQoLissuesassomeofthepatientshad died.

Methods

Patients

The ENT Department at Derby Hospitals NHS Foundation Trust is part of the regional head and neck cancer net-workcoveringsouthernDerbyshireandeasternStaffordshire (England,UK),servingapopulationofover800,000.A ret-rospective review of the departmental electronic cancer database wasundertakenbetweenJanuary 1994 and Jan-uary2008.PatientswhohadTLforsquamouscellcarcinoma (SCCa) of the larynx and hypopharynx were included, as werethosewhohadTLasasalvageprocedureforrecurrence following either primary RT or transoral CO2 laser

resec-tion(TOLR).Recurrencewasdefinedashistologicalevidence of lesion at least 12months after completion of the pri-marytreatment.Patientswithprimarycervicaloesophageal cancers and those who had less than 6months follow-up were excluded. The departmental database and patient casenoteswerereviewedforepidemiologicaldata,tumour stage,complicationsandsurvivaloutcomes.

Allpatients werestaged accordingtotheInternational UnionAgainstCancer(UICC,2002)/AmericanJoint Commis-sionon Cancer(AJCC, 2002) stagingsystem. Preoperative stagingof tumour wasperformed by endoscopyand radi-ological imaging (CT neck and chest). The management of allpatients wasdiscussed at thehead andneck multi-disciplinaryteam(MDT)meeting.Patientswerecounselled regardingpossibletreatmentoptionsandinformedconsent forTLwasobtained.Allpatientsreceivedaprimary tracheo-oesophagealpuncture,whichwasusedforfeedinguntiloral intake was established. Therapeutic neck dissection was performed at the time of laryngectomy in patients with cervicalnode involvement.Alloperationswereperformed by either JS or SM, whowere the senior surgeons in the department.PostoperativeRTwasgiventotheprimarysite and neck basedon clinicopathological risk factors includ-ingstatusofresectionmargins,perineuralinvasion,lymph nodeinvolvementandthepresenceofextracapsularnodal spread.

Complicationswerecategorisedasearlyandlateonset. Early complications were defined as those arising within fourweeks of surgery and late complications were those occurringsubsequently.Wherepatientshaddiedinthe com-munity, their General Practitioner (GP) was contacted to obtainthe dateandcause ofdeath. The standard follow-upregimeinourinstitutionfollowingTLismonthlyreview inthe1styear,2-monthlyinthe2ndyear,4-monthlyinthe 3rdand4thyearand6-monthlyinthe5thyear.Patientsare normallydischargedfromfollow-upafter5yearsbutwere advisedtoreturniftheyhadanyconcerns.Inaddition,all patientshadaccesstotheClinicalNurseSpecialistinHead andNeckCancer,includingthosewhohadbeendischarged.

Ethicalconsiderations

InstitutionalReviewBoardapprovalwasnotrequiredforthis retrospective review. The encrypted electronic database was kept on a hospital computer in a secured location, accessedonlybypassword.

Statisticalanalysis

StatisticalanalysisofthedatawasperformedwithSPSS14.0 computersoftware(SPSSInc.,IL,USA).Allsurvival probabil-itieswereestimatedbyusingtheKaplan-Meiermethodfrom thedayofTL.Log-ranktests(CoxMantel)wereperformed tocomparedifferencesbetweentheestimates.Resultswere regardedasstatisticallysignificantifP≤0.05.The cumula-tive5-yeardiseasespecificsurvival(DSS)anddisease-free survival(DFS)probabilities wereevaluated. Mean survival period,togetherwithstandarderror(SE)and95%confidence interval(95%CI)werealsocalculated.

Results

Thereview periodspanned14years.Seventy-onepatients (61males, 10females) fulfilled the inclusion criteria for thisstudy. The meanage of patients was64years (range 40—84years). The postoperative follow-up period ranged from 6months to 128months (mean 42months). Patients stayedinhospitalfor anaverage of16days(range12—20) aftersurgery.

