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LONG-TERM OROPHARYNGEAL AND LARYNGEAL FUNCTION IN PATIENTS WITH

ADVANCED HEAD AND NECK CANCER

UITNODIGING

VOOR HET BIJWONEN VANDE OPENBARE VERDEDIGING

VAN HET PROEFSCHRIFT

LONG-TERM OROPHARYNGEALAND LARYNGEAL FUNCTION

IN PATIENTS WITH ADVANCEDHEAD AND NECK CANCER

DOOR SOPHIE KRAAIJENGA

OP VRIJDAG 8 JULI 2016 OM11:00 UUR IN DE AULA

DER UNIVERSITEITSINGEL 411 TE AMSTERDAM

AANSLUITEND BENT UUITGENODIGD VOOR EEN

RECEPTIE TER PLAATSE

PARANIMFEN

CAROLINE BAMBACHVERONIQUE KRAAIJENGA

SOPHIE KRAAIJENGA

RHIJNVIS FEITHSTRAAT 31-I1054 TV AMSTERDAM

[email protected] – 42 07 74 78

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SOPHIE ANNE CHARLOTTE KRAAIJENGA

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LONG-TERM OROPHARYNGEAL AND

LARYNGEAL FUNCTION IN PATIENTS WITH



COLOFON

Cover by: Anne Olde Kalter | www.lafarme.nlLayout by: Nicole Nijhuis | GildeprintPrinted by: Gildeprint | EnschedeISBN: 978-94-6233-316-1Online: http://dare.uva.nl

Printingofthisthesiswaskindlysupportedby:ACTA|NKI-AVL|PatiëntenverenigingHoofd-Hals|NederlandseVerenigingvoorKNO-Heelkunde|Straumann|OlympusNederlandBV|ALK-AlbelloBV|ATOSMedicalBV|Chipsoft|MediTopMedicalProducts|PENTAXNederlandBV|DosMedicalBV-kno-winkel.nl|DalecoPharmaBV|MedaPharmaBV|

TheresearchdescribedinthisthesiswasperformedattheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,theNetherlands.TheresearchwaspartlyfundedbyW.M.deHoopandtheVerweliusFoundation.Allrightsreserved.Nopartofthisbookmaybereproducedinanyform,byprint,photocopy,electronicdatatransferoranyothermeans,without prior permission of the author.

Copyright©byS.A.C.Kraaijenga2016

LONG-TERM OROPHARYNGEAL AND

LARYNGEAL FUNCTION IN PATIENTS WITH


ACADEMISCHPROEFSCHRIFT

terverkrijgingvandegraadvandoctoraan de Universiteit van AmsterdamopgezagvandeRectorMagnificus

prof.dr.D.C.vandenBoom

tenoverstaanvaneendoorhetCollegevoorPromotiesingesteldecommissie,inhetopenbaarteverdedigenindeAuladerUniversiteit

opvrijdag8juli2016,te11:00uur

door

Sophie Anne Charlotte KraaijengageborenteUtrecht

PROMOTIECOMMISSIE

Promotores: Prof.dr.M.W.M.vandenBrekel,UniversityofAmsterdam Prof.dr.F.J.M.Hilgers,UniversityofAmsterdam

Co-promotor: Dr.L.vanderMolen,TheNetherlandsCancerInstitute,Amsterdam

Overigeleden: Prof.dr.A.J.M.Balm,UniversityofAmsterdam Prof.dr.J.J.deLange,UniversityofAmsterdam Prof.dr.C.R.N.Rasch,UniversityofAmsterdam Prof.dr.H.A.M.Marres,RadboudUniversityNijmegen Dr.L.W.J.Baijens,UniversityofMaastricht

FaculteitderTandheelkunde

CONTENTS

CHAPTER 1. Generalintroductionandoutlineofthesis 9

CHAPTER 2. Currentassessmentandtreatmentstrategiesofdysphagiain 29 headandneckcancerpatients:asystematicreviewofthe2012/13 literature.CurrOpinSupportPalliatCare.2014;8:152-163.

PART 1. LONG-TERM EVALUATION CHAPTER 3. Evaluationoflong-term(10years+)dysphagiaandtrismusin 51 patientstreatedwithconcurrentchemoradiotherapyforadvanced headandneckcancer.OralOncol.2015;51:787-94.

CHAPTER 4. Assessmentofvoice,speech,andrelatedqualityoflifeinadvanced 71 headandneckcancerpatients10years+afterchemoradiotherapy. OralOncol.2016;55:24-30.

CHAPTER 5. Prospectiveclinicalstudyonlong-termswallowingfunctionandvoice 91 qualityinadvancedheadandneckcancerpatientstreatedwith concurrentchemoradiotherapyandpreventiveswallowingexercises. EurArchOtorhinolaryngol.2015;272:3521-31.

CHAPTER 6. Hyoidbonedisplacementasparameterforswallowingimpairment 113 inpatientstreatedforadvancedheadandneckcancer. EurArchOtorhinolaryngol.Online2016Apr16.

PART 2. PROSPECTIVE STUDIES CHAPTER 7. Effectsofstrengtheningexercisesonswallowingmusculatureand 135 functioninseniorhealthysubjects:aprospectiveeffectivenessand feasibilitystudy.Dysphagia.2015;30:392-403.

CHAPTER 8. Efficacyofanovelswallowingexerciseprogramforchronicdysphagia 161 inlong-termheadandneckcancersurvivors.Submitted.

CHAPTER 9. Feasibilityandpotentialvalueoflipofillinginpost-treatment 187 oropharyngealdysfunction.TheLaryngoscope.Online2016Apr14.

CHAPTER 10. Generaldiscussionandfutureperspectives 203

CHAPTER 11. Summary 221 SummaryinDutch|Samenvatting 227 ListofAbbreviations 233 Authorsandaffiliations 235 PhDportfolio 237 About the author 243 Acknowledgement|Dankwoord 245

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CHAPTER 1General introduc.on and outline of thesis

CHAPTER 1General introduction and outline of thesis

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CHAPTER 1General introduc.on and outline of thesis

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Generalintroductionandoutlineofthesis|11

1GENERAL INTRODUCTION

Head and neck cancerThe head and neck region is frequently affected by cancer.With approximately 550.000newcasesofheadandneckcancer(HNC)annually1,itaccountsforthesixthmostcommonmalignancyglobally.IntheNetherlands,in2014therewerealmost3000patientsdiagnosedwithanewprimaryHNC2.Malesaresignificantlymoreaffectedthanfemales,witharatiorangingfrom2:1to4:13.

Tumors of the head and neck aremostly squamous cell carcinomas, arising from themucosalliningoftheupperaerodigestivetract4.Thesitesoforiginofsquamouscelltumorsinclude the oral cavity, nasal cavities, nasopharynx, oropharynx, hypopharynx, and larynx(Figure 1). Since the upper aerodigestive tract is easily exposed to inhaled or ingestedcarcinogens,itisnotsurprisingthattheprimaryriskfactorsassociatedwithHNCaretobaccouse,alcoholconsumption,humanpapillomavirusinfection(fororopharyngealcancers),andEpstein-Barrvirusinfection(fornasopharyngealcancers)5.

Figure 1. Illustrationofvarioustumorsitesintheheadandneckregion6.- Oralcavity: lip,floorofmouth,oral tongue,alveolar ridge, retromolar trigone,hardpalate,and

buccalmucosa;- Nasopharynxandnasalcavities;- Oropharynx: softpalate, tonsils,posteriorand lateralpharyngealwalls,baseof the tongue,and

vallecula;- Hypopharynx:pyriformsinus,lateralandposteriorhypopharyngealwalls,andpost-cricoidregion;- Larynx:supraglottic,glottic,andsubglotticlarynx

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12 | Chapter 1

TreatmentManagementofHNCrequiresconsiderationoftumorsiteandstage(includingregionallymphnodesanddistantmetastases),treatment-relatedoncologicalandfunctionaloutcomesandmorbidity,physicianpreferencesandskills,andpatient-specificfactorssuchascomorbidityand preference4, 7. The main treatment modalities consist of surgery, radiotherapy (RT),andchemotherapy,as singlemodalityoras combined treatment.Currently,patientswithlocalized(stageI,II)diseasegenerallyreceiveeithersinglemodalitysurgeryorRT.Patientswith (locally) advanced (stage III, IV) tumorson theotherhand increasingly are receivingmultimodalitytreatment,likesurgerycombinedwith(chemo)radiationororgan-preservationtreatment,mostlyconsistingofconcurrentchemoradiotherapy(CRT)5,7.

Meta-analytic data from randomized controlled clinical trials have demonstratedimprovedloco-regionalcontrolandsignificantsurvivaladvantagesforthesecombinedCRTprotocolscomparedtosinglemodalityRT8-10.Unfortunately,preservationoftheorgandoesnotnecessarilymeanthatalsoits(oropharyngealand/orlaryngeal)functionispreserved,asithasbecomeclearthattheseintensifiedregimensareaccompaniedbymoreacuteandlatetoxicities7,11-14.Thismeansthatincreasinglythechallengeistochoosetheoptimaltreatmentfortheindividualpatient,notonlyfromasurvivalbutalsofromafunctionalperspective,toassurethepatientreceivesthebestchanceforcureattheexpenseofthemostacceptable/leastdebilitatingsideeffects4.

Oropharyngeal functionSwallowing in general, and the various phases of this process (oral, pharyngeal, andesophageal), requires a complex interactionbetween themuscles in the tongue, floor ofmouth,pharynx,andlarynx(Figure2).Duringtheoralpreparatoryandtransportphaseoftheswallowingprocess,theextrinsictonguemusclesareinvolvedbypushingthefoodbolusbackwards intotheoropharynx.Subsequently,thepharyngealphasestartswhenthefoodbolusreachesreceptorsinthepharynx,whichtriggertheswallowingreflex15. This phase is the mostcomplexonebecauseitinvolvesmanyevents,whichoccurinarapid,entirelyreflexivesequence.Thepalatalmusclesareactivatedtotightenandpullthesoftpalateupwardstopreventfoodmaterialfromenteringthenasopharynx.Thelarynxandpharynxarealsopulledupwardandthehyoidboneispulledintoananterior-superiordirection,bycontractionofthe longitudinalpharyngeal and the suprahyoidmuscles,whichassists in cricopharyngealsphincter relaxation too. Laryngeal closure by the epiglottis is achieved by contractionofthebaseof tongue, inordertopreventaspiration.Further, thetrueandfalsevocalcordsadducttoprotecttheairway.Simultaneously,thefibersofthesuperior,middle,andinferiorconstrictorpharyngealmusclescontractconsecutivelytosqueezethefoodbolusdownwardsthrough the pharynx. Finally, during the esophageal phase, the foodbolus is transportedintotheesophagus.Afterthisthirdandfinalphasetheswallowingact isfinished15-17. This



1complexphysiologiccourseofmuscleeventsandinteractionsisatriskinpatientstreatedforHNC,andunfortunately,swallowingimpairment/dysphagiaisnotuncommoninthispatientpopulation12,13.

Figure 2. Swallowingrequiresacomplexinteractionbetweenthemusclesinthetongue,floorofmouth,pharynx,andlarynx17.

Laryngeal functionNormalvoiceandspeechrequireprecisecoordinationofseveralrapid,complexneuromuscularactionsinthelarynx,thorax,andassociatedstructures.Thephonatoryprocess,orvoicing,startswhenairisejectedfromthelungsthroughtheglottis,creatingapressuredropacrossthelarynx,andeventuallyinitiatingoscillation(throughtheBernoulli-effect,seeFigure3)18,19. Therapidvibrationsofthevocalfoldsthenregulatethepressureandflowofairthroughthelarynx,andgeneratesound20.Thefrequencyofthesemucosalwavesdefinesthefundamentalfrequency (pitch)of thevoice,whereas thepressureof thepulmonaryairblownthroughthe vocal folds determines voice volume18.Thequalityofvoice isdependentonthemyo-elasticcharacteristicsof thevocal folds21.Also saliva, vocal fold lubrication,andhydrationare important factors for phonation22. Thequalityof voice is only slightly affectedby theresonancesandcharacteristicsofotherpartsofthevocaltract18,21.InFigure3aschematicoverview of the vocal tract is shown.

Speech requires movement of sound waves through the air. When the initial soundgeneratedinthelarynxtravelsthroughthevocaltract(consistingoftheoro-andnasopharynx,theoralandnasalcavities,andthelips),italtersbasedonthepositionofthepharynx,tongue,mouth,and lips. In thisway, individual speechsoundsareproduced20,and thisprocess is

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knownasarticulation.Becausespeechisbasedonthevolitionalcoordinatedmovementsofthearticulators,itcanbeaffectedseverelybychangesinmuscleortissuepropertiesofe.g.thetongue,orthesoftpalate21.

Figure 3. Airpassesthroughthevocaltract(shadedarearight23),asitisexpelledfromthelungsthroughthe actively closed glottis, and the pressure drop across the larynx initiates oscillation through theBernoulli-effect(left24)andthusvoice.

Treatment-induced toxicitiesSince the head and neck region encompasses several complex anatomical structuresessential for vital (oropharyngeal and laryngeal) functions such as swallowing, voice, andspeech,considerablefunctionaldeficitsmayoccurfollowingtreatment.Obviously,functionaldisorderscanoccuraftersurgicaltreatment,dependingontheextentoftheresectionandthereconstructiontechniquesused25.However,alsoorgan-preservationtreatmentwith(C)RT, the focal point of this thesis,may result in acuteor delayed complications. ThemostcommonacutetoxicitiesofCRTforHNCaremucositis,pain,dermatitis,xerostomia,lossoftaste, hoarseness,weight loss,myelosuppression, ototoxicity, nephrotoxicity, nausea, anddysphagia. Themost frequent late side effects of CRT are ototoxicity, xerostomia, loss oftaste,dysarthria,progressivefibrosis,trismus,andagaindysphagia7.

Swallowing impairmentDysphagia,acuteandchronic, iscurrentlythemostcriticalandpotentially lifethreateningclinicalprobleminpatientswithadvancedHNC.Withapotentialriskforaspiration,itmayevenresultindeathduetoaspirationpneumonia7,26-28.Theetiologyismultifactorial.Before



1treatment,thetumorintheupperdigestiveandrespiratorytractalreadybyitselfcancauseswallowing problems or aspiration. After organ-preservation treatment, exposure of theswallowingstructurestoradiation–evenmoresoifcombinedwithchemotherapy29–mightleadtodecreasedsensitivityandpharyngealresidue,withhighriskofconcomitant(silent)aspiration30. Additionally, post-treatment radiation-induced sequelae such as xerostomia,fibrosis, and/ormuscle atrophy canprofoundly affect the ability to clear the bolus, or toprotect the airway during swallowing31-33. A combination of decreased tongue strength,reducedhyolaryngealelevation,lackofpharyngealconstrictoractivity,lackofvelopharyngealor laryngeal valving forces, and/or insufficient opening of the esophageal inlet may allcontribute to dysphagia34-36. Eventually, the inability to swallowmay lead to problems ofpropernutritionalintake.Tubefeedingisoftenunavoidableintheacutephaseoftreatment,and10to30%ofpatientsstayconfinedtothissubstituteintakerouteatlong-termaswell37-

39.Consequently,thequalityoflifeinthesepatientsisoftensignificantlyreduced13,40.

Voice and speech problemsVoicequalityandspeechproductioncanbeaffectedbytumors involvingthetongue,softpalate,tonsils,orlarynx.Inpatientswithcancersoftheoralcavityandoropharynx,destructiveeffects of the tumor will mainly affect patients’ articulation and/or speech, whereas inlaryngealcancerpatients,thetumoroftenhasnegativeeffectsonvoicequality21,41.Moreover,organ-preservationtreatmentmayhaveadverseeffectsonbothvoiceandspeech,relatedtoradiationdosestotheoralcavity,pharynx,salivaryglands,and/or larynx22,42.Theadditionofconcurrentchemotherapytohigh-doseRTat leastdoublestheriskof laryngealedemaandthusdysfunction21,22,43-47.Asmentionedabove,sufficientairflow,saliva,andespeciallypharyngealandvocalfoldlubricationplayanimportantroleduringvoicing.Hence,radiation-induced vocal problems may occur due to observable dryness of the laryngeal mucosa,muscleatrophy,fibrosis,edema,anderythema22.Consequently,irregularvocalfoldvibrationand/orinsufficientglotticclosurewillresultindeterioratedvoicequality18,20.Patientsmainlycomplain about hoarseness, increased vocal effort, and breathiness. Recent studies thatevaluateddecreasedvoicequalitypost-treatmentshowedsignificantimpactonqualityoflifeandemotionaldistress43-46,48.

Duringspeech/articulation,theinitialsoundismodulatedbyvariationsofthevocaltract,toproducedifferent vowels. Speech canbeaffectedas result of radiation to the tongue,softpalate,orsurroundingmusculatureorsofttissueofthevocaltract21.Reducedspeechintelligibility and impaired articulation can occur when the tumor affects the tongue,velopharyngeal function(challengingthecapacity tobuildandrelease intraoralpressure),and/or theability tobuildbreathingpressures49.Consequently, thedisorders canhamperspeechintelligibilityandverbalcommunication,andmayaffectpatients’dailylifeactivitiesand interactions,which are associatedwith severe functional andpsychosocial problems,andreducedqualityoflife47,49,50.

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Preventive rehabilitationOver the last decades, survival rates formanyHNC sites are increasing, and the focus inHNC treatmenthasevolved fromoverall survival and loco-regional control, towards long-termqualityof lifeand late sideeffects.Hence, speechandswallowing rehabilitationhasbecome an inherent part of the multidisciplinary treatment of HNC patients. Severalinterventionstrategiesexist,includingtheapplicationofcompensatorytechniques(posturalchanges,diet/bolusmodifications)andswallowornon-swallowmaneuversand/orexercises.Successful rehabilitation depends largely on the cause of (oropharyngeal) dysphagia.However,althoughpreventiverehabilitationtherapyisofteneffectiveinsolvingsomeofthe(less severe) swallowing problems, inmore critical scenarios a permanent gastrostomy isoftennecessary39,51.

Variousmethodshavebeenconsideredtopreventorreducelong-termtoxicities.Initially,advancedRTtreatmentplanningtechniquessuchasIntensity-ModulatedRadiationTherapy(IMRT)weredeveloped,asrelationshipswerefoundbetweenradiationdosagetopharyngealstructures and swallowing function or trismus52-55. Compared with 3-dimensional (3D)conformalRT,IMRThastheabilitytopreciselydeliveraveryhighdosetothetumor,whileat the sametimeminimizing theamountof radiation to the tumor’s surroundingnormaltissues56.Thisreducestheradiationdosetothepharyngealmusculatureandstructures(i.e.thepharyngealconstrictormusclesandsalivaryglands)andlimitstheextentoftheirradiationfields,resultinginlesspost-treatmentdysphagiaandtrismus30,56-58.

Additionally, multiple studies have demonstrated benefits of maintained use of theswallowingmusculatureduringtreatment (the ‘use itor lose it’concept,seebelow).Thiscan be achieved by avoiding periods of nothing per oral (e.g. feeding tube dependency)duringandaftertreatmentas longaspossible,andbyadherencetotargeted(preventive)swallowingexercisesthatkeepallstructures involved inswallowing‘inmotion’topreventnon-useatrophy.Maintainedoralintake(insteadofstandard/prophylacticgastrostomytubeplacementwithoutanyintake)hasbeenshowntoleadtobetterswallowingfunctionafterCRT,probablydue tocontinueduseof theswallowingmusculature33,59,60.However, somestudies reportedbetter (swallowing) outcomeswith prophylactically placedpercutaneousendoscopicgastrostomy(PEG)tubestomaintainweightandnutritionduringtreatment,ascomparedtothoseplacedreactively61,62.Todate,thereisnoactualconsensusonwhethertoplace aPEG tubeprophylacticallyor reactively. Forpreventive rehabilitationprograms,benefitsalreadyhavebeendemonstrated.Theseprogramshavebeenassociatedwithalonglistofpositiveeffects:improvedqualityoflife63,betterbaseoftongueretractionandbettermaintainedepiglottic inversion64, superiormusclemaintenanceand functional swallowingability65, better oral intake and clinician-rated swallowing function66, improved mouthopening67,68,betteroralintakeandshorterdurationoffeedingtubedependency60,69,70,andlessaspiration, lessPEGdependency, and lesshospitalization39 post-treatment.Moreover,



1vanderMolenetal.inthefirstRCTonthistopicdemonstratedthatcompliancewiththesepreventiveexerciseswasquitegood,withamajorityofpatients(69%)beingabletoperformtheexercisesbothduringthecourseoftheirtreatment,andafteritscompletionforupto10weekspost-treatment67,68. Inorder to further limit restrictions indaily lifeactivityandfunctioning after treatment, multidisciplinary HNC rehabilitation programs subsequentlyalsohaveshownsignificantandclinicallyrelevantimprovementsinhealth-relatedqualityoflife71.However,sincedysphagiacandevelopand/orprogressyearsafterCRT37,72,long-term,preferablyprospective,functionaldatashouldbecollectedtoassessdeglutitionandotherfunctions(i.e.voice,speech)inHNCsurvivors73.

Exercise therapyAsmentionedbefore,preventionofnon-useatrophyhasbecomeincreasinglyimportantinpatientswithadvancedHNCundergoing(C)RT.Manyexerciseshavebeendevelopedinthefieldofdysphagia74.Theseincluderangeofmotionorresistanceexercises(withorwithoutmedicaldevicessuchastheTheraBite®device),behaviouralswallowexercisessuchasthe(super-)supraglotticswallow15,75,76, theeffortfulswallow15,77,78, theMendelsohnmaneuver75,79,andtheMasako(tongue-holding)maneuver78,andnon-swallowexercisessuchastheShaker(head-raising)exercise80(Table1).

Especially the Shaker exercise, a combination of an isometric and isokinetic head-liftexercise,hasproventobeeffectiveinstrengtheningthesuprahyoidmusculatureandreducingpost-swallow aspiration in patients with dysphagia, by improving elevation and anteriorexcursionofthehyolaryngealcomplex,andupperoesophagealsphincter(UES)opening74,81,82. TheeffectivenessoftheShakerexerciseaspreventiverehabilitationexerciseforHNCpatientsundergoingCRTwasrecentlyalsodemonstrated36.AsanalternativetherapeuticinterventionforpatientswhofindtheShakerexerciseinthesupinepositionphysicallychallenging83,Yoonet al. investigatedanotherexercise toactivate the suprahyoidmusculature: the chin tuckagainstresistance(CTAR)84.Thisexerciseinvolvestuckingthechinashardaspossibleonarubberball.ThoughtheCTARexerciseisperformedinaseatingposition,thetrajectoryoftheheadandneckflexionduringtheCTARexercisemirrorsthatoftheShakerexercise.TheCTARexercisecanbecarriedoutforbothisometricandisokinetictaskstoo,andstrengthensthe suprahyoidmuscles in the sameway as the Shaker exercise does84.Moreover, itwasdemonstratedthattheCTARexercisegeneratesevengreatermuscleactivityinthesuprahyoidmusculaturecomparedtothehead-liftexercise.Similarly,thejawopeningagainstresistance(JOAR)exercise,whichisthoughttoimprovehyolaryngealelevation,UESopening,andtimeforpharynxpassageaswell85,86, canbeapplied inan isometricandan isokineticmanner.Thesereportssuggest that thegoalof strengthening thesuprahyoidmusculaturewithanassociated increase inUESopeningmightbeaccomplishedwithavarietyof techniques74. However, although these trainingmaneuvershave someprovenefficacy, it is not entirely

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clearwhetherthesemaneuversactuallyresultinbetterswallowingfunctioninpatientswithdysphagia.

Table 1.Summaryofbehaviouralswallowandnon-swallowmaneuversorexercisescommonlyusedindysphagiatherapy(adaptedfromDysphagia Management in Adults and Children, by Groher and Crary, 201674).

Technique Performance Intent Physiology Outcomes

Side-lying Lie down with strongersidelower

Slowsbolus;Providestimetoadjust and protect airway

Emphasizespharyngealcontraction

Lessaspiration

Chin-up Elevate chin Propelbolustobackof mouth

Widensoropharynx;Increases PES pressure

Betteroraltransport

Chin-down Lower chin Improves airway protection

Narrowsoropharynx Lessaspiration

Head-turn Turn head to rightorleft

Reducespost-swallow residue and aspiration

Redirectsbolustostrongersideofpharynx;Lowers PES pressure

Increased amount swallowed;Lessresidueandlowerriskofaspiration

Supraglotticswallow

HoldbreathSwallow Gentle cough

Reducesaspirationbyincreasingglottalclosure

Horizontalglottalclosure;Increasedmovement of swallow structures

Reducedaspiration;Increasedlaryngealexcursion

Super-supraglotticswallow

HoldbreathBear downSwallowGentlecough

Reducesaspirationbyincreasingglottcalclosure

Horizontalandanteroposteriorglottalclosure;Increasedmovement of swallow structures

Reducedaspiration;Increasedlaryngealexcursion

Mendelsohn maneuver

Squeezeswallow at apex

Improvesswallowingcoordination

Increasedandprolongedhyolaryngealexcursion

Improvedswallowingcoordination;Lesspost-swallowresidue;Lessaspiration

Effortfulswallow

Swallow harder Increaseslingualforce on bolus

Increasedtongue-palatepressures;Increaseddurationofswallow;Increasedtonguebasemovement

Less residue

Head-lift(Shaker)exercise

Isokineticandisometric head-liftfromsupineposition

Reducespost-swallowaspiration

Improvedelevationandanteriorexcursionofthehyolaryngealcomplex;ImprovedUESopening

Lessaspiration

Abbreviations:PES=pharyngo-esophagealsphincter;UES=upperesophagealsphincter.



1Swallowing rehabilitation principlesCurrently, the possibilities of achieving permanent changes in swallowing physiology byexercise-based dysphagia interventions are increasingly investigated87-89. The primary objectiveistoeffectchanges(i.e.improvedstrength,durationandtiming)inthephysiologiccomponents of swallowing, which will have direct influences on bolus flow kinematicsthroughthepharynx90.Additionally,inordertoachievelong-termeffects,theexerciseshouldbe‘rehabilitative’,meaningthattheexerciseshouldresultinpermanentchangesinaswallow(i.e.makingtheswallowstrongerorfaster)89-91.

Basedonthesamemethodsusedinphysical(orsports-)rehabilitation,therehabilitativeexercisesshouldaddressallprinciplesofstrengthtraining(i.e.specificity,individuality,andtransference)derivedfromrepeatedstrengthorendurancetraining92,93.SincedysphagiainHNCpatientscanbeassociatedwithcentralandperipheralsensorimotordeficits90,neuralplasticity ishere the coreprinciple89.Neuralplasticitymeans ‘theabilityof thebrainandnervous system to structurally and functionally change’89. Several specific principles inthis field of exercise rehabilitation should be incorporated into therapy92. First, theuse it or lose it principle, indicating that disuseof the swallowingmechanism, i.e. by a nothingper oral status, will result in muscle atrophy and diminished cortical representation andinnervation89-91.Second,theuse it and improve itprinciple,implicatingthatpatientsshouldpurposefully swallowmoreoften to improve swallowing (inotherwords: it isessential tobuildcompetenceofswallowing,notjustallowingapatienttocompletethe(simple)actofswallowing)89-91.Third,byimplementingtaskspecificityintoatrainingregimen,thetrainingtaskwillresembletheend-goalasmuchaspossible,andperformanceofaspecifictaskwillbeimproved.Thisshouldbeincorporatedinaregimenofadequateload,repetition,volume,anddurationofexercises, to forcecentralandperipheralmotorunitadaptations89-93. The principle transferencemeansthatcomplexneural,biochemical,andhemodynamicsystemsactivatedduringexercisecanhavewidespreadeffectsthroughoutrelatedorparallelsystemsof the body89-91,93.Inthisway,othermotorunitscanlearntoparticipateinthetaskoreventakeover thetask89.Finally, intensitydefines ‘theamountofeffortnecessary ina trainingprogram’90, 91, 93. Sufficient intensity is achieved with mechanical or resistive loading, theamount or repetition of practice, andwith adequate duration of training over time93. As recentlyasAugust2015,Langmoreetal.reportedthatincreasingordecreasingthe‘resistiveload’ofswallowingisanelusivechallenge89,achallengeworthwhiletobetakenon.

As swallowing is considered a submaximal muscular activity, the muscular strengthgeneratedtosuccessfullycompletetheswallowingactislessthantheso-called1-repetitionmaximum(1RM), i.e.themaximalforcethatcanbegeneratedbytheswallowingmusclesinasinglerepetition93.Consequently,strengthtrainingregimensshouldstartwithaninitialresistanceof60%to75%of1RM94,95.Moreover,tomaximizeimprovementsovertime,theapplicationoftheso-called‘progressivemuscleoverload’principleduringtheexerciseperiodhastobeanessentialpartofthetrainingregimen89,92,93.

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Correlation with voice and speechDuringswallowing,voiceandspeechproduction,moreorlessthesamemusclegroupsareused.Aswehaveseen,oropharyngealdysfunctionisassociatedwithcentralandperipheralsensorimotordeficits90,andalsolaryngealfunctionsmaybeaffected,resultinginvoicedeficitsor dysarthria41,90.Consequently,asplasticityisexperiencespecific,intensivestrengthtrainingoftheswallowingmusculatureandstructuresmighthavepositiveeffectsonvoicequalityandspeechintelligibilityaswell.Itremainstobeseenifimprovementofswallowingfunctioninpatientswithchronicdysphagiawillresultinimprovedvoiceandspeechoutcomesaswell.

Surgical procedures Whenrehabilitative(conservative)measuresareinsufficienttohelpensuresafeoralintake,surgicaltreatmentmaybeconsidered.Theprimarygoalsoftreatmentaretoimprovefoodtransfer,thatis,topreventmalnutritionanddehydration,andtoreducetheriskofaspiration.Theapproachchosendependsinpartuponthecauseofthe(oropharyngeal)dysphagia.

Defective relaxation of the upper esophageal sphincter (UES), for instance, resultingin less powerful propulsion, can sometimes be remedied by reducing the tonus of thepharyngealmusculature.Thiscanbeobtainedbyacricopharyngealmyotomy,eitherviaanopenprocedure,orendoscopicallyusingaCO2laser96-98.Asaresult,thefoodboluscaneasierovercome the reduced resistance of theUES, and enter the esophagus. Also temporarilyeffectsofweakeningthecricopharyngealmusclebyesophagealdilatationorbotulinumtoxininjection successfullyaredescribed inpatientswithUESdysfunctionbasedonunderlyingmuscle spasm or hypertonicity96,99.However,bothprocedureshavetheirrisksandpossiblecomplicationssuchaspharyngocutaneousfistulaformation,(retropharyngeal)infection,orpostoperativeaspirationpneumonia98,100.Moreover,the improvementrate ismuchhigherforidiopathicdysfunctionandneurologicdysphagia,ascomparedtoswallowingdysfunctionasresultofHNCtreatment98.

Another invasive surgical technique to treat dysphagia and aspiration is hyolaryngealsuspension. As already mentioned, the larynx elevates and moves anteriorly under thetonguebaseduringswallowing,tomoveitfromthepathofthefoodbolus,andtoassistinUESopening.Ifthereisseriouslimitationinlaryngealelevation,apermanenthighpositionofthelarynxcanbeobtained,bysuspensionofthehyoidboneandadherentthyroid-cricoidcomplextotheanteriormandible101.Sincethevocalcordsarenotmanipulated,thevoiceshould remain unimpaired101.Currently,theprocedureisoftencombinedwithamyotomyoftheUES,topermanentlyopentheentranceoftheesophagus.Kosetal.evaluatedthelong-termresultsoflaryngealsuspensionandUESmyotomyin17patientswithlife-threateningaspiration,and1yearaftertreatmentitwasfoundthatfulloralintakewithoutaspirationwasachievedinmostofthepatients36.



1Finally, as ‘last refuge’, a functional total laryngectomy (TL) canbe considered inHNC

patients with a dysfunctional larynx after organ preservation treatment, if there is noreasonable likelihoodof functional recovery. Ina seriesof25patientsof theNetherlandsCancerInstitute,itwasshownthatswallowingproblems,whichoccurredinallbut1patient(96%),decreasedconsiderablyafterfunctionalTL,withonly4of14patients(29%)havingpersistentdysphagiaafter2years. Inconcordance,tubefeedingalsodecreasedfrom80%priortosurgeryto29%at2yearspost-treatment102.

Theabovedescribedmethods,exceptTL,playasubordinateroleinHNC-relateddysphagiaafter(C)RT,notonlybecausetheresultsarerelativelylow98,butalsobecausethecomplicationrisksareveryhighaftersuchsurgicalprocedures.Thepriortreatmentoftencausesdelayedhealing.Forinstance,afterTLforadysfunctionallarynxthepharyngocutaneousfistularatewasover50%102.

This shortdescriptionof surgical techniques isgiven for completeness sake. Since thecurrentthesisfocusesonnon-surgicalorminimalinvasivesurgicaltechniquesfortreatmentofchronicdysphagia,nofurtherattentionwillbepaidtothesesurgicalprocedures.

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OUTLINE OF THIS THESIS

This thesis startswith general aspects of oropharyngeal function following treatment foradvancedheadandneckcancer.Chapter 2consistsofasystematicreviewonthecurrentassessmentandtreatmentstrategiesofpatientswithheadandneckcanceranddysphagia.

Part1consistsofcross-sectionalcohortstudiesonlong-termoropharyngealandlaryngealfunction following organ-preservation treatment for advanced head and neck cancer.In Chapter 3 and Chapter 4 a patient population previously treated with concurrentchemoradiotherapyisstudiedonlong-termfunctionalswallowing,mouthopening,andvoiceandspeechoutcomesatmorethan10yearspost-treatment.InChapter 5acohortofpatientspreviouslyalsotreatedwithpreventiveswallowingrehabilitationisevaluatedmorethan5years post-treatment. In Chapter 6theparameterhyoidbonedisplacementforswallowingimpairmentisinvestigatedintherehabilitatedpatientpopulation.

Part2describesprospectivestudiesonnon-surgicalorminimalinvasivetreatmentstrategiesfororopharyngealandlaryngealdysfunction,basedontheinsightsobtainedwiththecross-sectionalstudiesinPart2.Chapter 7describesanewlydevelopedswallowingexerciseaidandthefeasibilityandeffectsofstrengtheningexercisesonswallowingmusculatureandfunctionachievable with this tool in senior healthy subjects. In Chapter 8 this dedicated treatment regimenisstudiedinaphase-1/2clinicaltrialamongpatientswithchronic,therapy-resistantdysphagia. In Chapter 9 the feasibility and potential value of an experimental treatment(lipofilling)isstudiedinpatientswithpost-treatmentoropharyngealdysfunction.

Finally, in Chapter 10, the results obtained in the current thesis are discussed. Futureperspectivesaredwelledupon.ThisthesisendswithageneralsummaryinChapter 11.



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97. QuSH,LiM,LiangJP,SuZZ,ChenSQ,HeXG.Laryngotracheal closure and cricopharyngealmyotomy for intractable aspiration anddysphagia secondary to cerebrovascularaccident.ORL JOtorhinolaryngol Relat Spec.2009;71:299-304.

98. Hoesseini A, Honings J, Taus-MohamedradjaR, van den Hoogen FJ, Marres HA, van denBroek GB, et al. Outcomes of endoscopiccricopharyngeal myotomy with CO2 lasersurgery:Aretrospectivestudyof47patients.HeadNeck.2016.

99. Ahsan SF,Meleca RJ, Dworkin JP. Botulinumtoxininjectionofthecricopharyngeusmusclefor the treatment of dysphagia. OtolaryngolHeadNeckSurg.2000;122:691-5.

100. Brigand C, Ferraro P, Martin J, DuranceauA. Risk factors in patients undergoingcricopharyngeal myotomy. Br J Surg.2007;94:978-83.

101. Hillel AD, Goode RL. Lateral laryngealsuspension: a new procedure to minimizeswallowing disorders following tongue baseresection.Laryngoscope.1983;93:26-31.

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28 | Chapter 1

102. Theunissen EA, Timmermans AJ, Zuur CL,Hamming-VriezeO,PauldeBoerJ,HilgersFJ,et al. Total laryngectomy for a dysfunctionallarynx after (chemo)radiotherapy. ArchOtolaryngol Head Neck Surg. 2012;138:548-55.

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CHAPTER 2Current assessment and treatment strategies of

dysphagia in head and neck cancer pa.ents:

a systema.c review of the 2012/13 literature

S.A.C. Kraaijenga L. van der Molen

M.W.M. van den Brekel F.J.M. Hilgers

Curr Opin Support Palliat Care. 2014; 8: 152-‐163.

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CHAPTER 2Current assessment and treatment strategies of

dysphagia in head and neck cancer pa.ents:

a systema.c review of the 2012/13 literature


M.W.M. van den Brekel F.J.M. Hilgers

Curr Opin Support Palliat Care. 2014; 8: 152-‐163.

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30|Chapter2

ABSTRACT

Purpose of review: Dysphagia,or swallowing impairment, isa serious sequelofheadandneckcancer(HNC)anditstreatment.ThisreviewfocusesontherapidlygrowingliteraturepublishedduringthepasttwoyearsaboutthecurrentassessmentandtreatmentstrategiesofdysphagiainHNCpatients.

Recent findings: Functional swallowingassessmenthasbecome standardof care inmanyHNCcentres,topreventoridentify(silent)aspiration,tooptimizefunctionaloutcomes,andtodeterminetheappropriaterehabilitationstrategy.Alsopreventiveswallowingexercisesareconsideredmoreandmoreinthepre-treatmentsettingwithpromisingresultson(pharyngeal)swallowing function. However, there is a lack of consensus regarding type, frequency, orintensityoftheexercises.Furthermore,long-termfollow-upofswallowingfunctionmightbenecessary,giventhepotentialforlong-termsequelsfollowingHNCtreatment.

Summary:Regardingdysphagiaevaluationthereisstillalackofauniform‘gold-standard’forbothassessmentandtreatmentstrategies.Morehighqualitydata,adequatelycontrolled,adequately powered and randomized, on prophylactic and therapeutic swallowingexercisesareneeded,withlongerfollow-upandbetteradherencetotreatment,forbetterunderstandingtheeffectsofchemo-andradiotherapydosage,andoffrequency,timinganddurationoftreatment,toimproveswallowingfunctionandoptimizequalityoflife.

KEY WORDSHead andNeck Cancer – FunctionalOutcomes –Dysphagia – Assessment – Treatment –QualityofLife


Systematicreviewof2-yearsdysphagialiteratureinheadandneckcancer|31

2

INTRODUCTION

Asswallowingisoneofthemainfunctionsinwhichoral,pharyngealandlaryngealfunctionscooperate,tumorsinthisareaandtreatmentsequelscanseriouslyimpairswallowingfunction.Combinedchemo-radiotherapy(CRT)regimensareincreasinglyusedasprimarytreatmentof advanced-stage head and neck cancer (HNC). Although thesemodalities are generallyseenasorgan-preserving, unfortunately functionpreservation isnot alwayspossible.CRThassignificantsurvivalbenefitforseveraltumourscomparedtoradiotherapyalone,buttheincidenceofacuteandlong-termtoxicities(secondarytoxerostomia,radiationfibrosisandchangesininnervation)ishigheraswell1.Alsosurgicaltreatmentsaffectswallowingfunction,in terms of delayed pharyngeal transit times and high aspiration incidence (12-50%)2. Swallowingdisordersdependmainlyonextentofresection–especiallyoftongue(base)andpharyngeal/ laryngeal structures – and reconstruction techniques used3, 4. However, evenin caseof laryngectomy, inwhichaspiration is precluded,patients canhavedysphagia asprotrusionintheoro-/neopharynxcanbecomeproblematic.

Thereisgeneralconsensusthatadverseeffectsoftreatmentonswallowingfunctionaremorepronouncedthanonotheraerodigestivetractfunctions,suchasspeechandbreathing1,5.Besides,locallydestructiveeffectsofthetumourpriortotreatment(dependingonsiteandstage),andqualityofrehabilitationareinfluentialfactorsaswell.Severedysphagialimitsoralintakeandcanprofoundlyaffectbothcompliancetotreatmentandpost-treatmentrecovery,asitmaycontributetomalnutrition,dehydrationandaspirationpneumonia.Furthermore,long-termdysphagianegativelyimpactspatient’ssocialcontactsandqualityoflife(QOL)andcanbedetrimentaltopatients’nutritionalbalance(tubefeedingdependency).

Todate, studies about reducingdysphagia primarily focusedon reducingCRT-inducedtoxicities. Variousmethods have been considered, such as IntensityModulatedRadiationTherapy(IMRT)toreducepharyngealmusculaturedose1,6,7.Furtheron,preventiveswallowingexercisesseemtobenefitHNCpatients8.However,whileIMRTandearlyswallowingtherapyarepromising,stillupto2/3ofHNCpatientspresentwithdysphagiawhendiagnosed4,whichmayevenriseupto75%post-treatment9.

Giventhelackofanuniformassessmentmethod10,evaluatingdysphagiaisstillachallenge.Optimaltreatmentstrategiesremainuncertaintoo,sincemoststudiesabout(preventiveandrehabilitation)strategiesstillareratherlimitedinsizeandscope.ThepurposeofthisreviewwastosummarizecurrentassessmentandtreatmentstrategiesfordysphagiafollowingHNC,andtogivedirectionsforthefuture.

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32 | Chapter 2

METHODOLOGY

OnOctober31,2013,asystematic literaturesearchwasperformed inMEDLINE/Pubmed,EMBASE, and Cochrane, to identify all recently published articles on assessment andtreatmentofdysphagiafollowingHNC.

Search strategyAllpossiblesynonymswereincluded,combinedwithrelevantMesh-andEMTREE-termsforthesearchinMEDLINEandEMBASErespectively(Table1).LimitsaspublicationlanguageinEnglish,publicationdatesince2012,researchinhumanadults,andrelevantstudydesignswereused.Titles/abstractsofallhitsweresubsequentlyscreenedonrelevance(matchingdomain,determinant,andoutcome).Possiblyrelevantarticleswereobtainedfull-textandevaluated independentlybytworeviewers.Successively,relatedarticlesandreferencesoftheselectedarticlesandreviewswerescreenedbythereviewers.

Table 1. Search terms

MED

LIN

E, E

MBA

SE*

& C

OCH

RAN

E

#1:(“HeadandNeckNeoplasms”[Mesh]ORheadandneckcancer[ti/ab]ORHNC[ti/ab])#2:(headandneck[ti/ab]ORoralcavity[ti/ab]ORnasopharyn*[ti/ab]ORoropharyn*[ti/ab]ORhypopharyn*[ti/ab]ORlaryn*[ti/ab]NOTesophag*[ti/ab])#3:(“Neoplasms”[Mesh]ORcancer*[ti/ab]ORtumor[ti/ab]ORtumors[ti/ab]ORtumour*[ti/ab]ORneoplasm*[ti/ab]ORmalignanc*[ti/ab]ORcarcinoma*[ti/ab])#4:#1OR(#2AND#3)

#5:(“deglutition”[Mesh]OR“deglutitiondisorders”[Mesh]ORdeglutition[ti/ab]ORswallow[ti/ab] OR swallowing[ti/ab] OR dysphagia[ti/ab] OR odynophagia[ti/ab] OR “nutritionalstatus”[Mesh] OR nutritional status[ti/ab] OR nutrition[ti/ab] OR oral intake[ti/ab] OR tubefeeding[ti/ab]OR“RespiratoryAspiration”[Mesh]ORaspiration[ti/ab]ORpenetration[ti/ab])

#6: (“diagnosis”[Mesh] OR assessment[ti/ab] OR diagnose[ti/ab] OR diagnostic[ti/ab] ORdiagnostics[ti/ab])#7: (“therapeutics”[Mesh]OR “rehabilitation”[Mesh]OR therapy[ti/ab]OR treatment[ti/ab]OR therapeutic*[ti/ab] OR rehabilitation[ti/ab] OR intervention[ti/ab] OR exercise[ti/ab] ORtherapeuticexercise[ti/ab])#8:#6OR#7#9:#4AND#5AND#8

*InEmbaseEMTREEtermswereusedinsteadofMeshterms

Critical appraisalSusceptibilitytobiaswasassessedfortheselectedrelevantarticles,accordingtopreviouslydefinedcriteriafromtheCochraneHandbookforSystematicReviewsofInterventions11.Riskonbiaswasscoredlow(A),moderate(B),orhigh(C)(Table2). Whendiscordantjudgmentoccurredbetween reviewers, consensuswasgainedbydiscussion. Subsequently, relevantarticleswithlow/moderateriskonbiasweresummarizedanddiscussed.



2

Table 2.Criteriaanddefinitionof riskonbias,describedby theCochraneHandbook forSystematicReviews

Criteria Riskonbias Interpretation Relationshiptocriteria

clear descriptionof

studygroup gender,age,tumorstageandlocation

A. Low all criteria met plausible bias very unlikelytoseriouslyalter the results

followed treatment

exactsurgicalintervention,typeof(C)RT

B. Moderate one or more criteria partly met

plausible bias that raises some doubt about the resultspatient

inclusion criteria

noselectionbias

C.High one or more criteria not met

plausible bias that seriouslyweakensconfidenceintheresults

follow-up length;>3months

%dropouts reasons for drop outs

reliability of outcome measures

referenced,validatedorself-madetests,swallowingobservationby1ormoreobservers,inter-andintra-raterreliabilitypercentage

RESULTS

Theabove-describedsearch(January1,2012toOctober31,2013)resultedin1141articles(MEDLINE/Pubmed:459,EMBASE:681,Cochrane:1).Afterscreeningontitle/abstract,69articlesremainedforfull-textevaluationofwhich26qualifiedforriskonbiasanalysis1,3,4,8-10,12-31.Seven(systematic)reviewarticles1,4,10,16,21,27,29wereexcludedforthisassessmentandsummarizedseparately(seeTable3).Theremaining19articleswerecohort-orcase-controlstudies,ofwhich11weresingledoutforadditionalattentionbasedonlow/moderateriskonbias(Table4).Furthermore,relatedarticlesandreferenceswerescreened,whichyieldedone additionalarticlewithlowriskonbias32(Figure1showsconsortflow-chart).Theresultswillbediscussedintwoseparatesections.Firstly,dysphagiaassessmentwillbeaddressedwithanemphasisontimingandonthevarioustoolsused.Secondly,optimaldysphagiatreatmentwillbediscussedwithspecialfocusontreatmentgoalsandoptions.

Assessing DysphagiaIntotal11studiesorreviewsdiscusseddysphagiaassessment3,4,8,9,14,18,19,21,23,29,30(Tables3and4).

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34 | Chapter 2

TimingRaber-Durlacher e.a. emphasized in their review that dysphagia evaluation should startpre-treatment, sincemany patientsmay presentwith swallowing difficulties already pre-treatment29.AlsoTippettandWebsterstressthatpatientsshould bequeriedabouttheirpre-treatment swallowing status8. Moreover, pre-treatment assessment provides informationforpredictingpost-treatment functionand for comparison, sinceall treatmentmodalitiesmayresultinswallowingdysfunction29.AccordingtoRussi,surgicalinterventionsmightcausespecific anatomic/neurologic damage conditioning site-specific patterns of dysphagia andaspiration4,as“ingeneral,surgicalprocedureswithlargerdefectsproducegreaterdeficits”.However, swallowing function is more adversely affected after chemotherapy (CT) and/or radiotherapy (RT), predominantly due to generalizedweakness andun-coordination indeglutition4. Though, as patients generally are treated with both modalities, individualroles of RT/CT in swallowing disorders are difficult to distinguish4. Both acute and long-termswallowingdysfunctionmayoccur.Cartmille.a.reportedthatswallowingfunctionwassignificantlyworse2-yearspost-treatmentcomparedtobaseline14.

Assessment toolsThe described swallowing assessment tools include clinical, instrumental, subjective, andglobalfunctionalevaluations3,4,8,9,14,18,19,21,23,29,30.

Evaluationshouldstartwithclinicalassessments(medicalhistoryandphysicalexamination)toscreenfordysphagia, identifypossibleaetiology,determineriskofaspiration,ascertainneedfornon-oralnutrition,andrecommendadditionalprocedures4,21.

Secondly, as stressed by several authors, instrumental assessments provide objectiveinformation about swallowing function and safety4, 21, 29, especially Videofluoroscopy ofSwallowing (VFS) or Fiberoptic Endoscopic Examination of Swallowing (FEES)4, 18, 21, 29. VFSobjectively assesses the swallowing process, and findings can be scored using variouscriteria,e.g.thePenetration-Aspiration-Scale.FEESisanotherappropriatemethodtoassessdysphagia,which directly visualizes the pharyngeal swallowing phase by using transnasalendoscopy.While observed rates of swallowing-related abnormalities are acceptable andappropriate dietary recommendations and rehabilitation programs can be formulatedbasedonFEESobservations,DeutschmannreportedthatFEESislesssuitableforpredictingaspiration18.Cine-MRI,describedbyKreefte.a.isanother(additional)instrumenttoevaluateswallowing function in patients with oral/oropharyngeal cancer. It directly visualizes thedynamics of swallowing, and abnormal findings are thought to correlate with subjectivecomplaints23.Overall,instrumentaltestingiscrucialtodocumentswallowingfunctioninHNCpatients.VFS is commonlyused, since it ismore suitable fordiagnosingaspirationduringthe swallow and more informative for detecting problems below the upper esophagealsphincter.Atbedside,however,FEESisoftenusedbecauseofitsaccessibility.Allinall,the



2

choiceofexaminationseemstodependuponclinicalpresentation,availableinstrumentsandclinician’spreferences4,21,29,30.