Thirty-eight(54%)patientswerediagnosedwithlaryngeal SCCaand33 (46%)had hypopharyngealSCCa.Mostof the patients(83%)presentedwitheitherT3orT4SCCa(Table1) andhadStageIVdisease.Theremaining17%hadT1orT2 tumoursatpresentation,allofwhomhadpreviously under-goneeitherRTorTOLR.Ofthe54patientswhohadsurgery astheprimarytreatmentmodality,46(65%)hadTLandeight (11%)total laryngo-pharyngectomy (two jejunal free-flap, sixgastricpull-upreconstructionprocedure).Theremaining 17(24%)patientshadsalvagesurgery,ofwhom16(23%)had previouslybeentreatedwithRTandonepatienthadTOLR. Of these, 15 patients had TL and two had total laryngo-pharyngectomyandjejunalfree-flapreconstruction.Nearly halfofthecohort(48%)hadneckdissectionproceduresat thetimeoflaryngealresection.

Althoughtherewerenointra-operativecomplications,24 earlypostoperativecomplicationswererecorded(Table2).

Table1 Clinicalstagesoflaryngealcancer(n=38)andhypopharyngealcancer(n=33).

Larynx(n=38) Untreated Previouslytreated

T2 T3 T4 Total T1 T2 T3 T4 Total N0 3 2 9 14 4 2a _{4 1 10} N1 1 3 4 1 1 N2 1 5 6 1 1 N3 1 1 Total 3 4 18 25 4 2 5 1 13

Hypopharynx(n=33) Untreated Previouslytreated

T2 T3 T4 Total T2 T4 Total N0 2 11 13 N1 1 1 3 5 1 2 3 N2 1 7 8 2 2 N3 2 2 Total 1 4 23 28 1 4 5

a_{IncludesonepatientpreviouslytreatedwithtransoralCO}

2laserresection.

Table2 Summaryofearlyandlatecomplications.

Description Numberofcases(%)

Earlycomplication Pneumonia 4(17) Cardiacarrhythmias 4(17) Hypocalcemia 4(17) Pharyngo-cutaneousfistula 3(13) Woundhaematoma 2(8)

Deepveinthrombosis 2(8)

Woundinfection 2(8)

Chyleleak 2 (8)

Erosionofbrachiocephalicartery 1(4)

Total 24(100) Latecomplications Neopharyngealstenosis 4 (29) Tracheo-stomalstenosis 3(21) Tracheo-oesophagealpuncture related 3(21) Neuromaoftheneck 1(6) Oesophagealstricture 1(6)

Pharyngealleak 1(6)

Hypothyroidism 1(6)

Jejunalanastomoticstenosis 1(6)

Total 14(100)

The most common was related to the cardiorespiratory system(34%),frequentlyassociatedwithpre-existing medi-calco-morbidities.Transienthypocalcaemiawhichresolved priortohospitaldischargewasrecordedinfourcases.All cases of chyle leak and pharyngo-cutaneous fistula (PCF) weremanagedconservatively.OfthethreecaseswithPCF, only one patient had primary RT prior to TL. The two cases of wound infection, managed conservatively with antibiotics,didnot resultinwound dehiscence.Onefatal complicationoferosionofthebrachiocephalicarterydueto

thelaryngectomy tube wasnoted.The mostcommonlate complication was neopharyngeal stenosis (29%), followed by trachea-stomal stenosis (21%) and problems with the tracheo-oesophagealpuncturesite(Table2).Bothcasesof oesophagealandjejunalanastomoticstenosisweredilated endoscopically. There was one case of hypothyroidism, whichrequiredlong-termthyroxinereplacement.

Twenty-six patients (36.6%) remained alive during the review period (Fig.1), of whom 11 had been treated for laryngeal SCCa and15 for hypopharygealSCCa. The com-monestcauseofdeathwasduetolocoregionalrecurrence (36%),followedbymedicalco-morbidities(Table3).There were eight (11.3%) recorded cases of distant metastasis, the most common being to the lung. Six patients (8.5%) hadasecondprimarycancerdiagnosed.Theaveragetime intervaltodiagnosisofthesecondprimarywas17.6months (range 3—55). The overall mean survival period following TL was 42.4months (SE 2.8, 95% CI 37.0—47.9). Survival outcomewasnotstatisticallysignificantbetweenthemale

Figure1 Laryngealandhypopharyngealsquamouscell car-cinoma, 5-year disease specific survival(DSS) compared. NS (P=0.090).

Table3 Causeofdeathfollowingtotallaryngectomy. Causeofdeath Numberofdeaths(%) Erosionofbrachiocephalicartery 1(2)

Locoregionalrecurrence 16(36) Distantmetastasis

Lung 6(14)

Liver 1(2)

Bone 1(2)

Secondprimarycarcinoma

Bronchogenic 2 (4) Oesophagus 2 (4) Tonsil 1(2) Tongue 1(2) Medicalco-morbidities Cardiovasculardisease 6(14) End-stagerespiratorydisease 3(7)

Bronchopneumonia 3(7)

Acuterenalfailure 1(2)

Septicaemia 1(2)

Total 45(100)

and female cohorts (P=0.75). The overall DSS and DFS was0.39and0.54respectivelyat5years.Although the 5-yearDSS(Fig.2)andDFS(Fig.3)wasbetterforlaryngeal SCCacomparedtohypopharyngealSCCa,thedifferencewas notstatisticallysignificant(P=0.090,P=0.54respectively). Patients treated for laryngeal SCCa had a mean survival periodof47.5months(SE3.4,95%CI40.9—54.2)compared to36.5months(SE4.3,95%CI28.0—45.0)for hypopharyn-gealdisease.

Those who had laryngeal recurrence after primary RT demonstrated statistically better survival probability thanthosewhohadhypopharyngealrecurrence(P=0.011,

Fig.3).Thesepatientssurvivedameanof53.2months(SE 4.7, 95% CI44.1—62.4) compared to19.6months (SE 6.0, 95% CI 7.9—31.3) in those with recurrent hypopharyngeal

Figure2 Laryngeal andhypopharyngealsquamouscell car-cinoma5-yeardisease-freesurvival(DFS)ratescompared.NS (P=0.54).

Figure 3 Previously treated laryngeal and hypopharyngeal squamouscellcarcinoma5-yeardiseasespecificsurvival(DSS) ratescompared(P=0.011).

disease.The mean periodto recurrenceafter completion of primary RT was 12.9months (range 0—53) for laryn-gealSCCaand14.5months(range0—72)forhypopharyngeal SCCa.PatientswhohadTLastheprimarytreatment modal-ityforlaryngealSCCademonstratedanon-significanttrend towardspoorersurvival(mean44.5months,SE4.5,95%CI 35.7—53.2) than primary RT. However, patients who had primary TL for hypopharyngeal SCCa had better survival probability(P=0.127)comparedtothosewhohadprimary RT.Thosewhohadsurgerysurvivedameanof39.5months (SE4.7,95%CI30.2—48.7)comparedto19.6months(SE6.0, 95%CI28.0—45.0)in patientswhohadprimaryRT.Ofthe 54patients who had TL as the primary treatment modal-ity,83% wereStage IVdisease atpresentation. The mean survivalperiodforStageIVlaryngealSCCawas44.8months (SE4.6, 95% CI 35.8—53.8),compared to36.2months (SE 4.7,95% CI 26.9—45.4) for Stage IV hypopharyngeal SCCa (P=0.333).

Laryngeal SCCa patients who were N0 at presenta-tionhad statisticallybetter survival (P=0.049), averaging 51.9months(SE3.9,95%CI44.7—59.1),comparedtothose who were N positive (mean 38.7months, SE 6.2, 95% CI 26.5—50.9).This trendwassimilarlyobservedin hypopha-ryngeal SCCa, although it did not achieve statistically significance(P=0.122).Thosewithoutcervicalinvolvement survivedameanof46.3months(SE6.9,95%CI32.7—59.9), comparedto31.5months(SE5.1,95%CI28.0—45.0)inthose whohadcervicallymphadenopathy.