Thirdly,somepsychometricallyvalidated(patient-reported)QOLforms(EORTC-HN/-C30,FACT-HN,MDADI etc.) are available to assess functional outcomes inHNCpatients. Chene.a. discuss that the MD Anderson Dysphagia Inventory (MDADI), which is specificallyvalidatedforHNCpatients,isveryusefulforevaluatingtheimpactofdysphagiaonQOLinHNCpatients31,33.OthersubjectivequestionnairesapplyingtospecificaspectsofswallowingandtheirimpactonQOLincludetheSydneySwallowQuestionnaire(SSQ),theSwallowingQualityofLife(SWAL-QOL)questionnaire,andthePatientConcernsInventory(PCI).TheSSQ,originallydesignedforevaluationdifficultiesinneuromyogenicdysphagiapatients,accordingto Dwivedi is also useful for swallowing evaluation in oral/oropharyngeal cancer patientstreatedwithprimarysurgery9. TheSWAL-QOLisvalidatedtoidentifypatientswithswallowingproblems,especiallyaftertreatmentfororal,oropharyngeal,andlaryngealcancer,aspointedoutbyseveralgroups15,34.According toGhazalie.a. thePCImightbevaluable for routinescreeningofself-reportedswallowingdysfunction,sinceitenablespatients’concernstobeaddressedduringout-patient-clinicconsultations19.Inaddition,therearesomeclinician-ratedperformancescales.ThePerformanceStatusScaleforHNCpatients(PSS-HN)35,anexpert-rated instrumentwith three subscales (eating in public, understandability of speech, andnormalcyofdiet),ismostrecommendedwithinHNCtreatment.TheDysphagiaOutcomeandSeverityScale(DOSS)isanothersimple,easy-to-usescale,developedtosystematicallyratefunctionaldysphagiaseveritybasedonobjectiveassessment,andtomakerecommendationsfor diet level, independence level andnutrition36. Another simple, comprehensiveway toassesspatients’functionalimpairmentistheFunctionalIntraoralGlasgowScale(FIGS),usedbyEllabane.a.todeterminepatients’abilitytospeak,chewandswallow.However,thisscaleisonlyusefulfollowingsurgeryoforalcavitytumours3.

From this systematic literature search it became clear that, althoughpatient-reportedmeasuresarecommonlyappliedandprovidecomplementaryperspectives1,inmoststudiescorrelationwithobjectiveoutcomesispoor10,29,37. Van der Molen e.a. assessed pre-treatment organ function in advancedHNC through variousoutcomemeasures andpatients’ views.VFSidentifiedlaryngealaspiration/penetrationin18%ofpatients,whereasonly7patients(13%)perceivedthisasproblematic,andonly2of7patientswithobjectivetrismusactuallyperceived trismus37. Therefore, combining several subjective and objective evaluationsremains mandatory21,29.

Finally, aspointedoutbyHutchesonand Lewin, it seemsappropriate to record someglobalindicatorsoffunctionalstatus(e.g.changesinbodyweight/bodymassindex,dietarychanges,tube-andtracheotomy-dependency)assurrogatemeasuresoffunction,becausetheseareoftenavailableinpatientrecordsandusuallyeasytointerpret1.

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36 | Chapter 2

Tabl

e 3.

Resultsinclud

edre

view

s

Stud

yFocus

Results

Conc

lusio

n

Batth,201

3,

Review

The

curr

ent l

itera

ture

abo

ut th

e fe

asib

ility

an

ddo

simetric

param

etersofIM

RTto

maintainsw

allowingfunctio

ninHNC

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nts

RTdosesto

thesw

allowingorgansatrisk

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ldbelim

itedto<40

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to<55

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ph

aryngealcon

stric

tors

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ucingthe

incide

nceofdysph

agia,b

utcon

troversie

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gardingthede

lineatio

nof

swallowingstructuresand

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rtan

t dos

imet

ric p

aram

eter

s

Cousins,201

3,

Review

Interven

tionsfo

reati

ngand

drin

king

prob

lemsfollowingtreatm

entforHNC

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e is

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e ev

iden

ce to

sup

port

interven

tionsaim

edatimproving

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djawm

obilityfo

llowingHNC

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ent,bu

tstudiesarelimite

dbyth

eir

sizean

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e

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ighqu

ality

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ieswhichinclud

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iredforp

atien

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onprogram

mes

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eview

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giaan

dothe

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ction

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iotherap

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aryngealcan

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cesup

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rden

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agia

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nctio

naloutcomessho

uldbe

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edinpha

seIIIo

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ls to

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liabl

e co

mpa

rison

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wee

n treatm

ent regim

ens

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,20

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eview

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nctio

naloutcomes,m

etho

ds

ofpretreatm

entfun

ction

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ents,

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redu

ceorp

reventfu

nctio

nal

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ons,and

posttreatmen

treha

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oncon

siderati

onsinpati

ents

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oralcavity

and

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aryngealcan

cers

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nalreh

abilitatio

naft

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ent

requ

iresindividu

lized

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ingan

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ld

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ultid

isciplinaryteam

Spee

chand

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tcom

esare

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ldeterminan

tsofQ

OLdu

ringHNC

surv

ivor

ship

Paleri,201

3,

Review

Strategiesto

improvelong

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allowing

morbidityand

qua

lityoflifefo

llowingCR

TforH

NC

1.Ben

efitssee

mto

existfo

rpreventati

ve

exerciseprogram

stoadd

ressoraland

ph

aryngealstructures2.B

ettersw

allowing

outcom

esarelikelywhe

nna

sogastric

(in

preferen

ceto

gastrostomy)tu

besareused

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plem

ente

nteralnutriti

onduringCR

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iatio

ndo

sere

stric

tiontosw

allowing

structureswith

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lead

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er

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tcom

es

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dforb

ettersw

allowing

outcom

esto

beexpe

rienced

;more

prospe

ctivestud

ies,ta

king

intoaccou

nt

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backofthe

stud

iespu

blish

ed

sofar,ne

edto

bepe

rformed

togen

erate

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denceinth

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ported

re

sults

Rabe

r-Du

rlacher,

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gialiteraturebe

twee

n19

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usassessm

enttoo

lsford

ysph

agia,

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lefactors,exist

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ctivestud

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giaan

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ervarious

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entm

odalitiesarenee

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2

Tabl

e 3.

Resultsinclud

edre

view

s

Stud

yFocus

Results

Conc

lusio

n

Batth,201

3,

Review

The

curr

ent l

itera

ture

abo

ut th

e fe

asib

ility

an

ddo

simetric

param

etersofIM

RTto

maintainsw

allowingfunctio

ninHNC

patie

nts

RTdosesto

thesw

allowingorgansatrisk

shou

ldbelim

itedto<40

Gyforthe

glottic/

supraglotticlarynxand

to<55

Gyforthe

ph

aryngealcon

stric

tors

IMRT

ispromising

forred

ucingthe

incide

nceofdysph

agia,b

utcon

troversie

sexistre

gardingthede

lineatio

nof

swallowingstructuresand

themost

impo

rtan

t dos

imet

ric p

aram

eter

s

Cousins,201

3,

Review

Interven

tionsfo

reati

ngand

drin

king

prob

lemsfollowingtreatm

entforHNC

Ther

e is

som

e ev

iden

ce to

sup

port

interven

tionsaim

edatimproving

swallowingan

djawm

obilityfo

llowingHNC

treatm

ent,bu

tstudiesarelimite

dbyth

eir

sizean

dscop

e

Larger,h

ighqu

ality

stud

ieswhichinclud

ePR

Om

easuresarerequ

iredforp

atien

t-centred reha

bilitati

onprogram

mes

Hutcheson

,20

12,R

eview

Dyspha

giaan

dothe

rfun

ction

aloutcomes

afterche

morad

iotherap

yforlaryngealand

ph

aryngealcan

cers

Growingeviden

cesup

portsthebe

nefitof

preven

tivesw

allowingtherap

ytore

duce

thebu

rden

ofd

ysph

agia

Analysisoffu

nctio

naloutcomessho

uldbe

includ

edinpha

seIIIo

rgan

preservati

on

tria

ls to

allo

w re

liabl

e co

mpa

rison

s bet

wee

n treatm

entregim

ens

Hutcheson

,20

13,R

eview

Clinicallyfu

nctio

naloutcomes,m

etho

ds

ofpretreatm

entfun

ction

alassessm

ents,

strategiesto

redu

ceorp

reventfu

nctio

nal

complicati

ons,and

posttreatmen

treha

bilitati

oncon

siderati

onsinpati

ents

with

oralcavity

and

oroph

aryngealcan

cers

Functio

nalreh

abilitatio

naft

ertreatm

ent

requ

iresindividu

lized

plann

ingan

dshou

ld

beguide

dbyam

ultid

isciplinaryteam

Spee

chand

swallowingou

tcom

esare

principa

ldeterminan

tsofQ

OLdu

ringHNC

surv

ivor

ship

Paleri,201

3,

Review

Strategiesto

improvelong

-termsw

allowing

morbidityand

qua

lityoflifefo

llowingCR

TforH

NC

1.Ben

efitssee

mto

existfo

rpreventati

ve

exerciseprogram

stoadd

ressoraland

ph

aryngealstructures2.B

ettersw

allowing

outcom

esarelikelywhe

nna

sogastric

(in

preferen

ceto

gastrostomy)tu

besareused

tosup

plem

ente

nteralnutriti

onduringCR

T3.Rad

iatio

ndo

sere

stric

tiontosw

allowing

structureswith

IMRT

lead

stobett

er

swallowingou

tcom

es

Thereisatren

dforb

ettersw

allowing

outcom

esto

beexpe

rienced

;more

prospe

ctivestud

ies,ta

king

intoaccou

nt

thedraw

backofthe

stud

iespu

blish

ed

sofar,ne

edto

bepe

rformed

togen

erate

moreconfi

denceinth

epreviouslyre

ported

re

sults

Rabe

r-Du

rlacher,

2012

,Review

Dyspha

gialiteraturebe

twee

n19

90-201

0Vario

usassessm

enttoo

lsford

ysph

agia,

relatedtom

ultip

lefactors,exist

Moreprospe

ctivestud

ieson

thecourseof

dyspha

giaan

dim

pactonQOLaft

ervarious

treatm

entm

odalitiesarenee

ded

Russi,20

12,

Review

Themaincausesofd

ysph

agiainHNC

patie

ntsan

drecommen

datio

nsfo

rpati

ents

subm

itted

toRT

Thecausesofd

ysph

agiaafte

rCRT

might

bedue

togen

eralize

dweaknessan

dun

-coordina

tionindeglutiti

on.The

individu

al

roleofC

Tan

dRT

indysph

agiaisdiffi

cultto

disting

uish

InHNCpa

tients,dise

asecontrolhasto

be

con

sidered

togetherwith

functio

nal

impa

ctonsallowingfunctio

n.SLPsshou

ld

beinclud

edinam

ultid

isciplinaryap

proa

ch

toHNC

RCT =rand

omize

dcontrolledtrial,PC

=prospectivecoho

rtstud

y,RC

=re

trospe

ctiveco

hortstud

y,HNC=he

adand

neckcancer,Q

OL=

qua

lityoflife,CRT

=chem

orad

iatio

n,RT=radiothe

rapy,C

T=chem

othe

rapy,IMRT

=intensity

mod

ulated

radiothe

rapy,M

RI=m

agne

ticre

sona

nceim

aging,PRO

=pati

ent

repo

rted

outcome,SLP=spe

echlang

uagepatho

logist,N

A=no

nap

plicab

le

R1R2R3R4R5R6R7R8R9


38 | Chapter 2

Tabl

e 4.Resultsinclud

edarticles

Stud

yFocus

SwallowingOutcomes

Results

Conc

lusio

n

Author,year,

type

Patie

nts

Assessmen

t/Treatmen

tPr

imar

ySe

cond

ary

Lowriskonbias(totalscoreA)

Carn

aby-

Man

n,201

2,

RCT

58HNCpa

tients

treatedwith

CRT

Treatm

ent:Usualcare,

sham

swallowing-,o

ractive

swallowingexercisesdu

ring

CRTtreatm

ent

Musclesizean

dcompo

sition

(T2-

weigh

tedMRI)

Functio

nal

swallowability,

dietaryintake,

chem

osen

sory

functio

n,nutriti

on,

salivati

on,and

complicati

ons

Lessdeterioratio

ninsw

allowing

musculature,and

bett

er

functio

nalswallowing,m

outh

open

ing,che

mosen

soryacuity,

andsalivati

onra

teinth

eactive

trea

tmen

t arm

Patie

ntscompleti

ngth

esw

allowingexercisesdu

ring

CRTtreatm

entd

emon

strated

supe

rior m

uscl

e m

aint

enan

ce

andfunctio

nalswallowingab

ility

Cartmill,2

012,

PC12

oro

-ph

aryngeal

cancerpati

ents

treatedwith

CRT

Assessmen

t:Toxicity

(dysph

agiaand

salivary)

ratin

gs,d

ietaryto

lerance,

weigh

t,an

dpa

tient-rated

sw

allowingan

dgene

ral

functio

n

Swallowingan

dxerostom

ia(C

TCAE

su

bsca

les

for

dyspha

giaan

dsalivary)

Oralintake,

weigh

t,functio

nal

swallowing

(RBH

OMS

measures),w

eigh

t,

andpa

tient-

ratedsw

allowing

(MDA

DI)a

nd

gene

ral(FACT-HN)

functio

n

Swallowingan

dsalivarytoxicity

at 2

yea

rs p

ost-t

reat

men

t was

sig

nifican

tlydeteriorated,with

themajority

requ

iring

ong

oing

dietaryrestric

tionan

drepo

rting

a

significan

tnegati

veim

pactonthe

physicalaspectsofswallowing

Thelongterm

swallowingan

dnu

trition

alproblem

shigh

light

thene

edfo

rong

oing

spe

ech

patholog

y,dieteti

c,socialw

ork,

andpsycho

logyinvolvem

entin

assis

tingpa

tientstore

turnto

theirp

retreatm

ento

ralintake

/bod

yweigh

t,an

dad

apta

nd

adjustto

poten

tiallylifelong

ne

gativeHNCtreatm

entrelated

sequ

els

Ellaba

n,201

3,

PC62

surgically

trea

ted

oral

cancerpati

ents

Assessmen

t:Fu

nctio

nal

intrao

ralG

lasgow

scale

(FIGS)

Oralfun

ction

(FIGS

score)fo

llowing

surgicalre

section

in

theflo

orofm

outh

(FOM)

Tum

or

characteristics,

surgical-a

ndCRT

pa

ram

eter

s

Tumorsite

and

size

,surgical

access,resectio

nan

dreconstructio

nshow

edsignifican

tinflu

enceonoralfu

nctio

n(FIGS

score)fo

llowingsurgicalre

section

inth

eFO

M

TheFIGSisasim

plean

dco

mpr

ehen

sive

way

of

assessingapa

tient’sfunctio

nal

impa

irmen

tfollowingsurgeryin

theFO

M



2

Hutcheson

,20

13,R

C49

7ph

aryngeal

cancerpati

ents

trea

ted

with

de

finitiveRTor

CRT

Treatm

ent:Proa

ctive

swallowingtherap

yan

dmaintaining

oralintake

durin

gtreatm

ent

Fina

ldiet(oral

intakestatus)a

fter

treatm

ent,du

ratio

nofgastrostomy

depe

nden

ce,and

ad

here

nce

to a

sw

allowingexercise

regimen

Patie

nt,tum

or,

and

trea

tmen

t characteristics

Mainten

anceofo

ralintakedu

ring

treatm

enta

ndsw

allowingexercise

adhe

renc

e w

ere

inde

pend

ently

associated

with

bett

erlong

-term

dieta

fterR

TorCRT

and

shorterd

urati

onofgastrostomy

depe

nden

ce(a

djustedfortum

or

andtreatm

entb

urde

n)

Mainten

anceofo

ralintake

throug

houtRTorCRT

and

ad

herencetosw

allowing

exercisesareinde

pend

ently

associated

with

bett

erlongterm

sw

allowingou

tcom

es;p

atien

ts

who

eith

ereatore

xercise

fare

betterand

pati

entswho

do

bothhavethehigh

estrateof

returnto

are

gulard

ieta

nd

shortestdurati

onofgastrostomy

depe

nden

ce

Kotz, 2

012,

RCT

26HNCpa

tients

treatedwith

CRT

Treatm

ent:Targeted

sw

allowingexercisesorno

exercisesthroug

houtCRT

tr

eatm

ent

Functio

nalO

ral

IntakeScale(FOIS)

and

Perf

orm

ance

StatusScalefo

rHNC

patie

nts(PSS-H&N)

Patie

nt,tum

or,

and

trea

tmen

t characteristics

Theinterven

tiongrou

pha

dsig

nifican

tlybett

erscoresaft

er

3 an

d 6

mon

ths

of tr

eatm

ent

versusth

econtrolgroup

,with

out

significan

tdifferen

cesdirectly

andaft

er9and

12mon

thsof

trea

tmen

t

Prop

hylacticsw

allowing

exercisesdu

ringCR

Ttreatm

ent

improved

swallowingfunctio

nat

3 an

d 6

mon

ths

post

-tre

atm

ent

Molen

van

der,

2013

,RCT

29 a

dvan

ced

HNCpa

tients

treatedwith

CRT

Treatm

ent:Ro

utine

sw

allowingexercisesan

dsw

allowingexercises

base

d on

the

Ther

aBite

JawM

otion

Reh

abilitatio

nSy

stem

Vide

ofluo

roscop

y:

swallowing

functio

n,

pene

trati

onand

/oraspira

tionscale

(PAS

),an

dpresen

ce

of re

sidue

Maxim

um

inte

rinci

sor m

outh

op

ening(M

IO),

weigh

tcha

nges,

Functio

nalO

ral

IntakeScale(FOIS),

and

som

e st

udy-

specificqu

estio

ns

All t

umor

- and

trea

tmen

t-rel

ated

prob

lems(excep

txerostomia)

dim

inish

ed a

t 1 y

ear p

ost-

treatm

ent;on

lyweigh

tgain

additio

nallyim

proved

at2

years

post-treatmen

t,with

aslight

butsignifican

tben

efitforth

eexpe

rimen

talgroup

Bothre

habilitati

onprogram

sar

e fe

asib

le a

nd s

how

ed

good

com

pliancede

spite

the

burden

someCR

T,with

limite

doverallfun

ction

alproblem

sat1

and

2 ye

ars

post

-tre

atm

ent

Zhen

,201

2,PC46

surgically

treatedtong

ue

cancerpati

ents

Treatm

ent:Sw

allowing

exercisesdu

ring2wee

ks

followingtreatm

ent

Swallowingfunctio

n(M

DADI)

Swallowing-related

QOL(M

DADI)

TheoverallM

DADIscorewas

betterinth

eexpe

rimen

talgroup

compa

redwith

thecontrolgroup

Swallowingexercisesim

proved

dyspha

giaan

dQOLinsurgically

treatedtong

uecan

cerp

atien

ts

R1R2R3R4R5R6R7R8R9


40|Chapter2

Mod

erateriskon

bias(totalscoreB)

Deutschm

ann,

2013

,RC

116HNC

patie

nts

afterprim

ary

trea

tmen

t

Assessmen

t:Fibe

r-op

tic

endo

scop

icevaluati

onof

swallowing(FEES)

Swallowing-

rela

ted

adve

rse

even

ts(a

spira

tion

pneu

mon

ia,

obstruction

,pr

esen

ce o

f a

feed

ingtube

forp

rogressiv

emalnu

trition

)

OtherFEES

characteristics:

sensati

onof

epiglottisan

dtong

uebase,vocal

foldadd

uctio

n,

pharyngeal

resid

ue,PAS

,and

di

et a

dvic

es

The

over

all r

ate

of a

dver

se e

vent

s was10.1%

The

PAS

scor

e w

as th

e on

ly

stati

sticallysignifican

tpredictorof

adve

rse

even

ts

The

obse

rved

rate

of

swallowing-relatedad

verse

even

tsisaccep

table;FEES

guidesapp

ropriateand

safediet

recommen

datio

nsinth

eHNC

popu

latio

n

Dwived

i,20

12,

PC54

oral/

orop

haryn-geal

cancerpati

ents

trea

ted

with

prim

arysurgery

Asse

ssm

ent:

Sydn

ey

SwallowQue

stion

naire

(SSQ

)

Evalua

tionof

swallowingfunctio

nbyPRO

diffi

culties

Clin

ico-

demog

raph

ic

varia

bles

Tumorsite

and

(T)stage,p

atien

t’s

age,and

type

ofrecon

struction

directlyaffe

ctpost-treatmen

tsw

allo

w o

utco

me

TheSSQisausefultoo

lfor

evalua

tionofsw

allowinginHNC

patie

nts

Gha

zali,201

2,

PC20

4po

st-

treatm

ento

ral/

oro-ph

aryngeal

patie

nts

Assessmen

t:Patie

nt

ConcernsInventory(PCI)

andUW-QOLqu

estio

nnaire

Itemson

swallowing

functio

n(PCIand

UW-QOL)

Swallowingprob

lemswere

repo

rted

byrespectively17

%

ofPCIand

21%

ofU

W-QOL

resp

onde

nts

Both

sur

veys

con

curr

ently

en

abledallpati

entsto

disc

uss

theirswallowingiss

uesan

dtoaccesapp

ropriatem

ulti-

disc

iplin

aire

trea

tmen

t

Kree

ft,201

2,

PC23

pati

entswith

ad

vanced

oral/

oro-ph

aryngeal

canc

er

Assessmen

t:cine

MRI

Ora

l mob

ility

on

cine

MR

Ora

l mob

ility

on

vide

ofluo

roscop

y(VHS)and

QOL

questio

nnaires

Impa

iredmob

ilityoncine

MRI

wassignifican

tlycorrelatedto

moresw

allowingprob

lems,on

vide

ofluo

roscop

yno

t

Cine

MRIisapromising

new

techniqu

easanad

junctto

stan

dardexaminati

onsfor

evalua

tionofsw

allowing

inpati

entswith

oraland

orop

haryng

ealcan

cer

Tipp

et,2

012,

RC53

HNCpa

tients

trea

ted

with

CR

T.

Assessmen

t:Vide

ofluo

ro-

scop

icstud

ies(VFSS)

Vide

ofluo

roscop

ic

swallowing

para

met

ers

Xerostom

ia,

Trism

us,P

EGtu

be

depe

nden

cy,H

PV-

stat

us

Pharyngealim

pairm

entswere

common

onpo

sttreatmen

tVFSS,

but t

hese

did

not

pre

clud

e or

al

intakeduringtreatm

ent

Futherre

searchdire

ction

sinclud

ede

term

iningclinical

correlatesofd

ysph

agiaseverity,

investigatin

gcompliancewith

treatm

ent,an

dexam

ining

relatio

nshipoforalintakean

ddyspha

gia

RCT=rand

omize

dcontrolledtrial,PC

=prospectivecoho

rtstud

y,RC

=re

trospe

ctivecoh

ortstudy,H

NC=he

adand

neckcancer,Q

OL=qu

ality

oflife

,CRT

=che

morad

iatio

n,

RT=rad

iotherap

y,CT

=che

mothe

rapy,IMRT

=in

tensity

mod

ulated

rad

iotherap

y,MRI=m

agne

ticreson

anceim

aging,PRO

=pati

entrepo

rted

outcome,SLP=spe

ech

lang

uagepatho

logist,N

A=no

nap

plicab

le



2

Mod

erateriskon

bias(totalscoreB)

Deutschm

ann,

2013

,RC

116HNC

patie

nts

afterprim

ary

trea

tmen

t

Assessmen

t:Fibe

r-op

tic

endo

scop

icevaluati

onof

swallowing(FEES)

Swallowing-

rela

ted

adve

rse

even

ts(a

spira

tion

pneu

mon

ia,

obstruction

,pr

esen

ce o

f a

feed

ingtube

forp

rogressiv

emalnu

trition

)

OtherFEES

characteristics:

sensati

onof

epiglottisan

dtong

uebase,vocal

foldadd

uctio

n,

pharyngeal

resid

ue,PAS

,and

di

et a

dvic

es

The

over

all r

ate

of a

dver

se e

vent

s was10.1%

The

PAS

scor

e w

as th

e on

ly

stati

sticallysignifican

tpredictorof

adve

rse

even

ts

The

obse

rved

rate

of

swallowing-relatedad

verse

even

tsisaccep

table;FEES

guidesapp

ropriateand

safediet

recommen

datio

nsinth

eHNC

popu

latio

n

Dwived

i,20

12,

PC54

oral/

orop

haryn-geal

cancerpati

ents

trea

ted

with

prim

arysurgery

Asse

ssm

ent:

Sydn

ey

SwallowQue

stion

naire

(SSQ

)

Evalua

tionof

swallowingfunctio

nbyPRO

diffi

culties

Clin

ico-

demog

raph

ic

varia

bles

Tumorsite

and

(T)stage,p

atien

t’s

age,and

type

ofrecon

struction

directlyaffe

ctpost-treatmen

tsw

allo

w o

utco

me

TheSSQisausefultoo

lfor

evalua

tionofsw

allowinginHNC

patie

nts

Gha

zali,201

2,

PC20

4po

st-

treatm

ento

ral/

oro-ph

aryngeal

patie

nts

Assessmen

t:Patie

nt

ConcernsInventory(PCI)

andUW-QOLqu

estio

nnaire

Itemson

swallowing

functio

n(PCIand

UW-QOL)

Swallowingprob

lemswere

repo

rted

byrespectively17

%

ofPCIand

21%

ofU

W-QOL

resp

onde

nts

Both

sur

veys

con

curr

ently

en

abledallpati

entsto

disc

uss

theirswallowingiss

uesan

dtoaccesapp

ropriatem

ulti-

disc

iplin

aire

trea

tmen

t

Kree

ft,201

2,

PC23

pati

entswith

ad

vanced

oral/

oro-ph

aryngeal

canc

er

Assessmen

t:cine

MRI

Ora

l mob

ility

on

cine

MR

Ora

l mob

ility

on

vide

ofluo

roscop

y(VHS)and

QOL

questio

nnaires

Impa

iredmob

ilityoncine

MRI

wassignifican

tlycorrelatedto

moresw

allowingprob

lems,on

vide

ofluo

roscop

yno

t

Cine

MRIisapromising

new

techniqu

easanad

junctto

stan

dardexaminati

onsfor

evalua

tionofsw

allowing

inpati

entswith

oraland

orop

haryng

ealcan

cer

Tipp

et,2

012,

RC53

HNCpa

tients

trea

ted

with

CR

T.

Assessmen

t:Vide

ofluo

ro-

scop

icstud

ies(VFSS)

Vide

ofluo

roscop

ic

swallowing

para

met

ers

Xerostom

ia,

Trism

us,P

EGtu

be

depe

nden

cy,H

PV-

stat

us

Pharyngealim

pairm

entswere

common

onpo

sttreatmen

tVFSS,

but t

hese

did

not

pre

clud

e or

al

intakeduringtreatm

ent

Futherre

searchdire

ction

sinclud

ede

term

iningclinical

correlatesofd

ysph

agiaseverity,

investigatin

gcompliancewith

treatm

ent,an

dexam

ining

relatio

nshipoforalintakean

ddyspha

gia

RCT=rand

omize

dcontrolledtrial,PC

=prospectivecoho

rtstud

y,RC

=re

trospe

ctivecoh

ortstudy,H

NC=he

adand

neckcancer,Q

OL=qu

ality

oflife

,CRT

=che

morad

iatio

n,

RT=rad

iotherap

y,CT

=che

mothe

rapy,IMRT

=in

tensity

mod

ulated

rad

iotherap

y,MRI=m

agne

ticreson

anceim

aging,PRO

=pati

entrepo

rted

outcome,SLP=spe

ech

lang

uagepatho

logist,N

A=no

nap

plicab

le

Total1141

Title/Abstract InclusionsOriginal research papersLanguage: EnglishPublication date: 2012-13 Research in humans

1062Title/Abstract Exclusions Not (C) relevant: 993The other articles were considered rather (B) or absolutely (A) relevant

Related Articles1

DomainHNC patients with curative

treatment

Cochrane1

OutcomeAssessment or Treatment

DeterminantDysphagia

Embase681

Medline459

69

26

Full Text Exclusions Not Relevant: 28Oral presentation: 13Full Text N/A: 2

12

(Systematic) reviews7

Research papers19

Risk on Bias AssessmentHigh (C) risk of bias: 8The other articles were scored with low (A) ormoderate (B) risk on bias

Doubles79

Figure 1.

Treating DysphagiaTenstudiesorreviewsreportedondysphagiatreatment1,8,10,12,13,16,21,22,27,31(Tables3and4).

Treatment goalsAll authors stated that efficientmanagement of dysphagia symptomsmust be achieved.Goalsoftreatmentareto improvefoodtransfer(preventingmalnutrition/dehydration),toreduceaspiration,andtoenhanceQOL.AccordingtoTippettandWebster8, absence of pre-

R1R2R3R4R5R6R7R8R9


42 | Chapter 2

treatmentdysphagiaisnotpredictiveforpost-treatmentdysphagia,whichisquiteobvious,sinceall treatmentmodalitieshavethepotentialtoadversely impactswallowingfunction.Thisunderscorestheneedforearly(preventive)interventioninallpatients(atrisk)toaddressanticipatedswallowing-relateddifficulties8.

Treatment optionsSeveralstrategiesarediscussed,includingcompensatorytechniques(posturalchanges,dietmodifications),non-swallow(Shaker)exercises,swallowing(Mendelsohn,Masako,effortfulswallow,(super-)supraglotticswallow)exercises,andrangeofmotionorresistanceexercises.Theapproachchosendependsupontheaetiology,andanappropriatetherapyprogrammayincludeeitheroneorcombinationsoftheabovestrategies,alltofacilitatebolustransitduringswallowing.Additionally,swallow-related issuessuchas trismusandxerostomiashouldbetaken intoaccount,sincetheseareknownto impactQOLaswell8. There is also evidence nowsupportingthatfunctionalinterventionscanimprovejawmobilityandrangeofmotionfollowingHNCtreatment(e.g.byapplyingtheTheraBite®device)12,38.

When conservativemeasures are insufficient to help ensure safe oral intake, surgicalinterventionsorothertherapiesmaybeconsidered.Weaknessofpharyngealmusculature(lesspowerfulboluspropulsion)sometimescanbesurgicallyremediedbyreducingtonusoftheesophageal sphincter.Alternative treatmentsareneuromuscularelectrical stimulation(NMES)ordilatation.Combiningtheselatterrehabilitationregimensmightimproveswallowingfunctioninpatientswithradiation-induceddysphagia,aswasrecentlydemonstratedbyLongandWufornasopharyngealcancerpatients25.

Use it or lose itMultiplestudieshavedemonstratedbenefitsofmaintaineduseofswallowingmusculature(‘useitorloseit’)duringCRTtreatment,byavoidingperiodsofnothingperoral(NPO)andadherence to targetedswallowingexercises1,12,13,17,22,27,32.VanderMolene.a. in thefirstrandomizedcontrolled trial (RCT)aboutHNCpatientsundergoingCRTwith rehabilitation,concluded that preventive exercises were helpful in reducing extent and/or severity ofvariousfunctionalshort-termeffects12,38,withlimitedproblemsatone-andtwo-yearspost-treatment12.According toCarnaby-Manne.a. andCrary,prophylacticexercisesmay resultinmaintenanceoforalandoropharyngealmusculature,improved(strengthof)swallowingfunction,andlessdysphagia-relatedaspirationpneumoniae13,17. If exercisesareintroducedpre-treatment, swallowing function is still (more or less) intact and RT- and/or atrophy-relatedmuscledamagehasnotoccurredyet,aswasstressedinthereviewofCousinsandtheRCTofvanderMolene.a.12,16. Therefore,rehabilitationshouldbeaddressedduringpre-treatmentcounsellingandpatientsshouldadheretotheexercisesduring/aftertheoncologicintervention.



2

Surgicallytreatedpatientsbenefitfromswallowingexercisesaswell,toimproveswallowingfunction(oralcontrolandpharyngealtransit)andQOL,asZhene.a.showedforpatientswithdysphagiaposttongueresection31.Hence,referral toaspeech languagepathologist (SLP),priortoanytreatmentisconsideredmandatoryinmultidisciplinaryHNCmanagement1.

Furthermore, prophylactic tube feeding (with NPO periods) is often applied duringtreatment for providing adequate nutritional supplementation27. However, this reducespatient’s need formaintaining oral intake and thus swallowing,whichmight causemoreswallowingproblemspost-treatment27,32.Hutchesone.a.evaluatedtheeffectsofmaintainingoralintakethroughout(C)RTtreatmentandswallowingexerciseadherenceonpost-treatmentswallowingoutcomes(finaldietpost-treatmentanddurationoffeeding-tubedependence).They found significant better long-term outcomes (better oral intake status and shorterdurationofgastrostomydependence)forbothparametersindependently32.

DISCUSSION

In HNC treatment, (C)RT techniques have evolved rapidly, especially the introduction ofIMRT to reducedysphagia, since relationshipswere foundbetweendosage topharyngealstructuresandswallowingfunction39.However,althoughIMRTisthebestorgan-sparingRTtechniquethatisalreadywidelyusedandcertainlyreducestoxicitytopharyngealstructures,itmaystillsignificantlyimpairswallowingfunction,even2-yearsaftertreatment14.Therefore,inrecentyears,moreattentionhasbeendrawntodysphagiaanditsdevastatingimpactonQOLinHNCpatients.Likewise,surgicaltreatmentspotentiallyyieldseverefunctionaldeficitsinHNCpatients,mostnotablywithregardtoswallowingfunction,butonlylimitednumbersofstudieshavebeenpublishedconcerningfunctionalconsequencesaftersurgery2.

Thepurposeofthisreviewwastoevaluatecurrentassessmentandtreatmentstrategiesof dysphagia in all HNC patients. In general, swallowing outcomes and training havebecome increasingly important inHNC rehabilitation. Functional success is best achievedwithamultidisciplinaryteamincludingSLPs,whoplayanindispensablerolein(preventive)dysphagiarehabilitation1,4,8,16,21,29.

Optimizingswallowingoutcomesbeginswithcomprehensivebaselineassessments,sinceHNCpatientscomprisealreadypre-treatmentanelevatedriskfordysphagia37,andshouldbecontinuedper/post-treatment.Validatedmeasuresfrominstrumentalexaminationsareconsideredgold-standard,becausethesearenotconfoundedbysubjectivefactorsinherenttopatient-reportedmetrics1.However, FEESandVFS studies contain some subjectivity aswellbecausecliniciansapplypersonalinterpretationsofvariouscriteria.Theinter-observervariation in interpreting these studies in quite high. Therefore, instrumental, clinician-reported examinations always should be combinedwith complementary patient-reportedoutcomes21,29.

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Furthermore, this review confirms the low degree of standardized outcomes in HNCtreatment. Three RCTs coupling prophylactic swallowing therapy with avoidance of NPOintervals demonstrated positive effects on important functionalendpoints13, 22, 38. Van der Molene.a.inthefirstRCTonthistopicdemonstratedthatcompliancewasquitegood,withamajorityofpatients(69%)beingabletoperformtheexercisesduringtreatment38,whichresultedinlimitedfunctionalproblemsatone-andtwo-yearspost-treatment12. In their study onthistopic,Carnaby-Manne.a.,randomizingpatientstostandardcare,sham-,andactiveexercises,demonstratedtheeffectivenessofinitiatingpreventivetherapypre-treatment,intermsofsuperiormusclemaintenanceandfunctionalswallowingability13.Similarly,Kotze.a.performedaRCTonmultipleprophylacticswallowingexercises,oneofthefirstexaminingthe super-supraglotticswallow.Significantlybetter scoreswere found in theexperimentalarmthree-andsix-monthspost-treatment(althoughthiseffectwasnotseenimmediatelyoratnine-and12-monthspost-treatment),whichprovidesadditionalevidencethatpatientsshouldadheretotheexercises–especiallyduringtreatment22. Unfortunately,thereislackof consensus regarding time, type, frequency, or intensity of exercises, which suggestsfurther research by RCTs assessing optimal treatment strategies. Also longer follow-upwithcontinuationofexercisesisneeded,giventhepotentialforlong-termsequels,eveninabsenceofswallowingdisorderspre-orshortlypost-treatment.Compliancemightimprovewhenpatientsarecounselledmoreintensively,aswasdemonstratedbyvanderMolene.a.38. Besides,maintenanceoforal intakeduring treatment seems tobeassociatedwithbetterlong-termswallowingoutcomes,aswell32.Hutchesone.a. foundan independent,positiveassociation foreatingduring treatment inapproximately500patients,whohadcompleteresponsetodefinitive(C)RTforpharyngealcancers.However,theretrospectivedatasetdidnotcontrolforacutetoxiceffectssuchasmucositisorodynophagia,whichbothcanaffectpatients’ability toeat (andexercise)during treatment.Therefore, theremighthavebeenselectionbiasinthegroupsthateitherdidordidnotneedafeedingtube.Futureprospectivestudies should examine these factors, to ensure the observed effects are not merely areflectionofseverechangesfromtreatment,thatprecludeswallowingactivityduring(C)RT.Interestingly,onlyfewstudiesabout(prolonged)tubeplacementanddependencyper-/post-treatment,anditsnegativeimpactonswallowing,wereidentifiedinoursearch.Inordertolimittherateoftubeplacementduringtreatment(toimprovelong-termswallowingfunction),furtherresearchonthistopic isrequired.Furthermore,there isroomfor improvement indelineatingradiationfieldsandadjustmentsduringtreatment,tobettersparesalivaryglandsand pharyngeal muscle/mucosa structures, and to further reduce dosage to functionallyimportant structures.

Finally,thisliteraturereviewclearlydemonstratestheincreasinginterestinandawarenessaboutthistopic,consideringthenumerousreviewsaboutvariousassessmentandtreatmentstrategies for dysphagia –which all stress the importanceof further longitudinal studies.



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However,data fromprospective studies,whichactuallyevaluated these topics (especiallyfrom RCTs), and data on dysphagia in patients who underwent a laryngectomy or othersurgicaltreatments,arestilllimited.

CONCLUSION

Overthelastyears,functionalswallowingassessmentandtreatmenthavebecomestandardofcareinheadandneckcancerpatients,giventheseriousimpactofdysphagiaonqualityof life.However,thereisstillnouniform‘gold-standard’foreitherassessmentortreatmentstrategies. More high quality data, adequately controlled, adequately powered andrandomized,onprophylacticandtherapeuticswallowingexercisesareneeded,withlongerfollow-upandoptimaladherencetotreatment,inordertobetterreducetoxicityofchemo-andradiotherapy,andpossiblymodifysurgicalresectionsandreconstructions.Inaddition,frequency, timing and duration of therapy need further studies to improve swallowingfunctionandoptimizequalityoflife.

KEY-POINTS

- Xerostomia, fibrosis, mucositis, and anatomical changes (neuropathies) are themajor sequels affecting swallowing function following head and neck cancertreatment;

- Swallowing function has amajor impact on quality of life during head and neckcancersurvivorship;

- Pre-, per- and post-treatment functional swallowing assessment is an importantshort-andlong-termcomponentofcomprehensivecareinheadandneckcancerpatients;

- Headandneckcancerpatientsbenefitfrompre-,per-andpost-treatmentswallowexercises thataddressall structures involved inswallowing (the ‘use itor lose it’concept);

- Thereisalackofconsensusregardingdysphagiatherapy,despitegrowingevidencesupportingthebenefitsofpreventiveswallowingtherapy.

ACKNOWLEDGEMENTS

ThedepartmentofHeadandNeckOncologyandSurgeryreceivesanunrestrictedresearchgrantofAtosMedicalAB,Sweden.

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REFERENCES

Papers of particular interest, published within the annual period of review, have been highlighted as special (*) or outstanding (**) interest.


2. Kreeft AM, van der Molen L, Hilgers FJ,Balm AJ. Speech and swallowing aftersurgical treatment of advanced oral andoropharyngealcarcinoma:asystematicreviewof the literature. Eur Arch Otorhinolaryngol.2009;266:1687-98.

3. EllabbanMA, Shoaib T, Devine J, McMahonJ, Morley S, Adly OA, et al. The functionalintraoral Glasgow scale in floor of mouthcarcinoma: longitudinal assessmentof 62 consecutive patients. Eur ArchOtorhinolaryngol.2013;270:1055-66.

4. Russi. Swallowing dysfunction in headand neck cancer patients treated byradiotherapy: Review and recommendationsof the supportive task group of the ItalianAssociation of Radiation Oncology. CancerTreatmentReviews.2012;38:1033-49.

5. Langendijk JA, Doornaert P, Verdonck-deLeeuwIM,LeemansCR,AaronsonNK,SlotmanBJ. Impact of late treatment-related toxicityon quality of life among patients with headandneckcancertreatedwithradiotherapy.JClinOncol.2008;26:3770-6.

6. Mowry SE, Tang C, Sadeghi A, Wang MB.Standard chemoradiation versus intensity-modulated chemoradiation: a quality of lifeassessmentinoropharyngealcancerpatients.EurArchOtorhinolaryngol.2010;267:1111-6.


8. TippettDC,WebsterKT.Rehabilitationneedsof patients with oropharyngeal cancer.OtolaryngolClinNorthAm.2012;45:863-78.

9. Dwivedi. Evaluationof swallowingbySydneyswallow questionnaire (SSQ) in oral andoropharyngeal cancer patients treated withprimarysurgery.Dysphagia.2012;27:491-7.

10. Batth SS, Caudell JJ, Chen AM. Practicalconsiderations in reducing swallowingdysfunction following concurrentchemoradiotherapy with intensity-modulated radiotherapyforheadandneckcancer.HeadNeck.2014Feb;36(2):291-8.

11. Higgins JP, Green S. Cochrane Handbookfor Systematic Reviews of InterventionsVersion 5.1.0 [updated March 2011]. TheCochraneCollaboration;2011.Availablefromwww.cochrane-handbook.org. [Assessed 8 november2013].

12. (**)vanderMolenL,vanRossumMA,RaschCR, Smeele LE, Hilgers FJ. Two-year resultsof a prospective preventive swallowingrehabilitation trial in patients treated withchemoradiationforadvancedheadandneckcancer. Eur Arch Otorhinolaryngol. 2014May;271(5):1257-70.

This first prospective RCT on preventive (standard or experimental) swallowing rehabilitation for advanced head and neck cancer patients treated with chemoradiotherapy, showing quite good compliance and limited functional problems at 1- and 2-years post-treatment.


14. Cartmill B, Cornwell P,Ward E, DavidsonW,Porceddu S. Long-term functional outcomesand patient perspective following alteredfractionation radiotherapy with concomitantboost for oropharyngeal cancer. Dysphagia.2012;27:481-90.

15. Cnossen IC,deBreeR,RinkelRN,EerensteinSE, Rietveld DH, Doornaert P, et al.Computerizedmonitoringofpatient-reportedspeech and swallowing problems in headandneck cancerpatients in clinical practice.SupportCareCancer.2012;20:2925-31.



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16. (*) Cousins. A systematic review ofinterventionsforeatinganddrinkingproblemsfollowingtreatmentforheadandneckcancersuggests a need to look beyond swallowingandtrismus.OralOncology.2013;49:387-400.

This review evaluates several rehabilitation interventions (swallowing exercises alone/combined with other interventions, jaw mobility exercises with/without medical devices, mechanical devices alone, and swallowing interventions combined with jaw mobility interventions) in order to improve the physical difficulties (swallowing and jaw mobility), but also the functional and psychosocial difficulties with eating and drinking following HNC treatment.

17. Crary.Functionalandphysiologicaloutcomesfrom an exercise-based dysphagia therapy:Apilotinvestigationofthemcneilldysphagiatherapy program. Archives of PhysicalMedicineandRehabilitation.2012;93:1173-8.

18. Deutschmann. Fiber-optic endoscopicevaluationof swallowing (FEES):Predictorofswallowing-relatedcomplicationsintheheadandneckcancerpopulation.HeadandNeck.2013;35:974-9.

19. GhazaliN,KanatasA,ScottB,LoweD,ZuydamA, Rogers SN. Use of the Patient ConcernsInventory to identify speech and swallowingconcerns following treatment for oral andoropharyngeal cancer. J Laryngol Otol.2012;126:800-8.

20. Hunter KU, Schipper M, Feng FY, Lyden T,HaxerM,Murdoch-KinchCA,etal. Toxicitiesaffecting quality of life after chemo-IMRTof oropharyngeal cancer: prospective studyof patient-reported, observer-rated, andobjective outcomes. Int J Radiat Oncol BiolPhys.2013;85:935-40.

21. (**)Hutcheson KA, Lewin JS. Functionalassessment and rehabilitation: how tomaximize outcomes. Otolaryngol Clin NorthAm.2013;46:657-70.

This review correctly underscores the need for both standardized, comprehensive baseline assessments (speech and swallowing outcomes) as functional, individualized rehabilitation post-treatment in oral cavity/oropharyngeal cancer patients.


23. KreeftAM,RaschCR,MullerSH,PameijerFA,Hallo E, Balm AJ. CineMRI of swallowing inpatientswithadvancedoralororopharyngealcarcinoma: a feasibility study. Eur Arch Otorhinolaryngol.2012;269:1703-11.

24. Krisciunas.Surveyofusualpractice:Dysphagiatherapy in head and neck cancer patients.Dysphagia.2012;27:538-49.

25. LongYB,WuXP.Arandomizedcontrolledtrailof combination therapy of neuromuscularelectricalstimulationandballoondilatationinthetreatmentofradiation-induceddysphagiainnasopharyngealcarcinomapatients.DisabilRehabil.2013;35:450-4.

26. MoreYI,TsueTT,GirodDA,HarbisonJ,SykesKJ, Williams C, et al. Functional swallowingoutcomesfollowingtransoralroboticsurgeryvs primary chemoradiotherapy in patientswith advanced-stage oropharynx andsupraglottiscancers. JAMAOtolaryngolHeadNeckSurg.2013;139:43-8.

27. (**)PaleriV,RoeJW,StrojanP,CorryJ,GregoireV, Hamoir M, et al. Strategies to reducelong-term postchemoradiation dysphagiain patients with head and neck cancer: Anevidence-based review. Head Neck. 2014Mar;36(3):431-43.

This review discusses the evidence for three important strategies to improve swallowing function after chemoradiation: preventative swallowing exercises, maintenance of oral intake (continued oral swallowing), and radiation dose restriction to swallowing structures by using IMRT.

28. Pauloski BR, Logemann JA, Rademaker AW,LundyD,SullivanPA,NewmanLA,etal.Effectsof enhanced bolus flavors on oropharyngealswallowinpatientstreatedforheadandneckcancer.HeadNeck.2013;35:1124-31.

29. Raber-DurlacherJE,BrennanMT,Verdonck-deLeeuwIM,GibsonRJ,EilersJG,WaltimoT,etal.Swallowingdysfunctionincancerpatients.SupportCareCancer.2012;20:433-43.

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30. RoeJW,CardingPN,Rhys-EvansPH,NewboldKL, Harrington KJ, Nutting CM. Assessmentand management of dysphagia in patientswith head and neck cancer who receiveradiotherapy intheUnitedKingdom-aweb-basedsurvey.OralOncol.2012;48:343-8.

31. ZhenY,WangJG,TaoD,WangHJ,ChenWL.Efficacy survey of swallowing function andquality of life in response to therapeuticintervention following rehabilitationtreatment in dysphagic tongue cancerpatients.EurJOncolNurs.2012;16:54-8.

32. (*) Hutcheson KA, Bhayani MK, Beadle BM,GoldKA,ShinnEH,LaiSY,etal.Eatandexerciseduring radiotherapy or chemoradiotherapyforpharyngealcancers:useitorloseit.JAMAOtolaryngolHeadNeckSurg.2013;139:1127-34.

Data from almost 500 patients from this retrospective observational study show independent positive associations of both maintaining oral intake throughout (chemo-)radiotherapy treatment and adherence to preventive swallowing exercises with better long-term swallowing outcomes.

33. ChenAY,FrankowskiR,Bishop-LeoneJ,HebertT,LeykS,LewinJ,etal.Thedevelopmentandvalidation of a dysphagia-specific quality-of-lifequestionnaireforpatientswithheadandneck cancer: theM. D. Anderson dysphagiainventory.ArchOtolaryngolHeadNeckSurg.2001;127:870-6.

34. McHorneyCA,RobbinsJ,LomaxK,RosenbekJC, Chignell K, Kramer AE, et al. The SWAL-QOL and SWAL-CARE outcomes tool fororopharyngeal dysphagia in adults: III.Documentation of reliability and validity.Dysphagia.2002;17:97-114.