Twenty-twopatients,referredbytheirGPswitha suspi-cionofheadandneckcancer,wereseenwithintwoweeks (average10days)inarapidaccessspecialisedclinic,as rec-ommendedbycurrent nationalguidelines [11].The mean duration from first clinic appointment to operation was 43.7days(SE37.1).Theremainingpatientswereidentified in routine ENT clinics or after referral from other non-specialised hospital clinicians, with the average duration from referral to ENT clinic appointment of 21.4days (SE 12.4, range 2—46) and the average duration from clinic appointmenttooperationof53days(SE34.5).Nostatistical differenceinsurvivalprobabilitywasnotedbetweenthese

twogroups(P=0.37),althoughpatientswhohadbeenseen withintwoweekshadbettersurvival.

Discussion

Synopsisofkeyfindings

The overallsurvival rate was36.6%,witha meansurvival periodof 42.4monthsafter surgery.Patientswithprimary laryngeal cancers had better survival probabilities than thosewithhypopharyngealcancers.Thosewhohadsalvage surgeryforlaryngealrecurrencehadsignificantlybetter sur-vivalprobabilitythanhypopharyngealrecurrence.Advanced nodalandTstagewerebothpoorprognosticindicatorsfor survival.Therewasa non-significantsurvivaladvantagein patientswhohadprimarysurgerycomparedwiththosewho hadsalvage surgeryfor recurrence afterRT.Interestingly, itwasobservedthatpatientswhohadsalvage surgeryfor laryngealSCCahad bettersurvival thanthose who under-wentTLastheprimarytreatment modality, althoughthis trendwasnotstatisticallysignificant.

Comparisonswithotherstudies

Patients with hypopharyngeal cancer had poorer survival outcome than those with laryngeal cancer, comparable withresultsreportedbyHalletal.[3].Likewise,patients withrecurrent laryngeal cancer had longermean survival periodthanthosewithrecurrenthypopharyngealcancer[4]. Stoeklietal.reportedthatthe5-yearDSSfor39casesafter salvageTLwas0.63,withmortalityrateof49%.Incontrast, theoverallmortalityaftersalvagesurgeryinthisstudywas 65%. Other studies have reported poorer mortality rates, ashighas85% at 25months follow-upin 20 salvagecases reportedbyYoungetal.[5].Thepresentoverall5-yearDSS waspoorerthansome reportedstudies. Ina cohortof 83 StageIVlaryngealSCCastudiedbySpectoretal.,the5-year DSSwashigherat0.45,althoughthereportedDFSof0.29 waslowerthanthisstudy[6].Theoverallcomplicationrate of38%waslowerthanthatreportedbyHalletal.(48%)[3]. Noflapfailurewasreportedinthisstudy.

Pharyngo-cutaneousfistulaformation

The reported incidence of PCF formation after laryngec-tomyvariesfrom6.5%to20%inlargercaseseries[3,5,7,8]. Onlya smallproportionof patients(4%) inthis study suf-fered with a PCF. This may be due to the higher rate of primaryTL(75%)performedcomparedtosalvage laryngec-tomy.Itisalsoourdepartment’spracticetocommenceearly enteralfeedingviatheprimarytracheo-oesophagealfistula ratherthan naso-gastric tube until contrastswallow con-firmsanastomoticintegrity.Wakisakaetal.encountereda 27% rate of PCF after TLin their cohort of 63 cases [9]. Theyreportedanincreasedincidenceof PCFformationin patients whohad prior RT or combination chemo-RT, and concludedthattheadditionofchemotherapytoirradiation delaysPCFclosure.Inaddition,Boscolo-Rizzoetal.reported that diabetes mellitus, preoperative hypoalbuminemia, chronicpulmonarydiseases andchronic hepatopathywere

independent predictors for PCF formation [10]. The low numberofcasesinthisstudyprecludedmultivariateanalysis forcorrelationofriskfactorstooccurrenceofPCF.