35. List MA, Ritter-Sterr C, Lansky SB. Aperformance status scale for head and neckcancerpatients.Cancer.1990;66:564-9.

36. O’Neil KH, Purdy M, Falk J, Gallo L. TheDysphagia Outcome and Severity Scale.Dysphagia.1999;14:139-45.

37. vanderMolenL,vanRossumMA,AckerstaffAH, Smeele LE, Rasch CR, Hilgers FJ.Pretreatmentorganfunctioninpatientswithadvanced head and neck cancer: clinicaloutcomemeasuresandpatients’views.BMCEarNoseThroatDisord.2009;9:10.

38. vanderMolenL,vanRossumMA,BurkheadLM, Smeele LE, Rasch CR, Hilgers FJ. Arandomized preventive rehabilitation trialin advanced head and neck cancer patientstreated with chemoradiotherapy: feasibility,compliance, and short-term effects.Dysphagia.2011;26:155-70.39.39.

39. vanderMolenL,HeemsbergenWD,deJongR, vanRossumMA, Smeele LE,RaschCR, etal. Dysphagia and trismus after concomitantchemo-Intensity-Modulated RadiationTherapy (chemo-IMRT) in advanced headand neck cancer; dose-effect relationshipsfor swallowing and mastication structures.

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CHAPTER 3Evalua.on of long-‐term (10-‐years+) dysphagia and trismus

in pa.ents treated with concurrent chemoradiotherapy

for advanced head and neck cancer

S.A.C. Kraaijenga I.M. Oskam

L. van der Molen O. Hamming-‐Vrieze

F.J.M. Hilgers M.W.M. van den Brekel

Oral Oncol. 2015; 51: 787-‐794.

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ABSTRACT

Objectives:Assessmentoflongterm(10-years+)swallowingfunction,mouthopening,andqualityoflife(QOL)inheadandneckcancer(HNC)patientstreatedwithchemo-radiotherapy(CRT)foradvancedstageIVdisease.

Materials and Methods: Twenty-twodisease-free survivors, participating in amulticenterrandomized clinical trial for inoperableHNC (1999-2004),were evaluated to assess long-termmorbidity.Theprospectiveassessmentprotocolconsistedofvideofluoroscopy(VFS)forobtainingPenetrationAspirationScale(PAS)andpresenceofresiduescores,FunctionalOralIntakeScale (FOIS) scores,maximummouthopeningmeasurements,and (SWAL-QOLandstudy-specific)questionnaires.

Results: At a median follow-up of 11-years, 22 patients were evaluable for analysis. Tenpatients(45%)wereabletoconsumeanormaloraldietwithoutrestrictions(FOISscore7),whereas12patients(55%)hadmoderatetoseriousswallowingissues,ofwhom3(14%)werefeedingtubedependent.VFSevaluationshowed15/22patients(68%)withpenetrationand/oraspiration(PAS≥3).Fifty-fivepercentofpatients(12/22)haddevelopedtrismus(mouthopening≤35mm),whichwassignificantlyassociatedwithaspiration (p=.011).Subjectiveswallowingfunction(SWAL-QOLscore)wasimpairedacrossalmostallQOLdomainsinthemajorityofpatients.PatientstreatedwithIMRTshowedsignificantlylessaspiration(p=.011),less trismus (p =.035), and less subjective swallowing problems than those treated withconventionalradiotherapy.

Conclusion: Functional swallowing and mouth opening problems are substantial in thispatientcohortmorethan10-yearsafterorgan-preservationCRT.PatientstreatedwithIMRThadlessimpairmentthanthosetreatedwithconventionalradiotherapy.

KEY WORDSHeadandNeckCancer–Chemoradiotherapy–Dysphagia–Swallowing–MouthOpening–IMRT


Long-termdysphagiaandtrismusinadvancedheadandneckcancer|53

3

INTRODUCTION

Headandneckcancer(HNC)patientsareatrisktodevelopsubstantialfunctionalimpairmentsafterorgan-preserving treatmentwith chemoradiotherapy (CRT)1.Dysphagia is commonlythemostseverefunctionalimpairmentfollowingthistreatment.Givenitsseriousimpactonqualityoflife(QOL),assessmentofdeglutitiondisordershasbecomeanimportantfunctionalendpoint measure2.ItisthereforenotsurprisingthatpreventionofdysphagiahasbecomeamajorfocuspointinHNCresearch.Inthepastdecade,improvedradiotherapyprotocolswithintensitymodulatedradiotherapy(IMRT)havebeenintroducedtoreduceradiationdosageto swallowingmusculature and structures,with the intention todecreasepost-treatmentdysphagia3,4.Morerecently, theprevalenceofdysphagiaalsohas ledtothedevelopmentofpreventiveexerciseprograms.Theseexerciseprogramsareassociatedwithbetterpost-treatmentswallowingfunction,inparticularontheshort-term5-10,andprobablyalsolonger-term11. However, since dysphagia can develop and/or progress years after CRT12, 13, longterm(10-years+)prospectivelycollectedswallowingandmouthopeningdataareofgreatimportancetoassessdeglutitioninHNCsurvivors14.Inthisstudytheprospectivelycollectedobjectiveandsubjectivefunctionalresultsat10-years+post-treatmentwillbereportedinapatientcohorttreatedwithCRTforadvanced,anatomicalandfunctionalinoperableHNC.

MATERIAL AND METHODS

This study concerns the long term follow-up of all disease-free and evaluable patients,whoparticipated in a randomized clinical trial (M99RAD)on twodifferent cisplatin-basedchemoradiationtreatmentprotocolsforadvancedHNC15.Theoriginalcohortconsistedof237patientsdiagnosedwithadvanced(stageIV),anatomicalorfunctional16inoperablesquamouscell carcinoma of the oral cavity, oropharynx, or hypopharynx. Patients were includedbetweenDecember1999andNovember2004.Thechemotherapyprotocolconsistedeitherof100mg/m2cisplatinina40minutesintravenous(IV)infusionondays1,22,and43,orofaweeklyhigh-dose intra-arterial (IA) injectionof150mg/m2cisplatin incombinationwithintravenoussodiumthiosulphaterescueinweeks1,2,3,and4.Radiotherapy(70Gyin35fractions) was administered over seven weeks, starting concurrently with chemotherapy.Since IMRThadbeengradually introduced inour Instituteduringthetrialperiod, roughlyonefourthoftheoriginalpatientpopulationwastreatedwithIMRT4,17,whiletheremainingpatientsweretreatedwithconventionalradiotherapy(RT).Duringtreatment,patientswereencouragedtomaintainanoraldiet foras longaspossibleandprophylactictubefeedingwasnotapplied.A(nasogastricorgastric)feedingtubeonlywasgivenwhenthecarefullymonitoredintakebecametroublesome.Intheperiodthetrialwasconducted(1999-2004),

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the conceptof standardpreventive swallowing rehabilitationwasnot yetdeveloped, andswallowing exerciseswere givenpost-treatment ‘ondemand’,when removal of a feedingtubeappearedtroublesomebecauseofaspirationand/orwhensufficientoralintakecouldnotberegained.

Theoriginal(phaseIII)trialcomparedstandardIVwithIAcisplatininfusionononcologicaloutcomesin237patients17andQOLin207patients18,19.Regardingoncologicaloutcomesandtoxicities,resultsshowedthatCRTwithIA infusionisnotsuperiortoCRTwithIVinfusion.Toxicityresultswerecomparableinbotharms,althoughsiteanddegreeoftoxicitydiffered.In short, renal toxicity was significantly lower in the IA treatment arm, and neurologicaltoxicitywassignificantlymoreprevalentintheIAarm17.RegardingQOLresults,nostatisticallysignificantdifferencesbetweenthegroups(IA,IV)werefound,andnostatisticallysignificantchangesovertime(1-yearversus5-yearspost-treatment)wereobservedforthetotalpatientgroupduringfollow-upassessments19.Therefore,inthepresentstudy,functionalswallowingand mouth opening results are reported for the combined patient cohort still alive andevaluable at 10-years+ post-treatment. All patient data and reasons for exclusion after5-yearsand10-years+follow-upareprovidedinaconsortflow-chart(Figure1).Ascanbeseen,at10-years+post-treatment,besidesthe20evaluablepatientsfromthe5-yearcohort,4additionalsurvivors,whohadbeenunresponsiveorrefusedtoparticipateatthe5-yearsevaluationpoint,werealsowilling toparticipate. Twopatientshadmajor salvage surgeryforrecurrentdiseaseduringfollow-up,andwereexcludedfromswallowing/mouthopeninganalysis,sincethefunctionaloutcomesinthesepatientswerenolonger(only)attributabletotheCRT.Furthermore,twopatientshadminor(laser)surgeryforasecondprimaryattheoropharynx (pharyngeal arch and alveolar process, respectively) at 10-years and11-yearspost-treatment.Subsequently,due toa recurrence thealveolarprocesspatient twoyearslateradditionallyrequiredlocalresectionwithbonegrafting.Theselattertwopatientswerekeptinthefunctionalanalysisofintotal22patients.

Multidimensional assessmentAssessmentoffunctionalsequelswasperformedwithstandard,multidimensionalobjectiveandsubjectiveoutcome-measures20,21.First,theprotocolincludedstandardvideofluoroscopy(VFS)todetermineswallowingfunction.AllVFSstudieswerecarriedoutbyanexperiencedspeech language pathologist. Patients were seated upright and were asked to swallowdifferentconsistenciesofvaryingamountstwice(1,3,5and10ccthinliquid;3and5ccpaste;aswellassolid[Omnipaquecoatedcake]).Testingwasdiscontinuedifthecliniciansjudgedtheswallowingpotentiallyharmfultothepatient.AllVFSstudieswerereviewedinreal-time,slowmotion,andframe-by-frame,andratedinconsensusbytwoexperiencedresearchers(authorsSKandLM).ResultswereexpressedintermsofthePenetrationandAspirationScale(PAS),aswellasanoverall ‘presenceofresidue’score.ThePAS,atoolwithanacceptable



3

reliability,consistsofa8-pointsscale, ranging from1–8 (score1:materialdoesnotentertheairway;score2:materialenterstheairway,remainsabovethevocalfolds,andisejectedfromtheairway;score3:materialenterstheairway,remainsabovethevocalfolds,andisnotejectedfromtheairway;score4:materialenterstheairway,contactsthevocalfolds,andisejectedfromtheairway;score5:materialenterstheairway,contactsthevocalfolds,andisnotejectedfromtheairway;score6:materialenterstheairway,passesbelowthevocalfolds,andisejectedintothelarynxoroutoftheairway;score7:materialenterstheairway,passesbelow thevocal folds,and isnotejected fromthe tracheadespiteeffort; score8:materialenterstheairway,passesbelowthevocalfolds,andnoeffortismadetoeject)22. The overall‘presenceofresidue’scorerangesfrom0–3(score0:noresidue,toscore3:residueaboveandbelow thevallecula,withminimal residue judgedasnormal). To interpretandcompareresults, individualtestresultswereclusteredwiththehighestscorerepresentingthe total PASor residue scoreperpatient. ThePASwas also simplifiedbydividing it intothreecategories(1:normal;2–5:penetration;6–8:aspiration),whichroughlycorrespondstonormal,mild-to-moderate,andsevereperformance23.

Randomized(n=207)

Pre-treatment (baseline)

Reasons for exclusion (n=53)- Death (n=31)- Salvage surgery (n=2)- Severe comorbidity (n=5)- Travel distance (n=5)- Patient refusal (n=1)- Unresponsive/missing (n=9)

Analyzed(n=71)

5-years post-treatment

Analyzed(n=22)

10-years+ post-treatment

Included survivors not available at

5-years (n=4)

Reasons for exclusion (n=136)- Death (n=112)- Salvage surgery (n=10)- Severe comorbidity (n=2)- Patient refusal (n=4)- Unresponsive/missing (n=6)- Protocol violations (n=2)

Figure 1. Consortflowchartshowingthenumberofpatientsparticipatingat10-years+post-treatmentandpreviousQOLassessments(baselineand5-yearspost-treatment),includingreasonsforexclusionafter5-yearsand10-years+follow-up.At10-years+post-treatment,4additionalsurvivorswerewillingtoparticipate,whowereunresponsiveorrefusedtoparticipateat5-yearspost-treatment.

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56|Chapter3

Secondly, oral intake/nutritional status was assessed with the Functional Oral IntakeScale(FOIS;rangefrom1–7withscore1:nothingbymouth,score2:tubedependentwithminimal/inconsistentoralintake,score3:tubedependentwithconsistentoralintake,score4:totaloraldietofasingleconsistency,score5:totaloral intakeofmultipleconsistenciesrequiring special preparation or compensations, score 6: total oral intake of multipleconsistencieswithoutspecialpreparationbutwithspecificfoodlimitations,andscore7:totaloraldietwithoutrestrictions),andwithdataonoralnutritionalsupplements,tubefeedingdependency,weightchanges,andBodyMassIndex(BMI).

Furthermore, maximum interincisor (mouth) opening (MIO) wasmeasured in mm todeterminetrismus.MIOwasmeasuredusingdisposableTheraBiterangeofmotionscales(AtosMedical,Sweden),andtrismuswasdefinedasaMIOof≤35mm24.

Patients’ subjective swallowing and mouth opening impairment was assessed withqualityof life (QOL)questionnaires.Thefirstquestionnairewas theSwallowingQualityofLife Questionnaire (SWAL-QOL), which was administered to assess patients’ perceivedswallowingdisorder.TheSWAL-QOLhasbeentranslatedandvalidatedforusewithDutchoral, oropharyngeal, and laryngeal cancer patients [25, 26]. The SWAL-QOL consists of44-items that assess theeffectsof swallowingdifficultieson10QOLdomains (30 items),includingfoodselection,eatingduration,eatingdesire, fear,burden,mentalhealth,socialfunctioning, communication, sleep, and fatigue. Each domain ranges from 0–100 with ahigherscoreindicatingmoreimpairment.Alsoasymptomscale(14additionalitems)andatotalSWAL-QOLscore(the23itemsofthefirstsevenscaleslistedabove)canbecalculated.Finally,thequestionnaireincludesthreeseparatequestionsregardingnutritionintake,liquidsintake,andgeneralhealth[27].Acut-offscoreof14points(orhigher)hasbeenestablishedfor identifyingHNCpatientswith clinically relevant swallowingproblems25,26. Additionally,a Dutch structured study-specific questionnaire was used, which aimed at assessing inmore detail complaints during the last week concerning diet/swallowing and concerningmastication/mouth opening, in part based on the EORTC C30/HN35, as described earlier(AppendixI)20.Therewere6questionsineachcategorywithmostly4possible,structuredanswers.Fordietandswallowing thesequestionswere: “What is theconsistencyofyourdiet?” “Doyouhaveproblemswith swallowing solid food?” “Doyouhaveproblemswithswallowingsoft/mincedfood?”“Doyouhaveproblemswithswallowingliquidfood?”“Doyouhavetoswallowrepeatedlytogetridofthefood?”“Isitpainfultoswallow?”Formasticationandmouthopeningthesequestionswere:“Doyoustillhaveyourown(setof)teeth?”“Howoftendoyoucleanyourteeth/dentures?”“Howdoyouexperienceyourmouthopening?”“Doyouexperienceproblemswitheating,becauseofalimitedmouthopening?”“Doyouexperience problems with speech, because of a limitedmouth opening?” “Do you haveproblemswithchewingyourfood?”.



3

Statistical analysisDescriptivestatisticsweregeneratedforallcontinuousoutcomemeasures(i.e.MIO,SWAL-QOL)atthe10-years+assessmentpoint.Dataweresummarisedasmedianswithassociatedrange.Spearman’srankcorrelationwasusedtodeterminesignificantassociationsbetweenobjective and subjective outcome variables (e.g. FOISwith SWAL-QOL score). TheMann-Whitney U test was used to compare outcome variables between two unpaired groups(IMRT vs. conventional RT). Percentages of reported/measured disorderswere calculatedfor categoricaloutcomeparameters, comparable to themethodsdescribedbyLogemannet al.28. Pearson’s Chi-Square testwas used to test associations/differences in proportionbetweentwoormoregroups.AlldatawerecollectedandanalyzedinSPSS(Chicago,Illinois;version22.0),andasignificancelevelofp <0.05wasused.

RESULTS

Patients’ characteristics At 10-years+ post-treatment (median 134 months; range 109–165 months), 22 patients(13male,9female;currentmeanage:62years,range42–74)wereevaluableAllpatientswereincompleteremission.Themajorityofpatients(82%)hadaprimarytumorlocatedattheoropharynx.AllpatientswerecurativelytreatedwithCRTforadvanced(stageIV)HNC.Eightpatients(36%)weretreatedwithstandardIVcisplatininfusionand14patients(64%)withhigh-doseIAcisplatininfusion.Tenpatients(45%;IA/IV:6/4)weretreatedwithIMRTand12patients(55%;IA/IV:8/4)withconventionalRT.Regardingnutritionandoralintake,duringtreatmentultimately19of22patients(86%)needednasogastric/gastrictubefeeding(including5patientswhoalreadyhadafeedingtubeatbaseline),whichwasdiscontinued/endedaftertreatmentassoonasnutritionalrequirementscouldbemaintainedorallyagain(seeTable1forthenumberofpatientswithafeedingtubeatthevariousassessmentpoints).

Theclinicalpatients’andtumorcharacteristicsoftheanalyzedpatientcohortat10-years+post-treatment(n=22)andtheoriginalpatientcohortatbaseline(n=207)arelistedinTable2.Therewerenosignificantdifferencesinproportionbetweenthesetwogroupswithrespecttogender,tumorsite,stage,ortreatment(p >.05).

Table 1.Numberofpatientswithnasogastricorgastricfeedingperassessment.

Baseline 7-weeks 12-weeks 1-year 5-years 10-yearsPre-CRT DuringCRT Post-CRT Post-CRT Post-CRT Post-CRT

Yes 5 19 12 5 3 3No 17 3 10 17 19 19

Abbreviations:CRT=chemo-radiotherapy

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58|Chapter3

Table 2. Clinicalpatient-,tumor-andtreatmentcharacteristicsforthelongtermanalysedpatientcohort(n=22)andtheoriginalpatientcohort(n=207).

207patients 22patients Statisticsat baseline 10-years+

Chi-Square P valueCharacteristic n (%) n (%)Meanage,y(range) 55 (24-81) 62 (42-74) NA NAGender

Male 153 (74%) 13 (59%) 2.191 .139Female 54 (26%) 9 (41%)

Tumor siteOral cavity 33 (16%) 1 (4.5%) 2.755 .252Oropharynx 136 (66%) 18 (82%)Hypopharynx 38 (18%) 3 (14%)

TstageT2 4 (2%) 1 (4.5%) 3.291 .193T3 61 (29%) 10 (45%)T4 142 (69%) 11 (50%)

NstageN0 37 (18%) 9 (41%) 8.177 .147N1 25 (12%) 3 (14%)N2a 10 (5%) 0 (0%)N2b 55 (27%) 5 (23%)N2c 60 (29%) 3 (14%)N3 20 (10%) 2 (9%)

ChemotherapyIV 103 (50%) 8 (36%) 1.429 .232IA 104 (50%) 14 (64%)

RadiotherapyIMRT (±25%) 10 (45%) NA NACONV (±75%) 12 (55%)

Abbreviations:y=years;IV=intravenous;IA=intra-arterial;IMRT=Intensity-ModulatedRadiotherapy;CONV=conventionalradiotherapy

Functional resultsSwallowingandmouthopeningresultsperpatient(n=22)aresummarizedinTable3.



3

Tabl

e 3.Swallowingan

dmou

thope

ning

datacollection

perpati

ent.

PATI

ENT

TUMOR

TREATM

ENT

OBJEC

TIVE

OUTC

OMES10-YEAR

SSU

BJEC

TIVE

OUTC

OMES10-YEAR

SSex

Age

Base

line

weigh

tSi

teStage

CTx

RTx

Feed

ing

tube

Nutriti

on/Intake

VFS

Mou

thope

ning

Swallowing

Masticati

onPn

eum

onia

(≥2ha

lfyr)

TNM

Weigh

tFO

IS

Tube

PAS

Resid

ueM

IOTr

ismus

Difficulty

Pain

Difficulty

Pain

1 M

7010

6kg

orop

hT3

N0

IVIM

RTye

s105

kg

7no

1ye

s46

mm

nono

nono

nono

2 M

6595

kg

orop

hT4

N2c

IVIM

RTye

s80

kg

7no

5ye

s58

mm

noye

sno

yes

nono

3 M

6475

kg

orop

hT3

N0

IAIM

RTye

s68

kg

6no

3ye

s41

mm

nono

nono

nono

4 M

6479

kg

orop

hT4

N2b

IAIM

RTye

s80

kg

7no

1ye

s10

mm

yes

nono

nono

no5

M63

93kg

orop

hT3

N2b

IVIM

RTye

s96

kg

6no

1ye

s40

mm

nono

nono

nono

6F

5866

kg

orop

hT3

N2c

IVIM

RTye

s65

kg

2ye

s6

yes

10m

mye

sye

sno

yes

noye

s7

M58

70kg

hypo

T3N

1 IA

IMRT

yes

78kg

6no

8ye

s52

mm

noye

sno

nono

no8

M57

89kg

hypo

T2N0

IAIM

RTye

s102

kg

7no

8ye

s40

mm

nono

nono

nono

9 M

5688

kg

orop

hT3

N2b

IAIM

RTno

90kg

7no

1ye

s40

mm

noye

sye

sye

sye

sno

10F

4265

kg

oral

T3N0

IAIM

RTye

s67

kg

7no

1ye

s21

mm

yes

nono

nono

no11

F67

83kg

orop

hT4

N0

IACO

NV

yes

60kg

6no

8ye

s32

mm

yes

nono

nono

no12

M64

68kg

orop

hT4

N1

IACO

NV

yes

69kg

7no

8ye

s25

mm

yes

yes

yes

yes

yes

no13

F67

62kg

orop

hT4

N2b

IACO

NV

yes

64kg

7no

8ye

s23

mm

yes

nono

nono

no14

M69

64kg

orop

hT4

N0

IV*

CON

Vye

s78

kg

1ye

s8

yes

15m

mye

sye

sye

sye

sye

sno

15F

6343

kg

orop

hT3

N0

IACO

NV

yes

44kg

6no

8ye

s34

mm

yes

yes

yes

yes

yes

no16

F62

45kg

orop

hT4

N1

IVCO

NV

yes

45kg

5no

6ye

s23

mm

yes

yes

nono

nono

17F

6254

kg

orop

hT4

N3

IVCO

NV

yes

56kg

2ye

s7

yes

40m

mno

yes

nono

noye

s18

M70

90kg

orop

hT3

N0

IA**

CON

Vye

s92

kg

6no

8ye

s27

mm

yes

yes

noye

sno

no19

F60

54kg

orop

hT3

N2c

IVCO

NV

yes

54kg

5no

8ye

s 8

mm

yes

yes

noye

sno

no20

F60

62kg

orop

hT4

N2b

IACO

NV

yes

63kg

5no

8ye

s23

mm

yes

yes

noye

sno

yes

21 M

7478

kg

hypo

T4N0

IACO

NV

no77

kg

7no

1ye

s46

mm

nono

nono

nono

22 M

5084

kg

orop

hT4

N3

IACO

NV

yes

84kg

7no

1ye

s45

mm

noye

sno

yes

nono

*Th

ispa

tienthad

requ

iredlasersurgeryfo

rsecon

dprim

aryatth

eph

aryngealarchat10-yearsp

ost-treatmen

t.**

Thisp

atien

thad

requ

iredlasersurgery

forsecond

prim

aryatthe

alveo

larprocessat11-yearspo

st-treatmen

t,subseq

uentlyfo

llowed

bylocalresectio

nwith

bon

egraft

ingdu

etorecurrent

diseaseat13-yearsp

ost-treatmen

t.Ab

breviatio

ns:TNM=Tum

orNod

eMetastasis

;CTx=che

mothe

rapytreatm

ent;RTx=radiothe

rapytreatm

ent;FO

IS=

Functio

nalO

ralIntakeScale;VFS=Video

fluoroscopy;PAS

=Pen

etratio

nan

dAspiratio

nScale;M

IO=M

axim

alInterin

cisorO

pening

;M=m

ale;F=female;

hypo

=hypop

harynx;o

roph

=oroph

arynx;oral=

oralcavity

;IA=intra-arteria

l;IV=in

traven

ous;IM

RT=In

tensity-M

odulated

Rad

iotherap

y;CONV=

conven

tiona

lrad

iotherap

y;kg=kilogram

s;m

m=m

illim

etres;NA=no

tapp

licab

le.

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60|Chapter3

Swallowing function and dietary intakeVFS evaluation of swallowing function showed more than normal post-swallow contrastresidue in all patients, mainly at the vallecula and piriform sinus and already occurringafter1ccsipsofthinliquid.Safeoralintakewasdemonstratedin7patients(32%),whereaspenetrationand/oraspirationoccurred in15patients (68%).Specifically,penetration (PASscore2–5)wasdemonstratedin2patients(9%),andaspiration(PASscore6–8)wasshownin 13 patients (59%),with 10 of 13 patientsmaking no effort to eject (silent aspiration).Aspiration(PAS≥6)occurredsignificantlylessinpatientstreatedwithIMRT(3of10patients)comparedtopatientstreatedwithconventionalRT(10of12patients;p=.011;Chi-Squaretest).

Regardingoralintake,10patients(45%)wereabletoconsumeanormaloraldietwithoutrestrictions(FOISscore7),whereas12patients(55%)hadrestrictions:10patientswereonlyabletoconsumeanoraldietwithspecificfoodlimitations(FOISscore6;n=6)orwithspecialpreparation (FOIS score5;n=3),and3patientswere feeding-tubedependent (FOIS score1–3).Threepatients(2of3withafeedingtube)hadahistoryofrepeated(≥2)aspirationpneumonia and/or other recurring pulmonary problems in the last 6months.Moreover,according to the study-specific questionnaire, 13 patients (59%) reported swallowingdifficulties,ofwhom4patientsalsoreportedpainfulswallowing.

ResultsoftheSWAL-QOLquestionnaire(n=22)aredescribedinTable4.Signsofimpairedswallowingfunction(score>14)werefoundacrossallQOLdomainswithexceptionofthedomainssleepandmentalhealth.Especiallyeatingdurationwasseverelyimpaired(medianscore=63;meanscore±SD=58±32),andsignificantlyassociatedwithlowerFOISscores(rs=-.61,p=.002).Similarly,socialfunctioning(rs=-.50,p=.019)andfearofeating(rs=-.48,p=.025)wereassociatedwithrestrictedoral intake (FOISscore).Generalburden (rs=-.54,p=.010),and fearofeating (rs=-.58,p=.005)correlatedwithrepeatedpneumonia.Patients treatedwith IMRT showed significantbetter scoreson thedomains food selection,eatingdesire,communication,mentalhealth,andsocialfunctioning(Mann-WhitneyUtest;seeFigure2andTable5).Noassociationsbetweenswallowingoutcomesandtumorsiteorstagewerefound.

Mouth opening and masticationMeanmaximummouthopeningat10-years+post-treatment(n=22)was32mm(median33mm,range8–58mm)with12patients(55%;CONV/IMRT:9/3)showingtrismus(asdefinedasaMIO≤35mm)atthisassessmentpoint.Thisconcernedmainlyoropharyngealcancerpatients(n=11;CONV/IMRT:9/2).Tenpatients(45%)reportedbesidesswallowingproblemsalsodifficultieswithmasticationand4patients(18%)reportedalsopainduringmastication.There was a significant lower incidence of trismus in patients treated with IMRT (3/10)versuspatients treatedwithconventionalRT (9/12;p=.035;Chi-Square test).Trismuswassignificantlyassociatedwithaspiration(p=.011).



3

Table 4. DistributionofdomainsbySWAL-QOLquestionnairevariablesin22HNCpatientsat10-years+post-treatment.

Variable N valid Min-Max Median Mean±SDGeneral burden 22 0–100 31.5 36±33Foodselection 22 0–75 25 27±24Eatingduration 22 0–100 63 58±32Eatingdesire 22 0–42 29 25±15Fearofeating 22 0–100 56.5 44±36Sleep 22 0–75 13 19±22Fatigue 22 0–67 21 25±22Communication 22 0–88 25 34±27MentalHealth 22 0–55 10 20±19SocialFunction 22 0–65 25 23±19Symptom score 22 0–75 41 41±23

Abbreviations:Min=minimum;Max=maximum;SD=standarddeviation.

Table 5. DistributionofdomainsbySWAL-QOLquestionnairevariablesin22HNCpatientsat10-years+post-treatment,dividedbyradiotherapytreatment(Intensity-ModulatedRadiotherapy[IMRT]versusconventionalradiotherapy[CONV])

Variable RTx N valid Min-Max Median Mean±SD StatisticGeneral burden IMRT 10 0–75 19 26.4±28.6 p = .203

CONV 12 0–100 44 44.1±34.6Foodselection IMRT 10 0–50 12.5 16.3±18.7 p = .043*

CONV 12 0–75 31.5 36.6±24.6Eatingduration IMRT 10 0–100 50 41.3±39.2 p = .059

CONV 12 50–100 69 72.1±16.9Eatingdesire IMRT 10 0–42 21 17.5±16.4 p = .050*

CONV 12 17–42 33 31.3±10.1Fearofeating IMRT 10 0–100 25 35.1±39.1 p = .314

CONV 12 0–94 63 50.8±33.0Sleep IMRT 10 0–63 6.5 18.9±23.9 p = .923

CONV 12 0–75 19 18.8±22.3Fatigue IMRT 10 0–67 17 24.2±24.8 p = .821

CONV 12 0–67 25 25.0±21.4Communication IMRT 10 0–50 6.5 18.8±23.0 p = .014*

CONV 12 25–88 50 46.9±22.8MentalHealth IMRT 10 0–40 2.5 10±13.9 p = .014*

CONV 12 5–55 30 27.9±20.1SocialFunction IMRT 10 0–45 7.5 ,13±15.7 p = .017*

CONV 12 0–65 27.5 31.3±18.0Symptom score IMRT 10 0–75 28.5 31.1±28.1 p = .123

CONV 12 21–68 46.5 48.8±14.8

Abbreviations:RTx=radiotherapytreatment;Min=minimum;Max=maximum;SD=standarddeviation;IMRT=Intensity–ModulatedRadiotherapy;CONV=conventionalradiotherapy.*p-valueaccordingtoMann-WhitneyUtest;significancelevelatp<0.05.

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62 | Chapter 3

Figure 2.DistributionofdomainsbySWAL-QOLquestionnairevariablesin22HNCpatientsat10-years+post-treatment, associated by radiotherapy treatment protocol (Intensity-Modulated Radiotherapy[IMRT]versusconventional radiotherapy [CONV]).Asteriskmeansstatisticaldifferencebasedonap value<0.05accordingtoMann-WhitneyUtest.

DISCUSSION

This is one of the first studies prospectively investigating long term (10-years+) QOL,swallowing function, andmouth opening inHNC patients treatedwith CRT for advanceddisease. Regarding swallowing function, both observer-rated and patient-reported severefunctionaldisordersandrelatedmorbidityproblemswerecommon inthispatientcohort.Resultsshowedoccurrenceofpenetrationand/oraspirationinalmost70%ofpatientsandprofoundpharyngealresidueinallpatients.Moreover,fourpatientswerestillfeedingtubedependentand/orhaddeveloped frequentaspirationpneumoniasand/orother recurringpulmonaryproblems.Forty-sixpercentofpatientswereabletoconsumeanormaloraldietwithoutrestrictions,butfourofthemstillreportedhavingswallowingdifficulties.Patients’perceivedswallowingfunction,asassessedwiththeSWAL-QOLquestionnaire,wasimpairedacrossmostQOLdomains(score>14)too,indicatingclinicallyrelevantswallowingproblemswithsignificantimpactonQOL25,26.Wedidnotfindanassociationbetweensiteofdiseaseand dysphagia severity. However, all patients had advanced (stage IV) disease and werepredominantly treated with large radiation fields, encompassing several organs at riskinvolvedinswallowing,regardlessofdiseasesite.



3

Onapositivenote,impairmentsweresignificantlylessprofoundinpatientstreatedwithIMRT – a treatmentmodality that during the trial period had gradually been introducedin our Institute. Although the patient population was rather small in the current study,resultsare inconcordancewithaprevious, larger-scalestudyfromour Institute, thatalsoshowed better xerostomia relatedQOL 2-3-years post-treatment in patients treatedwithIMRTcomparedtoconventionalRT4.Interestingly,anotherarticlefromourInstituteonlateefficacy/toxicity in thesamepatientpopulationrecently reported that treatmentprotocol(IVversusIAcisplatininfusion)mightalsoplayaroleinthis.Afteramedianfollow-upof7.5years,dysphagiaaccordingtotheRTOGtoxicitycriteriawasreportedtobeworseintheIVarm29.However,thepresentandpreviousstudiesonswallowingfunctionanddietaryintakedidnotrevealanysignificantdifferencesbetweenthetwoIAandIVchemotherapyprotocolsin this respect18,19.Theauthorsinthe‘7.5-yearsstudy’didnottakeintoaccounttheeffectsofthechangesinradiationtreatment(IMRTversusconventionalRT)duringthetrial.HavingthoseIMRT–conventionalRTdatatakenintoconsiderationnow30,itthereforeseemsmorelikelythattreatmentwithIMRTinsteadoftheIVcisplatininfusionhasbeencausingthemorefavourableswallowingoutcomesinthispatientcohort.

Regardingmouthopeningproblems, trismuswasobserved inmore thanfiftypercentof patients. This is substantially higher than the weighted prevalence of 31% followingconventionalRTwithchemotherapy,asrecentlydeterminedinareviewofseveralstudieswhere trismus was appropriately assessed31. The population of this study, with mainlyadvancedprimarieslocatedattheoropharynx32,mightbeareasonforthisdifference.Limitedmouthopeningmaymakepropermasticationoffoodmoredifficult,whichisinaccordancewithhalfofourpatientscomplainingaboutmasticationdifficulty.Furthermore,trismusmayresult incompromisedairwayclearancewithpoorbolusorganizationthat–togetherwithincreasedpharyngeal residue–has thepotential to lead toaspirationproblems31. Also in ourpatientcohortarelationshipbetweentrismusandaspirationwasfound.Anexplanationmightbethatthepatientswhodevelopedbothfunctionaldeficits(trismusandaspiration)receivedhigherRTdosesonthemusclescriticaltomasticationandswallowing33. The fact thattrismusoccurredsignificantlymoreinpatientstreatedwithconventionalRTcomparedtopatientstreatedwithIMRTconfirmssuchadose-effectrelationship.

To prevent CRT-induced swallowing disorders, maintenance of oral intake throughoutCRT treatment and/or preventive swallowing exercises (“eat or exercise” principle) haveindependently been associated with better post-treatment swallowing outcomes directlyafter treatment and at short-term follow-up34, 35. Also in a recent prospective clinical trialfromour institute,withacisplatin-basedCRTwith IMRTtherapyprotocol, resultsshowedminimal swallowing disorders at 6-years follow-up in patients, who were treated withpreventiveswallowingexercises11.Inthatstudycohort,noneofthetwenty-twopatientswasdependent on tube feeding at 6-years post-treatment, and it is likely that the favourable

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64 | Chapter 3

swallowingoutcomescanbeattributedbothtotheorgan-sparingIMRTandtothepreventiveand continuedpost-treatment rehabilitation programswhichwere applied. It is not clearwhetherthepooroutcomeinthecurrentcohortismainlycausedbythelackofpreventiverehabilitation,thelargerradiationfields,ortheprogressivefibrosisatlongtermfollowingRT.However,resultsprobablywouldhavebeenevenmoredismalifnot45%oftheselongtermsurvivorshadreceivedIMRT.

Regarding oral intake during treatment, the usefulness of prophylactic gastric tubeplacement tomaintainweightandnutritionduringtreatment iscurrentlyunderdebate36. The controversy ismainly aboutmaintainingweight during treatment versusmaintainingswallowingfunctionbytrainingoralintake37. As supported by several studies28,35,38,39,itseemsreasonabletoassumethatprophylacticgastrictubeplacementleadstoworsepost-treatmentswallowinganddietoutcomes,sincetheswallowingmusclesarenolongeractivelyusedandmayatrophy(the“useitorloseit”principle)39.Weightlossduringtreatmentisassociatedwithworseoncologicaloutcome37,butitisnotclearwhatlossisacceptable.However,initialbodymassindex(BMI)mayplayaroleinthat,sinceoropharyngealcancerpatientswithaBMI>25atthestartoftreatmentmayhaveabetteroverallsurvival37.

CONCLUSION

Functionalproblemsinthispatientcohortat10-years+postCRTtreatmentaresubstantial,with noticeable occurrence of dysphagia, recurrent aspiration pneumonia, feeding tubedependency,andtrismus. IMRTpatientsshowed lessswallowing impairmentandtrismus,though,thanpatientstreatedwithconventionalRT.

ACKNOWLEDGEMENTS

Wilma van Heemsbergen, epidemiologist and clinical researcher at the Department ofEpidemiology&Biostatistics at theNetherlandsCancer Institute, is greatly acknowledgedforhersupportandadviceinthestatisticalanalysis.Thisstudywasmadepossiblebygrantsprovidedby“StichtingdeHoop”andthe“VerweliusFoundation”.



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REFERENCES

1. vanderMolenL,vanRossumMA,BurkheadLM, Smeele LE, Hilgers FJ. Functionaloutcomes and rehabilitation strategies inpatients treated with chemoradiotherapyfor advanced head and neck cancer: asystematicreview.EurArchOtorhinolaryngol.2009;266:889-900.

2. Kraaijenga SA, van der Molen L, van denBrekel MW, Hilgers FJ. Current assessmentandtreatmentstrategiesofdysphagiainheadandneckcancerpatients:asystematicreviewofthe2012/13 literature.CurrOpinSupportPalliatCare.2014;8:152-63.


4. van Rij CM, Oughlane-Heemsbergen WD,AckerstaffAH,LamersEA,BalmAJ,RaschCR.ParotidglandsparingIMRTforheadandneckcancerimprovesxerostomiarelatedqualityoflife.RadiatOncol.2008;3:41.




8. Carnaby-Mann G, Crary MA, SchmalfussI, Amdur R. “Pharyngocise”: randomizedcontrolled trial of preventative exercisesto maintain muscle structure and swallowing function during head-and-neck

chemoradiotherapy. Int J Radiat Oncol Biol

Phys.2012;83:210-9.


10. van der Molen L, van Rossum MA, RaschCR, Smeele LE, Hilgers FJ. Two-year resultsof a prospective preventive swallowingrehabilitation trial in patients treatedwith chemoradiation for advanced headand neck cancer. neck cancer. Eur ArchOtorhinolaryngol.2014;271(5):1257–70.

11. Kraaijenga SA, van der Molen L, Jacobi I,Hamming-VriezeO,HilgersFJ,vandenBrekelMW. Prospective clinical study on long-termswallowing function and voice quality inadvanced head and neck cancer patientstreated with concurrent chemoradiotherapy andpreventiveswallowingexercises.EurArchOtorhinolaryngol.2015(Epub)

12. Rutten H, Pop LA, Janssens GO, Takes RP,Knuijt S, Rooijakkers AF, et al. Long-termoutcome and morbidity after treatmentwith accelerated radiotherapy and weeklycisplatin for locally advanced head-and-neckcancer: results of a multidisciplinary latemorbidityclinic. Int JRadiatOncolBiolPhys.2011;81:923-9.


14. Hutcheson KA, Lewin JS, Holsinger FC,Steinhaus G, Lisec A, Barringer DA, et al.Long-term functional and survival outcomesafter induction chemotherapy and risk-baseddefinitivetherapyfor locallyadvancedsquamous cell carcinoma of the head andneck.HeadNeck.2014;36:474-80.

15. Balm AJ, Rasch CR, Schornagel JH, HilgersFJ, Keus RB, Schultze-Kool L, et al. High-dose superselective intra-arterial cisplatinand concomitant radiation (RADPLAT) foradvancedheadandneckcancer.HeadNeck.2004;26:485-93.

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17. RaschCR,HauptmannM,SchornagelJ,WijersO,ButerJ,GregorT,etal.Intra-arterialversusintravenous chemoradiation for advancedheadandneckcancer:Resultsofarandomizedphase3trial.Cancer.2010;116:2159-65.

18. AckerstaffAH,BalmAJ,RaschCR,deBoerJP,Wiggenraad R, Rietveld DH, et al. First-yearqualityof life assessmentof an intra-arterial(RADPLAT)versusintravenouschemoradiationphaseIIItrial.HeadNeck.2009;31:77-84.




22. Rosenbek JC, Robbins JA, Roecker EB, CoyleJL, Wood JL. A penetration-aspiration scale.Dysphagia.1996;11:93-8.

23. McHorney CA, Martin-Harris B, Robbins J,Rosenbek J. Clinical validity of the SWAL-QOL and SWAL-CARE outcome tools withrespect to bolus flow measures. Dysphagia.2006;21:141-8.

24. Dijkstra PU, Huisman PM, Roodenburg JL.Criteriafortrismusinheadandneckoncology.IntJOralMaxillofacSurg.2006;35:337-42.

25. RinkelRN,Verdonck-deLeeuwIM,LangendijkJA,vanReijEJ,AaronsonNK,LeemansCR.The

psychometric and clinical validity of the SWAL-QOL questionnaire in evaluating swallowingproblems experienced by patients withoral and oropharyngeal cancer. Oral Oncol.2009;45:e67-71.


27. McHorneyCA,RobbinsJ,LomaxK,RosenbekJC, Chignell K, Kramer AE, et al. The SWAL-QOL and SWAL-CARE outcomes tool fororopharyngeal dysphagia in adults: III.Documentation of reliability and validity.Dysphagia.2002;17:97-114.


29. Heukelom J, Lopez-YurdaM,BalmAJ,WijersOB,ButerJ,GregorT,etal.Latefollow-upofthe randomized radiation and concomitanthigh-dose intra-arterial or intravenouscisplatin (RADPLAT) trial for advanced headandneckcancer.HeadNeck.2015(Epub).

30. Gupta T, Agarwal J, Jain S, PhurailatpamR, Kannan S, Ghosh-Laskar S, et al. Three-dimensionalconformalradiotherapy(3D-CRT)versus intensitymodulatedradiationtherapy(IMRT) in squamous cell carcinoma of theheadandneck:arandomizedcontrolledtrial.RadiotherOncol.2012;104:343-8.

31. Bensadoun RJ, Riesenbeck D, LockhartPB, Elting LS, Spijkervet FK, Brennan MT.A systematic review of trismus induced bycancer therapies in head and neck cancerpatients.SupportCareCancer.2010;18:1033-8.

32. Kamstra JI, Dijkstra PU, van Leeuwen M,RoodenburgJL,LangendijkJA.Mouthopeningin patients irradiated for head and neckcancer: A prospective repeated measuresstudy.OralOncol.2015(Epub).

33. vanderMolenL,HeemsbergenWD,deJongR, vanRossumMA, Smeele LE,RaschCR, etal. Dysphagia and trismus after concomitantchemo-Intensity-Modulated Radiation



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Therapy (chemo-IMRT) in advanced headand neck cancer; dose-effect relationshipsfor swallowing and mastication structures.RadiotherOncol.2013;106:364-9.



36. WopkenK,BijlHP,vanderSchaafA,vanderLaan HP, Chouvalova O, Steenbakkers RJ, etal. Development of a multivariable normaltissue complication probability (NTCP)model for tube feeding dependence aftercurative radiotherapy/chemo-radiotherapyin head and neck cancer. Radiother Oncol.2014;113:95-101.

37. OttossonS,SoderstromK,KjellenE,NilssonP,ZackrissonB,LaurellG.Weightandbodymassindex inrelationto irradiatedvolumeandtooverallsurvivalinpatientswithoropharyngealcancer: a retrospective cohort study. RadiatOncol.2014;9:160.

38. Mekhail TM, Adelstein DJ, Rybicki LA, LartoMA, Saxton JP, Lavertu P. Enteral nutritionduring the treatment of head and neckcarcinoma: is a percutaneous endoscopic gastrostomytubepreferabletoanasogastrictube?Cancer.2001;91:1785-90.


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Appendix I. ThetranslatedDutchstudyspecificquestionnaire.

StudyspecificquestionnaireA. Socio-demographicdata(12questions)

B. Complaintsoverthelastweek(12questions)

a. Dietandswallowing1. Whatisyourdietlike?

1=Ieatsolidfood 2=Ionlyeatsoft(minced)food3=Ionlyeatliquidfood 4=Ionlyhavetubefeeding5=combinationsoftdietandtubefeeding

2. Doyouhaveproblemswithswallowingsolidfood?1=notatall 2=alittle3=rather 4=quitealot

3. Doyouhaveproblemswithswallowingsoft/mincedfood?1=notatall 2=alittle3=rather 4=quitealot

4. Doyouhaveproblemswithswallowingliquidfood?1=notatall 2=alittle3=rather 4=quitealot

5. Doyouhavetoswallowrepeatedlytogetridoffood?1=yes 2=no3=sometimes

6. Isitpainfultoswallow?1=yes 2=no3=sometimes

b. Masticationandmouthopening1. Doyoustillhaveyourownteeth?

1=yes 2=yes,partially3=no,Ihaveaprosthesis 4=no,andIdon’twearaprosthesis

2. Howoftendoyoucleanyourteeth?1=acoupleoftimesaday 2=onceaday3=lessthanonceaday 4=notatall

3. Howdoyouexperienceyourmouthopening?1=normal 2=alittlebitlimited3=verylimited 4=Icannotopenmymouth



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4. Doyouexperienceproblemswitheating,becauseofalimitedmouthopening?1=notatall 2=alittle3=rather 4=quitealot

5. Doyouexperienceproblemswithspeech,becauseofalimitedmouthopening?1=notatall 2=alittle3=rather 4=quitealot

6. Doyouhaveproblemswithchewingyourfood?1=notatall 2=alittle3=rather 4=quitealot

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CHAPTER 4Assessment of voice, speech, and related quality of life

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CHAPTER 4Assessment of voice, speech, and related quality of life

in advanced head and neck cancer pa.ents

10-‐years+ aSer chemoradiotherapy


O. Hamming-‐Vrieze F.J.M. Hilgers

M.W.M. van den Brekel R.J.J.H. van Son L. van der Molen

Oral Oncol. Online 2016 Feb 10.

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ABSTRACT

Objectives: Assessment of long-term objective and subjective voice, speech, articulation,and quality of life in patientswith head and neck cancer (HNC) treatedwith concurrentchemoradiotherapy(CRT)foradvanced,stageIVdisease.

Materials and methods:Twenty-twodisease-freesurvivors,treatedwithcisplatin-basedCRTfor inoperableHNC (1999–2004),were evaluated at 10-years post-treatment. A standardDutchtextwasrecorded.Perceptualanalysisofvoice,speech,andarticulationwasconductedby two expert listeners (SLPs). Also an experimental expert system based on automaticspeechrecognitionwasused.Patients’perceptionofvoiceandspeechandrelatedqualityof lifewasassessedwiththeVoiceHandicapIndex(VHI)andSpeechHandicapIndex(SHI)questionnaires.

Results:Atamedianfollow-upof11-years,perceptualevaluationshowedabnormalscoresinupto64%ofcases,dependingontheoutcomeparameteranalyzed.Automaticassessmentof voice and speechparameters correlatedmoderate to strongwith perceptual outcomescores. Patient-reported problems with voice (VHI >15) and speech (SHI >6) in daily lifewerepresentin68%and77%ofpatients,respectively.PatientstreatedwithIMRTshowedsignificantlylessimpairmentcomparedtothosetreatedwithconventionalradiotherapy.

Conclusion: More than 10-years after organ-preservation treatment, voice and speechproblems are common in this patient cohort, as assessed with perceptual evaluation,automatic speech recognition, and with validated structured questionnaires. There werefewercomplaintsinpatientstreatedwithIMRTthanwithconventionalradiotherapy.

KEY WORDSHeadandNeckCancer–Chemoradiotherapy–VoiceQuality–SpeechIntelligibility–GRBAS–PerceptualEvaluation–AutomaticSpeechRecognition–Long-termeffects–IMRT


Long-termvoice,speech,andrelatedqualityoflifeinadvancedheadandneckcancer|73

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INTRODUCTION

Inpatientswithadvancedheadandneckcancer(HNC),boththetumoranditstreatmentwithcombinedchemoradiotherapy(CRT)canadverselyimpactvoiceandspeechoutcomes.Inpatientswithcancersoftheoralcavityandoropharynx,destructiveeffectsofthetumorwillmainlyaffectpatients’articulationand/orspeech,whereasinlaryngealcancerpatients,the tumor often has negative effects on voice quality1,2. Treatment effects of (chemo-)radiotherapyonvoicequalityandspeechpredominantlydependonradiationdosestotheorgansatrisksurroundingtheprimarytumorandlymphnodes.Whenthelarynxisincludedintheradiationfield,decreasedvoicequalitymaybeattributedtoimpairedvocalfoldvibration,incompleteglotticclosure,insufficientlubrication/drynessofthelaryngealmucosa,muscleatrophy,fibrosis, hyperaemia, and/orerythema3. Patientsoftencomplainabout increasedvocaleffort,breathiness,andhoarseness2.Radiationtreatmentfornon-laryngealcancermayalso influencevoiceandspeech,evenat long-term4,due to radiation-inducedanatomicalchangesofthevocaltract,e.g.scarring,edemaand/orfibrosisofstructuresin/aroundtheoral cavity or oropharynx5,6[1]. Consequently, reduced speech intelligibility and impairedarticulationmayaffectpatients’dailylifeactivitiesandinteractions,whichcanbeassociatedwithseverefunctionalandpsychosocialproblems,andreducedqualityoflife7,8.