2-weekwait(2WW)ruleforsuspectedheadand neckcancer

Patientsreferred under the2WW rulehad better survival outcome thanthose referredconventionally, although the differencewasnotstatisticallysignificant.Whilstthismay demonstratethebenefitsofrapidreferral,earlierdiagnosis andsurgery,otherfactorsalsoplayapartincluding discus-sioninaformalMDTandintroductionofnationalguidelines for the management of head and neck cancer [11]. The managementofallpatientsinthecurrentserieswere dis-cussedinaMDT.Furthermore,theoverallwaitingtimefor ENTclinicappointmentinourinstitutionhasbeenreducing, inkeepingwithcurrentguidelines.Theaverageperiodfrom dateofreferraltosurgerydifferedonlyby19daysbetween the two groups and this may also explain the statistical outcome. A 3-year review of over 1,1002WW referrals in a larger cancer centre reportedthat only 21.4% of these referralswerepositiveforheadandneckcancer[12].When comparedwithroutinereferralroutes,McKieetal.reported that the 2WW did not identify more early stage cancers

[12].Lyonsetal.alsofoundthat71%ofpatientsdiagnosed withcancerin theirdepartmentwerenotreferred bythe fasttrack 2WWsystem andthatonly 15%of patientswho werereferred tothefasttracksystem weresubsequently found tohave cancer[13].AstructuredsearchofPubMed revealedthatmostpublishedstudiestodatewereauditsof compliancewiththe2WWrule[14—16].

Clinicalapplicabilityofthestudy

Todate,fewUKcentreshavepublishedoutcomesfollowing TL.Bajaj etal. reviewed outcomesof 59 patients over a 6-year periodandreportedthat5-year survivalwas65.2%

[17].The patientcohortalsovariedfromT1toT4,which wassimilartothepresent study.The results inthis study have focused specifically on survival rates, complications andcausesofdeath.Qualityoflifeissueswerenotevaluated norweremortalitycorrelatedwithpre-existingmedical co-morbidities. Survival outcomes in patients referred under the2WWfor suspiciouscancerhave alsobeen reportedin thisstudy.Similaritiesinsurvivaloutcomeswithother stud-iesdonotnegatetheneedforU.K.specificdataaspatient cohortsdifferbetweenthesestudies.Outcomedataspecific tothepopulationbeingtreatedwouldimproveourabilityto councilpatientsregardingimportanttherapeuticdecisions andend-of-lifeissues.

SelectioncriteriaforTLhaveremainedthesame through-outthereviewperiod.Ingeneral,patientswhohadfailedRT orthosewithT3tumoursofthelarynxorhypopharynxwere eligibleforsurgery.Transorallaserresectionwasintroduced tothedepartmentin2003andsomepatientshadTLafter failedTOLR.ThetreatmentprotocolforRTforprimary car-cinomawasunchangedthroughouttheperiodofthestudy. Patients who had pre-TL tracheotomy, T4 tumours, neck node involvement (>1 node,>2cm, extracapsular spread) hadpost-TLRT.

Theresultsofthisstudyrepresentthecumulative experi-enceofTLofthedepartmentoveraperiodof14years.The studycohortcomprisedoffourgroups:laryngealor hypopha-ryngeal,primarytreatmentorsalvage.Itcanbearguedthat tomakebettersenseoftheoutcome,itwouldbebetterto considerthefourgroupsindividually.However,thenumber ofpatientsineachgroupwasrelativelysmall.Furthermore, theaimofthisretrospectivereviewwastoevaluatethe clin-icaloutcomes(survivalrate,complications,PCF)following TL,ratherthan tumourstaging, primarysite or outcomes basedonspecifictreatmentmodality.

Conclusions

While there is an increasing tendency towards laryngeal conservation,TL(primaryorsalvage)remainsarobust treat-mentoptioninselectedpatients.This treatmentmodality willcontinue toformpartofthearmamentarium of treat-mentoptionsavailabletopatientstreatedinourinstitution. Theresultsofthisstudyrepresenttheclinicaloutcomeof a cohort of patients after TL from the perspective of a districtgeneralhospitalintheUnitedKingdom.Unlike pre-vious publicationswhich have focused onoutcomesbased on tumourstaging, we have presented survival probabili-tiesfollowingTL.Outcomedatasuchasthiswouldimprove our ability tocouncil patients regarding important thera-peuticdecisionsandend-of-lifeissues.Futurereportsfrom thisdepartmentwouldexaminethecorrelationofmedical co-morbidities(ACE-27),alcohol andsmokingwithsurvival probabilities.

Disclosure

of

interest

Theauthorsdeclarethattheyhavenoconflictsofinterest concerningthisarticle.

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