Previous literature on voice quality and speech following CRT for advanced HNChas proposed the use of prospective, standardised multidimensional voice and speechassessment protocols, based on adequate scientific background with long-term follow-up1,7,9.In2009,Dwivediandcolleaguesstudiedspeechoutcomesfollowingoralcavityand/ororopharyngeal cancer, and recommended speechevaluationby variousmodalities, i.e.perceptualevaluation,acousticevaluation,andstructuredquestionnaires9.AlsoJacobietal.(2010)andSchusteretal.(2012)clarifiedintheirreviewsinthisareatheneedforstructured,standardised protocols,includingbaselineassessmentsandlong-termfollow-up1,7.

Despite these recommendations, prospectively collected voice and speech data stillare scarce4,10,11, especially at long-term2. At the same time, technology is improving, andautomatedmethodsofvoiceandspeechevaluationareunder developmentasanalternativeand/or adjunct to traditional, time-consuming perceptual evaluation of voice quality andspeech7,12,13.Inparticularinresearchsetting,automaticspeechrecognitionisalreadyused,toprovideglobalmeasuresofspeechintelligibilityand(toalesserextent)ofvoicequality14,15. However, also in clinical settings automatic speech evaluation can be used to ensuremultidimensionalassessments,whichcanbetimeefficientandfast.Theaimofthecurrentstudywastoreportonthelong-termobjectiveandsubjectivevoiceandspeechoutcomes,includingperceptualevaluation,automaticevaluation,andpatient-reportedoutcomes.

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Patient and treatment characteristicsAspartofarandomizedcontrolledclinicaltrialbetween1999and2004attheNetherlandsCancer Institute16, twenty-two HNC survivors treated with concurrent cisplatin-basedradiotherapyweredisease-free,evaluable,andwillingtoparticipateatlong-term(10-years+)post-treatment evaluation. For patients’ and treatment characteristics and reasons forexclusionat the long-termassessmentpointwe refer to the recentlypublishedpaperondysphagia in thesamepatientcohort17. In summary, theoriginalpatientcohortconsistedofpatientsdiagnosedwithstageIVcanceroftheoralcavity,oropharynx,orhypopharynx.Patientsweretreatedwithcisplatinaseitherastandard100mg/m2intravenous(IV)40mininfusionondays1,22,and43,orahigh-dose,targetedandrapid150mg/m2 intra-arterial (IA)cisplatininjectionwithintravenoussodiumthiosulphaterescueinweeks1,2,3,and4.Theprimarytumorareaandnecknodeswereirradiatedwith2Gyperfraction,in35fractionsover 7weeks, starting concurrentlywith chemotherapy. Ten patients (45%)were treatedwith intensity-modulated radiotherapy (IMRT), and 12 patients (55%) with conventionalradiotherapy.Basedonperceptualcategorization,threepatientswerecategorizedasaudiblynon-nativespeakers,whereastheothernineteenwerecategorizedasnative(with/withoutaudibleregionalordialectvariants).

Data collection Voice,speech,andarticulationoutcomeswerecollectedat10-years+post-treatmentfromspeechrecordingsconsistingofa189-wordDutchfairytalewithneutralcontentcontainingalmostallDutchphonemes(similartoearlierstudiesinourInstitute10,12;AppendixI).Patientswereaskedtoreadthetextaloudatacomfortableloudnessandpitchlevel.Allrecordingswere made in a sound-treated room using a Sennheiser MD421 Dynamic MicrophoneandanEdirol(Roland)R-1portable16-bit(44.1kHz)digitalwaverecorder.Themouth-to-microphonedistancewaskeptconstantatapproximately30cm.

Perceptual evaluationThestimuliforthelisteningexperimentconsistedoftwofragments,thefirst70words(A)andthefollowing68words(B),fromtheoriginal189-wordpassagereadbythepatients12,13. Thus,eachpatientwasratedtwicebyeachSLP,onceonfragmentAandonceonfragmentB.Stimulusmaterialwasmanuallyselectedbyanindependentexpert,excised,andequalizedat70decibelwiththePRAATprogram18.Fourpracticeitems,alistofwords,andsustained/a/ vowelswere also recordedbutnotused for the current analysis.During the listeningexperiment,allrecordingswerepresentedoveraSennheiserHD418headphone.



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Perceptual rating Two experienced speech language pathologists (SLPs), both Dutch native speakers, wereaskedasexpertlistenerstoratevoice,speech,andarticulationparametersindependently.Thelistenerswereblindedtopatientinformation.RecordingswerepresentedforevaluationusingtheOpenSourceprogramTEVA19{,#2}{TEVA,#2},whichrunsasaPRAATextension10,15,20. SemanticscaleswereusedtoratevoicequalityoncomputerizedVisualAnalogueScales(VAS).Included scaleswereoverall gradeof voicequality, roughness, breathiness, asthenia, andstrain(GRBAS)21.Alsoanumberofadditionalsemanticscaleswereincludedtorateoverallspeechintelligibility,theprecisionofarticulation,nasality,andprosody.TheGRBASscalewasnotused in its standardized form (ratingon0–3),but thedescriptorsof theGRBAS scalewereused tocomputerizeanddigitizeVASratings toscores ranging from0 (‘leastsimilartonormal’) to1000 (‘most similar tonormal’).The listenersdiscussedandadjustedscaledefinitionsduringtheevaluationof10practicesessions,withthesamerecordedtextavailablefrom a different patient population10. The final/experiment recordingswere presented inidenticalordertobothlistenersoneweeklater.Theexpertlistenerscouldrepeatthestimuliasoftenasnecessary.Approximately3minutesperpatientwerenecessarytocompletethefullexperiment.

Reliability and agreement SupplementTable1liststheintrarater(exactandclose)agreementanddisagreementforeachlistenerseparatedpervariableconvertedintoordinalcategories,bydividingthevisualanalogscaleintofourequalpartslabelled‘good’(normal),‘fair’,‘moderate’,and‘poor’(abnormal)15. Agreementoccurredin>73%perrater.Thestrengthofthecorrelationbetweentheindividualjudgments(test-retestreliabilityoffragmentAcomparedtofragmentB)ofeachraterona0–1000scalewasalsoquitehigh(single-measureIntraclassCorrelationCoefficient(ICC(3,1))for[consistency]usingatwo-waymixedmodel;seesupplementTable1forthecorrespondingICC(3,1) values and confidence intervals per variable). Therefore, for further analysis themeanopinion scoreswereused todefine theagreementanddisagreementbetween thetwo listeners.SupplementTable2provides the interrater reliabilityandagreementof theraters’meanopinionscores.Ascanbeseen,scoreswereinexactagreement(difference≤125points)in6to21cases(27–96%),incloseagreement(difference≤250points)in1to12cases(5–55%),andindisagreementin1to9cases(5–41%),dependingonthevariableanalyzed.Exceptforprosody,allvariablesdemonstratedICC(3,1)valuesof0.75orhigher, indicatinggoodreliability.ForprosodytheICC(3,1)was0.60,indicatingacceptablereliability22,23.Hence,foroverallanalysisofperceptualevaluation,averagescoresbetweenthetworaters’meanopinion scores were used to evaluate perceptual voice and speech parameters.

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Automatic speech recognition Automatic assessment of voice quality and speech was conducted with the AutomaticSpeechanalysis InSpeechTherapy forOncology (ASISTO)expert system [12,13,24].Theassessmentmodelsusedinthispaperhavebeendevelopedandtestedonspeechrecordingsof a similar groupofDutch speakerswithHNCbefore and after CRT [12, 13]. Perceptual variablesanalyzedwereAutomaticVoiceQualityIndex(AVQI)andtwodifferentsystemsfordeterminingRunningSpeechIntelligibility.TheselattertwoexpertsystemsaredevelopedbytheDepartmentofElectronicsandInformationSystems,UniversityofGent,Belgium;onefortext-aligned(ELIS[25])andoneforalignment-free(ELISALF)evaluation[12,13].AVQIresultsrangedfrom1–8with1meaning ‘mostsimilar tonormal’and8meaning ‘leastsimilar tonormal’.Similarly,RunningSpeechIntelligibilityresultsrangedfrom0–100with0meaning‘nophonemesrecognized’and100meaning‘allphonemesrecognized’.

Patient-reported outcomesPatients’ perceived voice and speech impairment and relatedqualityof lifewas assessedwithtwovalidatedspecificvoiceandspeechrelatedqualityoflifequestionnaires:theVoiceHandicapIndex(VHI)andtheSpeechHandicapIndex(SHI).

TheVHIisa30-itemquestionnairescoredona0–4pointscaleformeasuringpatients’suffering causedbydysphonia, specified into3 subscales (physical, functional, emotional)identifiedwith10itemseach.ThetotalVHIscorecanrangefrom0–120withahigherscorecorresponding to a higher degree of patient-reported vocal handicap (VHI score 0–30:minimalhandicap;31–60:moderatehandicap;60–120:significantandserioushandicap)[26,27].Acut-offscoreof15points(97%sensitivityand86%specificity)hasbeenestablishedtoidentifypatientswithHNCandvoiceproblemsindailylife[28].

Basedon theVHI, the SHI has beendeveloped as a valid speech assessment tool forpatients with HNC, to provide insight into the nature and severity of patients’ speechcomplaints. Instructionsandgradingare identicaltotheVHI,butnowadaptedtospeech-relatedproblemsindailylife[29,30].ThetotalSHIscoreiscalculatedbysummingthescoresonall30items(scorerange0–120),withahigherscoreindicatingahigherlevelofspeech-relatedproblems.Acut-offscoreof6orhigher(95%sensitivityand90%specificity)hasbeenestablishedforspeechproblemsindailylife,andadifferencescoreof12pointsorhigherhasbeenproposedascriterionforclinicallysignificancein-groupcomparisons[31].Furthermore,therearetwoSHIsubscales:psychosocialfunction(14items,scorerange0–56)andspeechfunction(14items,scorerange0–56).Thequestionnairealsoincludesaglobalquestion“howisyourspeechtoday”,with4responsecategories(‘good’,‘reasonable’,‘poor’,and‘severe’).



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Statistical AnalysisDescriptivestatisticsweregeneratedforallcontinuousoutcomemeasuresatthe10-years+-assessmentpoint.Dataweresummarisedasmedianswithassociatedrange.Spearman’srankcorrelationwasusedtodeterminesignificantassociationsbetweenperceptual,automaticand/orpatient-reportedoutcomevariables.TheMann-WhitneyUtestwasusedtocompareoutcomevariablesbetweentwounpairedgroups(i.e.IMRTvs.conventionalradiotherapy).Pearson’sChi-Squaretestwasusedtotestassociationsordifferencesinproportionbetweentwoormoregroups.AlldatawerecollectedandanalyzedinSPSS(Chicago,Illinois;version23.0),andasignificancelevelofp <0.05wasused.

RESULTS

At10-years+post-treatment(median134months;range109–165months),22patients(13male,9female;currentmeanage:62years,range42–74)wereevaluable.Allpatientswereincompleteremission.Themajorityofpatients(82%)hadaprimarytumorlocatedintheoropharynx.Theclinicalpatients’andtumorcharacteristicsoftheanalyzedcohortat10-years+post-treatment(n=22)andtheoriginalpatientcohortatbaseline(n=207)recentlyhavebeenextensivelydescribed17.Therewerenosignificantdifferencesinproportionbetweenthesetwogroupswithrespecttogender,tumorsite,stage,ortreatment(p >.05).InTable1theperceptual, automatic, andpatient-reportedvoiceand speechoutcomeparameters in22patientswithHNCat10-years+post-treatmentaredemonstrated.

Perceptual evaluationForperceptualevaluationbytheSLPs,meanscores(Table1)werealsoconvertedintoafour-pointordinalscale ‘good’, ‘fair’, ‘moderate’,and‘poor’,wherebythetop25%was labelledas ‘normal’,and the remainderas ‘deviant’ (Figure1).Ascanbeseen,prosodywasmostfrequentlyjudgedasdeviant(in64%ofcases),followedbyintelligibility(46%),articulation(36%), and voicequality (oneormoredeviant parameter(s) of theGRBAS; 32%). In total18/22patients(82%)showedimpairments(deviantscores)ononeormoreoftheoutcomeparameters.Exceptforoverallgradeofvoicequalityandbreathiness,whichweresignificantlymoredeviantinpatientswithhypopharyngealtumors(Mann-WhitneyUtest;grade:p =.040;breathiness: p =.005), no correlations between perceptual outcome variables and tumorcharacteristicswerefound.Speechintelligibilitystronglycorrelatedwitharticulation(r=0.93;p <.001),andnasality(r=0.67,p=.001),whereasoverallgradeofvoicequalitysignificantlycorrelatedwithroughness(r=0.94;p =.000),andstrain(r=0.89;p =.000).PatientstreatedwithIMRT(45%)showedsignificantbetterintelligibilityscorescomparedtopatientstreatedwithconventionalradiotherapy(55%;seeTable2).

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Table 1. Descriptivestatisticsanddistributionbydomainofperceptual,automatic,andpatient-reportedvoiceandspeechvariablesin22headandneckcancerpatientsat10-years+post-treatment.

Variable(score) Min–Max Median Mean±SDPerceptual evaluation

Grade 105–993 832 743±245Roughness 179–995 936 822±223Breathiness 387–999 995 934±145Asthenia 687–999 987 961±71Strain 360–998 969 888±186Nasality 6–991 877 794±284Prosody 293–998 721 693±214Speechintelligibility 113–987 771 689±256Articulation 94–983 842 722±270

Automatic evaluationVoicequality(AVQI) 3.7–6.1 4.7 4.9±0.6Intelligibility(ELIS) 62–94 83 82±9Intelligibility(ELISALF) 67–92 85 82±8

Subjective evaluationVoiceHandicapIndex 0–57 21 22±18

Physical domain 0–22 10 10±8Functionaldomain 0–19 6,5 7±6Emotionaldomain 0–18 3 5±5

SpeechHandicapIndex 0–65 21.5 24±20Speech domain 0–38 13.5 16±12Psychosocial domain 0–26 5 7±8

Abbreviations:Min=minimum;Max=maximum;SD=standarddeviation;AVQI=AutomaticVoiceQuality Index; ELIS: text-aligned Running Speech Intelligibility25; ELISALF: alignment-free RunningSpeechIntelligibility.

Automatic evaluationTable1showsthedescriptivestatisticsat10-years+post-treatmentforautomaticassessmentofvoicequality(AVQI)andspeechintelligibility.AVQIscoresrangedfrom3.66to6.08(with1meaning‘mostsimilartonormal’and8meaning‘leastsimilartonormal’).AtrendwasseenforamoderatecorrelationbetweenAVQIandperceptualvoicequalityscoresbytheSLPs(r=0.42;p =.051;seeFigure2).Patientswithatumor located inthehypopharynxshowedsignificantlyworseAVQIscores(n=3;mean5.77;range5.47–6.08)comparedtothepatientswith a tumor located in the oral cavity/oropharynx (n=19; mean 4.72; range 3.66–5.95;Mann-WhitneyU test;p =.009).Regarding (ELIS) speech intelligibility, scores ranged from62.21to93.87(Table1).Therewasasignificantcorrelationwithperceptualscoresofspeechintelligibility(r=0.74;p =.000;seeFigure2).



4Figure 1. Percentagesofpatients (n=22)with ‘normal’ or ‘deviant’ perceptual andpatient-reportedvoiceandspeechparameters.Note:forperceptualscoresthetop25%waslabelledas‘normal’,andtheremainderas‘deviant’.Forpatient-reportedoutcomeparameters‘deviant’scoreswerebasedonvalidatedcut-offs28,31.

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Figure 2. Relationship between automatic evaluation of voice quality (AVQI scores) and perceptualevaluationofvoicequalitybytheSLPs(left),andbetweenautomatictext-alignedevaluationofrunningspeechintelligibility(ELISscores)andperceptualevaluationofspeechintelligibilitybytheSLPs(right).

Patient-reported outcomesVoiceHandicap Index (VHI) and SpeechHandicap Index (SHI) scoreswere used to assesspatients’perspectiveandrelatedqualityoflifeofvoiceandspeechdysfunction.InTable1thedistributionofthevarioussubdomainsat10-years+post-treatmentareshown.Patientswith a physical voice disability mainly reported problems such as increased vocal effort,breathiness, and unpredictable/varying clarity of voice, resulting in functional disabilities

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suchaspoorunderstandabilitybyothers,inparticularduringphonecallsorinnoisyrooms.Patientswithspeechproblemsinsteadmoreoftencomplainedaboutunpredictably/varyingintelligibilityanduncleararticulation.Overall,deviantSHI scores (SHI>6)werepresent in77% of patients (17/22), whereas 68% (15/22) showed voice problems (VHI >15). In thepsychosocialvoiceandspeechdomainshardlyanydisabilitieswerereported(medianscores3and5,respectively;seeTable1).PatientstreatedwithIMRT(45%)showedsignificantbetterscoresonalldomainscomparedtopatientstreatedwithconventionalradiotherapy(55%;seeTable2).Correlationwithperceptualandautomaticoutcomemeasures(i.e.overallgradeofvoicequality,speechintelligibility)waspoor(r<0.4),exceptforthequestion“howisyourspeech today”,which significantly butmoderately correlatedwith automatically assessedspeechintelligibility(r=0.46,p =.032).

Table 2. Perceptual,automatic,andpatient-reportedvoiceandspeechvariablesin22patientswithHNCat 10-years+ post-treatment, divided by radiotherapy treatment (Intensity-Modulated Radiotherapy[IMRT]versusconventionalradiotherapy[CONV]).

Variable(score) RTx N valid Min-Max Median Mean±SD StatisticPerceptualvoicequality(Grade) IMRT 10 465–993 875 797±180 p=.38

CONV 12 105–993 813 698±288Automaticvoicequality(AVQI) IMRT 10 3.7–6.1 4.9 4.9±0.7 p=.82

CONV 12 4.0–6.0 4.7 4.8±0.5VoiceHandicapIndex IMRT 10 0–49 2 12.5±17.1 p =.021

CONV 12 9–57 26 30.2±14.3Physical domain IMRT 10 0–22 1.5 6.6±8.6 p =.050

CONV 12 3–22 16 13.7±6.3Functionaldomain IMRT 10 0–16 0.5 3.5±5.2 p =.007

CONV 12 0–19 8.5 9.6±5.3Emotionaldomain IMRT 10 0–14 0 2.4±4.5 p =.011

CONV 12 0–18 6.5 6.9±5.4Perceptualspeechintelligibility IMRT 10 416–987 873 828±171 p =.006

CONV 12 113–922 616 574±263Runningspeechintelligibility(ELIS) IMRT 10 71–94 83 84±6.4 p=.82

CONV 12 62–93 79 81±10.5Runningspeechintelligibility(ELISALF) IMRT 10 69–92 86 83±8.4 p=.50

CONV 12 67–91 82 81±8.7SpeechHandicapIndex IMRT 10 0–53 5.5 14.0±18.5 p =.021

CONV 12 10–65 27.5 31.4±18.2Speech domain IMRT 10 0–33 5.5 9.9±11.7 p =.030

CONV 12 7–38 21 20.8±10.6Psychosocial domain IMRT 10 0–20 0 4.0±7.0 p =.017

CONV 12 1–26 6 10.3±8.5

Abbreviations: RTx = radiotherapy treatment; Min = minimum; Max = maximum; SD = standarddeviation;IMRT=Intensity–ModulatedRadiotherapy;CONV=conventionalradiotherapy.*p-valueaccordingtoMann-WhitneyUtest;significancelevelatp<0.05.



4

DISCUSSION

This study assessed long-term (10-years+) objective and subjective voice and speechoutcomes following organ-preservation treatment for advanced HNC. Results of the 22evaluable patients showed considerable functional deficits in this respect. PerceptualevaluationbytheSLPs,ratingoverallspeechintelligibility,theprecisionofarticulation,theGRBAS criteria, prosody, andnasality, revealed that 86%of patients showed impairmentsononeormoreof theoutcomeparameters. Theautomaticexpert systemASISTO, ratingautomaticvoicequality index (AVQI)andrunningspeech intelligibility, seemedtosupporttheperceptualevaluationresultsoftheSLPs,sincethereweresignificant,moderatetostrongcorrelationswithoverallgradeofvoicequalityandwithspeechintelligibility.Subjectivevoiceandspeechcomplaintswereevaluatedinthepresentpatientcohortwith(sub)totalVHIandSHI scores,andrevealedmoderatebutclinically relevantdisabilities, thatwerepresent in68%and77%ofpatients,respectively.

Otherstudiesevaluatingpatient-reportedvoiceandspeechoutcomesaftertreatmentforHNCalsodemonstrateddecreasedvoicequalityfollowingCRT11,32,withimpactonqualityoflifeandpsychosocialfunction33.OneofthefirstVHIevaluationsafterCRTforstageIII-IVHNCwasperformedbyKeereweerandcolleagues.Mildtoseverevoice impairmentwasfoundinallofthe20participatingpatients,whowereatleast2.5yearsaftertreatment32. In the studyofVainshteinandcolleagues,almost20%ofpatientsreportedfurthervoiceworseningat 18- and 24-months follow-up after chemo-IMRT for stage III-IV oropharyngeal cancer,mostcommonlyduetoworseningvocalclarity11. Speech problems were also found in recent studiesthatevaluatedpost-treatmentSHIscores8,31.Rinkelatal.reportedimpairedspeechindailylife(SHI>6)in55%ofpatientswithprimaryHNC(allsubsitesandstagesincluded),whereasinourstudythiswas77%.ThehigherprevalenceofdisabilitiesinthecurrentstudymightbeattributabletothemoreadvancedtumorstagewithonlystageIVtumorsincluded.Furthermore, the follow-up time in the current study was considerably longer (11 yearsversusamaximumof5yearsintheotherstudies),whichmightreflectafurtherdeteriorationpostCRTovertime,asrecentlyalsowasfoundfordysphagiaissues17,34.

Interestingly,theproblemswerepredominantlyrelatedtoradiationtechnique,becausepatients treated with IMRT showed significantly less voice and speech problems on thevariousdomainscomparedtopatientstreatedwithconventionalradiotherapy.ThisisinlinewithotherstudiesthatfoundcorrelationsbetweenradiationdosetotheglottisandvoicequalityworseningorspeechimpairmentafterIMRT11,35.Intheliterature,ithasbeenfoundthatradiationdosetothelarynxcorrelateswithlaryngealedemaseverity,resultinginvocalcorddysfunctionandthuspoorvoicequality5,6.Thismightexplainwhythepatientswithahypopharynx tumor in thecurrent cohort showedmorevoiceproblemscompared to theothers,becausehighdoses to the larynxareunavoidable in thesepatients, although this

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concernedonlythreepatients.Fornon-laryngealHNC,IMRTmayreducetheradiationdosetothepharynx36,resultinginlessedema,fibrosis,andstructuralalterationofthevocaltract,andthusbetterspeechintelligibility35.OngoingclinicaltrialsinHNCarecurrentlytryingtooptimizetheIMRTprocesstofurtherimproveoutcomes37.

Relationtoradiationtechniquewaspreviouslyalsofoundfordysphagiaandqualityoflifeissues17,38.Itisthereforenotunlikelythatthepatientswhodevelopedbothfunctionaldeficits(dysphagiaandvoice/speechproblemsweresignificantlycorrelated inthecurrentcohort;results not published) received higher radiotherapy doses on the muscles or structurescritical to these functions. Besides, noneof the patients hadparticipated in a preventiverehabilitation program, which has been associated with better post-treatment functionaloutcomes2.

Althoughperceptualevaluationiscurrentlyawidelyusedassessmenttoolforvoiceandspeechevaluation,wealsoperformedautomaticassessmentof voicequality and speechintelligibilitywiththeexpertsystemASISTO24. This system has previously been shown to be as accurateasSLPs(n=13)forevaluationofpatientstreatedforHNC12.Toourknowledge,thisisthefirstpractical/clinicalapplicationofautomaticassessmentofvoicequalityandspeechinaHNCpatientpopulationwithconsiderablefunctionaldeficitsfollowingorgan-preservationtreatment.Additionally, the systemwasused to evaluatepossible bias/subjectivitywithinperceptualevaluation.TheASISTOscores for speech intelligibilitycorrelatedstronglywithperceptual mean opinion scores of speech intelligibility, while this correlation was onlymoderate and borderline significant for voice quality. Possibly, some bias can be blamedhere,sinceonlytwoSLPsparticipatedaslistenersinthepresentstudy,andtheyratedvoicequality as less severe compared to the system in15/22 (68%)ofpatients (Figure2). Thisindicatesthattheirjudgementmighthavebeensomewhat‘coloured’andthusoverratedbytheirextensiveexperiencewithpatientswithHNC.Intelligibilityresultscorrelatedwell,andthuswereprobablynotoverrated,whichisconceivablebecauseitiseasiertoscorewhetheroneunderstandssomethingthantoratevoicequality,aswasfoundinpreviousstudies12,39.

Despite theacceptablecorrelations, it isobvious thatperceptualevaluationbySLPs isstillnotidenticaltothatofacomputerprogram.Withregardstoradiationtechnique,minordifferences between groups can be statistically significant in one evaluation and just notanymoreintheother,especiallywhennumbersaresmallasinthecurrentstudy.Moreover,ourASRhasnotbeentrained/calibratedontheseverestpathologicalvoicesinHNCpatients,and earlier research with this tool has shown that very low perceptual scores are somewhat moredifficulttopredict12,39.ThismighthaveobscuredtheRT-inducedperceptualdifferencefound for SLP assessment.Nevertheless, thesedifferences inoutcomesbetween the twoevaluationmethodsthushavetobeinterpretedwithcaution.

We did not measure other acoustic voice parameters (e.g. voicedness, fundamentalfrequency),sincemultiplestudieshavedemonstratedthatthesemodalities(independently)



4

have no clear role in the management of patients with cancers of the oral cavity andoropharynx,duetolackofreproducibleresults,poorcorrelationwithotherspeechassessmentmethods(e.g.perceptiveorsubjectiveevaluation),andabsenceofstandardprotocols40,41. In fact,automaticevaluationwithASISTOcouldalsoapplyassuch‘acoustic’parameter,sinceAVQIisaweightedcombinationofacousticparameters42,andrunningspeechintelligibilityistherecognitionresultofaphonemerecognizerbasedontheaudiosignal12.Unfortunately,becausestandardizedproceduresofobjectivevoiceandspeechassessmentsdonotexist,yet,resultsaredifficulttocomparewithotherstudiesperformedatdifferentclinicsorcentres7.

CONCLUSION

Ten years after organ-preservation treatment, functional voice and speech problems arecommon in thispatientcohort,asassessedwithperceptualevaluation,automaticspeechrecognition,andwithvalidatedstructuredquestionnaires.TherewerefewercomplaintsinpatientstreatedwithIMRTthanwithconventionalradiotherapy.

ACKNOWLEDGEMENTS

Catherine Middag and Jean-Pierre Martens (Department of Electronics and InformationSystems, University of Gent, Belgium) are greatly acknowledged for their collaborationregardingASISTO;IreneJacobi(PhD,TheNetherlandsCancerInstitute)isacknowledgedforherhelpwiththespeechrecordings;KlaskevanSluis(SLP,TheNetherlandsCancerInstitute)is acknowledged for her collaborationwith the perceptual analysis. This studywasmadepossiblebygrantsprovidedbyAtosMedical(Sweden),“StichtingdeHoop”(TheNetherlands),andthe“VerweliusFoundation”(theNetherlands).

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4

18. Freedownloadableathttp://www.praat.org.

19. Open Source program TEVA; available athttp://www.fon.hum.uva.nl/IFASpokenLanguageCorpora/NKIcorpora/NKI_TEVA/.

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21. HiranoM.ClinicalExaminationofVoice.NewYork:Springer-Verlag.1981.

22. Shrout PE, Fleiss JL. Intraclass correlations:usesinassessingraterreliability.PsycholBull.1979;86:420-8.

23. Portney LG; Watkins MP. Foundations ofClinical Research: Applications to Practice;Appleton&Lange;1993.

24. ASISTO expert system; available at http://asisto.elis.ugent.be/.

25. ELIS: ‘ELektronica en Informatie Systemen’;availableathttps://elis.ugent.be/.

26. Jacobsen B JA, Grywalski C, Silbergleit A,JacobsenG,BenningerM.TheVoiceHandicapIndex (VHI): Development and Validation.American Journal of Speech-LanguagePathology.1997;6:66-70.

27. Verdonck-de Leeuw IM, Kuik DJ, De BodtM, Guimaraes I, Holmberg EB, Nawka T, etal. Validation of the voice handicap indexby assessing equivalence of Europeantranslations. Folia Phoniatr Logop.2008;60:173-8.

28. VanGoghCD,MahieuHF,KuikDJ,RinkelRN,Langendijk JA,Verdonck-de Leeuw IM.Voicein early glottic cancer compared to benignvoice pathology. Eur Arch Otorhinolaryngol.2007;264:1033-8.

29. RinkelRN,Verdonck-deLeeuwIM,vanReijEJ,AaronsonNK,LeemansCR.SpeechHandicapIndex in patients with oral and pharyngealcancer: better understanding of patients’complaints.HeadNeck.2008;30:868-74.

30. Dwivedi RC, St Rose S, Roe JW, Chisholm E,ElmiyehB,NuttingCM,etal. First reportonthe reliability and validity of speech handicap index in native English-speaking patientswith head and neck cancer. Head Neck.2011;33:341-8.

31. RinkelRN,Verdonck-deLeeuwIM,DoornaertP, Buter J, de Bree R, Langendijk JA, etal. Prevalence of swallowing and speechproblems in daily life after chemoradiationfor head and neck cancer based on cut-offscores of the patient-reported outcomemeasures SWAL-QOL and SHI. Eur ArchOtorhinolaryngol.2015June14[Epubaheadofprint].

32. Keereweer S, Kerrebijn JD, Al-MamganiA, Sewnaik A, Baatenburg de Jong RJ, vanMeerten E. Chemoradiation for advancedhypopharyngeal carcinoma: a retrospectivestudyonefficacy,morbidityandqualityoflife.EurArchOtorhinolaryngol.2012;269:939-46.



35. Nguyen NP, Abraham D, Desai A, Betz M,DavisR,SrokaT,etal.Impactofimage-guidedradiotherapy to reduce laryngeal edemafollowing treatment for non-laryngeal andnon-hypopharyngealheadandneckcancers.OralOncol2011;47(9):900–904.


37. Tejpal G, Jaiprakash A, Susovan B, Ghosh-Laskar S, Murthy V, Budrukkar A. IMRT andIGRT in head and neck cancer: Have wedelivered what we promised? Indian J SurgOncol.2010;1:166-85.

38. RathodS,GuptaT,Ghosh-LaskarS,MurthyV,Budrukkar A, Agarwal J. Quality-of-life (QOL)outcomes in patients with head and necksquamous cell carcinoma (HNSCC) treatedwith intensity-modulated radiation therapy(IMRT) compared to three-dimensionalconformal radiotherapy (3D-CRT): evidencefrom a prospective randomized study. OralOncol.2013;49:634-42.

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39. VanNuffelenG,MiddagC,DeBodtM,MartensJP. Speech technology-based assessment ofphonemeintelligibilityindysarthria.IntJLangCommunDisord.2009;44:716-30.

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41. Dwivedi RC, St Rose S, Chisholm EJ, ClarkePM,KerawalaCJ,NuttingCM,etal.Acoustic

parameters of speech: Lack of correlationwith perceptual and questionnaire-basedspeech evaluation in patients with oral andoropharyngeal cancer treated with primarysurgery.HeadNeck.2014Dec18[Epubaheadofprint].

42. MarynY,deBodtM,RoyN.TheAcousticVoiceQuality Index: Toward improved treatmentoutcomes assessment in voice disorders Journal of Communication Disorders2010;43:161–74.



4

Supp

lem

ent

Tabl

e 1.In

trarateragree

men

tan

ddisagree

men

tforvoicean

dspee

chparam

etersbe

twee

nmeanop

inionscores(c

onverted

intoordinal

catego

ries).

Rater1

Rater2

Spee

ch/voice

para

met

ern

Exact

agreem

ent

(%)

Clos

e agreem

ent

(%)

Dis-

agreem

ent

(%)

Int

rara

ter r

elia

bilit

y ICC(3,1)

n

Exact

agreem

ent

(%)

Clos

e agreem

ent

(%)

Dis-

agreem

ent

(%)

Int

rara

ter

reliability ICC(3,1)

Intelligibility

2213

(59)

5(23)

4(18)

0.86

(0.69-0.94

)22

18(8

2)2(9)

2(9)

0.78

(0.54-0.90

)Articulati

on22

12(5

4)6(27)

4(18)

0.80

(0.58-0.91

)22

18(8

2)3(14)

1(4.5)

0.92

(0.81-0.96

)G

rade

2215

(68)

7(32)

0(0)

0.91

(0.80-0.96

)22

15(6

8)5(23)

2(9)

0.77

(0.51-0.90

)Ro

ughn

ess

2217

(77)

4(18)

1(4.5)

0.89

(0.76-0.95

)22

17(7

7)4(18)

1(4.5)

0.80

(0.59-0.91

)Br

eath

ines

s22

22(1

00)

0(0)

0(0)

0.99

(0.99-1.00

)22

18(8

2)1(4.5)

3(14)

0.30

(-0.13-0.64

)As

then

ia22

19(8

6)2(9)

1(4.5)

NA

NA

2219

(86)

2(9)

1(4.5)

NA

NA

Stra

in22

15(6

8)6(27)

1(4.5)

0.83

(0.64-0.93

)21

19(9

0.5)

1(5)

1(5)

0.54

(0.16-0.79

)N

asal

ity22

15(6

8)4(18)

3(14)

0.84

(0.64-0.93

)22

13(5

9)6(27)

3(14)

0.85

(0.67-0.94

)Pr

osod

y22

14(6

4)5(23)

3(14)

0.83

(0.64-0.93

)22

10(4

5.5)

6(27)

6(27)

0.52

(0.14-0.77

)Ac

cent

2213

(59)

4(18)

5(23)

0.87

(0.72-0.95

)22

16(7

3)3(14)

3(14)

0.88

(0.74-0.95

)

Abbreviatio

ns:ICC

=In

traclassCorrelatio

nCo

efficien

t.Notes:A

gree

men

tsplitintoexactagree

men

t(tw

oscores±125

),closeagreem

ent(tw

oscores±250

),an

ddisagree

men

t(tw

oscoresdifferby>2

50).

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88 | Chapter 4

Supplement Table 2.Interrateragreementanddisagreementforvoiceandspeechparametersbetweenmeanopinionscores(convertedintoordinalcategories).

Speech/voiceparameter n

Exactagreement

(%)

Close agreement

(%)

Dis-agreement

(%)Interrater reliability

ICC(3,1)

Intelligibility 22 10(46) 5(23) 7(32) 0.88 (0.71-0.95)Articulation 22 13(59) 5(23) 4(18) 0.89 (0.73-0.95)Grade 22 16(73) 3(14) 3(14) 0.90 (0.77-0.96)Roughness 22 17(77) 3(14) 2(9) 0.90 (0.75-0.96)Breathiness 22 17(77) 1(4.5) 4(18) 0.79 (0.49-0.91)Asthenia 22 21(96) 1(4.5) 0(0) 0.87 (0.68-0.94)Strain 21 17(77) 1(4.5) 4(18) 0.76 (0.41-0.90)Nasality 22 14(64) 6(27) 2(9) 0.93 (0.83-0.97)Prosody 22 8(36) 5(23) 9(41) 0.60 (0.05-0.84)Accent 22 6(27) 12(55) 4(18) 0.89 (0.74-0.96)

Abbreviations: ICC= IntraclassCorrelationCoefficient.Notes:Agreement split intoexactagreement(twoscores±125),closeagreement(twoscores±250),anddisagreement(twoscoresdifferby>250).



4

Appendix I. Excerptfrom‘Devijvervrouw’byGodfriedBomans(inDutch).

FragmentA (70words)Erleefdeneenseenkoningeneenkoninginendiehaddenmaaréénkind.Datwasdeprins.Deprinswasergverwend.Toenhijnogindewieglag,kreeghijaleengoudenrammelaar.Hijatvaneengoudenbordjeenhijdronkuiteengoudenbekertje.Alzijnspeelgoedwasvangoud,enhetwerdsteedsmoeilijkeromhemietstegeven,wathijalniethad.

FragmentB (68words)Entoenhijachttienjaarwerd,hadhijalleswathijmaarbedenkenkonenhetwasallemaalvanzuivergoud.Maarhijwas toch jarigenermoesthem ietsgegevenworden.Deprinsstondbijhetraam,toenzijnoomsentantesbinnenkwamen.Zijhaddeniedereencadeautjeindehand,maarzewarenergverlegen,wantzebegrepenweldatdeprinshetalhad.

170 mm

12,7 mm 10 mm

170 mm 60 mm

240

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SOPHIE KRAAIJENGA



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CHAPTER 5Prospec.ve clinical study on long-‐term swallowing func.on

and voice quality in advanced head and neck cancer

pa.ents treated with concurrent chemoradiotherapy

and preven.ve swallowing exercises


I. Jacobi O. Hamming-‐Vrieze


Eur Arch Otorhinolaryngol. 2015; 272: 3521-‐3531.

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92|Chapter5

ABSTRACT

Importance: Concurrentchemoradiotherapy(CRT)foradvancedheadandneckcancer(HNC)isassociatedwithsubstantialearlyandlatesideeffects,mostnotablyregardingswallowingfunction, but also regarding voice quality and quality of life (QOL). Despite increasedawareness/knowledge on acute dysphagia in HNC survivors, long-term (i.e. beyond fiveyears)prospectivelycollecteddataonobjectiveandsubjectivetreatment-inducedfunctionaloutcomes(andtheirimpactonQOL)stillarescarce.

Objectives: Assessmentoflong-termCRT-inducedresultsonswallowingfunctionandvoicequalityinadvancedHNCpatients.

Design:Arandomizedcontrolledtrialonpreventiveswallowingrehabilitation(2006–2008).Setting: TertiarycomprehensiveHNCcentre.Participants: Twenty-twodisease-freeandevaluableHNCpatients.

Main Outcomes and Measures: Multidimensional assessment of functional sequels wasperformed with videofluoroscopy, mouth opening measurements, Functional Oral IntakeScale,acousticvoiceparameters,and(study-specific,SWAL-QOL,andVHI)questionnaires.Outcome-measures at 6-years post-treatment were compared with results at baseline and at 2-years post-treatment.

Results: Atameanfollow-upof6.1yearsmostinitialtumor-,andtreatment-relatedproblemsremainedsimilarlylowtothoseobservedafter2-yearsfollow-up,exceptincreasedxerostomia(68%) and increased (mild) pain (32%). Acoustic voice analysis showed less voicedness,increasedfundamentalfrequency,andmorevocaleffortforthetumorslocatedbelowthehyoidbone(n=12),withoutrecoverytobaselinevalues.Patients’subjectivevocalfunction(VHIscore)wasgood.

Conclusions and Relevance: Functional swallowing and voice problems at 6-years post-treatmentareminimalinthispatientcohort,originatingfrompreventiveandcontinuedpost-treatmentrehabilitationprograms.

KEY WORDSHeadandNeckCancer–Chemoradiotherapy–Dysphagia–Swallowing–Voice–PreventiveRehabilitation


Long-termswallowingandvoicequalityafterpreventiverehabilitation|93

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INTRODUCTION

Organ preservation protocols with concurrent chemo-radiotherapy (CRT) are increasinglyusedforprimarytreatmentoflocallyadvancedheadandneckcancer(HNC).Meta-analyticdatafromrandomizedcontrolledtrials(RCTs)showimprovedloco-regionalcontrolandoverallsurvivaladvantages for theseprotocolsascomparedtoradiotherapy (RT)alone1,butalsohigherincidenceofdysphagiasecondarytoCRT-inducedtissuereactionssuchasmucositis,fibrosis, neuropathies, andespecially xerostomia2,3. Bothacute and long-term swallowingproblems can result in decreasedoral intake andeventuallymay lead toweight loss and(prolonged)nasogastricorpercutaneousfeedingtubedependency.Furthermore,dysphagiacanadverselyaffectcompliancetotreatmentandpost-treatmentrecovery(e.g.becauseofaspirationproblems),andcandeterioratepatient’ssocialcontactsandqualityoflife(QOL)3. Since radiation fields frequently encompass the larynx, also substantial effects on voicequalityhavebeennoted,whicharecorrelatedtotheRTdosetothelarynx4-6.Combinationwithchemotherapyaggravatesthesenegativeeffectsonpatients’speech,dailylifeactivities,andagainQOL7-13.

Regarding dysphagia in the HNC field, many centers havemade attempts to preventorreduceswallowingsequels followingCRT.So far, focusprimarilyhasbeenonreductionof thedoseonpharyngealmusculaturewithadvancedRT treatmentplanning techniquessuchasintensitymodulatedradiationtherapy(IMRT)14-18.Morerecently,pre-,per-andpost-treatmentinterventionsensuringcontinueduseofswallowingmusculaturebyadherencetotargetedswallowingexercises(the‘useitorloseit’concept)areincreasinglysuggestedintheliteraturetobenefitHNCsurvivors19.Preventiverehabilitationprogramshavebeenassociatedwithalonglistofpositiveeffects:improvedQOL20,betterbaseoftongueretractionandbettermaintainedepiglottic inversion21, superiormusclemaintenanceand functional swallowingability22,betteroralintakeandclinician-ratedswallowingfunctionatthreeandsixmonths23,reducedextentandseverityofpenetrationand/oraspiration,lesstrismus,lessweightloss,andlesspain(bothshortterm24 and at one- and two-years post-treatment25),andbetteroralintakeandshorterdurationoffeedingtubedependency26 post-treatment. Also maintained oral intake (no feeding tube dependency) has been shown to lead to better swallowingfunctionafterCRT,possiblyduetocontinueduseoftheswallowingmusculature26-28.Benefitsfrompreventive(swallowing)exerciseshavebeenreportedinparticularontheshort-term(uptotwoyears)19.Eisbruchetal.wereamongthefirstprospectivelyevaluatingswallowingfunctioninHNCsurvivors,andtheseauthorsfoundobjectiveswallowingdysfunction(highincidenceofsilentaspiration)6–12monthsafterRT29.AlsoGoguenetal.describeddysphagiatobeonly partly resolved6–12months followingRT treatment30.Nguyenet al. reportedonsomewhatlonger-termdysphagiaseverityfollowingCRT.Afteramedianpost-treatmentfollow-up of 17months, severe dysphagiawas found in 45% of patients31,whereas after

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more than two years post-treatment (median follow-up 26months), it worsened in 20%of patients32.More recently,Hutchesonet al. retrospectively evaluateddysphagia inHNCpatients,whoweretreatedmorethanfiveyearsago.Aspirationandpharyngealresiduewerethenorminallpatients.Eighty-sixpercenthaddevelopedaspirationpneumoniaand66%weretubefeedingdependentasaconsequenceoftheirdysphagia33.Ackerstaffetal.,andMetreauet al., evaluated long-term (5-years) results in advanced (stage IV)HNCpatientsfollowingCRTtoo.WhileMetreauetal.retrospectivelyassessedahighrateofdysphagia-relatedmorbidity(feedingtube,oralsupplements,andpneumonia)andQOLalterations,theprospectivestudyofAckerstaffetal.foundQOLissuesafter5-yearsfollow-uptobesimilarto those at 1-year.A limitationof these latter two studies is thatnoobjectiveevaluationof swallowing function was performed in these studies regarding long-term functional/QOL evaluation following CRT.Moreover, none of these patient groupswas treatedwithpreventive (swallowing) exercises before, during, and/or after the course of treatment,whereasespeciallyaprospectiveevaluationof swallowing therapy in theHNCpopulationwouldbevaluable/informative3.

Regardingvoiceproblemsfollowing(C)RTforHNC,effortstopreventorreducesequelsfollowingtreatmentarescarcer.Furthermore,onlyfewstudieswithadequatepre-treatmentdatacollectionprospectivelyinvestigatedchangesinpatient-andobserver-ratedvoicequality6,9-11,34-36.Longestfollow-upwasayearinall.Adequatelycontrolledandrandomizeddataonvoiceoutcomesarescarceanyway,andtheavailablestudiesoftenuseddifferentdiagnostictests to assess voice quality. Voice problems after (C)RT treatmentmay be attributed toimpairedvocalfoldvibrationwithincompleteclosure,asaresultofdrynessofthelaryngealmucosa,muscleatrophy,fibrosis,hyperemia,anderythema8,37.Asaresult,abnormalacousticandaerodynamicmeasures(harmonics-to-noise-ratio,fundamentalfrequency,measuresofjitter,shimmer,andspectraltilt)havebeendemonstrated in irradiatedHNCpatients.Alsosubjectivevoiceproblems,oftenassessedwiththeVoiceHandicapIndex(VHI),arereportedin the available but limited literature on this topic6,38-42.

Earlier,wereportedabouttheone-andtwo-yearCRT-relatedfunctionaloutcomesfromapreviousprospectiveRCT,comparingtwopreventiveswallowingrehabilitationregimens25. Incomparisonwiththeliterature,swallowingproblemswerelimitedinbothtreatmentarms.Here,theprospectivelycollectedobjectiveandsubjectivefunctionalswallowingandvoiceoutcomesofthisstudyinthecombinedpatientcohortstillaliveat6-yearswillbereported.


Thisstudyconcernsthelong-termfollow-upofalldisease-freeandevaluablepatientsfromanoriginalcohortof55patientswithadvanced(stageIIIandIV),functionally43 or anatomically



5

inoperable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, larynx,or nasopharynx, who were treated with concurrent chemo-radiotherapy (CRT)24, 25, 44. Of theoriginalpatientcohortof55patients,49patientsactuallycompletedtreatment.Eachpatientreceived100mg/m2Cisplatinasa40minIVinfusionondays1,22,and43.Intensity-modulatedRT(IMRT)of70Gyin35fractionswasadministeredoversevenweeksstartingconcurrentlywithchemotherapy.Ofthe22evaluablepatients(seebelow)20(91%)receivedaradiationdoseof43.5Gyorhighertothelarynx,becauseofadvancedstageofthetumorsand/orpositivelymphnodes45.

The original study compared two preventive rehabilitation programs (consisting ofstandard logopaedic swallowing exercises or an experimental swallowing rehabilitationprogram, based on the TheraBite® JawMotion Rehabilitation SystemTM)23. Patients wereinstructed topracticedaily from the startof treatmentuntil1-yearpost-treatment. Sincebothtreatmentgroupsshowedmoreorlesssimilarresults,exceptforaslightbutsignificantweight increase at 2-yearswith the experimental program28, here the 6-years data of alldisease-freeandevaluablepatients(n=22)arecombined.Oftheadditionalsevenpatientsincludedinthe2-yearsassessment(n=29),inthemeantimethreehaddied,threesufferedfrom severe unrelated disease precluding their participation in this long-term evaluation(Alzheimer’sdisease,primary livercancer,progressiveobstructivepulmonarydisease)andone patient refused to participate. Although during a telephone interview with this lastpatientnoswallowingand/orvoicecomplaintswererevealed,hewasexcludedbecausemostmultidimensionalassessmentdataweremissing.Allpatientdataandreasonsforexclusionatthevariousassessmentpointsareprovidedintheconsortflowchart(Figure1).

Multidimensional assessmentAs previously published34,44, assessmentof functional (voiceand swallowing) sequelswasperformed with multidimensional objective and subjective outcome-measures. In short,the protocol included standard videofluoroscopy (VFS) to determine swallowing function,thePenetrationandAspirationScale(PAS;score1:materialdoesnotentertheairway,to8:materialenterstheairway,passesbelowthevocalfolds,andnoeffort ismadetoeject46),andanoverall‘presenceofresidue’score(score0:noresidue,toscore3:residueaboveandbelowthevallecula,withminimalresiduejudgedasnormal).Maximuminterincisor(mouth)opening(MIO)wasmeasuredinmmusingthedisposableTheraBiterangeofmotionscale,andtrismuswasdefinedasaMIOof≤35mm47.Oralintake/nutritionalstatuswasassessedwiththeFunctionalOralIntakeScale(FOIS;rangefrom1–7with1:nothingbymouthto7:nooralrestrictions),andwithdataontubefeedingdependency,weightchange,andBodyMassIndex(BMI).Painwasassessedwithavisualanalogscale(VAS)of0–100mmwithzerobeingnopainand100beingtheworstpossiblepain(VAS;score0–4mm:nopain,toscore75–100:severepain)48.

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Baseline(n=55)

Intervention(CCRT with preventive swallowing

rehabilitation)

Off study (n=20)Death (n=19)Administrative miss (n=1)

Off study (n=7)Death (n=3)Severe unrelated disease (n=3)

2 years follow-up(n=29)

6 years follow-up(n=22)

Off study (n=6)Death (n=2)Progressive disease (n=2) Change of treatment plan (n=1) Patient refusal (n=1)

10 weeks follow-up(n=49)

Total(n=27)

Figure 1. Consort flowchartwith patient data and reasons for exclusion at the various assessmentpoints.

Acoustic voice parameters (voicedness, fundamental frequency, harmonics-to-noiseratio,measuresofspectraltilt,jitterandshimmermeasures,andnasality)werederivedfromrecordingsinaquietroomofastandardDutchtextandsustained/a/.AcousticanalysiswasperformedwiththeprogramPRAAT(www.praat.org).

A study-specific questionnaire, in part based on the EORTC-HN and EORTC-C30, wasused to evaluate patients’ perception of swallowing function, mouth opening and voicequality,severalQOLaspects,andcompliancewiththeexercises44.Additionally,atthe6-years



5

assessmentpoint,theSWAL-QOLandtheVoiceHandicapIndex(VHI)questionnaireswereadministered.TheSWAL-QOLisoneofthevalidatedquestionnairesforassessingpatients’swallowingimpairment(44-itemsthatassess10QOLdomains,eachrangingfrom0–100withahigherscoreindicatingmoreimpairment)49,50.TheVHIisavalidated30-itemquestionnairescoredona0–4pointscaleformeasuringpatients’subjectivesufferingcausedbydysphonia,specifiedinto3subscales(physical,functional,emotional)identifiedwith10itemseach.ThetotalVHIscorecanrangefrom0–120withahigherscorecorrespondingtoahigherdegreeof patient-reported vocal handicap (VHI score 0–30:minimal handicap; 31–60:moderatehandicap; 60–120: significant and serious handicap)51, 52. At the start of the original RCT(2006)thesequestionnaireswerenotyetvalidatedintoDutch,andthusthesedataareonlyavailable at the 6-years assessment point. All (other) outcome-measures at 6-years post-treatment were compared with results at baseline and at 2-years post-treatment.

Statistical AnalysisAlldatawere collectedandanalyzed ina speciallydevelopedStatisticalPackageof SocialSciences database (SPSS, Inc, Chicago, Illinois; version 20.0). Concerning the functionaloutcomeparameters,percentagesofreported/measureddisorderswerecalculatedateachassessmentpoint,comparabletothemethodsdescribedbyLogemannetal.53.McNemar’stest with Bonferroni correction was used for pairwise comparisons among the variousassessmentpoints(baseline,2-years-and6-yearspost-treatment).Continuousvariables(i.e.weight andMIO)were compared bymeans of paired t tests. For acoustic voice analysis,patientsweredividedintoseveralsubgroupsaccordingtotumorsite.Independentsamplettestswereusedforcomparisonsbetweengroupsandpairedt test were used for pairwise (subgroup)comparisonsovertime.Forallanalyses,apvalueof≤0.05wasconsideredtobestatisticallysignificant.Overallsurvival(OS)wascalculatedfromrandomizationuntildeathorlasttimeofassessment.SurvivalcurvesweregeneratedwiththeKaplan–Meiermethod.Thelog-ranktestwasusedtoexaminethedifferenceinOSbetweensubgroups.

RESULTS

Patients’ characteristics Atapproximately6years (medianfollow-up74months,range67–83months)22patients(17males and5 females,meanage:63 years; range45–79years)weredisease-freeandevaluable.Threepatients(allstageIV;14%),whohadrequiredasalvageneckdissectionforresidualregionaldisease,werekeptintheanalysis.Patients’andtumorcharacteristicsofthetotalpatientgroupthatstartedandcompletedtreatment(n=49),oftheevaluatedpatients(n=22),andofthosewhowerenotevaluable(n=27),aregiveninTable1.ExceptforT-stage,

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therewerenosignificantdifferencesbetweenthegroupswithrespecttogender,meanage,tumorsite,orgeneraltumorstage(stageIIIorIV).

Table 1. Clinicalcharacteristicsofpatientsatbaseline(n=55),patientsatthe6-yearsassessmentpoint(n=22),andpatients,whowentoffstudy(n=27).Foracousticanalyses,tumorsitesweregroupedasabove hyoid bone* and below hyoid bone**, andaccording tovelopharyngeal tumorextension (NT group =Nasopharyngeal andTonsil tumors; LHBT group = Laryngeal,Hypopharyngeal, andBase of Tonguetumors).

Baseline PatientswhostartedtreatmentPre-treatmentn=55(%)

6-yrs evaluated patientsn=22(%)

Not evaluated patientsn=27(%)

GenderMale(%) 44(80) 19(86) 22(82)Female(%) 11(20) 3(14) 5(18)

Ageatbaseline(range) 58(32–79) 57(39–73) 56(32–78)Tumor site

*Nasopharynx(%) 7(13) 4(18) 3(11)*Oral/Oropharynx(%) 29(53) 10(46) 14(52)**Hypopharynx/Larynx(%) 19(35) 8(36) 10(37)

NTgroup(%) 13(24) 6(27) 5(19)LHBTgroup(%) 42(76) 16(73) 22(81)

TumorstageStageIII(%) 17(31) 10(45) 6(22)StageIV(%) 38(69) 12(55) 21(78)

TstageT1(%) 8(15) 5(23) 3(11)T2(%) 15(27) 9(41) 6(33)T3(%) 21(38) 7(32) 12(44)T4(%) 11(20 1(5) 6(22)

NstageN0(%) 6(11) 2(9) 2(7)N1(%) 15(27) 8(36) 6(22)N2(%) 28(51) 8(36) 18(67)N3(%) 6(11) 4(18) 1(4)

ExercisegroupStandardgroup(%) 28(51) 10(45) 12(44)Experimentalgroup(%) 27(49) 12(55) 15(56)



5

Swallowing functionTable 2 shows overall percentages of laryngeal penetration and/or aspiration, contrastresidue, tube feeding, abnormal FOIS score, trismus, patients’ perceived swallowing andmouthopeningissues(e.g.xerostomia),pain(VAS),meanmouthopening(MIO)andmeanweight.Ascanbeseen,somefunctionalproblemswerealreadypresentatbaseline,relatedtotumorsiteand/orextension.Furthermore,Table2showsthatmanyfunctionalandQOLaspectshadnotsignificantlychangedoverthevariousassessmentpoints,exceptincreasedxerostomia(baselinevs.6-years;p=.003),ultimatelyreportedbytwothirdsofthepatients.Despitethenon-significantdifferencesovertime,sometrendswillbediscussed.

Regardingswallowingfunction,thepercentagesoflaryngealpenetrationand/oraspirationandthe frequencyofmorethannormalresidueaboveandbelowthehyoidboneonVFS(n=18)remainedmoreorlessstableovertime(thisconcernedmainlypatientswithatumorlocatedatthelarynxorhypopharynx).Noneofthepatientswasdependentontubefeedingor on nutritional oral supplements at 6-years post-treatment. Regardingmouth opening,only1patient(5%),whohadbeentreatedforatumorlocatedattheoropharynx(tonsillarcarcinoma),showedtrismusatthe6-yearsassessmentpoint.Patients’perceivedtrismuswashigher, andwas reported by 6 patients (27%), ofwhom4 actually showed ameasurabledecreasedMIO(meandecrease8mm;range3–15mm)comparedtobaselinevalues.Painintheheadandneckregionwasalreadypresentin36%ofpatientsbeforetreatmentonset,decreased belowbaseline levels at 2-years post-treatment, and tended to increase againat6-yearspost-treatment (32%;p=.06).With respect toQOL issues related toswallowingfunction at 6-years post-treatment, xerostomia (n=15; 68%; especially in oropharyngealcancer (n=9) patients), and problemswith swallowing solids (50%)weremost frequentlyreported.

Voice qualityTable3showsthesubjectiveandobjectivevoiceparametersdividedintosubgroupsaccordingtotumorsiteabove/belowthehyoidbone(HB),andfortheparameternasalityaccordingto velopharyngeal tumor extension (nasopharyngeal and tonsil tumors) or not (laryngeal,hypopharyngeal,andbaseof tongue tumors).See table3 for thenumberofpatientspersubgroup.Forsubjectivevoiceanalysis(n=22),meanVHIscores,asassessedat6-yearspost-treatment,areshown.Foracousticvoiceanalysis(n=19),threepatientswereexcludedduetomissingdataorpoorqualityofthevoicerecordings.Fortheseparametersmeandifferencesbetween measures at baseline and measures at 6-years are shown.

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Table 2.Percentagesofdisordersandothermeasuresobservedatthevariousassessmentpointsafterconcurrentchemoradiotherapyin22advancedheadandneckcancerpatients.

Descriptionofdisorder Pre-treatment Post-treatment McNemar’sp value

n=22 Baseline 2-years 6-years pre vs. 2 yrs vs.n(%) n(%) n(%) 6 yrs 6 yrs

Videofluoroscopy(n=18)Aspirationorpenetration 3 (17) 3 (18) 4 (22) 1.0 1.0Residueaboveandbelowhyoid 17 (94) 11 (65) 14 (78) .38 .25

Feedingtube 0 (0) 0 (0) 0 (0) x x

Abnormaldiet(FOISscore1–6) 3 (14) 2 (9) 0 (0) .25 .50

Pain(VAS) 8 (36) 2 (9) 7 (32) 1.0 .06

Trismus 2 (9) 2 (9) 1 (5) 1.0 1.0

QOLaspect/issuePerceiveddecreasedmouthopening 1 (5) 5 (23) 6 (27) .06 1.0Xerostomia 4 (18) 13 (59) 15 (68) .003 .63Oral transport with solids 3 (14) 5 (23) 3 (14) 1.0 .63Oral transport with paste 2 (9) 1 (5) 1 (5) 1.0 1.0Oraltransportwithliquids 0 (0) 1 (5) 1 (5) 1.0 1.0Swallowingproblemswithsolids 8 (36) 11 (50) 11 (50) .51 1.0Swallowingproblemswithpaste 2 (9) 1 (5) 2 (9) 1.0 1.0Swallowingproblemswithliquids 1 (5) 0 (0) 2 (9) 1.0 .50Perceiveddifferentvoice 8 (37) 14 (64) 11 (50) 1.0 .51

Weightinkg(range) 82(51–106) 80(56–105) 81(57–110) .61* .54*

Mouthopeninginmm(range) 52(26–69) 52(20–70) 53(21–70) .87* .40*

Valuesmarkedbyasterisks(*)meancomparedmeanpvalues;xmeansnostatisticalanalysespossible.Videofluoroscopyrecordsat6-yearspost-treatmentwereavailablefor18patients.Ifpatientsneededtubefeeding,theQOLquestionsaboutoraltransportandswallowingproblemswerenotfilledin.CRT:Concurrentchemo-radiotherapy;HNC:HeadandNeckCancer;FOIS:FunctionalOralIntakeScale;QOL:QualityofLife.



5

Tabl

e 3.

Sub

jectiveand

objectivevoicepa

rametersdivide

daccordingtotum

orsite

.Forsub

jectivevoiceana

lysis

(n=2

2),m

eanVo

iceHan

dicapInde

x(VHI)scores,asassessed

at6

-yearspost-treatmen

t,areshow

n.Foracousticvoiceana

lysis

(n=1

9),m

eandiffe

rencesbetwee

nmeasuresatbaselinean

dmeasuresa

t6-yearsaresh

own.Forallacou

sticvoicepa

rameterse

xcep

tvoicedn

essa

ndfu

ndam

entalfrequ

ency,1pati

entw

ithatu

morbelow

thehyoid

bone

wasexclude

dbe

causeofth

epresen

ceofa

nasogastricfe

edingtube

atb

aseline.A

bove

hyo

id b

one

grou

p =Oralcavity,O

roph

aryngeal(ton

siland

ba

seofton

gue),and

Nasop

haryng

ealtum

ors;B

elow

hyo

id b

one

grou

p =Laryng

ealand

Hypop

haryng

ealtum

ors;N

T gr

oup=

Nasop

haryng

ealand

Ton

sil

tumors;L

HBT

gro

up=Laryngeal,H

ypop

haryng

eal,an

dBa

se o

f Ton

guetumors.

Abovehyoidbo

negroup

Belowhyoidbon

egrou

pTo

tal

NM

ean

SDN

Mea

nSD

NM

ean

SDVo

iceHan

dicapInde

x(VHI)score

146,86

14,13

821

,00

29,80

2212

.00

21,64

VHIp

hysic

aldom

ain

142,86

5,91

810

,13

10,11

225,50

8,27

VHIfun

ction

aldom

ain

142,71

5,18

85,88

8,97

223,86

6,76

VHIemoti

onaldom

ain

141,29

3,12

85,00

11,81

222,64

7,47

Voiced

ness/text/

12-1,50

8,19

70,14

7,38

19-0,89

7,73

Fund

amen

talfrequ

ency/text/

12-2,92

23,20

7-12,71

13,24

19-6,53

20,27

Harmon

ics-to-noisera

tio/a

/12

-1,81

4,72

6-0,52

3,55

18-1,38

4,30

Measuresofspe

ctralti

lt/a/

12-2,91

4,63

6-4,88

7,91

18-3,57

5,76

Jitter/a

/12

-0,00

0,65

6-0,21

0,47

18-0,07

0,59

Shim

mer/a

/12

2,60

3,28

6-0,37

4,54

181,61

3,88

NTgrou

pLH

TBgroup

Tota

lN

Mea

nSD

NM

ean

SDN

Mea

nSD

Nasality

/a/

6-3,59

6,61

120,72

6,04

18-2,15

6,59

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Regardingsubjectivevoiceoutcomesatthe6-yearsassessmentpoint,halfofthepatients(n=11;50%)perceivedtheirvoiceasdifferentfrombaseline.ThemediantotalVHIscoreat6-yearspost-treatmentwas3(mean=12;range0–91;n=22).PatientswithatumorlocatedbelowtheHB(‘belowHBgroup’) reportedhighertotalVHIscores (mean=21,median=11,range0–91),indicatingmorevoiceproblems,incomparisonwiththosewithatumorabovethehyoidbone(‘aboveHBgroup’;mean=7,median=1,range0–47).InparticularthephysicalandfunctionalsubscalesoftheVHIpredictedthetotalVHIscores.Emotionalvoiceproblemswerereportedby7patients,whoallhadhighphysicalandfunctionalVHIsubscores.Fivewere laryngeal cancerpatientsand2wereoropharyngeal cancerpatients. The latter tworeceivedahighradiationdose(>55Gy)tothelarynxandbothparotidglands.

Foracousticanalysisofallvoiceparametersexceptvoicednessandfundamentalfrequency(indicatingpitch),1patientwithatumorbelowtheHBwasexcludedbecauseofthepresenceofanasogastricfeedingtubeatbaseline.Ithastobenotedthatnoneofthepatientssufferedfrom a cold during voice recordings. Acoustic analysis of the read aloud text at baseline(n=19)showedthatpatientsinthe‘belowHBgroup’(n=7)presentedwithsignificantlylessvoicedness than the patients in the ‘aboveHB group’ (n=12; independent sample t test;p=.011).Overtime,therewasnoimprovementinbothgroups,andthedifferencewasstillsignificantat6-yearspost-treatment(p=.016).Therewasalsonosignificantimprovementintheharmonics-to-noiseratiofrombaselineto6-yearspost-treatmentinbothgroups.Meanfundamentalfrequencyduringtextaloudreadingat6-yearspost-treatmenthadnotchangedmuchforthe‘aboveHBgroup’,whileithadsignificantlyincreasedinthe‘belowHBgroup’(p=.044;seeFigure2).Jittermeasureshadincreasedaswellinthe‘belowHBgroup’,whileshimmermeasureswere stable over time. In contrast, in the ‘above HB group’ shimmerhad improvedwhile jitterwas stable.Measuresof spectraltilt (indicatingvocal effort)onsustained/a/atbaselineshowedmoreeffort inthe‘belowHBgroup’(p=.231).At6-yearspost-treatment,resultshadimproveduptothelevelofthe‘aboveHBgroup’(seeFigure3).Velopharyngealfunctionwasanalyzedbynasality(antiformants)insustained/a/.Thepatientswere divided into subgroups according to velopharyngeal tumor extension (‘NT group’:NasopharyngealandTonsiltumors;n=6)ornot(‘LHBTgroup’:Laryngeal,Hypopharyngeal,and Base of Tonguetumors;n=12).Whilethe‘NTgroup’showedimprovementsafter2-yearscomparedtobaseline,at6-yearspost-treatmentthemeasureshadworsenedagain.Alsointhe‘LHBTgroup’therewasatrendthatthemeasureshadworsenedcomparedtobaselinevalues(pairedt testp=.087).



5Figure 2. Changeinfundamentalfrequency(“pitch”)betweenmeasuresatbaselineandat6-yearspost-treatmentamongpatientswithatumorabovethehyoidbone(n=12)andbelowthehyoidbone(n=7).Negativevaluesmeanincreasedpitchbetweenthetwoassessmentpoints.

Figure 3. Change in measures of spectral tilt (“vocal effort”) between baseline and 6-years post-treatmentamongpatientswithatumorabovethehyoidbone(n=12)andbelowthehyoidbone(n=6).Negativevaluesshowadecreaseinvocaleffortbetweenthetwoassessmentpoints.

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General treatment outcomesBeyond6-yearsoftreatment,24oftheincluded55patients(44%)haddied;14patientshaddiedofprogressive(recurrentorresidual)disease,twopatientshaddiedofasecondprimarymalignancy(lungandliver)and8patientshaddiedduetoother/unknowncauses.The6-yearoverallsurvival(OS)rate,basedontheoriginalcohortof55patients,was60%.Bothtumorstageandsite(stageIV,oralcavity)werefoundtobeassociatedwithpoorerOSinthispatientcohort.Patientswitha tumor locatedat thenasopharynx (n=7) showed thebestOS.SeeFigure4fortheKaplan-MeiercurvesforOSpertumorstage.

Figure 4. Kaplan-Meiercurveforoverallsurvival(OS)pertumorstagewithpoorerOS(p=.067)forstageIVtumorscomparedtostageIIItumors.

DISCUSSION

Thisprospectiveclinicalstudyonswallowingfunctionandvoicequalityinadvancedheadandneckcancer(HNC)patientstreatedwithconcurrentchemoradiotherapy(CRT)andpreventiveswallowingexercisesshowsthatfunctionalswallowingandvoiceproblemsat6-yearspost-treatmentareminimal.Moreover,nosignificantchangessincetheone-year(voicequality34)ortwo-years(swallowingfunction25)assessmentpointsarefound.



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Swallowing functionIntheearlierreportsonthisCRT-preventiveswallowingrehabilitationtrial,outcomeswerecomparedwithan in-houseprecedingRCTonCRTwithasimilar (IMRT)therapyprotocol,except for the application of this preventive swallowing rehabilitation protocol. Since the5-yearsresultsofthislattertrialarepublishedaswell54,anddatafromprospectivestudieswithlongerfollow-upafterpreventiveswallowingrehabilitationstillarescarce19, itisagainpossibleandinterestingtoalsocomparethemorelong-termresultsofbothtrials.Regardingswallowing function andoral intake, in that earlier study itwas found that 7/71 patients(10%) still required tube feedingat5-yearspost-treatment,whereas in thepresent studyall patientswere able to consumeanormal oral diet at the6-years assessmentpoint. In the preceding CRT study, no objective evaluation of swallowing functionwas performed,which precludes comparison of those data available for the present study. Comparison to someextentispossiblewiththestudyofHutchesonetal.33,whichevaluatedlatedysphagia(dysphagicpatientswithamedianof9-yearspost-treatment),andincludedvideofluoroscopicstudies.Pharyngeal residueandaspirationwas found inallpatients,withsilentaspirationoccurring in 23/28 patients (82%). Six patients (21%) were feeding tube dependent and11patients (38%)haddeveloped trismus.However, only symptomaticdysphagic patientswereevaluatedinthatstudy,precludingestimateoftheprevalenceoflatedysphagia,andindepthscomparisonwithourfindings.

It’s not unlikely that the favorable swallowing outcomes in the present study can beattributed to thepreventiveandcontinuedpost-treatment rehabilitationprograms,whichwereappliedinthispatientcohort.Preventiverehabilitationprogramshavebeenassociatedwithbetterpost-treatmentswallowingoutcomesbefore20-26,especiallyontheshort-term19,andprobably,theexercisesappliedareassociatedwithbetterlong-termresultsaswell.

Patients’ perceived functional changes correlatedonlyweaklywithobjectiveoutcomemeasures.Regardingswallowingfunction,onlyoneofthefourpatientswhoshowedlaryngealpenetrationoraspirationonVFS,actuallyreportedofswallowingproblems.Withregardstotrismus,therewasonlyonepatient(5%)whoactuallyfulfilledthecriterionforanobjectivetrismus(MIO≤35mm).Interestingly,however,patients’perceivedtrismuswashigher(n=6,includingtheobjectivetrismuspatient;27%),andin4ofthese6patientstheMIOdidshowameasurabledecrease(mean8mm)comparedtobaselinevalues.Therefore,clinicaloutcomemeasuresshouldalwaysbecombinedwithpatients’views,inordertogainbestinsightintheextentofthefunctionalproblems.

Voice qualitySincecombinedCRTregimenscanhaveadverseeffectsonvoicequalityaswell,assessmentoffunctionalsequelsofCRTshouldincludepatients’voicequality,e.g.bycalculatingmeansofacousticparametersatthevariousassessmentpoints.Inthepresentcohort,duetopositive

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lymphnodes,thevastmajorityofpatients(20/22)receivedaradiationdoseof43.5Gyandhighertothelarynx,whichhasbeendescribedintheliteratureascut-offvaluefordevelopingvoice problems or chronic edema4,5.Voiceproblemscanalsooccurduetochangesinsalivaproductionandlubrication,mainlyasaresultofradiationdosetotheparotidglandandthelaryngealmucosa,whichcan leadto insufficient lubrication/drynessofthevocal folds37,55. Hence,thefactthatgenerallyallpatientswithatumorlocatedatthelarynxorhypopharynx(still)demonstratedlessvoicednessandincreasedfundamentalfrequencyatvoicerecordingsat 6-years post-treatment is understandable. Interestingly, although this concerned onlysix patients, patientswith a tumor located at the tonsil or nasopharynx,whohad shownimprovementsinnasalityatthe2-yearsassessmentpoint,showedincreasednasalityagainatthe6-yearsassessmentpoint.Previously,onlyfewstudieswithadequatepre-treatmentdataprospectivelyinvestigatedeffectsofCRTonvoicequality,andtheavailablestudiesoftenuseddifferentdiagnostictests9-11,34,36.Longestfollow-upwasayearinall,exceptforthestudyofVainshteinet.al.thatevaluatedvoicechangesuptotwoyearsfollowingCRT6.However,onlypatient-reportedvoicequalitywasassessedinthatstudy,whileespeciallyacousticvoiceparametersatlong-termfollow-upwouldbeinformative,sincechangesinvoicequality(i.e.morenasality)after6-yearsfollow-uparedemonstrableinourstudy.

Subjective voice complaints were evaluated in the present patient cohort with somestudy-specificquestions(“doyouperceiveyourvoiceasdifferentfrombaseline”?)andwith(sub)total VHI scores. Previously, subjective voice outcomes showed that 70%of patientsreportedtheirvoiceasdifferentfrombaselinetooneyearpost-treatment56.Besides,mostofthelaryngealandhypopharyngealcancerpatientsalreadypresentedwithvoiceproblemsatthetimeofdiagnosis.At6-yearspost-treatment,(still)halfofthepatients(50%)perceivedtheir voice as different from baseline. Patients with a functional and/or physical voicedisability(basedonVHIsubscores51)reportedofproblemssuchas increasedvocaleffort,breathiness,andhoarseness.Todate,therearelittlestudiesthatevaluatedVHIscoresafterCRTtreatmentforHNC,especiallyatlong-term.Inrecentstudiesthatevaluatedvoicequality,results showed decreases in voice quality following CRT6, 40, with an impact on QOL andemotionaldistress42.ThoughalmostthewholeVHIrange(0–91)wascoveredinourpatientpopulation(withvarioustumorsitesincluded)at6-yearspost-treatment,themediantotalVHIscorewasonlythree.Apparently,thesubjectivelyperceivedandacousticallymeasuredchangesinvoicequalitywerenotconsideredahandicapforthevastmajorityofourpatients.

LimitationsInprospectivetrials,patientsarelosttofollow-upbecauseofdeath,orofprogressive,residualorrecurrentdisease,whichalwaysformsalimitationinlong-termevaluationoffunctionaltreatment results. Moreover, there might be a survival bias towards patients with goodfunctionaloutcomes.Longer-termsevereunrelateddiseaseandpatientrefusalarefurther



5

decreasingthesampleonwhichconclusionshavetobebasedupon.Andobviously,ascanbeseeninTable1,morestageIIIthanstageIVpatientsaresurviving/evaluable(originally33-66,andat6-yearsalmost50-50).Asaresult,someselectionbiascannotbeexcludedinthepresentstudy,whichmightaswellinpartexplainthelimitedfunctionalproblemsintheanalyzedpatientcohort.However,exceptforinitialT-stage,thepatientgroupat6-yearspost-treatment(n=22)stilliscomparabletothegroupatbaseline(n=49)concerningmostpatientand tumor characteristics (age, gender, tumor site and stageetc.). Also thepatientswhowent“off-study”after initialtreatment(n=27)didnotdiffersignificantlyonmostoftheseparametersfromthecurrentlyanalyzedpatients(n=22).

CONCLUSION

This is one of the first studies investigating CRT-induced effects on swallowing functionandvoicequality inHNCpatients6-yearsafter treatment.Overall, functionalproblemsat6-yearspost-treatmentareminimalinthispatientcohort,possiblyduetothepreventiveandcontinuedpost-treatmentswallowingrehabilitationprogramsapplied.

ACKNOWLEDGEMENTS

Thisstudywasmadepossiblebygrantsprovidedby“StichtingdeHoop”andthe“VerweliusFoundation”.

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REFERENCES



3. Metreau A, Louvel G, Godey B, Le Clech G,JegouxF.Long-termfunctionalandqualityoflife evaluation after treatment for advancedpharyngolaryngeal carcinoma. Head Neck.2013;Epub.

4. Sanguineti G, Adapala P, Endres EJ, BrackC, Fiorino C, Sormani MP, et al. Dosimetricpredictors of laryngeal edema. Int J RadiatOncolBiolPhys.2007;68:741-9.

5. Nguyen NP, Abraham D, Desai A, Betz M,DavisR,SrokaT,etal.Impactofimage-guidedradiotherapy to reduce laryngeal edemafollowing treatment for non-laryngeal andnon-hypopharyngealheadandneckcancers.OralOncol.2011;47:900-4.

6. Vainshtein JM,GriffithKA,FengFY,VinebergKA,ChepehaDB,EisbruchA.Patient-ReportedVoice and Speech Outcomes After Whole-Neck IntensityModulatedRadiationTherapyand Chemotherapy for OropharyngealCancer: Prospective Longitudinal Study. Int JRadiatOncolBiolPhys.2014.



9. BibbyJR,CottonSM,PerryA,CorryJF.Voiceoutcomes after radiotherapy treatmentfor early glottic cancer: assessment usingmultidimensional tools. Head Neck.2008;30:600-10.

10. Kazi R, Venkitaraman R, Johnson C, PrasadV, Clarke P, Newbold K, et al. Prospective,

longitudinal electroglottographic studyof voice recovery following acceleratedhypofractionated radiotherapy for T1/T2larynxcancer.RadiotherOncol.2008;87:230-6.



13. LazarusCL,HusainiH,HuK,CullineyB, Li Z,Urken M, et al. Functional Outcomes andQuality of Life After Chemoradiotherapy:Baseline and 3 and 6 Months Post-Treatment. Dysphagia.2014.


15. Mowry SE, Tang C, Sadeghi A, Wang MB.Standard chemoradiation versus intensity-modulated chemoradiation: a quality of lifeassessmentinoropharyngealcancerpatients.EurArchOtorhinolaryngol.2010;267:1111-6.



18. Peponi E, Glanzmann C, Willi B, Huber G,StuderG.Dysphagiainheadandneckcancer



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patients following intensity modulatedradiotherapy(IMRT).RadiatOncol.2011;6:1.







25. van der Molen L, van Rossum MA, RaschCR, Smeele LE, Hilgers FJ. Two-year resultsof a prospective preventive swallowingrehabilitation trial in patients treated withchemoradiationforadvancedheadandneckcancer.EurArchOtorhinolaryngol.2013.




29. Eisbruch A, Lyden T, Bradford CR, DawsonLA, Haxer MJ, Miller AE, et al. Objectiveassessment of swallowing dysfunction andaspiration after radiation concurrent withchemotherapy for head-and-neck cancer. IntJRadiatOncolBiolPhys.2002;53:23-8.

30. Goguen LA, Posner MR, Norris CM, TishlerRB, Wirth LJ, Annino DJ, et al. Dysphagiaafter sequential chemoradiation therapy foradvancedheadandneckcancer.OtolaryngolHeadNeckSurg.2006;134:916-22.

31. NguyenNP,Moltz CC, Frank C, Vos P, SmithHJ, Karlsson U, et al. Dysphagia followingchemoradiationforlocallyadvancedheadandneckcancer.AnnOncol.2004;15:383-8.

32. NguyenNP,Moltz CC, Frank C, Vos P, SmithHJ, Karlsson U, et al. Evolution of chronicdysphagia following treatment for head andneckcancer.OralOncol.2006;42:374-80.


34. Jacobi I vdML, van Rossum M, Hilgers FJ.Pre- and Short-term Posttreatment VocalFunctioning in Patientswith AdvancedHeadand Neck Cancer Treated with ConcomitantChemoradiotherapy.Interspeech.2010:2582-85.

35. Adams G, Burnett R, Mills E, PennimentM.Objective and subjective changes in voicequality after radiotherapy for early (T1 orT2,N0) laryngeal cancer: a pilot prospectivecohortstudy.HeadNeck.2013;35:376-80.

36. Jacobi I, van Rossum MA, van der MolenL, Hilgers FJ, van den Brekel MW. Acousticanalysisofchangesinarticulationproficiencyin patients with advanced head and neckcancer treated with chemoradiotherapy. Ann OtolRhinolLaryngol.2013;122:754-62.

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38. OridateN,HommaA, Suzuki S,NakamaruY,Suzuki F, Hatakeyama H, et al. Voice-relatedquality of life after treatment of laryngealcancer. Arch Otolaryngol Head Neck Surg.2009;135:363-8.

39. Thomas L, Jones TM, Tandon S, Carding P,LoweD,RogersS.Speechandvoiceoutcomesin oropharyngeal cancer and evaluation ofthe University ofWashingtonQuality of Lifespeechdomain.ClinOtolaryngol.2009;34:34-42.

40. Keereweer S, Kerrebijn JD, Al-MamganiA, Sewnaik A, Baatenburg de Jong RJ, vanMeerten E. Chemoradiation for advancedhypopharyngeal carcinoma: a retrospectivestudyonefficacy,morbidityandqualityoflife.EurArchOtorhinolaryngol.2012;269:939-46.

41. Myers C, Kerr P, Cooke A, Bammeke F,Butler J, Lambert P. Functional outcomesafter treatment of advanced oropharyngealcarcinomawithradiationorchemoradiation.JOtolaryngolHeadNeckSurg.2012;41:108-18.




45. vanderMolenL,HeemsbergenWD,deJongR, vanRossumMA, Smeele LE,RaschCR, etal. Dysphagia and trismus after concomitantchemo-Intensity-Modulated RadiationTherapy (chemo-IMRT) in advanced headand neck cancer; dose-effect relationships

for swallowing and mastication structures.RadiotherOncol.2013;106:364-9.



48. JensenMP,ChenC,BruggerAM.Interpretationof visual analog scale ratings and changescores: a reanalysis of two clinical trials of postoperativepain.JPain.2003;4:407-14.

49. RinkelRN,Verdonck-deLeeuwIM,LangendijkJA,vanReijEJ,AaronsonNK,LeemansCR.Thepsychometric and clinical validity of the SWAL-QOL questionnaire in evaluating swallowingproblems experienced by patients withoral and oropharyngeal cancer. Oral Oncol.2009;45:e67-71.

50. Lemmens J,BoursGJ, LimburgM,BeurskensAJ. The feasibility and test-retest reliabilityof the Dutch SWAL-QOL adapted interviewversion for dysphagic patients withcommunicative and/or cognitive problems.QualLifeRes.2013;22:891-5.

51. Jacobsen B JA, Grywalski C, Silbergleit A,JacobsenG,BenningerM.TheVoiceHandicapIndex (VHI): Development and Validation.American Journal of Speech-LanguagePathology.1997;6:66-70.

52. Verdonck-de Leeuw IM, Kuik DJ, De BodtM, Guimaraes I, Holmberg EB, Nawka T, etal. Validation of the voice handicap indexby assessing equivalence of Europeantranslations. Folia Phoniatr Logop.2008;60:173-8.





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55. Hamdan AL, Geara F, Rameh C, Husseini ST,Eid T, Fuleihan N. Vocal changes followingradiotherapy to the head and neck for non-laryngealtumors.EurArchOtorhinolaryngol.2009;266:1435-9.


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CHAPTER 6Hyoid bone displacement as parameter for

swallowing impairment in pa.ents treated for

advanced head and neck cancer


W.D. Heemsbergen G.B. Remmerswaal


Eur Arch Otorhinolaryngol. Online 2016 Apr 16.

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ABSTRACT

Introduction: Reduced hyoid displacement is thought to contribute to aspiration andpharyngeal residues in head and neck cancer (HNC) patients with dysphagia. To furtherstudyhyoidelevationandanteriorexcursioninHNCpatients,thisstudyreportsontemporal/kinematicmeasuresofhyoiddisplacement,withtheadditionalgoaltoinvestigatecorrelationswithclinicalswallowingimpairment.

Methods: A single-blind analysis of data collected as part of a larger prospective studywas performed at three time points before and after chemoradiotherapy. Twenty-fivepatientshadundergoneclinicalswallowingassessmentsatbaseline,10-weeks,and1-yearpost-treatment. Analysis of videofluoroscopic studies was done on different swallowingconsistenciesofvaryingamounts.Thestudieswereindependentlyreviewedframe-byframebytwoclinicianstoassesstemporal(onsetandduration)andkinematic(anterior/superiormovement)measuresofhyoiddisplacement(ImageJ),laryngealpenetration/aspiration,andpresenceofvallecula/pyriformsinusresidues.Patient-reportedoral intakeandswallowingfunctionwerealsoevaluated.

Results:Meanmaximumhyoiddisplacementrangedfrom9.4mm(23%ofC2-4distance)to12.6mm(27%)anteriorly,andfrom18.9mm(41%)to24.9mm(54%)superiorly,dependingon bolus volume and consistency. Patients with reduced superior hyoid displacementperceived significantly more swallowing impairment. No correlation between delayed orreducedhyoidexcursionandaspirationorresiduescorescouldbedemonstrated.

Conclusion: Hyoiddisplacement is subject to variability fromanumberof sources.Basedontheresults,thisparameterseemsnotveryvaluableforclinicaluseinHNCpatientswithdysphagia.

KEY WORDSHeadandNeckneoplasms–Dysphagia–HyoidBone–Kinematics–Elevation–Displacement–Aspiration–Chemoradiotherapy


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INTRODUCTION

Dysphagia,aspiration,oreventheinabilitytoswallow,isoneofthemostdisablingadverseeffects of treatment with concurrent chemoradiotherapy (CRT) for advanced head andneck cancer (HNC). Inefficient or unsafe swallowing may lead to severe consequencesthatmayalterpatients’nutritionalstatusandqualityof life.Althoughmultipleswallowingabnormalitiesarelikelypresentinpatientswithdysphagia,reducedhyolaryngealelevation(hyoid bone displacement) is thought to be one of the prime contributors of impairedswallowing1-4.Duringthepharyngealphaseofswallowing,thehyoidboneusuallyelevatesandmovesanteriorlyunderthetonguebasebycontractionofthesuprahyoidmuscles,toinitiatesuperiorlaryngealmovementandcricopharyngealsphincteropening5.Unfortunately,inHNCpatients,hyoiddisplacementisoftenconsiderablyreduced,asaresultofradiation-induceddamagetoanatomicalstructuresinvolvedinswallowing3,6,7.Consequently,reducedverticalexcursionofthehyolaryngealcomplexmayleadtoincompleteairwayclosurewithanassociatedriskofaspiration,whilereducedhyoiddisplacementintheanteriordirectionwillleadtoreducedopeningoftheupperesophagealsphincter,resultinginpyriformsinusresidues,thusalsoincreasingtheriskoflaryngealpenetrationand/oraspiration4.

Videofluoroscopy (VFS) has become the gold standard for objective evaluation ofswallowing function,with thehyoidboneasanatomicalpointof interest. SeveralauthorshavereportedonhyoidexcursionbybiomechanicalanalysiswithVFS8-10.Accordingtotheliterature, hyoid movement can be influenced by various factors such as body height4,age and gender11-14, aetiology of dysphagia15, and bolus characteristics16,17. Unfortunately,themeasurementsarenotalwayseasyandreproducible,andarepronetomeasurementerrors18,19.Itisthereforenotsurprisingthatconflictingresultsofassociationbetweenhyoidmovement and aspiration are published9,10. Given the fact that hyoid excursion is widelyvariable in healthy adults20,itiscurrentlyrecommendedtomeasurehyoiddisplacementinanatomicallynormalizedunits, i.e. inpercentageofthedistancebetweenvertebraC2andC4.Inthisway,magnificationartefactsorsex-baseddifferencesattributabletovariationsinmeasurementtechniquearereduced10.

In HNC patients with dysphagia, Wang and colleagues3 recently assessed hyoid displacement in irradiated nasopharyngeal cancer patients. Hyoid excursion, especially intheanteriordirection,wasfoundtobesignificantlyreducedcomparedtothecontrolgroup.Correlationpatternsbetweenkinematicmeasuresandswallowingimpairment,however,werenotinvestigated.Similarly,twoothercasestudiesreportedonreducedhyoiddisplacementinHNCpatients7,21.Percentagesofrestrictedorreducedhyoidmovementrangedfrom42%to97%,dependingonprimarytumorsite.Correlationswereagainnotinvestigated.ThepresentstudyreportsonhyoiddisplacementparametersinanadvancedHNCpatientcohorttreatedwithCRT.Theprimaryaimwas to reporton temporalandkinematicmeasures related to

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hyoiddisplacementinthispatientcohort.Thesecondaryaimwastoinvestigatecorrelationswithpersisting (clinical) swallowing impairment,andtoassess thepossiblevalueof theseparameters for clinical care.


Patient populationPatientswerediagnosedwithadvanced(stageIIIandIV)squamouscellcarcinomaoftheheadandneckregionandtreatedwithconcurrentchemoradiotherapy(CRT)atTheNetherlandsCancerInstitutefrom2006to2008.Eachpatientreceived100mg/m2Cisplatinasa40minIV infusionondays1,22,and43. Intensity-modulatedradiotherapy(IMRT)of70Gyin35fractionswasadministeredoversevenweeksstartingconcurrentlywithchemotherapy22. In anattempttopreventswallowingsequelsfollowingtreatment,allpatientshadparticipatedin a clinical trial on preventive and continued post-treatment swallowing rehabilitation23. Informedconsentwasobtainedfromallindividualparticipantsincludedinthestudy.

Twenty-five patients had undergone objective and subjective swallowing assessmentsuntil1-yearpost-treatmentandwereincludedinthepresentstudy.Patientswereanalysedatbaseline(approximately2weeksbeforetreatmentonset),at10-weekspost-treatment,andat1-yearpost-treatment.AnoverviewoftheanalysedpatientsisdemonstratedinFigure1.Regardingtemporalanalysis,someVFSstudieswereexcludedduetopoorqualityormissingdata, resulting in a dataset of 22, 25, and24 swallow studies, for analysis at baseline, at10-weekspost-treatment,andat1-yearpost-treatment, respectively.Regardingkinematicanalysis, in eight patients poorVFS imagequality or obstructed viewof target structuresprecludedpreciseevaluationofhyoiddisplacement.At1-yearpost-treatment,threemoreswallow studies had to be excludeddue to poor image quality (n=1), obstructed viewofvertebraC2-C4(n=1),ormissingdata(n=1).Thisresultedin17patientsforanalysisatbaselineandat10-weekspost-treatment,and14patientsforanalysisat1-yearpost-treatment.

Objective swallowing assessmentPatients hadundergone a standardized, lateral VFSprotocol, imaging the lips, oral cavity,cervicalspine,andproximalcervicalesophagus.Anexperiencedspeechlanguagepathologist,clinical investigator,anda laboratoryassistantperformedallstudies.Patientswereseateduprightandwereaskedtoswallowdifferentconsistenciesofvaryingamounts(3ccand5ccthinliquid;3ccpaste;andsolidOmnipaquecoatedcake),deliveredorallybyaspoonorcup.Patientswereinstructedtosipandwaitforaverbalcuefromtheclinicalinvestigatorbeforeswallowing.Acoinofteneurocentswasfixedonthechinasreferencedistancetocorrectformagnification.



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All VFS studies were recorded at 25 frames per second andmatched (together with anexternalmicrophone)withanexternalcomputerviaaframegrabber(Terratec).Subsequently,thestudiesweresavedformovieeditingbyMagix (freedownloadathttp://magix-movie-edit-pro.en.softonic.com),anddigitallycapturedwithVirtualDub.EachVFSstudywasthenreviewedinreal-time,slowmotion,andframe-by-frame,andratedonclinical,temporal,andkinematicmeasuresindependentlybythetwoexperiencedresearchers.

Clinical measuresAccordingtotheprotocol,PenetrationAspirationScale(PAS)scoresandmorethannormalpost-swallowresiduescores(locatedatthetonguebase,vallecula,orpyriformsinuses)wereindependentlyassessed.ThePASisavalidated8-pointscale(score1:materialdoesnotentertheairway,toscore8:materialenterstheairway,passesbelowthevocalfolds,andnoeffortismadetoeject)withthelowestscorereferringtonormalswallowingfunctioning,whereashigherscoresrefertomoresevereswallowingdisability24.AspirationstatuswasdeterminedusingabinaryreductionofthePAS,withanysingleswallowwithascoreof≥3resultinginclassificationofthepatientasanaspirator9.Theoverall‘presenceofresidue’scorewasalsoassessed,rangingfrom0(noresidue)to3(residueaboveandbelowthehyoidbone,withminimalresidueinonlythepiriformsinusjudgedasnormal)25,26.

Temporal measuresHyoidelevationonsetanddurationwasreported inseconds,comparable to themethodsdescribed by Kendall et al.27. In short, B1 represents the firstmovement of the head ofthe foodbolus froma stable or ‘hold’ position that passes theposterior nasal spine andresultsinallorpartofthebolusenteringtheoropharynx.H1representsthefirstsuperior-anteriormovementofthehyoidbonethatresultsinaswallow.H2symbolizesthepointatwhichthehyoidbonereachesitsmaximumdisplacementduringtheswallow.Theonsetofhyoidelevationrelativetotheonsetofpharyngealtransit(‘hyoidelevationstarttime’)wascalculatedasH1minusB1.Thetimerequiredforthehyoidbonetoreachmaximalelevation(‘maximumhyoidelevationtime’)wascalculatedasH2minusH1.

Kinematic measuresTwo picture frames (stills) of each VFS swallow studywere generated in order to assessspatialmeasuresofhyoidmovement;oneshowingtherestingpositionofthehyoidbone,and the other showingmaximum displacement. The resting positionwasmarked as themomentjustbeforetheboluswaspropelledfromtheoralcavitytowardsthepharynx.Thepointofmaximumdisplacementwasdefinedasthepointjustbeforethehyoidbonebeganitsdescenttoarestingposition28,29.



6

Both stills were individually opened with the program ImageJ 1.32 for structuralmovementtracing(http://imagej.nih.gov/ij/).Thefollowingstructuresweretracedineachframe: theanterior-inferior cornerof vertebraC4 (for the remainderof this article: ‘C4’),theanterior-inferiorcornerofvertebraC2(‘C2’),theanterior-superiorcornerofthehyoidbone,and the lengthof thescaling referencecoin (known length19,75mm),asused forcalibration.Acoordinatesystemwasdefinedwiththeverticaly-axisrunningfromC2throughC4,andthehorizontalx-axisrunningperpendiculartothislinethroughC4.Allpictureframeswererotatedtoatruevertical/90°angle.TheangleofthelinebetweenC2andC4wasusedtorotatetheimagetothe90°angle.ImageJprovidedcalculatedvaluesofeachpoint(x,y),andthefollowingformulaswereusedtomeasureanteriorandsuperiorhyoiddisplacement:Anteriordisplacement: (x2– x1)– (C4x2–C4x1), and superiordisplacement: (y2– y1)–(C4y2–C4y1),wherex1andy1arethestarting(restframe)coordinatesofthehyoidbone,x2 and y2 are the compared image coordinates (maximum excursion coordinates), C4x1andC4y1 are the coordinates of the anchor point in the rest frame, andC4x2 andC4y2are the coordinates of the anchor point at maximum excursion28,29. Subsequently, hyoiddisplacementwastransformedintoanatomicallynormalizedunits,i.e.inpercentageofthedistance between vertebra C2 and C410.ThisprocesswassubsequentlycompletedforeachdifferentconsistencyandamountofeachsingleVFSswallowstudyonallthreedifferenttimepoints.Asanexample,twolateralVFSimageswiththemarkedpointsareshowninFigure2.

Subjective swallowing assessmentPatients’perceivedswallowingfunctionwasassessedatthevariousassessmentpointswithquestions from a larger study-specific questionnaire, addressing specific HNC issues suchaspain,oraldysfunction,speechproblems,swallowingdysfunction,andinterruptedsocialinteraction. The 17 study-specific questions regarding diet, swallowing, and chewing areshowninAppendixI[30].Especiallythequestionsregardingswallowingfunction(questions11–14)were taken intoconsideration.Each itemwasscoredona3-pointscale,and totalsubjective impairment scores were calculated using the sum score of these questions(maximumscore:11).

Reliability analysisAllVFSclinicalandtemporalassessmentsweredoneinconsensusbythefirstauthorandanexperiencedspeechlanguagepathologist(SLP).TheVFSkinematicmeasureswerecalculatedbyanothertrainedresearcher,with15%ofallmeasurementsrandomlyrepeated,tomeasureintraraterreliability,and15%withinonemonthrandomlyreviewedbythefirstauthor,asameasure of interrater reliability. Test-retest reliability was measured with two-way random intraclasscoefficients(ICC(2,1))forconsistency.Forintraraterreliability,anteriorandsuperiordisplacementshowedanICC(2,1)0.76and0.80,respectively.Forinterraterreliability,these

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coefficientswere0.79and0.83foranteriorandsuperiordisplacement,respectively,showingacceptableagreement.

Figure 2. Two lateralVFS images showing (1) the restingpositionof thehyoidbone (right), and (2)thehyoidboneduringmaximumdisplacement(left).Therelevantpointsaremarkedduringframe-by-frametracing.Withtheknownlength(19,75mm)ofthescalingreferencecoin,asusedforcalibration,theC2-C4distancewasmeasuredas51.76mm.Hyoiddisplacementwasthencalculatedabsolute(inmm)andinanatomicallynormalizedunits(%ofC2–C4distance).Anteriordisplacementwasmeasuredhereas(x2–x1)–(C4x2–C4x1)=(182,06–155,76)–(230,99–213,85)=9,16mm(17,7%ofC2-C4distance).Similarly,superiordisplacementwasmeasuredas(206,14–195,15)–(176,88–186,62)=20,77(40,1%ofC2-C4distance).

Statistical analysisAll measured temporal and kinematic data per assessment point were averaged acrosspatientsaccordingtobolussizeanddirectionofdisplacement.Dataweredescribedasmeanswithstandarddeviations.Wilcoxonsignedranktestwasusedtoteststatisticaldifferencesforvarioushyoiddisplacementparametersbetweenbaselineand10-weekspost-treatment,and between baseline and 1-year post-treatment. Secondly, correlations with subjectiveswallowing impairment (study-specific questions) were calculated with the Spearman’sranktest.AlldatawerecollectedandanalyzedinSPSS(Chicago,Illinois;version23.0),andasignificancelevelofp<0.05wasused.



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Table 1. Clinicalpatientandtumorcharacteristicsoftheinitiallyincludedpatients(n=25),thepatientsanalysedatbaselineand10-weekspost-treatment(n=17),andthepatientsanalysedat1-yearpost-treatment(n=14).

25patients 17patients 14patientsn(%) n(%) n(%)

GenderMale 19(76) 14(82) 12(86)Female 6(24) 3(18) 2(14)

Meanage,y(range) 59(39–77) 58(39–77) 58(39–77)Tumor siteNasopharynx 3(40) 3(18) 2(14)Oral/Oropharynx 12(48) 8(47) 7(50)Hypopharynx 10(40) 6(35) 5(36)

TumorstageStageIII 8(32) 7(41) 6(43)StageIV 17(68) 10(59) 8(57)

TstageT1 4(16) 4(24) 2(14)T2 7(28) 4(24) 4(29)T3 10(40) 6(35) 5(36)T4 4(16) 3(18) 3(21)

NstageN0 3(12) 2(12) 2(14)N1 7(28) 6(35) 5(36)N2 11(41) 7(41) 5(36)N3 4(16) 2(12) 2(14)

RESULTS

Details on the clinical characteristics of the study population are presented in Table 1.Pretreatment,2/17patients(12%)werediagnosedwithdysphagiaaccordingtothebinaryclassification fromthePASscoresobtained fromVFSassessment.At10-weeksand1-yearpost-treatment thesenumberswere3/17 (18%) and2/14 (14%), respectively.More thannormal residue above andbelow thehyoidbonewaspresent in 16/17 (94%)patients atbaseline, in8/17 (47%)patientsat10-weekspost-treatment,and in13/14 (93%)patientsat1-yearpost-treatment.Regardingpatients’perceivedswallowingimpairment,atbaseline6/17patients (35%) reported swallowing issues, based≥2positive answerson the study-specificquestionsregardingswallowingfunction.At10-weeksandat1-yearpost-treatmentthesenumberswere53%and29%,respectively.

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Temporal measuresBothhyoidelevationstarttime(theonsetofhyoidelevationrelativetotheonsetofpharyngealtransit;H1−B1)andmaximumhyoidelevationtime(H2–B1)werecalculated,separatedperconsistencyandassessmentpoint.Atbaseline,10-weeks,andat1-yearpost-treatment,22,25,and24patients,respectively,wereevaluated.AscanbeseeninTable2,hyoidelevationstarttimerangedfrom-.14±.28secondsfora5ccthinliquidswallowto.16±.43secondsforasolidswallow.Maximumhyoidelevationtimevariedfrom.47± .21secondsto .96±.94secondsfortheseconsistencies.Theonsetofhyoidelevationrelativetotheonsetoftheswallow,andthetimerequiredforthehyoidbonetoreachmaximalelevation,seemedtoincreasewithincreasesinbolussizeorconsistency,althoughthesechangeswerestatisticallynotsignificant(Wilcoxonsignedranktest;p>.05forthevariousassessmentpoints).Therewerealsonosignificantchangesovertimeforhyoidelevationstarttimeandmaximumhyoidelevationtime(p>.05forallconsistencies).

Table 2.Hyoidboneelevationonsetanddurationinseconds±SD

BolusSizeThinLiquid Thickliquid Solid3cc 5cc 3 cc cake Valid N

BaselineH1–B1 .02±.37 -.09±.18 .03±.50 .16±.43 22H2–H1 .67±.40 .51±.14 .69±.52 .96±.94 22

10-weeksH1–B1 -.08±.21 -.14±.28 .13±.58 .10±.33 25H2–H1 .58±.25 .47±.21 .81±.60 .92±.92 25

1-yearH1–B1 -.07±.20 -.09±.24 -.03±.35 .08±.34 24H2–H1 .64±.17 .74±.40 .79±.39 .87±.62 24

Abbreviations:B1:thefirstmovementoftheheadofthefoodbolusfromastableor‘hold’positionthatpassestheposteriornasalspineandresults inallorpartofthebolusenteringtheoropharynx;H1:thefirstsuperior-anteriormovementofthehyoidbonethatresultsinaswallow;H2:thepointatwhichthehyoidbonereachesitsmaximumdisplacementduringtheswallow;H1–B1:hyoidelevationonsetrelativetotheonsetofpharyngealtransit(=hyoidelevationstarttime);H2–B1:hyoidelevationduration(=maximumhyoidelevationtime);SD=standarddeviation.

Kinematic measuresTable 3A and 3B show the descriptive statistics for hyoid displacement (absolute inmm[A] and in ‘anatomically normalizedunits’4, i.e. percentageof C2-C4distance [B]). As canbeseen,meanmaximumanteriorandsuperiordisplacementrangedfrom9.4mm(23%ofC2-4distance)to12.6mm(27%),andfrom18.9mm(41%)to24.9mm(54%),respectively,dependingonbolusvolumeandconsistency.Nosignificantchangesovertimewerenotedfor all parameters, except for a swallow of 5 cc thin liquid, in which displacement was



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significantly increased in the superior direction at 10-weeks post-treatment compared tobaseline (Wilcoxonsigned rank test;as%C2–C4:p =.039).Thiseffectwaspredominantlyseeninpatientswithatumorintheoropharynx(change5.9mm;12.3%)andhypopharynx(change5.7mm;13.3%)andwasabsentinpatientswithatumorinthenasopharynx(change-1.2mm;-2.7%).

Table 3A. Hyoidbonedisplacement(absoluteinmm)

BolusSizeThinLiquid Thickliquid Solid3cc 5cc 3 cc cake Valid N

BaselineAnteriormean±SD 10.7±3.4 12.0±4.3 12.2±4.3 11.6±3.8 17Superiormean±SD 18.9±8.0 20.3±5.9 20.5±8.4 19.3±8.6 17

Follow-up10-weeksAnteriormean±SD 10.5±4.3 11.4±5.3 11.2±5.0 12.6±4.7 17Superiormean±SD 22.6±8.3 24.9±9.2 24.7±9.1 23.0±7.5 17

Follow-up1-yearAnteriormean±SD 9.4±4.3 9.9±4.1 10.7±4.4 12.5±5.0 14Superiormean±SD 19.9±7.6 23.3±7.4 19.9±7.7 21.9±6.9 14

Abbreviations:SD=standarddeviation;mm=millimetres;cc=cubiccentimetres

Table3B.Hyoidbonedisplacement(%ofC2-C4distance)

BolusSizeThinLiquid Thickliquid Solid3cc 5cc 3cc cake Valid N

BaselineAnteriormean±SD 23±7 26±9 26±8 25±8 17Superiormean±SD 41±17 44±12 45±17 42±18 17

Follow-up10-weeksAnteriormean±SD 23±9 25±11 25±10 27±10 17Superiormean±SD 49±18 54±19 53±21 50±16 17

Follow-up1-yearAnteriormean±SD 20±9 22±9 23±10 27±10 14Superiormean±SD 43±17 51±16 43±17 48±15 14

Abbreviations:SD=standarddeviation;mm=millimetres;cc=cubiccentimetres

Correlation with swallowing impairmentThenumberofpatientsshowingpenetration-aspirationonVFSassessmentswaslowinthecurrent study cohort (maximum 3 patients per assessment point), limiting the statisticalpowerto investigatecorrelationsbetweenpenetration-aspirationandhyoiddisplacement.

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Thepatientsshowingpenetrationoraspirationdidnotshowreducedhyoiddisplacementcomparedtothegroupmean.Nocorrelationsbetweendelayedorreducedhyoidexcursionand residue scores could be demonstrated. Regarding investigation of correlations withpatient-reported outcomes based on (sub) total scores of the study-specific questionsregardingswallowingfunction(questions11–14;Appendix I),superiorhyoiddisplacementsignificantly correlated with subjective swallowing impairment for various consistenciesand assessment points. Especially superior displacement at baseline correlated well with swallowing functionat1-yearpost-treatment (seeTable4 for thep-values fora5cc thinand3ccthick liquidswallow). InFigure3thisrelationshipfora5ccthinliquidswallowisillustratedinascatterplot.

Table 4. OverviewofSpearman’srankcorrelationsbetweensuperiorhyoiddisplacementatbaselineandsubjectiveswallowingimpairmentat1-yearpost-treatmentforathin(5cc)andthick(3cc)liquidswallow

Superior displacement

Problems swallowingliquids

Problems swallowingsoftfoods

Problems swallowingsolid foods

Swallowingmoreoften

Total subjective

score

Thinliquidswallow .41 .41 .73** .59* .72**Thickliquidswallow .41 .41 .68** .55* .67**

Note:*meansp<.05;**meansp<.01

Figure 3. Scatterplotoftherelationshipbetweensuperiorhyoidbonedisplacementfora5ccthinliquidswallowatbaseline(measuredas%oftheC2-C4distance)andsubjectiveswallowingimpairmentbasedonthestudy-specificquestionnaireat1-yearpost-treatment.



6

DISCUSSION

The primary aim of the present study was to report on temporal and kinematic hyoiddisplacement parameters in HNC patients treated with chemoradiotherapy, with thesecondary aim to investigate correlations with objective and subjective swallowingimpairment.Regardingthefirstaim,theonsetofhyoidelevationrelativetotheonsetoftheswallowdidnotchangesignificantlyovertimeorwithincreasesinbolussizeorconsistency,nordidthetimerequiredforthehyoidbonetoreachmaximalelevation.Maximumhyoiddisplacement–scaledincervical/anatomicalunits(%C2–C4distance)–rangedfrom23%to27%intheanteriordirection,andfrom41%to54%inthesuperiordirection.Theseresultsare somewhat lower in comparisonwith ‘normative’ data from the literature concerningpatientsreferredfordysphagiaassessment,withresultsrangingfrom36%to38%anteriorly,and from 51% to 57% superiorly4,9. Although the predominant aetiology of dysphagia inthosestudieswasneurogenic,wherebypatientswithahistoryofHNCwereexcluded,thispossiblyimplicatesthathyoiddisplacementinthecurrentpatientcohortwasalreadylimitedatbaseline,andmightexplainthelackofsignificantchangesovertime.Obviously,itisalsoquitedifficulttodemonstratedstatisticaldifferencesinthissmallHNCsample.Regardingthesecondaim,wehavenotseenstrongcorrelationsbetweenhyoiddisplacementenswallowingimpairment,exceptforasignificantassociationbetweenreducedsuperiorhyoidmovementand subjective swallowing impairment based on four study-specific questions regardingswallowingfunction,which,however,wasquitesmall.

Interestingly, in the current study cohorthyoiddisplacement inpatientswitha tumorat theoropharynx andhypopharynx had slightly increased in the superior direction for a5 cc thin liquid swallowat10-weekspost-treatmentcompared tobaseline.Though thesedifferencesweresignificantonlyforthe5ccthinbolus,thehighervaluesmayreflectextraeffortbeingexertedduringtheseswallows.Andifso,thiscouldindicatethatotherissues,e.g.poorsensation,non-hyoidmechanicalimpairment,arepresentandresponsiblefortheextraeffort. For future studies itmightbeof interest to also lookatoverall transittimesduringswallowing,whichcanbeprolongedwithincreasedeffort.Sincewedidnotseethiseffect inthepatientswithatumor locatedatthenasopharynx, it isalsopossiblethattheprimarytumor,orpainduetothetumor,impairedthemobilityofthehyoidboneatbaselineinthesepatients,andthathyoidmovementwas‘restored’againaftercompleteremissionat10-weekspost-treatment.However,therearemuchmoreparameterssuchastumorvolume,radiationdoseeffectsand/orexercisetherapywhichmighthaveplayedaroleinthis.In2011vanderKruisandcolleaguesrevealedintheirreviewsignificantimprovedhyoidexcursioninseveralstudiesfollowingtreatmentwithswallowingmanoeuvresand/orbolusmodification31. A similareffectmightbepresent in the currentpatientpopulation: theparticipation inapreventiveandcontinuedpost-treatmentswallowingrehabilitationprogrammightexplain

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these favourable10-weekshyoidelevationoutcomes32.Thiscouldmaybealsoexplain thelimitednumber of patientswhohad aspiration, and the lower rate ofmore thannormalresiduescoresat10-weekspost-treatment.Finally,patientswhoarecautiousorfearfulaboutswallowingsafety,thatis,whoperceivegreaterdifficulty,mayelevatethehyoidearly,asinthe ‘rest’or ‘hold’position. If so, theirhyoiddisplacementmaybereduced,ascomparedtohealthysubjects,orascomparedtoless-fearfulpatients.Consequently, ‘possible’hyoiddisplacement,orpotential forhyoiddisplacement,maybedifficult todetermine in thesecases.

Unfortunately, due to methodological issues (only 4 patients showing aspiration onVFSassessments),thehypothesisthatpatientswithpenetrationoraspirationwouldshowslower durations of hyoidmovement and/or reductions in kinematicmeasures could notbestatisticallyanalysed.Thesignificantassociationfoundbetweenreducedsuperiorhyoidmovement and subjective swallowing impairment based on four study-specific questionsregarding swallowing function was quite small. Possibly, other mechanical variables mayhavebeenimpairedandaccountedforpatients’reporteddysphagia.It isnotexactlyclearif hyoid elevation or anterior excursion is more important. Steele and colleagues (2011)reportedsignificantlyhigheroccurrenceofpenetration-aspirationinswallowswhereanteriormovement was restricted4.However,Molfenterandcolleagues(2014)foundatrendtowardslowermaximumsuperiorhyoidpositionandswallowingimpairment9.Inthecurrentpatientcohort correlations between residue ratings and hyoid displacement were also lacking.Residue, however,might be explained by other, non-hyoid,mechanical variables. Furtherresearchwithlargersamplesizesisnecessarytoconfirmthesecorrelation.

Althoughtheratersinthecurrentstudyusedwell-definedguidelines28,29and–followingseveral training sessions–maximumconsensuswas reachedabout thedefinitionsof themeasuredspatialvariables19, intra-and interraterreliability (withan ICC(2,1)rangingfrom0.76to0.83)wasacceptable,anddidnotreachthe levelof ‘excellent’reliability.Besides,allmeasurements and analyseswere very time consuming; not only because of the pre-experimental trainingsessions,butalsodue to inefficiency/lackof computerization in thecurrentmethodsused.Softwareforautomaticmeasurementandanalysisextendofhyoidmovement in the x-y coordinate systemovertimewasunfortunately not available inourInstitute. Consequently, all swallow studies were individually analysed, and the providedx and y coordinates by ImageJ were manually entered to Excel/SPSS to calculate themaximumanteriorandsuperiordisplacementvalues.Forfutureperspectivesitisthereforerecommendedtouseautomaticsystemsforanalysisofhyoiddisplacement.



6

CONCLUSION

InthisstudytemporalandkinematicmeasuresrelatedtohyoiddisplacementinadvancedHNCpatientsarereportedupto1yearaftertreatmentwithconcurrentchemoradiotherapy.Comparedtonormativedata,hyoidelevationandanteriorexcursionwasalreadylimitedatbaseline.Sincehyoiddisplacement issubjecttovariability fromanumberofsources, thisparameterseemsnotveryvaluableforclinicaluseinHNCpatients.

ACKNOWLEDGEMENTS

ThedepartmentofHeadandNeckOncologyandSurgeryreceivesanunrestrictedresearchgrantofAtosMedicalAB,Sweden.

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Appendix I. SelectionofthetranslatedDutchstudyspecificquestionnaire.

A. Diet,swallowingandchewingcomplaintsoverthelastweek(17questions)1. Doyoustillhaveyourownteeth?

1=yes 2=yes,partially3=no,Ihaveaprosthesis 4=no,andIdon’twearaprosthesis

2. Howoftendoyoucleanyourteeth?1=acoupleoftimesaday 2=onceaday3=lessthanonceaday 4=notatall

3. Howdoyouexperienceyourmouthopening?1=normal 2=alittlebitlimited3=verylimited 4=Icannotopenmymouth

4. Whatisyourdietlike?1=Ieatsolidfood 2=Ionlyeatsoft(minced)food3=Ionlyeatliquidfood 4=Ionlyhavetubefeeding5=combinationsoftdietandtubefeeding

5. Doyouexperienceproblemswitheating,becauseofalimitedmouthopening?1=notatall 2=alittle3=rather 4=quitealot

6. Doyouexperienceproblemswithspeech,becauseofalimitedmouthopening?1=notatall 2=alittle3=rather 4=quitealot

7. Doyouhaveproblemswithchewingyourfood?1=notatall 2=alittle3=rather 4=quitealot

8. Doyouhaveproblemswithmovingsolidfoodaroundinyourmouth?1=notatall 2=alittle3=rather 4=quitebad

9. Doyouhaveproblemswithmovingsoft/mincedfoodaroundinyourmouth?1=notatall 2=alittle3=rather 4=quitealot

10.Doyouhaveproblemswithmovingliquidfoodaroundinyourmouth?1=notatall 2=alittle3=rather 4=quitealot

11. Do you have problems with swallowing solid food?1 = not at all 2 = a little3 = rather 4 = quite a lot



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12. Do you have problems with swallowing soft/minced food?1 = not at all 2 = a little3 = rather 4 = quite a lot

13. Do you have problems with swallowing liquid food?1 = not at all 2 = a little3 = rather 4 = quite a lot

14. Do you have to swallow repeatedly to get rid of food?1 = yes 2 = no3 = sometimes

15.Doyouhavetodrinkduringamealtoeasefooddown?1=yes 2=no3=sometimes

16. Doyouhaveanormalamountofsaliva(spit)?1=muchless 2=abitless3=thesame 4=abitmore5=muchmore

17. Canyoukeepyoursalivainthemouthwithoutleakage?1=notatall 2=abit3=fairlywell 4=quiteeasily

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2. BingjieL,TongZ,XintingS,JianminX,GuijunJ. Quantitative videofluoroscopic analysis ofpenetration-aspirationinpost-strokepatients.NeurolIndia.2010;58:42-7.

3. Wang TG, Chang YC, Chen WS, Lin PH,Hsiao TY. Reduction in hyoid bone forwardmovement in irradiated nasopharyngealcarcinomapatientswithdysphagia.ArchPhysMedRehabil.2010;91:926-31.

4. SteeleCM,BaileyGL,ChauT,MolfenterSM,OshallaM,Waito AA, et al. The relationshipbetween hyoid and laryngeal displacementandswallowingimpairment.ClinOtolaryngol.2011;36:30-6.


6. ZuY,YangZ,PerlmanAL.Hyoiddisplacementinpost-treatmentcancerpatients:preliminaryfindings.JSpeechLangHearRes.2011;54:813-20.


8. Kim Y, McCullough GH. Maximal hyoidexcursion in poststroke patients. Dysphagia.2010;25:20-5.

9. Molfenter SM, Steele CM. Kinematic andtemporalfactorsassociatedwithpenetration-aspiration in swallowing liquids. Dysphagia.2014;29:269-76.

10. Steele CM, Cichero JA. Physiological factorsrelatedtoaspirationrisk:asystematicreview.Dysphagia.2014;29:295-304.

11. Logemann JA, Pauloski BR, Rademaker AW,ColangeloLA,KahrilasPJ,SmithCH.Temporal

and biomechanical characteristics oforopharyngealswallow inyoungerandoldermen.JSpeechLangHearRes.2000;43:1264-74.

12. Kendall KA, Leonard RJ. Hyoid movementduring swallowing in older patients withdysphagia.ArchOtolaryngolHeadNeckSurg.2001;127:1224-9.

13. Logemann JA, Pauloski BR, Rademaker AW,KahrilasPJ.Oropharyngealswallowinyoungerandolderwomen:videofluoroscopicanalysis.JSpeechLangHearRes.2002;45:434-45.

14. Kim Y, McCullough GH. Maximum hyoiddisplacement in normal swallowing.Dysphagia.2008;23:274-9.

15. Paik NJ, Kim SJ, Lee HJ, Jeon JY, Lim JY, HanTR. Movement of the hyoid bone and theepiglottis during swallowing in patientswith dysphagia from different etiologies. JElectromyogrKinesiol.2008;18:329-35.

16. Dodds WJ, Man KM, Cook IJ, Kahrilas PJ,Stewart ET, Kern MK. Influence of bolusvolume on swallow-induced hyoid movement in normal subjects. AJR Am J Roentgenol.1988;150:1307-9.

17. Nagy A, Molfenter SM, Peladeau-Pigeon M,StokelyS,SteeleCM.Theeffectofbolusvolumeon hyoid kinematics in healthy swallowing.BiomedResInt.2014;2014:738971.

18. Sia I, Carvajal P, Carnaby-Mann GD, CraryMA. Measurement of hyoid and laryngealdisplacement in video fluoroscopicswallowing studies: variability, reliability, andmeasurementerror.Dysphagia.2012;27:192-7.

19. Baijens L, Barikroo A, Pilz W. Intrarater andinterrater reliability for measurements in videofluoroscopyofswallowing.EurJRadiol.2013;82:1683-95.

20. Molfenter SM, Steele CM. Physiologicalvariability in the deglutition literature:hyoid and laryngeal kinematics. Dysphagia.2011;26:67-74.

21. LalPT,A;Verma,A;MariaDas,KP;Baijal,SS;Bajpai,R;Kumar,P;Srivastava,A;Kumar,S.Role



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of videofluorography in assessing functionalabnormalities in patients of head and neckcancer treated with chemoradiotherapy APJofClinicalOncology.2009;5:264-9.

22. vanderMolenL,HeemsbergenWD,deJongR, vanRossumMA, Smeele LE,RaschCR, etal. Dysphagia and trismus after concomitantchemo-Intensity-Modulated RadiationTherapy (chemo-IMRT) in advanced headand neck cancer; dose-effect relationshipsfor swallowing and mastication structures.RadiotherOncol.2013;106:364-9.



25. Logemann JA. Evaluation and treatment ofswallowing disorders: Pro-ed (2nd edition).Texas,Austin;1998.

26. Pauloski BR, Rademaker AW, LogemannJA, Stein D, Beery Q, Newman L, et al.Pretreatmentswallowingfunctioninpatientswith head and neck cancer. Head Neck.2000;22:474-82.

27. Kendall KA, McKenzie S, Leonard RJ,GoncalvesMI,WalkerA.Timingofevents innormalswallowing:avideofluoroscopicstudy.Dysphagia.2000;15:74-83.

28. LeonardRJ,KendallKA,McKenzieS,GoncalvesMI, Walker A. Structural displacements innormalswallowing:avideofluoroscopicstudy.Dysphagia.2000;15:146-52.

29. Leonard RJ KK. Dysphagia assessment andtreatment planning: a team approach. In:GroupSDSP,editor.1997.


31. van der Kruis JG, Baijens LW, Speyer R,Zwijnenberg I. Biomechanical analysis ofhyoidbonedisplacementinvideofluoroscopy:a systematic review of intervention effects.Dysphagia.2011;26:171-82.

32. Kraaijenga SA, van der Molen L, Jacobi I,Hamming-VriezeO,HilgersFJ,vandenBrekelMW. Prospective clinical study on long-termswallowing function and voice quality inadvanced head and neck cancer patientstreated with concurrent chemoradiotherapy andpreventiveswallowingexercises.EurArchOtorhinolaryngol.2015;272:3521-31

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CHAPTER 7Effects of strengthening exercises on swallowing

musculature and func.on in senior healthy subjects:

a prospec.ve effec.veness and feasibility study

S.A.C. Kraaijenga L. van der Molen M.M. Stuiver H.J. Teertstra F.J.M. Hilgers

M.W.M. van den Brekel

Dysphagia. 2015; 30: 392-‐403.

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136 | Chapter 7

ABSTRACT

Introduction:Headandneckcancer(HNC)patientsmaydevelopdysphagiaduetomuscleatrophyandfibrosisfollowingchemoradiotherapy.Strengtheningoftheswallowingmusclesthroughtherapeuticexerciseispotentiallyeffectiveforimprovingswallowingfunction.Wehypothesize that a customized Swallow Exercise Aid (SEA), developed for isometric andisokinetic strengtheningexercises (against resistance), canhelp to functionally strengthenthesuprahyoidmusculature,whichinturncanimproveswallowingfunction.

Methods: Aneffectiveness/feasibilitystudywascarriedoutwith10seniorhealthyvolunteers,whoperformedexercises3timesperdayfor6weeks.Exercisesincludedchintuckagainstresistance (CTAR), jaw opening against resistance (JOAR), and effortful swallow exerciseswith theSEA.Multidimensionalassessmentconsistedofmeasurementsofmaximumchintuckand jawopening strength,maximumtongue strength/endurance, suprahyoidmusclevolume, hyoid bone displacement, swallowing transport times, occurrence of laryngealpenetration/aspiration and/or contrast residue, maximum mouth opening, feasibility/compliance(questionnaires),andsubjectiveswallowingcomplaints(SWAL-QOL).

Results: After 6-weeks exercise,mean chin tuck strength, jaw opening strength, anteriortongue strength, suprahyoid muscle volume, and maximum mouth opening significantlyincreased (p <.05). Feasibility and compliance (median 86%, range 48–100%) of the SEAexercisesweregood.

Conclusion: This prospective effectiveness/feasibility study on the effects of CTAR/JOARisometric and isokinetic strengthening exercises on swallowingmusculature and functionshows that senior healthy subjects are able to significantly increase swallowing musclestrengthandvolumeaftera6-weektrainingperiod.Thesepositiveresultswarrantfurtherinvestigation of effectiveness and feasibility of these SEA exercises in HNC patients withdysphagia.

KEY WORDSHeadandNeckCancer–Deglutition–DeglutitionDisorders–Dysphagia–StrengthExercises–Isometric–Isokinetic–ChinTuck–JawOpening


Effectsofstrengtheningexercisesonswallowingmusculatureandfunction|137

7

INTRODUCTION

Swallowingingeneral,andthevariousphasesofthisprocess(oral,pharyngeal,andesophageal),requiresacomplexinteractionbetweenthemusclesinthetongue,floorofmouth,pharynx,andlarynx1-3.Thisintricatephysiologiccourseofmuscleeventsandinteractionsisatriskinpatientstreatedforheadandneckcancer(HNC),andswallowingimpairment/dysphagiaisnotuncommoninthesepatients.Itcanbecausedbythetumorextensionitself,butmaybeevenmore so,bytissue reactions resulting fromsurgical resectionsor (organpreserving)chemoradiotherapy(CRT),e.g.radiationfibrosisorchangesininnervationoftheswallowingmusculature.Additionallytheoccurrenceofacutemucositis,fibrosis,xerostomia,painandtrismusoftencausesevereswallowingproblems,which, inturn, limitoral intakeandmayrequirenasogastrictubefeeding4-7.

Tongue strengthalsoplays a role in the swallowingphysiology, particularly in theoralphase of the swallow8-10. InpatientstreatedwithprimaryCRT, lingualstrength isreduced,which further limits oral and pharyngeal structuralmovement during the swallow11. As a result,theswallowingmusclesarenolongeractivelyusedandmighteventuallyatrophy12,affectingbothoralandpharyngealphaseswallowingfunction,especiallyinthelong-term.

Recently,moreattentionhasbeendrawntopreventionofnon-useatrophy inpatientswith advancedHNCundergoingCRT. In compliantpatients, implementationof preventive(swallowing)exerciseshasdemonstratedtoimprovepost-treatmentswallowingfunctionandqualityof life13-17.Theseexercises includerangeofmotionorresistanceexercises (withorwithoutmedicaldevicessuchastheTheraBite®device),the(super-)supraglotticswallow1,18,

19,theeffortfulswallow1,20,21,theMendelsohnmaneuver19,22,theMasako(tongue-holding)maneuver21,andtheShaker(head-raising)exercise23.Especiallythelatterhasproventobeeffectiveinstrengtheningthesuprahyoidmusculatureandreducingswallowingproblems24,25,butwiththemajordrawbackthattheexerciseshouldbecarriedoutinasupineposition.This appears to be quite strenuous, and the compliancewith this exercise is less due tosternocleidomastoidmusclediscomfort,especiallyinelderly,frailpatients26,27.

AsanalternativetherapeuticinterventionforpatientswhofindtheShakerexerciseinthesupinepositionphysicallychallenging,Yoonetal. investigatedanotherexercisetoactivatethesuprahyoidmusculature:thechintuckagainstresistance(CTAR)27.Thisexerciseinvolvestuckingthechinashardaspossibleonarubberball,whichisplacedbetweenthechinandchest.Theauthorsstatethatitcanbecarriedoutforbothisometricandisokinetictasks,anditwouldallowelderly/frailpatientstoperformtheexercisesbasedontheircurrentstrengthlevel,withouthavingtobestrongenoughtoperformaheadliftfromthesupineposition.Assuch,itcouldqualifyasanalternativetotheShakerexerciseandpotentiallyimproveexercisecompliance27.

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138 | Chapter 7

The TheraBite® device, originally developed for passive range of motion exercises inirradiated patients with trismus and/or patients with mandibular hypomobility28, 29, canalsobeused inHNCpatients toaidswallowingexercisesduringCRT treatment.With thisdeviceitappearstobepossibletoimprovehyo-laryngealelevationandswallowingmusclemaintenance,andthusfunctionalswallowingability15,16.

Based on the positive experience with the TheraBite as an exercise tool with goodcompliance15,16,andtheideatocombineprovenisometricandisokineticstrengthexercisesinasingleusefulhandhelddevicethatisapplicableinaseatedposition,wedevelopedanewSwallowExerciseAid (SEA). Thedevice consistsof commercially availableandcustomizedcomponents,toenableexercisesagainstvariable/increasingresistance,allowingadaptationto individualperformance improvement,andtoprovideadequatetactile feedback. Inthisway, a variation of exercises can be performed, which have the potential to functionallystrengthenthesuprahyoidandpharyngealmusclesrelevantforswallowing.Theeffectivenessandfeasibility/complianceofanexerciseprotocolusingthisdevicewasstudied inhealthysubjectswithamultidimensionalassessmentprotocol.


Thepresentstudywasdesignedasanuncontrolledprospectiveeffectivenessandfeasibilitystudywitha6-weekfollow-upperiod,andwasundertakenattheDepartmentofHeadandNeckOncologyandSurgeryoftheNetherlandsCancerInstitute–AntonivanLeeuwenhoekinAmsterdam,theNetherlands.

Participants/volunteersThestudypopulationconsistedof10healthy,malesubjectswithouthistoryofswallowingimpairmentorotherdysphagia symptoms (median total SWAL-QOLscoreatbaseline4.5,which isbelowthedefinedcut-offscoreof14byRinkeletal. forswallowingproblems30).Medianageatbaselinewas60years(range52–73years);medianweightwas88kg(range70–92kg).ThisageandgendergroupwaschosentomimictheagedistributionoftheHNCpatientpopulation31,32,andbecauseHNCoccursmorefrequentlyinmalesthaninfemales,with a ratio ranging from3:1 to 4:131, 32.Moreover, in thisway genderwas not an effectmodifier in this small-scale effectiveness and feasibility study. See Table 1 for volunteers’characteristicsatbaseline.

The Swallow Exercise Aid TheSEAwasconstructedwithcommerciallyavailableparts,i.e.theTheraBiteJawMobilizationdevicecomplementedwithoneortwoTheraBiteActiveBandsmadeoutofsiliconerubber



7

(AtosMedical,Hörby, Sweden), and subsequently remodeledbyour Institute’s technicianby adding a chest bar to one of the mouthpieces of the TheraBite (see Figure 1). TheActiveBandcanbeplacedatvarious,markedpositionsaroundthehandle.TheforcerequiredtocompressthechinbarontothechestbarwithoneActiveBandinthemaximumposition,accordingto themanufacturer’sspecifications, is50Newton (N). IfasubjecthadenoughstrengthwithoneActiveBandat itsmaximumpositiontocompletethesetofexercises,asecondActiveBandwasaddedatanyoneofthemarkedpositions.Thisconfigurationallowsprogressiveoverload,whichisaprerequisiteforeffectivestrengthtraining33.

Table 1. Volunteers’characteristics(n=10)

Subject Gender Age Weight FOIS Follow-up Assessments(years) (kg) (score)

1 M 52 70 7 6wks,2days All2 M 66 88 7 6wks,2days NoMRI3 M 67 91 7 6wks,2days All4 M 61 80 7 6wks,2days All5 M 54 88 7 6wks,2days All6 M 73 92 7 6wks,2days All7 M 56 87 7 6wks,2days All8 M 61 88 7 6wks,2days All9 M 57 82 7 4wks,4days All

10 M 58 88 7 6wks,2days All

Abbreviations:FOIS=FunctionalOralIntakeScale.Ageandweightareassessedatbaseline.

Figure 1.SwallowExerciseAid(SEA)withActiveBand,chintuckandjawopeningextension,chinbar,andchestbar;insertshowspossibleadditionofasecondActiveBandtofurtherincreaseresistance.

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140|Chapter7

InterventionThetrainingprogramconsistedofthreeexercises,visualizedinFigure2:

The first exercise, the chin tuck against resistance (CTAR) exercise,was performed bypressing the chindownwards against the chinbar,while keeping themouth closed, untilthechinbarreachedthechestbarattachment(providingtactilefeedback).Inthisway,theexercise–comparabletotheShaker23andthe‘ball’CTARexercise27–focusedontrainingthesuprahyoid muscles.

Thesecondexercise,thejawopeningagainstresistance(JOAR)exercise,wasperformedbypressingthemandibledownwhileopeningthemouth,toagaincompressthechinbarontothechestbar.Giventhatsuprahyoidmusclesparticipateinopeningthejaw34,thisexercisefocusednotonlyonthesuprahyoidmuscles,butalsoonotherjawopeningmusculature.

Thethirdexercise,theeffortfulswallow(ES)exercise,wasperformedwiththechinplacedon the chinbar (presseddownwards for approximately50%),whereby the subjectswereaskedtoswallowwiththemandibledownandmouthclosed,comparabletotheformerlydescribedTheraBiteswallowingexercise15.Thisexerciseishypothesizedtonotonlystimulatethe suprahyoid and jaw muscles involved in mouth opening, but also the pharyngealmusculature,comparabletoaneffortfulswallow1,20,21.

Figure 2. SwallowingExerciseAid(SEA)exercises(printedwithpermissionofsubject).Top left:startposition;topright:exercise1;chintuckagainstresistance(CTAR)exercise;bottomleft:exercise2;jawopeningagainstresistance(JOAR)exercise;bottomright:exercise3;effortfulswallowexercisewith50%ofmaximumclosure.



7

Exercise protocolAll subjectswere asked to perform the SEA exercises three times per day for six weeks.Prior to participation, subjects received awritten instruction sheet. Theywere instructedtoholdtheSEA in theirpreferredhand, toplacethechestbarontothesternumwithoutexcessivepressure,andtoplacethechinontothechinbar.TheActiveBandwasplacedonthe(individual)indicatedpositionofthedevice,toensureaspecifiedamountofresistance.

Comparable with the Shaker exercise23, the CTAR and JOAR exercises consist of bothisometricandisokineticstrengthexercises.Theisokineticexerciseswereperformed30timesconsecutivelyatafixedpaceof1spercontraction.Theisometricexerciseswereperformedthreetimes,maintainedfor60s,witha60srestperiodbetweeneachofthethree.Thesetwoexerciseswerecarriedoutfirst,with60srestbetweeneachsession.Subsequently,theeffortful swallow exercise was performed 10 times consecutively, after another 60s restperiod.Thetotaldurationofthethreeexerciseswasestimatedtobe15minutespersession.

For the exercise prescription, only start-intensity was specified for individual subjectsbased on baseline strength assessments (dynamometry and 30-repetition maximum).Progressionof intensitywasbasedonself-perceivedexertion;allsubjectswere instructedthat the exercises should be perceived as strenuous, inducing substantial local musclefatigue,andtoincreaseresistancewhenevertheyfeltableto(thatis:iftheycouldcompletetheexercisewithoutsubstantialexertion).

SubjectsreceivedthreedailySMStextmessagesasaremindertopracticeandwereaskedtorecordtheirperformancesbyusingtallysheetsinaspecialexerciselog.Allsubjectswereinstructedtostoptheexercisesiftheyfeltdiscomfortorpainonthechest/chinorin/aroundtheirtemporomandibularjointduringtheexercises.

Multidimensional assessment All outcome parameters were recorded prior to participation (at baseline) and two daysafterthe6-weekpracticeperiod(post-training).Thetotaldurationofthemultidimensionalassessment protocol was estimated to be 60 minutes per session. Primary outcomeparameters were maximum chin tuck/jaw opening strength, maximum tongue strength/endurance,suprahyoid(swallowing)musclevolume,andhyoidbonedisplacement(HBD).

Muscle strengthMusclestrengthsweremeasuredwitha‘handheld’dynamometer(MicrofetTM,Biometrics,Almere, the Netherlands) mounted into an adapted ophthalmic examination frame (seeFigure3),toavoidvariationsinheadandchinpositionandtoensureconsistentcompression.Asuperiorfixedbeltstabilizedthesubject’shead,andtheheightofboththechinrestandthesuperiorbeltcouldbeadjustedtothesubject’sdimensions.Subjectswereinstructedtositstraight,andtopresstheirchindownonthedynamometeraspowerfulaspossible,once

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142 | Chapter 7

withtheirmouthandteethclosed(liketheCTARexercise),andoncebyopeningtheirjaw/mouth(liketheJOARexercise).Thedynamometerdigitallymeasuredthemaximalisometricchin tuck/jaw opening strength in Newton. Both measurements were preceded by onefamiliarizationsession,inordertoexcludelearningcurveeffectsandtoimprovereliabilityofthe values obtained35.Afterthefamiliarizationsession,bothmeasurementswererepeatedthreetimes,witha60-secondsrestperiodbetweenthetrials.Themeanmaximumpressureofthehighesttwoofthreevalueswascalculatedandusedasthesubjects’maximumchintuck/jaw opening strength35. Test-retest reliability with Intraclass Correlation Coefficient(ICC(2,1)) of this set-upwas assessed in 14 (different) volunteers. Themaximal chin tuckstrengthshowedanICC(2,1)of0.98(95%CI0.93–0.99)andthemaximaljawopeningstrengthshowedanICC(2,1)of0.97(95%CI0.92–0.99)(whichmeansamaximalmeasurementerrorof17Nforchintuckstrengthand18NforjawopeningstrengthinthisSEAsample).

Figure 3. Musclestrengthtestset-upwithanadaptedophthalmicexaminationframeandadynamo-meter (MicrofetTM) fixedat the chin rest (printedwithpermissionof subject). Left:measurement1(mouthclosed,comparabletoCTARexercise);right:measurement2(mouthopened,comparabletoJOARexercise).



7

Tongue strength and enduranceThe Iowa Oral Performance Instrument (IOPI) was used to measure maximum tonguepressures(atanteriorandposteriorlocations)andendurancebymeansofasmallair-filledbulb.Thereisampleevidencetosupportthistoolforevaluating(isometric)tonguestrengthand endurance33,36.Subjectshadtopresstheirtongueupwardsontheair-filledbulb,inordertosqueezethebulbagainstthehardpalate.PressureswereexpressedinkPaanddigitallydisplayedonthedevice.Afteronefamiliarizationsession,threetrialsofmaximum(anteriorandposterior)tonguepressurewereobtainedforeachsubject,witha2-minuterestperiodbetween the trials. Themeanmaximumpressureof thehighest twoof three valueswascalculated and used as the subjects’ maximal (anterior/posterior) tongue strength. Alsoendurancemeasureswereanalysedatanteriortonguelocationfollowingthestrengthtask,afterabreakofat least5minutes.Subjectswereaskedtomaintain50%oftheirmaximaltonguestrengthaslongaspossible.

Muscle volumeMagneticResonanceImaging(MRI)at3Tesla(PhilipsAchievarelease3.2.1,PhilipsMedicalSystems,Best,TheNetherlands)wasusedtovisualisetheswallowingmusclesintheoralcavityandpharynx16.Adedicated16-channelSENSEneurovascularcoilwasused.BothT1(TurboSpinEcho (TSE), TRA:TR/TE:1761/10,ETL:6, reconvoxel:0,5x0,5x1,5mm,FOV:100x100x91,2 nex; SGT:TR/TE:1490/10ms, ETL:7, recon voxel:0,5x-,5x1,5mm, FOV:100x200x91,2 nex;COR:TR/TE:877/10,ETL:7,reconvoxel:0,28x0,28x1,5mm,FOV:99x110x180,3nex)and3DT2(VistaCOR:TR/TE:1874/200ETL:66,reconvoxel:04x0,4x0,75,FOV:100x110x181,3nex)wereacquired.TotaldurationoftheMRI-investigationwas20minutes.Subjectswereinstructedto liedownwhile keeping their tongue (relaxed) to the lower teethduring scanning. Theacquired imageswerestoreduntoaPACSWorkstation (CarestreamHealth Inc,Rochester,USA). Post-processing (volume measurements) was done using the Philips IntellispacePortal Tumor Tracking Application (PhilipsMedical Systems, Best, the Netherlands).Withthis application the contours of the muscle groups were delineated in three orthogonalplanes (T1 coronal, transversal, and sagittal), and controlledwithoverlying T2 images.Asan example, in Figure 4 a graphic representation of the delineatedmuscle contour withcorrespondingvolumecalculationinthecoronalorthogonalplaneisshown.Musclevolumesof the suprahyoidmuscles (the combination of the geniohyoid, mylohyoid, and digastric(anteriorbelly)muscles)weredetermined.Itappearedthatthemeasurementsofindividualmuscleswasnotpractical,becauseofthreereasons:the individualmusclesarenoteasilydistinguishedfromeachotherwithMRI(especiallythegeniohyoideusandmylohyoideus),the individualmusclesare small, thereforemeasuringwillhavea relatively large inherentvariabilityandinaccuracy,andthird:theycanfunctionallybeconsideredasonegroup,andwesupposedanequalreactiontoexercise.

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144 | Chapter 7

Figure 4.GraphicrepresentationofdelineatedsuprahyoidmusclecontourwithcorrespondingvolumecalculationinthecoronalorthogonalplaneassessedwithMRI.

Videofluoroscopy swallowing parametersVideofluoroscopy (VFS) is a validated method for objective assessment of all phases ofthe swallowing physiology1. The swallowing act was recorded in a lateral field of viewencompassingthelipsanteriorly,thecervicalvertebraeposteriorly,thesoftpalatesuperiorly,andthelowerendofthecervicalesophagusinferiorly.Theconsistenciesandamountsusedwere1,3,5,and10ccthinliquid,3and5ccpasteliquid,andaOmnipaquecoatedpieceofgingerbread.Subjectswere instructedtosipandwait foraverbalcuefromtheclinicalinvestigator before swallowing, with clear instructions to sip as usual, without excessiveforce. Theprimaryoutcomemeasurewas anterior/superiorHBD,which is definedas theanterior/superiordistancetraveledbythehyoidbonetothepointofmaximaldisplacementduring a swallow from its position during hold37, 38. Measures were done based on the methodsoftheseauthors,by‘subtracting’thestillofhyoidelevationstarttime(HEST)fromthatofmaximumhyoidelevationtime (MHET).HEST isdefinedas thetimebetween thefirstsuperior-anteriordisplacementof thehyoidbonethatresults inaswallowminusthetimeofthefirstmovementoftheheadoftheboluspasttheposteriornasalspine(onsetofpharyngealtransit).MHETisdefinedasthetimebetweentheframeinwhichthehyoidbonehadreached itsmaximumsuperior-anteriorexcursionduringtheswallow,andagainpharyngealtransitonsettime39.OtherVFSparametersassessedwerepresenceoflaryngealpenetrationand/oraspiration40,andoccurrenceofcontrastresidue.

Additional outcome parameters in the multidimensional assessment protocol weremouthopening, subjective swallowing complaints, and feasibility and compliance of/withtheSEAexercises.Maximummouthopeningwasmeasuredinmillimetersusingdisposable



7

TheraBiterangeofmotionscales.Subjectiveswallowingcomplaintswererecordedpre-andpost-trainingwiththe44-itemSwallowingQualityofLife(SWAL-QOL)questionnaire41,whichassesses patients’ swallowing impairment based on 10 QOL domains, each ranging from0–100withahigherscoreindicatingmoreimpairment.FeasibilityoftheSEAexercises(useof theexercise regimen, familiaritywith theexercises,andoccurrenceofadverseevents)wasmonitoredwithastudy-specificquestionnaire.CompliancewiththeSEAexerciseswasmonitoredwithtallysheetsinadailyexerciselog.

Imaging assessment proceduresBothMRIandVFSassessmentsweredonebytwoassessorsindependently:thefirstauthorandonededicatedheadandneckradiologist(forMRI;JT),ortheparticipatingSLP(forVFS;LvdM).ForMRI,bothassessorswereblindedtopre-orpost-interventionstatusoftheimage.Thedelineatedmusclevolumeswerereviewed inaconsensusmeeting,whilemaintainedblinding, and the consensus volumes were used in the analysis. For VFS categoricalmeasurements,asimilarblindedconsensusprocedurewasfollowed,inthisrespectwiththeparticipatingSLP.ForVFSanteriorandsuperiorHBDassessments,10%ofthemeasurements(stillsofall consistencies in lateral viewpre-andpost-intervention)were repeatedby thefirstauthor(asameasureofintraraterreliability)and10%werereviewedbytheSLP(asameasureof interrater reliability).Measurementsweredeemed inconcordance ifpairwisetestingshowedagreaterthan95%chanceofmeasuringstatisticallyindistinguishablevaluesin the two measurement sessions25.

Statistical analysesDescriptivestatisticsweregeneratedforalloutcomemeasures.Datafrommusclestrengthtests,IOPImeasurements,MRI,VFS,andquestionnairesofthetotalstudypopulationweresummarisedasmediansandmediandifferences,whereby95%confidenceintervalsforthemediandifferenceswereobtainedwithbootstrapping.Wilcoxonsignedranktestswereusedto compare the repeatedmeasurements. A two-sided p-value of 0.05was considered toindicatestatisticalsignificance.StatisticalanalysiswasperformedusingStatisticalPackageofSocialSciences(SPSS)softwareversion20.0.

RESULTS

For9subjects,thepost-interventionmultidimensionalevaluationprotocolwascarriedouttwodaysafterthe6-weekexerciseperiod.Inonesubject,thishadtobedonealreadyafterfour and a halfweeks since he had professional commitments abroad. All collected dataareshowninTable2. Inthefollowingparagraphsthemostrelevant/significantresultsaredescribed in more detail.

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146 | Chapter 7

Tabl

e 2.Datacollection

persub

jectbeforean

daft

erth

e6-wee

kexerciseperiod.

S01

S02

S03

S04

S05

S06

S07

S08

S09

S10

Med

ian

Med

ian

diffe

rence

95%CI

diffe

rence

p va

lue

Chintu

ckstrength(N

)Pr

e19

8,5

81,0

51,0

63,0

228,5

83,0

78,0

132,0

126,5

100,0

82.0

Post

242,4

99,2

93,4

118,1

238,9

142,4

112,5

152,3

132,0

189,5

132.0

38.5

20.3–5

9.4

p=.0

05Jawope

ning

strength(N

)Pr

e12

8,5

70,5

36,5

55,0

232,0

69,0

94,0

96,5

54,0

100,0

82.3

Post

229,8

117,0

87,8

107,9

283,4

145,0

102,1

125,4

120,0

189,5

122.

752

.128

.9–8

9.5

p=.0

05An

t.tong

uestrength(kPa)

Pre

70,5

54,5

57,0

55,0

74,5

58,5

45,5

49,0

60,0

57,5

57.4

Post

72,0

65,0

58,0

64,0

73,5

57,5

57,0

54,0

61,5

62,0

61.8

2.9

-1.0–9

.0p=

.016

Post. ton

guestrength(kPa)

Pre

75,0

75,5

57,5

64,0

63,5

47,0

49,5

47,5

56,0

53,5

56.8

Post

76,5

76,5

57,5

64,0

70,0

46,0

56,5

45,5

60,0

63,5

61.8

1.3

-1.0–7

.0p=.08

0An

t.tong

ueend

uran

ce(s)

Pre

4430

3031

2410

671

1927

2930

.0Po

st53

2961

3235

260

4116

4737

39.0

8.5

-3.0–2

0.0

p=.12

6Suprahyoidm

usclemass(cm

2 )Pr

e27

,3x

24,1

22,5

32,1

26,8

29,5

26,8

27,4

22,2

26.8

Post

29,5

x27

,523

,834

,332

,934

,129

,630

,823

,429

.62.

91.3–

4.6

p=.0

08Mou

thope

ning

(mm)

Pre

4267

5661

5249

6048

5146

51.5

Post

4270

5664

5253

6450

5252

52.5

2.5

0.0–

4.0

p=.0

18An

t.HBD

1ccth

inliq.(m

m)

Pre

8,19

13,57

7,76

12,33

10,14

9,73

12,6

9,98

9,47

8,83

9.9

Post

12,09

15,45

7,96

7,61

11,58

13,7

9,19

14,97

14,45

8,83

11.8

1.7

-3.4–2

.9p=.17

3Sup.HBD

1ccth

inliq.(m

m)

Pre

22,25

15,56

6,2

13,32

13,85

20,74

13,1

17,09

24,42

14,73

15.1

Post

14,33

22,35

15,05

14,4

22,71

15,91

28,72

9,56

27,36

27,69

19.1

4.9

-1.9–1

3.0

p=.16

9An

t.HBD

3ccth

inliq.(m

m)

Pre

8,62

11,58

8,28

11,35

12,18

9,3

14,61

11,87

8,97

13,03

11.5

Post

13,43

12,2

9,29

8,41

9,86

15,91

11,58

14,97

x11

,64

11.6

0.6

-2.9–3

.8p=.59

4Sup.HBD

3ccth

inliq.(m

m)

Pre

17,99

14,76

10,34

13,32

14,36

22,86

14,11

19,47

13,96

14,3

14.3

Post

12,53

21,13

14,61

12,4

22,71

16,35

25,93

4,57

x26

,49

16.3

4.3

-3.7–1

1.8

p=.59

4



7

Ant.HBD

5ccth

inliq.(m

m)

Pre

14,51

9,57

7,25

9,87

12,68

9,3

13,1

9,98

7,97

13,87

9.9

Post

14,78

11,79

10,18

9,6

13,71

15,46

12,78

15,8

13,42

11,64

13.1

1.6

-0.3–2

.6p=.09

3Sup.HBD

5ccth

inliq.(m

m)

Pre

21,97

19,55

4,14

15,3

13,85

28,78

20,15

12,35

14,45

13,04

14.9

Post

12,09

24,38

16,83

6,79

27,42

15,46

22,34

2,5

34,58

27,29

19.6

3.5

-9.9–1

3.5

p=.38

6An

t.HBD

10ccthinliq.(m

m)

Pre

15,84

10,78

8,8

11,35

14,7

9,73

15,62

8,08

6,97

13,03

11.1

Post

15,67

10,98

9,73

11,2

14,57

15,46

13,57

14,97

5,68

11,24

12.4

-0.1

-1.8–0

.6p=.95

9Sup.HBD

10ccthinliq.(m

m)

Pre

7,09

20,74

5,17

9,87

16,38

21,16

21,16

13,29

10,97

14,3

13.8

Post

13,88

28,44

16,83

11,6

27,42

16,35

30,33

026

,84

25,69

21.3

8.4

1.7–

11.4

p =.093

Ant.HBD

5ccth

ickliq.(mm)

Pre

13,76

10,38

9,31

15,3

20,79

9,3

15,12

9,5

9,47

15,98

12.1

Post

17,02

12,6

11,51

10,8

15,85

15,46

10,78

14,14

18,58

15,65

14.8

2.2

-4.5–3

.3p=.44

5Sup.HBD

5ccth

ickliq.(mm)

Pre

12,19

21,54

2,06

3,94

9,28

30,89

10,59

11,39

9,96

15,98

11.0

Post

6,27

24,38

13,72

8,8

23,99

18,56

21,55

025

,29

19,67

19.1

4.3

-4.3–1

1.3

p=.33

3An

t.HBD

pasteliq.(m

m)

Pre

14,38

11,18

8,28

13,82

19,27

11,85

11,59

12,35

11,97

17,66

12.2

Post

15,67

15,45

14,17

12,8

16,72

1912

,38

xx

18,06

15.6

1.0

-1.0–5

.1p=.16

1Sup.HBD

pasteliq.(m

m)

Pre

8,66

20,07

-0,49

11,71

15,55

19,69

12,92

7,21

8,04

8,79

10.8

Post

9,78

16,59

11,77

11,01

26,44

11,74

23,86

xx

19,44

14.9

6.2

-2.2–1

1.5

p=.16

1Hyoidelevatio

nstartti

me(s)

Pre

0,42

-0,36

-0,09

-0,03

-0,2

0,15

0,24

0,05

-0,13

0,17

0.04

Post

0,42

0,12

-0,07

0,34

0,31

0,33

0,23

0,42

0,07

0,13

0.22

0.1

-0.0–0

.4p=.09

3Max.hyoidelevatio

ntim

e(s)

Pre

1,16

0,57

0,55

1,03

0,71

0,76

0,68

0,84

0,43

0,85

0.77

Post

0,94

0,59

0,49

0,81

0,82

0,88

0,74

0,98

0,4

0,72

0.74

-0.1

-0.2–0

.0p=.24

1TotalSWAL

-QoLscore

Pre

22,9

8,9

01,8

47,1

7,1

016

,70

04.5

Post

22,9

29,5

01,8

56,0

7,1

066

,60

04.5

0.0

0.0–

10.3

p=.10

9

Abbreviatio

ns:S01

toS10

=su

bject1

tosu

bject1

0;CI=con

fiden

ceinterval;N

=New

ton;kPa=kilopa

scal;s=se

cond

s;cm2=cc=cub

iccen

timeters;m

m

=millim

eters;HBD

=hyoidbon

edisplacemen

t;an

t.=an

terio

r;sup.=sup

erior;liq.=

liqu

id;m

ax.=

maxim

um;SWAL

-QOLscore=Sw

allowingQua

lityof

Lifescore(a

highe

rscorem

eansworsequa

lityoflifebased

onsw

allowingfunctio

n);x=notavailable.

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148 | Chapter 7

Muscle strengthAfter6-weeksofswallowingtraining,medianchintuckstrengthsignificantlyincreasedwith38.5N(95%CI20.3to59.4N;p=.005),fromamedianof82.0Ntoamedianof132.0N.Themedianjawopeningstrengthsignificantlyincreasedwith52.1N(95%CI28.9to89.5N;p =.005),fromamedianof82.3Nto122.7N.TheindividualimprovementsarevisualizedinFigures5and6.

Figure 5. Changeinindividualmaximumchintuckstrengthafterthe6-weekexerciseperiod.

Tongue strength and enduranceMediananteriortonguestrength(IOPI)significantly increasedwith2.9kPa(95%CI-1.0to9.0kPa;p=.016),fromamedianof57.4kPatoamedianof61.8kPa.Therewasatrendforposteriortonguestrengthincreasewithamedianincreaseof1.3kPa(95%CI-1.0to7.0kPa;p=.080).Theincreaseinanteriortongueendurancewithamedianof8.5secondswasnotstatisticallysignificant(p=.126).



7

Figure 6. Changeinindividualmaximumjawopeningstrengthafterthe6-weekexerciseperiod.

Muscle volumeAfter 6-weeks of swallowing training,median suprahyoidmuscle volume (themylohyoid,geniohyoidandanteriorbellyofdigastricmusclescombined)significantlyincreasedwith2.9cm3(95%CI1.3to4.6cm3;p =.008),fromamedianof26.8cm3 to a median of 29.6 cm3. The individualimprovementsarevisualizedinFigure7.

VFS swallowing parameters AscanbeseeninTable1,HBDoutcomeswerequitevariableoverthevariousconsistenciesand subjects, anddid not differ significantly overtime.After the 6-week exercise period,HBDhadincreasedinparticularinthesuperiordirectioncomparedtotheanteriordirection.Asanexample, the lowest increasewasseenfora5cc thin liquidswallow(superiorHBDincreasedwithamedianof3.5mm)andthehighestincreasewasseenfora10ccthinliquidswallow (superior HBD increasedwith amedian of 8.4mm). At both assessment points,subjectsshowednormalswallowingfunctionontheVFS.Therewasnolaryngealpenetration/aspirationormorethannormalcontrastresidueseenaftertheswallow(thisappliedtoallconsistencies).Meanhyoidboneelevationstarttimeandhyoidbonemaximumelevationtimedidnotdiffersignificantlybetweenthetwoassessmentpoints(mediandifference0.1sand-0.1srespectively).

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150|Chapter7

Figure 7.Changeinindividualmusclevolumeofsuprahyoidmusclesafterthe6-weekexerciseperiod.

Additional outcome parametersAlthoughnone of the tested subjects had any swallowing complaints, trismus, or dietarylimitations,stillwefoundanincreaseinmouthopeningafterthetrainingprogram.Medianmaximal inter-incisoropeningsignificantly increasedwith2.5mm(95%CI0.0 to4.0mm;p =.018), fromamedianof51.5mmtoamedianof52.5mm.Therewereno subjectiveswallowing complaintsor adverseevents. Total durationof theexerciseswas reported tobe15to20minutes.FeasibilityoftheSEAexerciseswasconsideredacceptable, i.e.“timeconsuming,butdoable”.Outof129exercisesessions(3timesadayduring6weekswithoneadditionaldayattheendoftheexerciseperiod),mediancompliancewas86%(range48–100%).Exceptforonesubject,allparticipantshadatleastpracticed1sessionaday,andnoneoftheparticipantshadmissedmorethan2sessionsconsecutively.HalfoftheparticipantsaddedasecondActiveBandduringthe6weeksexerciseperiod,becauseofincreasedeaseof closing the chin bar onto the chest bar. None of the subjects reported unacceptablediscomfortorpainonthechest/chinorin/aroundtheirtemporomandibularjointduringtheexercises.



7

DISCUSSION

Thisprospectiveeffectivenessand feasibilitystudyontheeffectsof thisnewlyassembledSwallowExerciseAid (SEA), enabling chin tuck against resistance (CTAR) and jawopeningagainstresistance(JOAR)exercises,showsthatseniorhealthysubjectsareabletoimproveandincreaseswallowingmusclestrengthandvolumeaftera6-weektrainingperiod,evenattheabsenceofswallowingproblems.Theincreasesinmusclestrengtharehighlysignificantandpotentiallyclinicallyrelevant.Moreover,withamedianincreaseof38.5Nand52.1N,they exceedthepossiblemeasurementerrorassociatedwiththemeasurementsetup,whichwas17Nforchintuckstrengthand18Nforjawopeningstrengthinthissample,basedontheestablishedreliability.Therefore, theobserved increase inswallowingmusclestrengthcanbeattributedtothe6-weekexerciseregimenwithconfidence.Ontopofthat,subjects’anterior tongue strength andmouth opening significantly increased aswell. The positiveresultsfoundinthisstudywarrantatrialforthisSEAinheadandneckcancer(HNC)patientswithdysphagia.

The results found in this study are more or less in concordance with some earlier studies on strengthening the suprahyoidmusculature by JOAR and/or CTAR exercises, applied toimproveswallowingfunction.Wadaetal. investigatedtheeffectsof theJOARexerciseondecreasedupperesophagealsphincter(UES)openingonvideofluoroscopyineightpatientswithdysphagiawhileswallowing,andtheseauthorsfoundsignificantimprovementsintheextent of upward hyoid bonemovement, amount of UES opening and time for pharynxpassageafterfourweeksoftraining34.Althoughthatstudypopulationconsistedofonlyeightpatients andnoobjective assessment of suprahyoidmuscle strengthwas performed, thesignificantincreaseinupwardmovementofthehyoidbonefollowingfourweeksofpracticesuggests that the suprahyoidmusculature (especially themylohyoidmuscle and anteriorbellyofthedigastricmuscles)werestrengthened.Thiswouldbeinlinewiththesignificantimprovedsuprahyoidmusclestrength(andvolume)foundinthepresentstudyaftersixweeksofcomparableJOARandCTARexercises,althoughwedidnotfindasignificantincreaseinhyoid bone displacement (HBD),which is not surprising in this group of healthy subjectswithoutswallowingissues.

Asalreadybrieflymentionedintheintroduction,Yoonetal.recentlyinvestigatedtheCTARexerciseforbothisometricandisokinetictasksincomparisonwiththeShakerexercise,bymeasuringmaximumandmeansurfaceelectromyography(sEMG)activityofthesuprahyoidmuscles during the exercise regimen27. The CTAR exercisewas performed by tucking thechinashardaspossibleonarubberball,placedbetweenthechinandchest.BothexercisesresultedinelevatedmaximumandmeansEMGvalues,reflectingsuprahyoidmuscleactivity.Giventhefactthatsuprahyoidmuscleactivity/strengthisstronglycorrelatedwithhyoidbonedisplacement42andthusanimportantindicatorofswallowingfunction34,andgiventhefact

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152|Chapter7

thatsuprahyoidmusclestrengthsignificantlyimprovedinourstudy,itcanbeassumedthatthe CTAR and JOAR exerciseswith the SEA positively affect swallowing function too. Theobserved increased suprahyoid muscle volume contributes to this hypothesis. Compared to theShakerexercise,interestingly,Yoonetal.foundthattheCTARexercisewitharubberballresultedinsignificantlygreatermaximumandmeanactivationlevelsduringtheisometricandisokinetictasks,eventhoughitwasreportedaslessstrenuous.Thislatterfactmightfurtherincreasecompliancewiththeballexercise,asidefromtheadvantagethatnoinconvenientand uncomfortable supine position is needed, which also allows elderly/frail patients toperformtheexercisesbasedontheircurrentstrengthlevel27. The same holds true for the SEA,whichhas the additional advantageof usingoneor twoelastic siliconeActiveBandsto specifyand increase theamountof resistanceduring theexercises.Theclosureof thechinbarontothechestbarandtheoptiontoaddasecondelasticbandtofurtherincreaseresistancealsogivebiofeedbackforpatient’sperformance.Thislatterfactwasalsosupportedbyanecdotalfeedbackfromourvolunteers,andmightfurtherimprovesubjects’compliancewiththeexercises.However,thelackofastructuredprotocolforexerciseprogressionmayhaveresultedinasub-optimaltrainingeffect.Thisunderscoresthepotentialoftheexerciseregimen,giventhelargeeffectsizesthatweobservedinthisstudy.Infutureclinicalstudies,astructuredprescriptionforexerciseprogressionmayresultinevengreatergainsinmusclestrength.

Despite thephysiological rangeofmotionduringmouthopening,andthe fact thatallsubjectsalreadyshowedanormalmaximummouthopening(>35mm)atbaselinewithoutswallowing complaints or dietary limitations, therewas a small but statistically significantincreaseinmaximummouthopeningafterthe6-weekexerciseperiod.Afollowingtrial inHNCpatients(withdamagedswallowingmuscles)willevaluateifmaximummouthopeningcanalsoincreaseinthesepatients,followingsixweeksofswallowingtraining.

AlthoughsubmentalsEMGrecordingsarecommonlyusedinthefieldofdysphagiaresearchandmeasuredsEMGactivityisthoughttoreflectactionsofthesuprahyoidmusculature,wechosenot to record sEMGactivity. Themain reason is that it isnotpossible todelineatewhich individual muscle (i.e. mylohyoid, anterior belly of the digastric, geniohyoid, andgenioglossus)contributesmosttothederivedsEMGrecordings43.Instead,weusedmusclevolumemeasurementswithMRI,which provides information on possible hypertrophy ofthemusclesofinterest.Inaddition,MRImightbemoreusefulinaclinicalresearchsetting,becauseinmostpatientswithadvancedheadandneckcancerMRIsarereadilyavailablefordiagnosisandtreatmentresponseevaluation.

A limitationof thecurrent study is thatassessmentofmuscle functionwas limited tomaximalmusclestrengthfortheperformedexercises.Asaresult,wecannotbesurehowwelltheincreaseinswallowingmusclestrengthresultsinoverallbetterfunctionalswallowingability(duetopotentialspecificityeffects).Regardingtheliterature,maximalchin-tuckand



7

jaw-openingstrengthareassociatedwithbetterswallowingfunction27,34.However,tobetterunderstandhowtheseexercisesinfluenceswallowingfunction,futurestudiescouldincludemeasurements of lingua-palatal pressures produced during effortful and non-effortfulswallows.Furthermore, thesamplesizeof thispreliminary studywas limited to10highlymotivatedsubjects,therefore,theresultsshouldbeinterpretedwithsomecaution.

CONCLUSION

Thisprospectiveeffectivenessandfeasibilitytrialontheeffectsofchintuckagainstresistance(CTAR)andjawopeningagainstresistance(JOAR)isometricandisokineticstrengthexerciseson swallowingmusculature and function, shows that senior healthy subjects are able toimprove and increase swallowing muscle strength and volume after a 6-week period ofextensiveswallowingtraining.ThepositiveresultsfoundinthisstudywarrantatrialwiththisSEAinHNCpatientswithdysphagia.

ACKNOWLEDGEMENTS

Thisstudywasmadepossiblebygrantsprovidedby“StichtingdeHoop”andthe“VerweliusFoundation”. AtosMedical(Hörby,Sweden)isacknowledgedforprovidingtheTheraBitesandActiveBands,usedforthecustomizedSEAs.

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REFERENCES

1. Logemann JA. Evaluation and treatment ofswallowing disorders. Texas, Austin: Pro-ed(2nded);1998.

2. PerlmanAL, Schulze-Delrieu, K.S.Deglutitionand its disorders. San Diego: SingularPublishing;1997.


4. Lazarus CL, Logemann JA, Pauloski BR,Colangelo LA, Kahrilas PJ, Mittal BB, et al.Swallowing disorders in head and neckcancer patients treated with radiotherapyand adjuvant chemotherapy. Laryngoscope.1996;106:1157-66.

5. SmithRV,KotzT,BeitlerJJ,WadlerS.Long-termswallowingproblemsafterorganpreservationtherapy with concomitant radiation therapyand intravenous hydroxyurea: initialresults. Arch Otolaryngol Head Neck Surg.2000;126:384-9.



8. Lazarus CL, Logemann JA, Pauloski BR,Rademaker AW, Larson CR, Mittal BB, et al.Swallowing and tongue function followingtreatmentfororalandoropharyngealcancer.JSpeechLangHearRes.2000;43:1011-23.

9. RobbinsJ,KaysSA,GangnonRE,HindJA,HewittAL, Gentry LR, et al. The effects of lingualexercise in stroke patients with dysphagia.ArchPhysMedRehabil.2007;88:150-8.

10. Clark HM, Henson PA, BarberWD, StierwaltJA,SherrillM.Relationshipsamongsubjectiveand objective measures of tongue strength

andoralphaseswallowingimpairments.AmJSpeechLangPathol.2003;12:40-50.

11. Lazarus C. Tongue strength and exercisein healthy individuals and in head and neck cancer patients. Semin Speech Lang.2006;27:260-7.




15. vanderMolenL,vanRossumMA,BurkheadLM, Smeele LE, Rasch CR, Hilgers FJ. A randomized preventive rehabilitation trialin advanced head and neck cancer patientstreated with chemoradiotherapy: feasibility,compliance, and short-term effects.Dysphagia.2011;26:155-70.


17. van der Molen L, van Rossum MA, RaschCR, Smeele LE, Hilgers FJ. Two-year results of a prospective preventive swallowingrehabilitation trial in patients treated withchemoradiation for advanced head andneck cancer. Eur Arch Otorhinolaryngol.2014;271:1257-70.

18. Logemann JA, Pauloski BR, Rademaker AW,Colangelo LA. Super-supraglottic swallow inirradiated head and neck cancer patients.HeadNeck.1997;19:535-40.



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19. Lazarus C, Logemann JA, Gibbons P. Effectsof maneuvers on swallowing function in adysphagic oral cancer patient. Head Neck.1993;15:419-24.



22. KahrilasPJ,LogemannJA,KruglerC,FlanaganE.Volitionalaugmentationofupperesophagealsphincter opening during swallowing. Am JPhysiol.1991;260:G450-6.

23. ShakerR,KernM,BardanE,TaylorA,StewartET, Hoffmann RG, et al. Augmentation ofdeglutitive upper esophageal sphincteropening in the elderly by exercise. Am JPhysiol.1997;272:G1518-22.

24. Shaker R, Easterling C, Kern M, Nitschke T,Massey B, Daniels S, et al. Rehabilitation ofswallowing by exercise in tube-fed patientswith pharyngeal dysphagia secondary toabnormal UES opening. Gastroenterology.2002;122:1314-21.


26. Easterling C, Grande B, Kern M, Sears K,ShakerR.Attainingandmaintainingisometricand isokinetic goals of the Shaker exercise.Dysphagia.2005;20:133-8.


28. BuchbinderD,CurrivanRB,KaplanAJ,UrkenML. Mobilizationregimensforthepreventionof jaw hypomobility in the radiated patient:a comparison of three techniques. J OralMaxillofacSurg.1993;51:863-7.

29. Kraaijenga S, van derMolen L, van TinterenH,HilgersF,SmeeleL.Treatmentofmyogenictemporomandibular disorder: a prospectiverandomized clinical trial, comparing amechanical stretching device (TheraBite(R))with standard physical therapy exercise.Cranio.2014;32:208-16.

30. RinkelRN,Verdonck-deLeeuwIM,LangendijkJA,vanReijEJ,AaronsonNK,LeemansCR.The psychometric and clinical validity of the SWAL-QOL questionnaire in evaluating swallowingproblems experienced by patients withoral and oropharyngeal cancer. Oral Oncol.2009;45:e67-71.

31. Mehanna H, Paleri V, West CM, Nutting C.Headandneckcancer--Part1:Epidemiology,presentation, and prevention. BMJ.2010;341:c4684.

32. JemalA,BrayF,CenterMM,FerlayJ,WardE,FormanD.Globalcancerstatistics.CACancerJClin.2011;61:69-90.



35. Adams V, Mathisen B, Baines S, Lazarus C,Callister R. A systematic review and meta-analysisofmeasurementsoftongueandhandstrength andenduranceusing the IowaOralPerformance Instrument (IOPI). Dysphagia.2013;28:350-69.

36. HewittA,Hind J, Kays S,NicosiaM,Doyle J,Tompkins W, et al. Standardized instrumentforlingualpressuremeasurement.Dysphagia.2008;23:16-25.

37. LeonardRJ,KendallKA.Dysphagiaassessmentand treatment planning: a team approach.SanDiego:SingularPub.Group.;1997.


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39. Kendall KA, McKenzie S, Leonard RJ,GoncalvesMI,WalkerA.Timingofevents innormalswallowing:avideofluoroscopicstudy.Dysphagia.2000;15:74-83.


41. Lemmens J,BoursGJ, LimburgM,BeurskensAJ. The feasibility and test-retest reliability of the Dutch SWAL-QOL adapted interviewversion for dysphagic patients withcommunicative and/or cognitive problems.QualLifeRes.2013;22:891-5.

42. Crary MA, Carnaby Mann GD, GroherME. Biomechanical correlates of surface electromyography signals obtained duringswallowing by healthy adults. J Speech LangHearRes.2006;49:186-93.

43. Palmer PM, Luschei ES, Jaffe D, McCullochTM. Contributions of individual musclesto the submental surface electromyogramduring swallowing. J Speech Lang Hear Res.1999;42:1378-91.



7

Appendix I. SEAinstructieformulier

Oefeningen

Erkunnen3verschillendeoefeningenwordenuitgevoerdmetdeSwallowExerciseAid(SEA):

*Oefening 1 en 2bestaanuitbewegende(isokinetische)enstatische(isometrische)krachtoefeningen

- Debewegendeoefeningwordt30keerachterelkaaruitgevoerd(1keerperseconde)

- Destatischeoefeningwordt3keer(gedurende1minuutvasthouden)achterelkaaruitgevoerd

met1minuutrusttussendeoefeningen

*Oefening 3bestaatuiteenslikoefeningdie10keerwordtuitgevoerd

Alleoefeningenworden3keerperdagwordenuitgevoerd:’sochtends,’smiddagsen’savonds.

Alleswordtgedocumenteerdwordenophetdaarvoorbestemde‘PatiëntenLogboek’

Algemene instructies

- HoudtdeSEAindehandvanvoorkeur

- Schuif de ActiveBand naar de (vooraf bepaalde) positie, om een specifieke hoeveelheid

weerstandteverkrijgen

- Plaatsdeborststeun(‘chestbar’)ophetborstbeen,zonderveeldrukuitteoefenen

- Plaatsdekinopdebovenstekinsteun(‘chinbar’)

Figuur 1.DeSwallowExerciseAidmetActiveBand,‘chinbar’(kinsteun)en‘chestbar’(borststeun).

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158|Chapter7

Oefening 1 (7 min.)

- Plaats de borststeun op de borst zonder veeldrukuitteoefenen

- Plaatsdekinopdekinsteun

- Houdt demond gesloten en duwmet de kindekinsteunnaarbeneden,zodatdezecontactmaaktmetdeborststeun

Duur en hoeveelheid:

- Herhaal de oefening 30 keer, met een ritmevan 1 herhaling per seconde (= isokinetischeoefening)

- Houdtnuminimaal1minuutrust

- Herhaal de oefening en zorg ervoor dat dekinsteun gedurende 60 seconden contact maakt met de borststeun (= isometrischeoefening)

- Houdtweerminimaal1minuutrust

- Herhaaldezelaatsteoefeningnogtweekeer met daartussen steeds 1 minuut rust

Oefening 2 (7 min.)


- Plaatsdekinopdekinsteun

- Duw met de onderkaak de kinsteun naarbeneden,door de mond te openen,zodatdezecontactmaaktmetdeborststeun


- Herhaal de oefening 30 keer, met een ritmevan 1 herhaling per seconde (= isokinetischeoefening)

- Houdtnuminimaal1minuutrust

- Herhaal de oefening en zorg ervoor dat dekinsteun gedurende 60 seconden contact maakt met de borststeun (= isometrischeoefening)

- Houdtweerminimaal1minuutrust

- Herhaaldezelaatsteoefeningnogtweekeer met daartussen steeds 1 minuut rust

Oefening 1

Oefening 2



7

Oefening 3 (<1 min.)


- Plaats de kin/onderkaak op de bovenstekinsteun

- Houdtdemond open (tandennietopelkaar)maardelippengesloten

- Slikmetdelippengesloten,tegendeweerstandvan de SEA


- Herhaaldezeoefening10keer,metongeveereenritmevan1herhalingper2seconden

Oefening 3

170 mm

12,7 mm 10 mm

170 mm 60 mm

240

mm

boe

kenl

egge

r 230

mm



UITNODIGING










PARANIMFEN


SOPHIE KRAAIJENGA



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CHAPTER 8Efficacy of a novel swallowing exercise

program for chronic dysphagia in long-‐term

head and neck cancer survivors

S.A.C. Kraaijenga L. van der Molen M.M. Stuiver R.P. Takes

A. Al-‐Mamgani M.W.M. van den Brekel

F.J.M. Hilgers

Submi\ed.

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162 | Chapter 8

ABSTRACT

Background: Theefficacyofrehabilitativeexercisesforchronicdysphagiatreatmentinheadandneckcancer(HNC)survivorshasnotbeenstudiedextensivelyandisambiguous.

Methods:Aprospectiveclinicalphase2studyusinganintensivestrengthtrainingprogramwascarriedoutin18HNCsurvivorswithchronicdysphagia.Bothswallowandnon-swallowexerciseswereperformedfor6-8weekswithanewlydevelopedtoolallowingforprogressivemuscleoverload,includingchintuck,jawopening,andeffortfulswallowexercises.Outcomeparameterswerefeasibility,compliance,andparametersforeffect.

Results: Overallandspecificcompliancewiththe3dailyexercisesessionswere89%and97%,respectively.Afterthetrainingperiod,chintuck,jawopening,andanteriortonguestrengthhadsubstantiallyimproved.Allbutonepatientsreportedtobenefitfromtheexercises.

Conclusions: Feasibilityandcompliancewerehigh.Someobjectiveandsubjectiveeffectsofprogressiveloadonmusclestrengthandswallowingfunctioncouldbedemonstrated.

KEY WORDSHeadandNeckCancer–Deglutition–DeglutitionDisorders–Dysphagia–Rehabilitation–StrengthTraining–SwallowExerciseAid–ChinTuck–JawOpening


Strengtheningexercisesinlong-termheadandneckcancersurvivorswithchronicdysphagia|163

8

INTRODUCTION

Dysphagia is a significant complication in patients treated with radiotherapy (RT) orconcurrent chemoradiotherapy (CRT) for advanced head and neck cancer (HNC). It mayincreaseinseverityovertime,evenyearsaftertreatment,asaresultofprogressivefibrosisand/ornon-useatrophyfollowingradiationtotheswallowingmusculatureandstructures1-8. Givenitsassociatedmorbidityanddevastatingimpactonphysicalandemotionalwellbeing,thereisagreatdemandforaccurate,evidence-baseddysphagiamanagement9,10.GrowingevidencesupportsthebenefitofpreventiveswallowingtherapytoreducetheincidenceandseverityofdysphagiaafterCRT,althoughnotall studiesdemonstrateaneffectdependingon the chosen endpoints11-17. Moreover, also post-treatment swallowing rehabilitation ispotentially effective for reducing laryngeal penetration and/or aspiration in patientswithchronicdysphagia18-24.

Severalswallowinginterventionsareappliedfordysphagia,varyingfromcompensatorytechniques(e.g.posturalchanges,diet/bolusmodifications)torehabilitativetechniquesthataimtostrengthentheswallowingmusculature.Rehabilitativetechniquesincludeswallowingmaneuvers such as the effortful swallow25-27, and non-swallow exercises such as tonguestrengtheningexercisesandtheShaker(head-lift)exercise18,28.Swallowexercisesareusedduringtheswallowwiththeaimtoincreasethesuccessoftheswallowitselfbytrainingtheinvolved muscles25,29.Non-swallowexercisesaimtoimproverangeofmotionandstrengthoftheswallowingandneckmusculature(i.e.thetongueorsuprahyoidmusculature),whileallowingpatientstoprogressthroughatrainingprotocolsafely,withoutlimitationsthatmaybeimposedduringactualswallowing29.

Typically,repetitiveexercisesareusedbasedonmethodsappliedinsportsmedicine30-33. Theexercisesshouldbebuiltonallprinciples(i.e.specificity,individuality,andoverload)thatadhere to strengthorendurance training29,30,32-35. Swallowing is considereda submaximalmuscularactivity.Thismeansthatthemuscularstrengthgeneratedtosuccessfullycompletetheswallowingactislessthantheso-called1-repetitionmaximum(1RM),i.e.themaximalforcethatcanbegeneratedbytheswallowingmusclesinasinglerepetition30,32.Consequently,most strength training regimens startwith an initial resistance of 60–75% of 1RM19, 31, 36. Tomaximize improvementsovertime, theapplicationof theprogressivemuscleoverloadprincipleduringtheexerciseperiodhastobeanessentialpartofsuchatrainingregimen29,32,

35.Recently,LangmoreandPisegna(2015)reportedthatincreasingordecreasingtheresistiveloadofswallowingisstillanelusivechallenge35.

Basedonthepositiveexperienceswithajawmobilizationdevice(TheraBite®,AtosMedical,Sweden)thatshowedgoodcomplianceandcost-effectiveness13,37,recentlyanadapteddevicewas developed, that enables both swallow and non-swallow exercises. The device allowsadaptationtoindividualpatient’scapacity,andthusforapplyingprogressiveoverloadduring

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thetrainingprogram.Moreover,itprovidesadequatetactilefeedbackduringtheexercises,andvisualfeedbackontheresistancelevel38.TheeffectivenessandfeasibilityofthisSwallowExerciseAid(SEA)-basedexerciseregimenhasbeendemonstratedinaprospectivestudyinsenior healthy subjects38.Complianceappearedtobehigh(86%),andtherewasasignificantincreaseofswallowingmusclestrengthandvolume,anteriortonguestrength,andincreasedmouthopeningaftersixweeksofintensiveswallowingtraining.Althoughtheseresultsarepromising, it remainstobedemonstratedwhether inpatientswithchronicdysphagiathetargeted,oftenatrophiedand/orfibrosedmusclegroupsaretrainablewithsuchatool,andwhether increased strength indeed has an impact on swallowing function.Many studieshavetestedtheeffectsoftrainingonnormal,healthyindividuals39-42,butnotinpatientswithdysphagia35.Therefore,asanextstep,aprospectiveclinicalstudywasconductedinaHNCpatientcohortwithchronic,therapy-resistantdysphagia,withtheprimaryaimtoassessthefeasibilityandcompliance,andthesecondaryaimtoestablishtheshort-termefficacyofthisSEA-basedstrengthtrainingprotocol.


Thepresent studywasdesignedasamulticenter,uncontrolled,prospectiveclinicalphase2 study. The studywas undertaken at theDepartments ofHead andNeckOncology andSurgeryof theNetherlandsCancer Institute–AntonivanLeeuwenhoek (Amsterdam)andthe Radboud University Medical Center (Nijmegen), both in the Netherlands. The studywasapprovedbythelocalethicalcommitteesofbothinstitutes,andinformedconsentwasobtainedfromeachparticipantpriortoinclusion.ThestudyfollowedtheguidelinesoftheHelsinkiDeclaration.

PatientsDuring the enrolment period (November 2014–December 2015), patients with chronic,therapy-resistant dysphagia, and in complete remission after treatment with RT orconcurrentCRTforadvancedHNC,wererecruitedattheoutpatientclinicofbothinstitutes.Thedysphagiahadtobepersistentforatleast1year,despiteprevioustargetedswallowingexerciseprograms.Thediagnosisdysphagiawasbasedonthepresenceofpenetrationand/oraspiration(PAS≥4)onatleast1bolusonrecent(<3months)videofluoroscopy,and/oronaseriouslylimitedintakeofanormaldiet(FOIS≤4),i.e.feedingtubedependency.Attheendoftheenrolmentperiod,18patientswereincludedandsignedinformedconsent.Medianageatbaselinewas65years(range42–74years);medianweightwas69kg(range45–98kg);medianBMIwas22(range16-31).



8

TreatmentAllpatientshadcompletedafulldoseof60-70Gray(Gy)astargetvolumetotheprimarytumor,except foronepatient,whohadreceived treatmentwitha totaldoseof39Gyasplannedtargetvolume.Electivenodalareasweregivenatotaldoseof44Gy.Onepatientwasre-irradiatedandhadreceivedanadditionaldoseof46Gywithaboostto56Gyoneyearafterinitialtreatmentduetolocalrecurrence.Theprescribeddosewasdeliveredin30-35fractions,aseitherthree-dimensional(3D)conventionalradiotherapy(3D-RT)in8patients(44%),orasintensity-modulatedradiationtherapy(IMRT)in10patients(56%).Concurrentchemotherapywasgivenin8patients(44%).PatientstreatedsurgicallyforHNC,exceptforanykindofneckdissection,wereexcluded.Withamedianof119months(10years)post-treatment,patientswerewellpast thestagesof recoveryofacute toxicity. InTable1 thepatientandtreatmentcharacteristicsatbaselineareshown.

The Swallow Exercise Aid ThetechnicalandfunctionalfeaturesoftheSEAhavebeendescribedextensivelybefore38. In short,theSEAisconstructedonthebasisoftheTheraBiteJawMobilizationdevice,modifiedwithanaddedchestbartothelowermouthpiece(seeFigure1).ItiscomplementedwithanActiveBandthatcanbeplacedatvarious,markedpositionsaroundthehandle.Toincreaseresistance,theActiveBandcanbemovedperpositiontowardsthefinalposition6.TheforcerequiredforcompressingthechinbarontothechestbarwithoneActiveBandaroundthehandlerangesfrom4Newtoninposition1(minimalresistiveload)to50Newtoninposition6 (maximal resistive load; seeTable2). If required,a secondActiveBandcanbeadded tofurtherincreaseresistance.Thisconfigurationenablestheprogressiveoverloadneededforeffectivestrengthtraining32.

Figure 1. SwallowExerciseAid(SEA)withActiveBand,chintuckandjawopeningextension,chinbar,and chest bar.

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166 | Chapter 8

Tabl

e 1.Pati

ents’and

treatm

entc

haracteristi

csatb

aseline(n=1

8).

Patie

ntTu

mor

Trea

tmen

tNutriti

onalstatus

Pneu

mon

iaN

o.G

ende

rAg

eLocatio

nTN

MYear

RTDo

seCh

emo

FOIS

PRG

Weigh

tBM

I≥2

lastyr

1M

42O

roph

arynx

T4N

2c20

07IM

RT68

Gy

yes

1ye

s85

22,8

no

2M

71O

roph

arynx

T2N

119

873-D

60Gy

no6

no72

24,9

no3

M71

Paroti

cglan

dTxN

320

13IM

RT70

Gy

yes

1ye

s76

24,3

no

4M

58O

roph

arynx

T3N

2a20

08IM

RT70

Gy

yes

2ye

s45

16,1

yes

5M

71H

ypop

harynx

T1N

119

843-D

68 G

yno

1ye

s70

21,8

yes

6M

71 O

ral c

avity

T2N

119

843-D

60Gy

no4

no98

30,9

no7

M62

Oroph

arynx

T2N

020

14IM

RT66

Gy

no2

no72

21,7

no8

V60

Oroph

arynx

T3N

2c20

04IM

RT70

Gy

yes

6ye

s67

23,3

yes

9V

61H

ypop

harynx

T2N

120

04IM

RT70

Gy

yes

7no

4817

,2ye

s10

*M

65O

roph

arynx

T4N

320

14IM

RT68

Gy

yes

5no

5819

,6no

11M

69N

eckmetastasis

TxN

120

12IM

RT39

Gy

no6

no65

20,5

no12

*M

65H

ypop

harynx

T2N

120

073-D

68 G

yno

7no

6221

,6ye

s13

*M

74O

roph

arynx

T2N

020

033-D

68 G

yno

6no

6218

,1ye

s14

*V

67O

roph

arynx

T3N

2c20

003-D

68 G

yno

6no

7629

,7no

15*

M65

Larynx

T3N

2c20

023-D

68 G

yno

3ye

s76

24,0

yes

16M

46O

roph

arynx

T4N

220

11IM

RT70

Gy

yes

4no

8224

,0no

17V

72 O

ral c

avity

T2N

019

993-D

60Gy

no6

no59

21,2

yes

18V

65N

asop

harynx

T2N

120

11IM

RT70

Gy

yes

6no

6823

,0no

Note:pati

entsin

dicatedbyadot(*

)wereinclud

edatthe

Rad

boud

University

;allothe

rpa

tientswereinclud

edatthe

Nethe

rland

sCa

ncerIn

stitute.

Abbreviatio

ns:TNM=Tum

orNod

eMetastasis

;RT=Ra

diothe

rapy;IMRT

=In

tensity-M

odulated

Rad

iotherap

y;3-D=Three

-Dim

ensio

nalR

adiotherap

y;

FOIS=Fun

ction

alOralIntakeScale;PRG

=Percutane

ousRa

diolog

icGastrostomy;BMI=Bod

yMassInde

x;yr=

year.



8

Table 2. EstimatedresistanceinNewtonatvariouspositionsoftheActiveBand.

Baselinechintuckstrength(1RM)

PositionofActiveBand Estimatedresistance(60–70%of1RM)

0–12N 1 1–8N13–24N 2 9–16N25–36N 3 17–25N37–50N 4 26–34N51–65N 5 35–44N66–80N 6 45–54N

Abbreviations:1RM=onerepetitionmaximum;N=Newton.

InterventionThe trainingprogram consists of three (non-swallowand swallow) exercises, visualized inFigure2:

Figure 2.SwallowingExerciseAid (SEA)exercises (printedwithpermissionofpatient).Top left:startposition;topright:exercise1;chintuckagainstresistance(CTAR)exercise;bottomleft:exercise2;jawopeningagainstresistance(JOAR)exercise;bottomright:exercise3;effortfulswallowexercisewith50%ofmaximumclosure.

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168 | Chapter 8

Thefirstexercise,thechintuckagainstresistance(CTAR)exercise,isperformedbypressingthechindownwardsagainstthechinbar,whilekeepingthemouthclosed,untilthechinbarreachesthechestbarattachment(providingtactile feedback).Thisexercise–comparableto the Shaker18,25, 28 andanotherCTARexercise43 – is directedat the suprahyoidmuscles,andaimsatimprovementofhyolaryngealelevationandupperoesophagealsphincter(UES)opening.

The secondexercise, the jawopeningagainst resistance (JOAR)exercise, isperformedbypressingthemandibledownwhileopeningthemouth,againcompressingthechinbaragainst the chest bar. This exercise targets the jaw opening musculature, including thesuprahyoidmuscles,andaimsatimprovementofhyoidelevation,amountofUESopening,andtimeforpharynxpassage23.

Thethirdexercise,theeffortfulswallowexercise,isperformedwiththechinplacedonthechinbar(presseddownwardsfor50%),wherebythesubjectsswallowwiththemandibledown and mouth closed, comparable to the formerly described TheraBite swallowingexercise13. This exercise is hypothesized to also stimulate the pharyngealmusculature, toincreasetonguebaseretractionanddecreasetheamountofpharyngealresidue,comparabletoaneffortfulswallow25-27.

Exercise protocolPrior to participation, the patients visited the clinical investigator and received a writteninstructionsheet.Toallowfor thecalculationof test-retest reliabilityof thechintuckandjaw opening strengthmeasurements,muscle strength testingwas performed during thatfirstvisit.Aftera3-week interval, thepatientsagainvisitedthe investigator for theactualinstructionvisit,andtheyreceivedthenecessaryinstruments.TheywereinstructedtoholdtheSEAintheirpreferredhand,toplacethechestbarontothesternumwithoutexcessivepressure,andtoplacethechinontothechinbar.Subsequently,allbaselinemeasurementswereperformed, includingthemusclestrengthtests.TheActiveBandwasthenplacedontheappropriatepositionof thedevice, toensureaspecifiedamountof resistance,basedonthemostrecentchintuckstrength(seeTable2).TheindividualstartingpositionoftheActiveBand was determined following the principle of 1-repetition maximum (1RM), i.e.forthisstudythemaximumchintuckstrengthassessedatbaseline(seebelow).Aforceofapproximately60–70%ofthe1RMwasusedasinitialresistance32.Subsequently,progressionofintensitywasbaseduponinterimstrengthmeasurementsandself-perceivedexertion.

Comparablewith the Shaker exercise28, theCTARand JOARexerciseswereperformedbothasisometricandisokineticexercises.Theisokineticexerciseswereperformed30timesconsecutivelyatafixedpaceof1spercontraction,withtheaimtoimprovemaximalmusclestrength32.Theisometricexerciseswereperformedthreetimes,maintainedfor60s,witha60srestperiodbetweeneachofthethree,withtheaimtoimproveenduranceofsustained



8

muscle activity32. These two exerciseswere carried out first,with 60s rest between eachsession.Subsequently,theeffortfulswallowexercisewasperformed10timesconsecutivelyasanisokineticflexion,afteranother60srestperiod.Thetotaldurationofthethreeexercisesis25minutespersession38.

AllpatientswereaskedtoperformtheSEAexercisesthreetimesdailyforatleast6andmaximum8weeks,whichisbasedonBurkheadetal.(2007),whosuggestedthatatleast5weeksofstrengthtrainingareneededbeforeameaningfulgaininstrengthinskeletalmusclescan be achieved32.Duringtheexerciseperiod,thepatientsvisitedtheclinicalinvestigatorformid-termevaluations(includingmusclestrengthtests)afterthefirstweek,andsubsequentlyevery2weeks.Patientswereaskedtorecordtheirperformancesbyusingtallysheetsinaspecialexerciselog(seeAppendixI).Whenpatientsfelttheexercisesbecametooeasy,theywereallowedtoadvancetheActiveBandtothenextpositioninconsultationwiththeclinicalinvestigator.Patientswereinstructedtoceasetheexercisesiftheyfeltdiscomfortorpainonthechest/chinorin/aroundtheirtemporomandibularjointduringtheexercises.

Multidimensional assessment Theoutcomeparameterswere recordedprior toparticipation (atbaseline) and twodaysafter thepracticeperiod (post-training).Primaryoutcomeparameterswere feasibilityandcompliance of this SEA-based strength training protocol in this HNC patient cohort withchronicdysphagia.Secondaryoutcomemeasureswereparameterstoobtainanestimateofeffect:maximumchintuckandmaximumjawopeningstrength,maximumtonguestrength/endurance,maximummouthopening,presenceoflaryngealpenetrationoraspiration,oralintake, hyoid bone displacement, subjective swallowing complaints, and general healthstatus.

Feasibility and complianceFeasibilityoftheSEAexercises(e.g.easeofhandlingofthedevice,practicalityoftheexerciseregimen,familiaritywiththeexercises,occurrenceofadverseevents)wasmonitoredwithastudy-specificquestionnaire(seeAppendix II foratranslationinEnglish).CompliancewiththeSEAexerciseswasmonitoredinterimbytheclinicalinvestigatorandatthepost-treatmentassessmentpointwithtallysheetsfromthedailyexerciselog(AppendixI).

Swallowing muscle strengthMuscle strengths for chin tuck and jaw opening weremeasured in Newton (N), using a‘handheld’dynamometer(MicrofetTM,Biometrics,Almere,theNetherlands)mountedintoanadaptedophthalmicexamination frame (seeFigure3), toavoidvariations inheadandchin position and to ensure consistent compression38. A superior fixed belt stabilized thepatient’shead,andtheheightofboththechinrestandthesuperiorbeltcouldbeadjusted

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170|Chapter8

tothepatient’sdimensions.Patientswereinstructedtositstraight,andtopresstheirchindownonthedynamometeraspowerfulaspossible,oncewiththeirmouthandteethclosed(liketheCTARexercise),andoncebyopeningtheirjaw/mouth(liketheJOARexercise).Bothmeasurementswereprecededbyone familiarizationsession, inorder toexclude learningcurve effects and to improve reliability of the values obtained44. After the familiarizationsession, both measurements were repeated three times, with a 60-seconds rest periodbetweenthetrials.Themeanmaximumpressureofthehighesttwoofthreevalueswasusedasthepatients’maximumchintuck/jawopeningstrength44.

Test-retestreliabilitycoefficients(ICC(3,2))forthisset-upwere0.89(95%CI0.70–0.93)formaximalchintuckstrength,and0.97(95%CI0.90–0.99)formaximaljawopeningstrength,inthese18patients.Thisimpliesasmallestdetectablechange(SDC)of15Nforchintuckstrengthand7.5Nforjawopeningstrengthinthissample.

Figure 3.Musclestrengthtestset-upwithanadaptedophthalmicexaminationframeandadynamometer(MicrofetTM)fixedatthechinrest(printedwithpermissionofpatient).Left:measurement1(mouthclosed, comparable to CTAR exercise); right:measurement 2 (mouth opened, comparable to JOARexercise).Note: ifpatients feelmorecomfortable,during the JOARexercise theymayalsohold thehandle bars.

Tongue strength and enduranceThe Iowa Oral Performance Instrument (IOPI) was used to measure maximum tonguepressures(atanteriorandposteriorlocations)andendurancebymeansofasmallair-filledbulb32,45.Patientshadtopresstheirtongueupwardsontheair-filledbulb,inordertosqueezethebulbagainstthehardpalate.PressureswereexpressedinkPaanddigitallydisplayedonthedevice.Afteronefamiliarizationsession,threetrialsofmaximum(anteriorandposterior)



8

tonguepressurewereobtainedforeachpatient,witha2-minuterestperiodbetweenthetrials. Themeanmaximum pressure of the highest two of three valueswas used as thepatients’ maximal (anterior/posterior) tongue strength. Also endurance measures wereanalysedatanteriortonguelocationfollowingthestrengthtask,afterabreakofatleast5minutes.Patientswereaskedtomaintain50%oftheirmaximaltonguestrengthaslongaspossible.

VideofluoroscopyVideofluoroscopy(VFS)wasusedforobjectiveassessmentofallphasesof theswallowingphysiologyaccording to theprotocolof Logemannetal. (1998)46. Inbrief, the swallowingactwasrecordedinuprightpositioninalateralfieldofview.Theconsistenciesandamountsusedwere3and10ccthinliquid,5ccthickenedliquid,andanOmnipaquecoatedpieceofgingerbread.Eachboluswasrepeatedtwice,resultinginatotalof8swallowsperpatientperassessment.

SwallowingfunctionwasevaluatedwiththevalidatedPenetrationAspirationScale(PAS)score47,rangingfrom1–8(score1:materialdoesnotentertheairway,toscore8:materialenterstheairway,passesbelowthevocalfolds,andnoeffortismadetoeject).Ifapatientaspiratedon2consecutivebolusesofthinliquidofthesamevolume,largervolumesofthinliquidwerenotadministeredanymore.Similarly,ifbolusesofmoresolidfoodweredeemednot to be safe (i.e. high likelihood of severe aspiration), these boluseswere avoided. AllbolusesdeemedtobeunsafeweregivenaPASscoreof824. Overall median PAS scores and median PAS scores per consistency were calculated24.OtherVFSparameterssuchaspresenceofcontrastresidueandanterior/superiorhyoidbonedisplacementwerealsoassessed48,49. Theoverall ‘presenceof residue’ score ranges from0–3 (score0: no residue, to score3:residueaboveandbelowthevallecula,withminimalresiduejudgedasnormal)46,50.

PASandamountofresiduescoreswerescoredbytwoevaluatorsindependently:thefirstauthorandtheparticipatingSLP.Bothevaluatorswereblindedtopre-orpost-interventionstatusoftheswallowstudy.Subsequently,thescoreswerereviewedinaconsensusmeeting,undermaintainedblinding,andtheconsensusscoreswereusedforanalysis.Forhyoidbonedisplacement,10%ofthemeasurements(stillsofallconsistencies in lateralviewpre-andpost-intervention)wererepeatedbythefirstauthor(toassessintraraterreliability),and10%werereviewedbytheSLP(toassessinterraterreliability).Measurementsweredeemedinconcordance ifpairwisetestingshowedagreaterthan95%chanceofmeasuringclinicallyindistinguishablevaluesinthetwomeasurementsessions22,38.

Oral intake and nutritional statusOralintakewasassessedwiththeFunctionalOralIntakeScale(FOIS)andnutritionalstatuswithBMIandweightchange.TheFOISrangesfrom1–7withscore1:nothingbymouth,toscore7:totaloraldietwithoutrestrictions.

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Mouth openingMaximummouthopeningwasmeasuredinmillimeterswiththedisposableTheraBiterangeofmotionscale.Twomeasurementswereperformedatbothassessmentpoints,withthehighestvaluerecordedasthemaximummouthopening.TrismuswasdefinedasaMIOof≤35mm51.

Patient-reported outcomesSubjectiveswallowingcomplaintswere recordedpre-andpost-trainingwith thevalidatedDutch version of the 44-item SwallowingQuality of Life (SWAL-QOL) questionnaire52. The SWAL-QOLassessespatients’ swallowing impairmentbasedon10qualityof lifedomains,each ranging from0–100withahigher score indicatingmore impairment. Feasibilityandcompliancewereassessedwithastructuredstudy-specificquestionnaire(seeAppendixIIfortheEnglishtranslationofthisquestionnaire).Thestudy-specificquestionnairealsocontainedaratingofglobalperceivedbenefit,andanopenquestiontospecifywhattheexperiencedbenefitwas.Additionally,healthstatuswasassessedwiththeEQ-5Dquestionnairetoprovideasimple,genericmeasureofhealthforclinicalandeconomicappraisal53. TheEQ-5Dconsistsofadescriptivesystemcomprisingfivedimensions(mobility,self-care,usualactivities,pain/discomfortandanxiety/depression)withthreelevels(noproblems,someproblems,severeproblems)foreachdimension,andavisualanaloguescale(VAS)recordingtherespondent’sself-ratedhealthonaverticalVASrangingfrom0to10053.

Statistical analysesTheaimedsamplesizewas20HNCpatients,basedonthepreviousimprovements(cohen’sd>0.6)demonstratedinthehealthyvolunteersample38.Inthisway,thestudywouldhave80%powertodetectaneffectsize(cohen’sd)of0.70withapowerof80%andanalphaof0.05,whileallowingfora10%attritionrate,usingapairedt-test.Foralloutcomemeasuresdescriptivestatisticsweregenerated.Datafrommusclestrengthtests,IOPImeasurements,VFS,mouthopening,andquestionnairesofthetotalstudypopulationweresummarisedasmediansandmediandifferences,with95%confidenceintervalsforthemediandifferencesobtainedwithbootstrapping.StatisticalanalysiswasperformedusingStatisticalPackageofSocialSciences(SPSS)softwareversion23.0.

RESULTS

Although the aimwas to include 20 patients, due to the strict inclusion criteria only 18patientscouldbeincludedduringtheplannedstudyperiodof1year.Ofthese18patients,twopatientswithdrewfromthestudy.Onepatientdecidedtowithdrawfromthestudyafter



8

the second baseline assessment point, before starting the exercise program. The secondpatientdecidedtoresignfromthestudyafter3weeksofexerciseduetosubstantialpainaroundthetemporomandibularjointduringtheexercises.Therewasnoobvioussubstrateforthatdiscomfort,butthepatientstilloptedout.Atthefinalcheckatthesecondbaselineassessmentpoint,athirdpatientappearedtonotmeettheinclusioncriteria,becausesheonlyhadslightlyaffectedoralintake(FOISscore:6)andnopenetration/aspirationdemonstratedduringVFSassessment.Shestilloptedtocompletetheprogram,butwasexcludedforfurthereffectanalysis.Hence,16patientscompletedtheexerciseprogram,resultinginanoverallcomplianceof89%,butonly15patientswereincludedforfurthereffectanalysis.AllcollecteddataareshowninTable3and4.Inthefollowingparagraphsthemostrelevantresults(n=15)are described in more detail.

Feasibility and compliancePatientsexecuted,asintended,theexercisesminimally6andmaximally8weeks(mean:47days,median:45days,range:40–56days).Allbutonepatienthadpracticedatleast1sessiondailyduringtheexerciseperiod.Thetotaldurationoftheexerciseswasreportedtobe20–30minutespersession.Thepatientswerefamiliarwiththeexercisesafteramedianof1week.Onepatientreportedtheexercisesas ‘veryunpleasant’,4patientsas ‘abitunpleasant’,8patientsas‘neitherpleasantnorunpleasant’,and2patientsas‘abitpleasant’.Themediancomplianceintermsofthe3dailyexercisesessionswas97%(range86–100%).Atthestartoftreatment,6patientsreported(some)musclepainaroundtheirtemporomandibularjointsduringtheexercises,whichdisappearedwithin1houraftercompletingtheexercisesinallofthem.Therewasonepatientwithanepisodeofaspirationpneumoniaduringthefirstweekof the trial period.

Muscle strength Allpatientsstartedatposition2–4oftheActiveBandandallbutthree(#4,#8and#9)hadultimatelyreachedposition6.Twopatients(#2and#7)wereabletogopastposition6byaddingasecondActiveBandtofurtherincreaseresistiveload.Attheendoftreatment,anincreaseinmedianchintuckstrengthof13.5N(95%CI2.0–29.5N)wasobserved,fromamedianof31.5N(95%CI6.8–45.4N)atbaselinetoamedianof49.5N(95%CI11.8–71.5N)post-treatment(effectsizewithcohen’sd=0.7).Themedianjawopeningstrengthincreasedwith22N(95%CI11.0–35.3N),fromamedianof21.5N(95%CI10.5–28.0N)atbaselinetoamedianof43.5N(95%CI27.3–57.5N)attheendoftreatment(cohen’sd=1.8).TheindividualimprovementsarevisualizedinFigures4and5.

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174 | Chapter 8

0

10

20

30

40

50

60

70

80

90

100

Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8

Strength

(N)

Chin Tuck Against Resistance (CTAR)

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Patient 9

Patient 10

Patient 11

Patient 12

Patient 13

Patient 14

Patient 15

Figure 4. Changeinindividualmaximumchintuckstrengthafterthe6to8-weeksexerciseperiod.

0

20

40

60

80

100

120

Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8

Stre

ngth

(N)

Jaw Opening Against Resistance (JOAR)

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Patient 9

Patient 10

Patient 11

Patient 12

Patient 13

Patient 14

Patient 15

Figure 5. Changeinindividualmaximumjawopeningstrengthafterthe6to8-weeksexerciseperiod.



8

Tongue strength and enduranceMediananteriortonguestrength(IOPI) increasedwith3.0kPa(95%CI0–6.5kPa), fromamedian of 34.5 kPa (95%CI 30.5–42.3 kPa) at baseline to amedian of 40.0 kPa (95%CI32.5–49.3kPa)attheendoftreatment.Therewerenomeaningfulimprovementsobservedforposteriortonguestrength,oranteriortongueendurance.

Swallowing and mouth openingForthickenedliquidswallows,thePASscorehadclinicallyimprovedin5patients(33%):fromaspirationtopenetrationin3patients(#5,#10,and#12),andfromaspiration/penetrationto normal swallowing in 2 patients (#9 and #15; Table 4). The PAS scores had clinicallydeterioratedin3patients(#6,#7,and#11;20%).ThemeanPASscoreforthickenedliquidswallows showed a small tomoderate effect size (cohen’s d = 0.3). No clinically relevantimprovements in other consistencies were observed. There were also no improvements in anterior or superior hyoid bone displacement for the various consistencies used. Based on theFOISscores,oralintakehadimprovedin4patients(#2,#6,#10,#13),andhadstayedthesameintheremaining11patients.Therewerealso4patientswhohadgainedsomeweightfollowingtheexerciseperiod (#2,#8,#12,and#15;Table4),whereas2patientshad lostsomeweight(#4and#14).Mouthopeninghadslightlyincreasedwithamedianof1.0mmafterthetrainingprogram(95%CI0–1.0mm).

Patient-reported outcomesResultsoftheSWAL-QOLquestionnaire,dividedpersubdomainareshowninTable4.Overall,nomajor improvements at the post-treatment assessment point were observed. After amedianof3weeks,14outof15patients reported tobenefit fromtheexercises, varyingfrom‘a littlebit’(n=6),to‘quiteabit’(n=7),andto‘a lot’(n=1).Patientsmainlyreportedmoreconfidenceandeaseduringswallowing(somepatientshadactuallytriedtoeatmeatorbreadagain),andlesscoughing/chokingduringameal.

Patients’overallself-ratedhealth,asassessedwiththeEQ-5Dquestionnaire,showedasmallimprovementfromamedianof70toamedianof75aftertreatment.Therewerenoimprovementsononeofthefivedimensionsofthisquestionnaire.

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176 | Chapter 8

Table 3. Strengthtrainingdataperpatientbeforeandafterthetrainingperiod.Note:patient#2and#7wereabletoaddasecondActiveBandon(position2of)theSEAattheendoftheexerciseperiod.ThepositionoftheActiveBandwasspecifiedforexercise1and2.Forexercise3thesameresistanceasusedforexercise2wasapplied.

Patient ActiveBand Swallowingmusclestrength Tonguestrength&endurance MouthopeningPosition CTAR(N) JOAR(N) Anterior(kPa) Posterior(kPa) Endurance(s) MIO(mm)

1 Pre 4 - 3 40.0 25.0 34.5 37.0 22 21Post 6-5 71.5 55.5 47.0 48.0 29 21

2 Pre 4 - 4 46.5 48.5 32.5 29.5 48 40Post 6*-6* 84.0 108.5 34.0 29.0 43 41

3 Pre 4 - 2 45.5 16,0 33.5 28.5 44 15Post 6 - 6 92.5 34.5 40.0 37.5 28 15

4 Pre 2 - 2 0 0 39.5 35.0 55 20Post 4 - 4 0 0 65.0 32.0 51 21

5 Pre 3 - 3 33.5 25.0 39.0 35.0 20 38Post 6 - 6 63.0 103.0 42.0 36.5 25 37

6 Pre 2 - 2 8.5 17.0 48.5 30.5 12 37Post 5-6 33.0 57.5 43.0 41.5 42 38

7 Pre 6 - 4 71.5 47.0 66.0 52.5 36 54Post 6*-6* 85.0 84.5 69.0 38.5 38 55

8 Pre 1 - 2 4.5 13.0 15.5 14.0 40 37Post 5-5.5 6.0 21.5 17.0 15.5 41 35

9 Pre 1 - 2 0.5 7.5 45.0 42.0 37 48Post 5-5 2.0 7.0 51.5 47.5 51 51

10 Pre 3 - 4 31.5 38.0 18.0 10.5 22 29Post 6 - 6 49.5 51.5 15.5 12.5 34 30

11 Pre 3 - 3 29.0 28.0 35.5 12.5 5 51Post 6-5 37.5 32.5 35.5 10.0 3 54

12 Pre 4 - 3 59.0 21.5 30.5 31.0 11 33Post 6-5 69.5 43.5 32.5 29.0 11 33

13 Pre 4 - 2 39.5 10.5 63.0 47.0 14 31Post 6-5 56.0 43.5 70.0 53.5 12 40

14 Pre 3 - 2 5.0 2.0 27.5 25.5 12 20Post 6 - 6 7.5 22.0 22.5 28.5 37 21

15 Pre 3 - 2 21.5 22.5 31.0 33.0 31 42Post 6-5.5 16.0 52.0 36.5 40.5 30 43

Median(95%CI)pre 31.5(7–45) 21.5(11–28) 34.5(31–42) 31(27–36) 22(12–39) 37(25–41)

Median(95%CI)post 49.5(12–72) 43.5(27–58) 40.0(33–49) 36.5(29–42) 34(27–42) 37(26–42)

Median(95%CI)change 13.5(2–30) 22.0(11–35) 3.0(0–7) 2.0(-1–8) 1.0(-2.0–9.5) 1.0(0–1.0)

Abbreviations:CTAR=ChinTuckAgainstResistance; JOAR= JawOpeningAgainstResistance;ANT=anterior;POST=posterior;END=endurance;MIO=MaximalInterincisorOpening;N=Newton;kPa=kilopascal;s=seconds;mm=millimetres;CI=ConfidenceInterval.



8

Tabl

e 4.VFS,n

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on,and

pati

ent-rep

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allowingfunctio

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178 | Chapter 8

DISCUSSION

Thisstudyprospectively investigatedthefeasibility,compliance,andshort-termefficacyofanintensivestrengthtrainingprotocolwithadedicatedSwallowExerciseAid(SEA)inHNCpatientswithchronicdysphagiaaftertreatmentwith(chemo-)radiotherapy,whohadbeenrefractoryforusualcare.Regardingthefirstaimofthestudy,theresultsshowedthattheexerciseswere indeed feasible in the current patient cohortwith often atrophied and/orfibrosedswallowingmuscles,withalmostallpatientsexecutingtheexercisesaccordingtotheprotocol.Thepatientswerealsocompliantwiththeprescribedexercises.Despitetheirlong-lastingdysphagia,theywereeagertoparticipate,resultinginhighoverallcompliance(89%), andhigh compliancewith regards to the setdaily exercise sessions (97%). The15evaluatedpatientshadmissedonly0to14%(median3%)ofthetargetednumberofexercisesessions.Themajorityofpatientsevencontinuedpracticingafterthestudyperiod,becausetheyexperiencedclinicalbenefits(i.e.moreconfidenceandeaseduringswallowing/eating)sincetheyhadstartedtheirexercises.Theclosureofthechinbarontothechestbarandtheoptiontoincreaseresistancewiththisbandgavebiofeedbackforpatient’sperformance.Thiswassupportedbyanecdotalfeedbackfromourpatients,andisastrongpointofthedevice,sinceitimprovespatients’compliancewiththeexercises38.

Secondly,withrespecttotheshort-termefficacyofthisSEA-basedexerciseregimen,itcanbeconcludedthattheswallowingmusclesarestilltrainable.Resultsofthestrengthtestsshowedsubstantialimprovementsinstrengthofthetrainedmusclesinalmostallpatients,withamedianincreaseof13.5Nforchintuckstrength,21.5Nforjawopeningstrength,and3.0kPa foranterior tonguestrength.Thiscoincideswellwith theobservation thatallbutthreepatientshadbeenabletoultimatelyreachposition6oftheActiveBand,withtwoofthembeingabletoaddasecondband.

Itshouldbenoted,though,thattheposteriortonguestrengthdidnotincreasemuch,andthatthemedianincreaseinchintuckstrengthof13.5Nisjustbelowthesmallestdetectablechange (SDC) of 15N, based on the established reliability, implicating that the observedincreaseinchintuckstrengthcannotbeattributedtotheexerciseregimenwithcompleteconfidence. Three patients (#4, #8, and #9) showed no major improvements in musclestrength.Their scores remainedbelow10N, and theywere considered ‘non-responders’.However,halfofthepatientsachievedanincreaseinchintuckstrengththatwellexceededtheSDC,andthemedianincreaseinjawopeningstrengthof22NiswellabovetheSDCof7.5Nforthistest,which indicatesthatthis increase isconfidentlyattributabletotheSEAexercises.AscomparedtotheformerlyICCvaluesobtainedfromhealthysubjects38,thetest-retestreliabilityofthemusclestrengthassessmentsetupinthecurrentpatientpopulationwas good.Hence, the current ICC values indicate that themuscle strengthmeasurementprocedureishighlyreliableandsuitableforfutureuseinindividualpatients.



8

Interestingly, themedian strengthsof31.5and49.5N for chin tuckand jawopening,respectively, at the post-treatment assessment point were still considerably lower thanthe>80Nachievedby10healthy subjects at thepre-treatmentassessmentpoint inourprevious study38.Thiswasalsodemonstrated formaximumanteriorandposterior tonguestrength,withmaximumvaluesof36.5to40kPainourHNCpatientcohort,ascomparedtovaluesof>60kPainhealthysubjects38.Thisclearlyunderlinesthatdamaged,atrophiedand/orfibrosedmusclesduetoradiationloose(partof)theirfunction.Onecouldquestionwhether6to8weeksofstrengthtrainingisenoughtoachievesufficientincreaseinmusclestrengthforclinical improvements inthese(oftenfeedingtubedependent)patientsmorethan10-yearspost-treatment.Ontheotherhand,mostincreaseinmusclestrengthintheindividualpatientswasobservedinthefirstweeksoftreatment.Inparticularinthisstage,central andneuromuscularadaptations (andnotyethypertrophy)dooccur.Thequestionisthereforewhetherongoingtrainingwill leadtoafurtherincreaseinmusclestrength,orwhetheraplateauwillbereachedafteroptimizationoftheremainingmusclefunction.Atleast,thepresentstudyshowsthatthesedamagedmusclesare,uptoacertainpoint,stilltrainable.

To date, there are no large clinical trials that have studied and proven efficacy forrehabilitative(swallowand/ornon-swallow)exercisesfortheir long-termeffect inpatientswithHNCandchronicdysphagia24,35,exceptfortheShakerexercise18,25,28.Asswallowexercisesareappliedtomakeaswallowstrongerorfaster29,theadvantageofnon-swallowexercisesisthattheyallowpatientstoimprovethroughatrainingprotocolsafelywithoutlimitationsthatmaybe imposedduring swallowing,orduringnothingperoral status. Especially thecombinationofswallowandnon-swallowexercises,leadingtodifferentactivationpatternsencounteredduringvariousswallowingcircumstances,maybemoreeffective32.Obviously,theeffortfulswallowexerciseofthecurrentSEA-basedexerciseprotocolisinconcordancewiththespecificityprincipleofneuralplasticity29,34,35. And also the muscle overload principle isapplicabletotheSEAexercises.Bycontrast,theamountofloadintheShakerexerciseisnoteasilyquantifiable,andcannotbemanipulatedprogressivelyoverthecourseoftreatment32. Moreover, the sternocleidomastoid muscles are probably significantly more activatedand fatiguedduring the Shaker exercise thanduring the SEAexercises42. As swallowing isasubmaximalactivity32,whereby increase inmusclevolumeisnotthefocalpoint, forthecurrentstudyaresistiveloadofapproximately60–70%oftheestimated1RMwasmaintainedastheresistancelevel.Besides,inthisHNCpatientpopulationwithchronic,severedysphagia,hypertrophyisanywaynotexpected.

Unfortunately,theincreaseinmusclestrengthsdidnotresultinoverallbetterfunctionalswallowing ability, since the clinical swallowing outcomes (i.e. FOIS and PAS scores), andhyoidelevationdidnotimproveafterthetrainingperiod.Apparently,6to8weeksofstrengthtrainingareprobablynotenough for achieving improvements in clinical endpoints in this

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180|Chapter8

challengingpatientpopulation.Althoughresultsofthestudy-specificquestionnairerevealedsome improvements as perceived by the patients themselves (and certainly no harm),theseresultsdidnotcorrespondwiththeimprovementsinmusclestrength.AsreportedbyLangmoreetal.(2015),thesuggestionismadethat‘thesimpleactofpracticingswallowingwill improve thepatients’ skill,ease,and rateofeating,helping themtomoresafelyandefficientlyswallowmorechallengingfoods’24.ThisisinlinewitharecentstudyofHutchesonet al., who found in particular small improvements in functional status or quality of lifeafteranindividualized,high-intensityswallowingtherapyprograminmoreorlessthesamepatientpopulation,with fewmajor improvements suchas tube removalor improvedPASscores54.However,anotherexplanationcouldbethatothermusclesinvolvedinswallowingplayanimportantrole,orthatfibrosisornervedysfunctionatlong-termprohibitfunctionalimprovementinspiteofimprovedmusclestrength.

Inconclusion,thisstudyinvestigatedaSEA-basedstrengthtrainingprotocolwithswallowand non-swallow exercises for the rehabilitation of chronic, therapy-resistant dysphagiainHNCpatients. Feasibility and complianceappeared tobehighand someobjectiveandsubjective effects of progressive load on muscle strength and swallowing function weredemonstrated, indicating that the swallowingmuscles at long-term still are trainable. Tofurtherstudytheefficacyandeffectivenessofrehabilitativeexercisesinpatientswithchronicdysphagia, larger, prospective studies of longer duration ensuring adequate numbers ofpatients,andstructuredtreatmentprotocolsareneeded16,32.

Since significant benefits of preventive exercises during organ-preservation treatmentalready have been demonstrated14,16,55,56,andmajorclinicalimprovementsatlong-termseemdifficult,startingrehabilitationbeforetreatmentonset,oratleastassoonaspossibleincaseofpost-treatmentrehabilitation,ispreferable.Further,aminimumbaselinemusclestrengthof10Norhigherseemstoberequired,sincethenon-respondersallshowedbaselinemusclestrengthsbelow10N,andthedeviceappearedtoworkbetterwiththeresistanceminimallyonposition2orhigher.Therefore,asanextstepinthevalidationprocessoftheSEA-basedexerciseprotocol,afollowingphase3randomizedcontrolledtrialinthepreventiveorearlyrehabilitationsettingofHNCtreatmentisplanned.



8

ACKNOWLEDGEMENTS

WimKraan,emeritus-technicianattheNetherlandsCancerInstitute,isgreatlyacknowledgedfor the technical construction of the Swallow Exercise Aid (SEA). Jan-Ove Persson (AtosMedical, Hörby, Sweden) and Corina J van As-Brooks (PhD, SLP, MBA; Atos Medical andNetherlandsCancerInstitute)areacknowledgedfortheir inputinthedevelopmentoftheSEA. Merel Latenstein (SLP; the Netherlands Cancer Institute), Hanneke Kalf (SLP, PhD;RadboudUniversity)andSimoneKnuijt(SLP;RadboudUniversity)areacknowledgedfortheirsupportwiththepatientselection.Prof.dr. J.H.A.M.Kaanders isgreatlyacknowledgedforsortingouttherelevantdataonpreviousradiotherapytreatmentintheRadboudUniversity,Nijmegen.

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182 | Chapter 8

Appendix I. Patientexerciselog

M14SEA

Phase-1/2clinicaltrialonthetreatmentofchronicdysphagiainheadandneckcancerpatientswithdedicatedstrengtheningexercisesusingtheSwallowExerciseAid

Patient Exercise Log

Name: ……………..……………………………………….

Dateofbirth:…..………………………………..……..

Instructions: Please note if you have performed your exercisesthreetimesadayduringthetotal

exerciseperiod

*Ifyouhaveperformedyourexerciseslessthan3timesaday,pleasenotethenumber

ofpracticesessionsduringthatday

*Ifyouhaven’tperformedyourexercisesoneday,pleaseleavethatdayempty

Week Exercise 1 Exercise 2 Exercise 3 Remarks

1/2/3/45/6/7/8

ChinTuckAgainstResistance

JawOpeningAgainstResistance

EffortfulSwallow

30 x 3 x 60s 30 x 3 x 60s 10 xMonday Morning

AfternoonEvening

Tuesday MorningAfternoonEvening

Wednesday MorningAfternoonEvening

Thursday MorningAfternoonEvening

Friday MorningAfternoonEvening

Saturday MorningAfternoonEvening

Sunday MorningAfternoonEvening



8

Appendix II. Study-specificquestionnaire

Please fill in this questionnaire at the follow-up visit at the end of the exercise period.

1) Haveyouperformedyourexercisesthreetimesaday?1=yes(continuetoquestion6)2=no,Ihaveexercisedapproximately……timesaday 3=no,Ihaveexercisedapproximately……timesaweek

2) Afterhowmanydaysdidyoustopwithyourexercises?Afterday#:

3) Whydidyoustopwithyourexercises?

4) Didyoure-continueyourexercisesafteryouhavingstoppedearlier?1=yes

2=no(continuetoquestion6)

5) Afterhowmanydaysdidyoure-continue?After……days

6) Howmanydaysdidyouperformtheexercisesintotal?Number of days:

7) Howdidyouexperiencetheexercises?1=veryunpleasant 4=quitepleasant 2=abitunpleasant 5=verypleasant3=notunpleasantorpleasant

8) Canyoutrytoexplainwhy?

9) Howmanydaysdidittakeyoutogetusedtotheexercises?Approximately……days:

10) Didyouhavethefeelingtobenefitfromtheexercises?1=notatall 3=quiteabit2=alittlebit 4=verymuch

11) Ifyes,canyoutrytoexplainwhatbenefit?

12) Afterhowmanydays,ifany,didyounoticethisbenefit?After……days:

13) Didyouhaveproblemsgettingusedtoorperformingtheexercises?

14) Whatisyourgeneralimpressionoftheexercises?

15) Wouldyoukeeppracticing,ifrecommendedbyyourtherapist?1=yes,absolutely 3=probablynot2=probably 4=no

16) Generalremarks:

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184 | Chapter 8

REFERENCES1. NguyenNP,Moltz CC, Frank C, Vos P, Smith

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18. Shaker R, Easterling C, Kern M, Nitschke T,Massey B, Daniels S, et al. Rehabilitation of



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21. Yeates EM, Molfenter SM, Steele CM.Improvements in tongue strength andpressure-generation precision following atongue-pressure training protocol in olderindividualswithdysphagia:threecasereports.ClinIntervAging.2008;3:735-47.



24. Langmore SE, McCulloch TM, Krisciunas GP,Lazarus CL, VanDaeleDJ, Pauloski BR, et al.Efficacyofelectrical stimulationandexercisefordysphagiainpatientswithheadandneckcancer:Arandomizedclinicaltrial.HeadNeck.2015.

25. Logemann JA. Evaluation and treatment ofswallowing disorders. Texas, Austin: Pro-ed;1998.



28. ShakerR,KernM,BardanE,TaylorA,StewartET, Hoffmann RG, et al. Augmentation ofdeglutitive upper esophageal sphincter

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38. Kraaijenga SA, van der Molen L, StuiverMM, TeertstraHJ, Hilgers FJ, van den BrekelMW. Effects of Strengthening Exerciseson Swallowing Musculature and Functionin Senior Healthy Subjects: a ProspectiveEffectivenessandFeasibilityStudy.Dysphagia.2015;30:392-403.

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39. Watts CR. Measurement of hyolaryngealmuscle activation using surfaceelectromyography for comparison of tworehabilitative dysphagia exercises. Arch PhysMedRehabil.2013;94:2542-8.

40. Hughes T, Watts CR. Effects of 2 ResistiveExercises on Electrophysiological Measuresof SubmandibularMuscleActivity.ArchPhysMedRehabil.2015.

41. Mishra A, Rajappa A, Tipton E, MalandrakiGA. The Recline Exercise: Comparisons withthe Head Lift Exercise in Healthy Adults.Dysphagia.2015;30:730-7.

42. Sze WP, YoonWL, Escoffier N, Rickard LiowSJ. Evaluating the Training Effects of TwoSwallowing Rehabilitation Therapies UsingSurface Electromyography-Chin Tuck AgainstResistance (CTAR) Exercise and the ShakerExercise.Dysphagia.2016.


44. Adams V, Mathisen B, Baines S, Lazarus C,Callister R. A Systematic Review and Meta-analysis of Measurements of Tongue andHand Strength and Endurance Using theIowa Oral Performance Instrument (IOPI).Dysphagia.2013.

45. HewittA,Hind J, Kays S,NicosiaM,Doyle J,Tompkins W, et al. Standardized instrumentforlingualpressuremeasurement.Dysphagia.2008;23:16-25.

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48. LeonardRJ,KendallKA.Dysphagiaassessmentand treatment planning: a team approach.SanDiego:SingularPub.Group.;1997.




52. Lemmens J,BoursGJ, LimburgM,BeurskensAJ. The feasibility and test-retest reliabilityof the Dutch SWAL-QOL adapted interviewversion for dysphagic patients withcommunicative and/or cognitive problems.QualLifeRes.2013;22:891-5.

53. Dolan P. Modeling valuations for EuroQOLhealthstates.MedCare.1997;35:1095-108.

54. HutchesonKA,KellyS,BarrowMP,BarringerDA,PerezDP,LittleLG,etal.OfferingMoreforPersistentDysphagiaafterHead&NeckCancer:The Evolution of Boot Camp SwallowingTherapy. http://wwwresearchposterscom/Posters/COSM/COSM2015/C058pdf.2015.



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CHAPTER 9Feasibility and poten.al value of lipofilling in

post-‐treatment oropharyngeal dysfunc.on

S.A.C. Kraaijenga O. Lapid

L. van der Molen F.J.M. Hilgers L.E. Smeele


The Laryngoscope. Online 2016 Apr 14.

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CHAPTER 9Feasibility and poten.al value of lipofilling in

post-‐treatment oropharyngeal dysfunc.on

S.A.C. Kraaijenga O. Lapid

L. van der Molen F.J.M. Hilgers L.E. Smeele


The Laryngoscope. Online 2016 Apr 14.

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ABSTRACT

Objective: Headandneckcancer(HNC)patientsmaydeveloporopharyngealdysfunctionasresultofvolumelossormuscleatrophyofthetongueorpharyngealmusculaturefollowingtreatmentwithsurgeryand/orchemoradiotherapy.Ifintensiveswallowingtherapyoffersnofurther improvement, and the functional problems persist, transplantation of autologousadiposetissue(lipofilling)mightrestorefunctionaloutcomesbycompensatingtheexistingtissuedefectsortissueloss.

Study Design: Case series.

Methods: Inthisprospectivepilotfeasibilitystudy,theapplicationoflipofillingwasstudiedinsevenHNCpatientswithchronicdysphagia.Theprocedurewascarriedoutundergeneralanesthesia in several sessions using the Coleman technique. Swallowing outcomes wereevaluatedwithstandardvideofluoroscopy(VFS)forobtainingobjectivePenetrationAspirationScale(PAS)andresiduescores.SubjectiveFunctionalOralIntakeScalescoresandSWAL-QOLquestionnaireswerealsocompleted.MRIwasusedtoevaluatethepost-treatmentinjectedfat.

Results:Fivepatientscompletedtheintendedthreelipofillingsessions,whiletwocompletedtwo injections. One patient dropped out of the study after two injections because ofprogressive dysphagia requiring total laryngectomy. Four of the six remaining patientsshowed improved PAS scores on post-treatment VFS assessments, with two patients nolongershowingaspirationforaspecificconsistency.Twopatientswerenolongerfeedingtubedependent.Patient-reportedswallowingandoralintakeimprovedinfouroutofsixpatients.

Conclusion: Basedontheresults,thelipofillingtechniqueseemssafeand–inselectedcases–ofpotentialvalueforimprovingswallowingfunctioninthis smalltherapy-refractoryHNCpatientcohort.

KEY WORDSHeadandNeckNeoplasms–Deglutition–DeglutitionDisorders–Lipofilling–FatTransfer–AutologousFatInjection


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INTRODUCTION

Patientswithadvancedheadandneckcancer(HNC)areusuallytreatedwith(acombinationof) surgery, radiotherapy, or chemotherapy. Despite increasing survival as a result ofimprovedtreatmentmodalitiesandcombinationsformostsites1,damagetotheanatomicalstructuresbytheprimarytumororitstreatmentmayadverselyimpactpatients’functionaloutcomeandqualityoflife.Swallowingproblemsoccurfrequentlyinthesepatients,andmaybeaconsequenceoftissueloss,fibrosis,mucositis,xerostomia,painand/ortrismus2,3. The situationmayevenworsenwhentheswallowingmusculatureisnolongeractivelyused,andso-called‘non-use’atrophyoccurs,causingfurtherdeteriorationofswallowing4.

Manyfactorscontributetodysphagia,aspirationandeventheinabilitytoswallow.Often,duetoinsufficientcontactbetweenthebaseoftongueandposteriorpharyngealwall,thefoodbolusisswallowedlesspowerful,leadingtostagnationoffood(‘residue’),withahighrisk of aspiration of the residue. A combination of decreased tongue strength, deficient/reducedhyolaryngealelevation,lackofpharyngealconstrictoractivity,lackoforopharyngealseal,orinsufficientopeningoftheesophagealinletmayalsoplayaroleinaspiration5,6.Longtermandevenlifelongfeedingtubedependencyissometimesunavoidable,andqualityoflifeinthesepatientsisoftenseriouslyimpaired7.

Current treatment strategies of dysphagia include continued use of swallowingmusculatureduringtreatment(the“useitorloseit”concept),byavoidingprolongedperiodsofnothingperoralandadherenceto(prophylactic)targetedswallowingexercises8.Althoughpromising results on pharyngeal swallowing function are reported9,10, severe, therapy-refractorydysphagiamaystillexistinsomepatients.

Lipofilling, or fat grafting, is a technique for transplanting autologous, living fat cellswithin one individual. Due to the regenerative properties of adipose tissue –stem cellshave been demonstrated at cellular level11–thetechniquecanbeusedforbothaestheticand reconstructive purposes. Common indications are tissue loss, pain, and/or fibrosisduetosurgery, irradiation,burns,orother (post-traumatic)causes12,13.Todate,except forskincontouringindications13, lipofillingisrarelyusedinHNCasthereis,tothebestofourknowledge, only one case history published about this technique being applied to treatoropharyngealdysfunctionfollowingtreatmentforHNC14.Inthatstudy,lipofillingfilledtheexistingdefectinthevalleculathatwasthecauseofsignificantstagnationofthefoodbolus,andtheaddedvolumeelevatedtheepiglottisandthusimprovedairwayprotection.Inthepresent study, the feasibility and potential value of lipofilling in sevenHNC patientswithchronic,therapy-refractorydysphagiawasprospectivelyassessed.

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PATIENTS AND METHODS

Thepresentstudywasdesignedasasmall-scaleprospectivepilotfeasibilitystudy,andwasundertakenattheDepartmentofHeadandNeckOncologyandSurgeryoftheNetherlandsCancer Institute in collaborationwith theDepartment of Plastic Surgery of theAcademicMedical Center, in Amsterdam, the Netherlands. The study was performed according toguidelinesofbothinstitutesandthoseoftheHelsinkiDeclaration.

Study cohortAllpatientshadchronicdysphagia(1-yearplus)asaconsequenceoftissuelossand/ormuscleatrophyaftertreatmentwithsurgeryor(chemo-)radiotherapyforadvancedHNC.Patientswereofferedtoparticipateaftertheirpersistent,seriouslydebilitatingdysphagiaappearedtobeunresponsivetointensiveswallowingtrainingbytheSpeechLanguagePathologist(SLP).Noneofthepatientshadbeenenrolledinapretreatmentprophylacticswallowingexerciseprogram15.

Theinitialstudycohortconsistedofsevenpatientstreatedbetween1997and2012foradvancedHNC,andincompleteremission.Sixpatientshadaprimarytumorlocatedattheoropharynx (tonsillar arch, pharyngeal wall, base of tongue, and/or vallecula). The otherpatienthadaprimarytumorintheoralcavity.ThepatientandtumorcharacteristicsoftheinitialpatientcohortaresummarizedinTable1.

Table 1.Patient-andtumorcharacteristicsatbaseline(n=7)

Patient Gender Age Tumor Treatment InjectionLocation TNM CRT Surgery

1 F 71 Baseoftongue Benign - 2007 Baseoftongue2 M 50 Tonsil T2N2b 2011 2012 Baseoftongue3 M 63 Vallecula T2N2b - 1997 Baseoftongue4 M 40 Tonsil T4N2c 2007 - Pharyngealwall5 F 59 Baseoftongue T3N2c 2004 - Baseoftongue6 M 66 Oral cavity T3N2c 1997 1997 Baseoftongue7 F 70 Pharyngealwall T3N2 2000 - Baseoftongue

Abbreviations:F=female;M=male;TNM=TumorNodeMetastasis;CRT=chemoradiotherapy

Informed consent was obtained and the patients were told about the experimentaldesignofthestudy.Patientswereawarethat-duetoabsorption(upto30-50%)ofadiposetissue16–multiple(probablyatleastthree)treatmentsessionswouldbenecessarybeforeatherapeuticeffectcouldbeexpected.Allpatientswerefreetoendtheirparticipationatanytimeduringthestudy.



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Onepatient(#7;Table1)droppedoutofthestudyduetoprogressiontototallaryngectomy.ThispatientwasadmittedatourInstitutebecauseofseverebowelobstructionnotrelatedto her second injection two weeks previously. During the unavoidable hospitalizationpatient’sphysicalconditiondeterioratedandshedevelopedtwiceaspirationpneumoniaandrespiratoryinsufficiency,whichbecamesoproblematicthatapermanenttracheotomywasunavoidable.Sheoptedtohaveatotal laryngectomyforcontrollingherseverelydisablingandpotentiallylife-threateningaspirationproblems.Thispatientthuswentoffstudyandwasnotfurtheranalyzed,butismentionedhereforcompletenessoftheoriginalstudycohort.

Procedure and techniqueThe lipofilling procedure was carried out under general anesthesia using the Colemantechnique17.Thistechniqueaimstopreventdamagetothefragileadiposecellsasmuchaspossibleduringtransplantation,andthustopromotetissuesurvival.Theprocedurestartswithharvestingfatcellsbyaspirationfromtheupperabdominalwallor innerthigh,afterinfiltrationofantibioticsand tumescencefluid (ringers lactate, lidocaine,andadrenaline).Adiposetissuefromtheinfra-umbilicalabdominalwallorinnerthighisverysuitableasdonorsitebecauseofthehighnumberoflocalfatcells,andthefactthatnopositionchangeontheoperatingtableisneeded12.Thefatsampleisthentransferredin10mltubesforcentrifugation,whichisdonefor3minutesat3100roundsperminute,producing1228xgcentrifugalforce.Afterthecentrifugationprocess,thespecimen,besidesfatcells,alsoconsistsofalayerofoil,alayeroffluid(includingbloodandtumescentfluid),andalayerofcellpellets/residue.Thetopsupernatantoilandbottombloodcellsanddebrisarethenremovedwiththedecantertechnique(seeFigure1).Theremaining,purifiedfatcellsaretheninjectedusing1ccsyringeswith blunt tip cannulas (St’rim, Thiebaud SAS, Paris, France) at the predetermined spots,afterthemucosaisfirstpuncturedusinga21Gneedle.Duringinjectionsmallaliquotsoffataretransferredwithmultiplepassesatdifferentdepths.Controlofthedepthofinjectionisperformedwiththenon-dominanthand.Thisisdonewithmultiplepassesinordertoassureevendistributionwithinthetissue.InFigure2alipofillinginjectionintothebaseoftongueisillustrated.Forreasonsofsafety,allpatientswerehospitalizedforobservationforonenightfollowingtheprocedure.

Multidimensional assessmentFunctional datawere collected usingmultidimensional objective and subjective outcomemeasures.Theprotocolincludedstandardvideofluoroscopy(VFS)todeterminetheinjectionsitesbasedonthedegreeofcontactbetweenthebaseoftongueandposteriorpharyngealwallduringswallowing,andtoobjectivelyassessgeneralswallowingfunction,PenetrationandAspirationScale(PAS)scores,andoverall‘presenceofresidue’scores.ThePASisatoolwithanacceptable reliabilityandconsistsof an8-point scale, ranging from1–8 (score1:

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materialdoesnotentertheairway,toscore8:materialenterstheairway,passesbelowthevocalfolds,andnoeffortismadetoeject)18.

Figure 1.Afterthecentrifugationprocess,thespecimen,besidesfatcells,alsoconsistsofalayerofoil,alayeroffluid(includingbloodandtumescentfluid),andalayerofcellpellets/residue.

Figure 2.Lipofillinginjectionintothebaseoftongue(#7;table1):intra-orallyalongneedleisarrangedat the lateral tongueedge, andunderpalpation thetipof theneedle is advanced into thebaseoftongue,wherethefatdepositionsareplaced.



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Theoverall ‘presenceof residue’ score ranges from0–3 (score0: no residue, to score3:residueaboveandbelowthevallecula,withminimalresiduejudgedasnormal)19,20.MagneticResonanceImaging(MRI)wasusedtovisualizethepotentialinjectionsiteintheoralcavityandpharynx(i.e.toestimatetongueandpharyngealwallmusclesandvolumes)andthepost-treatmentvolumesoftheinjectedfat.Additionally,patients’perceivedoralintake/nutritionalstatuswasassessedwiththevalidatedFunctionalOralIntakeScale(FOIS;rangingfrom1–7with score1: nothingbymouth, to score7: total oral dietwithout restrictions). Patients’perceptionofswallowingfunctionwasassessedwiththeSwallowingQualityofLife(SWAL-QOL)questionnaire21.TheDutchSWAL-QOLhasbeentranslatedandvalidatedforusewithoral,oropharyngeal,andlaryngealcancerpatients.Acut-offscoreof14points(orhigher)hasbeenestablished for identifyingHNCpatientswithclinically relevantswallowingproblemsswallowingproblems.Ascoredifferenceof12pointsormoreisproposedtobeusedinstudydesignswithmultipleassessments22,23.

All primary outcomeparameterswere recorded at baseline prior to participation andapproximately one to threemonths after the final fat injection. After each intervention,patientsconsultedtheprincipalclinicianattheoutpatientclinicandunderwentinterimVFSassessments if necessary.

RESULTS

Patient characteristicsAll patients had chronic dysphagia, with four patients being (completely) dependent onpermanenttubefeeding(FOIS≤3).Theothertwopatientshadarestricteddietofonlyoneconsistency (FOIS4)orwithspecific food limitations (FOIS6),andwere includedbecauseof recurrent aspiration pneumonia. Furthermore, two patients with dysphagia were alsodiagnosedwithsomedegreeofdysphonia(articulationdisorder).

At baseline, penetration and/or aspirationwas demonstratedwith VFS in all but onepatient.Absentorreducedcontactbetweenthebaseoftongueandpharyngealwallduringswallowing was demonstrated in all six patients, resulting in more than normal contrastresidueaboveandbelowthehyoidbone.Figure3showsastaticpre-operativeVFSimageofoneofthepatientswithasevereatrophiedtongue.Furthermore,volumelossoratrophyofthetonguewasconfirmedwithMRIinfivepatients.Intheotherpatienttherewasreducedtonsillartissue(asymmetry)intherighttonsillararch.

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Figure 3.Pre-operativestaticVFSimageofoneofthepatients(#6)withanatrophiedtongue.Ascanbeseen,duringswallowingthereishardlyanycontact(duetovolumeloss)betweenthebaseoftongueandposteriorpharyngealwall.

Procedure and techniqueIntotal17autologousfattransplantationswerecarriedoutfromOctober2013toFebruary2015,rangingfrom2to3sessionsperpatientwiththree-monthintervals.Onepatient(#4)noticedinsufficientimprovementfollowingtwolipofillingsessionsanddecidedtodiscontinuethe treatment. The other patients (n=5) had completed the planned (three) consecutivelipofillingsessions.Intotal20–35ccadiposetissuewastransplantedinthesepatients(Table2).Possiblecomplicationsatthesiteofinjection,suchasnecrosis,infection,orintravascularinjectionwerenotobserved.Therewerealsonocomplicationssuchasswelling/edemawithdyspnea,hematomaformation,scarformation,ordamagetotheunderlyingstructuresonthedonorsite.Postoperativepainwasnotreported.

Swallowing outcomesThefunctional(applicable)objectiveandsubjectiveswallowingoutcomesperpatientpre-andpost-treatmentareshowninTable2.Thepatient(#4)whodidnotcompletetheprotocoldidnotshowanyclinicallyrelevantimprovementontheoutcomeparameters.Oftheremaining5patients,at1-2monthsfollow-up4patientshadimprovedonthePASscores,with2patientsnolongershowingaspirationonfollow-upVFSassessmentsforaspecific(thinorthickliquid)consistency.Twoofthese4patientswerenolongerfeedingtubedependentfollowingthelipofillinginjections.Patients’subjectiveperspectiveontheirswallowingfunctionbasedon



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theSWAL-QOLsubscoreshadimprovedinthese4patients,aswell(seeTable3).Allpatientshaddistinguishablefatdepositsspreadoutatthebaseoftongueintheirpost-treatmentMRI(medianfollow-up14weeks).

Table 2. Functionalobjectiveandsubjectiveswallowingoutcomespre-andpost-treatment(n=6)

Injected fat Intake PAS ResidueNo. Amount FOIS Thinliquid Thickliquid Solid Thin Thick Solid

≤3cc 5cc ≥10cc ≤3cc 5cc 10cc cake1 3 29,5cc Pre 4 3 1 1 3 3 1 3

Post 6 3 1 1 3 3 1Change + = = + = ‒ +

2 3 30cc Pre 1 8 4 6 3 3Post 3 3 3 6 4 2 3 3 3Change + + + = =

3 3 20cc Pre 6 8 7 6 3 3Post* 5 6 6 6 4 4 3 3 3Change ‒ + + + = =

4 2 11 cc Pre 1 4 6 3 3Post 1 8 NA 3 1Change = ‒ ‒ = +

5 3 34,5cc Pre 1 NA NA 3Post 6 7 6 6 6 3 3Change + + + =

6 3 32 cc Pre 3 4 4 3 3 3 3Post 6 3 4 2 3 3 3 3Change + = + = = = =

Abbreviations/Notes: No. = number; FOIS = Functional Oral Intake Scale: range 1–7; higher scoresmeanbetteroralintake;PAS=PenetrationAspirationScale:range1–8;lowerscoresmeanbetter/saferswallowing function;Residue scores: range0–3with score0:no residue, to score3: residueaboveandbelowthevallecula;NA=notapplicable(i.e.notransportpossible);(+)meansimprovement,(‒)deterioration,and(=)equality;*meansminimalcompensationmaneuver(chinonchest)wasappliedwithoutinstruction.

Case historiesThefirstcaseconcernsa71-yearoldfemalewhohadundergonesurgicalresectionofalargebenignmucinouscystadenomaofthetonguein2007.Afterwardsshedevelopedfunctionalswallowing and articulation problems, primarily based on volume loss. Following threeconsecutivelipofillingsessionsintothebaseoftongue,thepatientcouldswallowsolidfoodmuchbetter,asalsoconfirmedwithVFSfindings,andreportedimprovedspeech.

Thesecondpatientunderwentradiotherapyin2011followedbysurgicalresectionandreconstructionin2012forarecurrentlefttonsillarcarcinoma.ExtensivetreatmentbytheSLP

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didnotimprovethepersistingswallowingproblems.However,followingthreefatinjectionsintothebaseoftongue,thepatientperceivedimprovementandwasabletoagainresumeconsistentoralintakealongsidehistubefeeding.

The third patient participated because of progressive dysphagia after a supraglotticlaryngectomy and bilateral cervical lymph node dissection followed by postoperativeradiotherapyforastageIVvalleculacarcinomain1997.VFSevaluationfollowingthethreelipofilling sessions showednomoreaspirationof thick liquids,andsolidswere swallowedmore easily.

Thefourthcaseconcernsa40-yearoldmaletreatedwithchemoradiotherapyin2007forastageIVoropharyngealcarcinoma.Severedysphagiawaspresentdirectlyaftertreatment.Previous treatments such as physical therapy, hyperbaric oxygen, esophageal dilatation,cricopharyngealmyotomy, and larynx suspensionwere carriedoutwithout success. Aftertwofatinjectionsthepatientnoticedinsufficientimprovementsanddecidedtodiscontinuethe treatment.

ThefifthpatientwithastageIVbaseoftonguetumorin2004wastreatedwithconcurrentchemoradiotherapy.Shedevelopedseveredysphagiaanddysarthriaduetooropharyngealscarring and base of tongue atrophy. Despite intensive swallowing training, the patientremainedcompletelydependentontubefeeding.Aspirationoccurredevenat1ccswallows.MRI showed an atrophic tongue, sagged posteriorly. After three lipofilling injections thepatientwasabletoeatanddrinkagainforthefirsttimesince10years.Thepatientwasverysatisfied,andMRIshowedincreasedtonguevolumeattherightbaseoftongue(Figure4),butVFSevaluationstillshowedaspiration.At8monthspost-lipofilling,sheremainshappywiththeprocedure,althoughsafeoralintakecannotbeguaranteed.

Thelastpatientwastreatedwithlocalresection,partialmandibulectomyandfreefibulareconstruction,andpost-operativeRTin1997forastageIVfloorofmouthcarcinoma.In2013hepresentedwithprogressivedysphagiarequiringpermanenttubefeeding.Sinceexercisetherapyformorethanoneyeardidnotimprovethepersistingproblems,heunderwentthreelipofillingproceduresintothebaseoftongue.Alreadyafterthesecondinjectionthepatientnoticed improvement in swallowing. Following the third injectionhe resumedoral intakeandhisfeedingtubewasremoved.VFSassessmentconfirmedimprovedPASscoresforthickliquids.Theeffectsarestillmaintainedat6monthsposttreatment.



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Table 3. Patients’perceivedSWAL-QOLscorespre-andpost-treatment(n=6)SWAL-QOL

General Burden

Foodselection

Eatingduration

Eatingdesire

Fearofeating

Sleep FatigueCommu-nication

Mental Health

Social Function

Symptom scale

1 Pre

Post 75.0 50.0 88.0 17.0 63.0 38.0 8.0 50.0 5.0 20.0 61.0

Change

2 Pre 50.0 100.0 100.0 17.0 50.0 0 0 50.0 50.0 60.0 45.0

Post 25.0 50.0 50.0 33.0 25.0 0 0 25.0 25.0 25.0 25.0

Change + + + + + = = + + + +

3 Pre 100.0 125.0 125.0 67.0 75.0 38.0 67.0 63.0 75.0 15.0 84.0

Post 0 0 63.0 17.0 44.0 0 0 25.0 10.0 10.0 36.0

Change + + + + + + + + + + +

4 Pre 25.0 25.0 75.0 25.0 38.0 38.0 33.0 100.0 30.0 25.0 45.0

Post 88.0 75.0 100.0 13.0 50.0 63.0 75.0 65.0

Change ‒ ‒ ‒ + ‒ + ‒ ‒

5 Pre 13.0 75.0 125.0 67.0 38.0 50.0 50.0 25.0 100.0 45.0 95.0

Post 0 0 0 17.0 0 38.0 42.0 0 0 20.0 11.0

Change + + + + + + = + + + +

6 Pre 88.0 75.0 88.0 50.0 56.0 38.0 50.0 100.0 45.0 55.0 57.0

Post 25.0 38.0 88.0 25.0 63.0 50.0 50.0 50.0 35.0 55.0 48.0

Change + + = + = ‒ = + = = +

Abbreviations/Notes:SWAL-QOL=SwallowingQualityofLifeQuestionnaire:range0–120;lowersoresmean better subjective swallowing function; a difference score of 12 points or more was used todemonstrateimprovement(+),deterioration(‒),orequality(=).

Figure 4. Pre and post-operative MRI showing increased tongue volume as a result of several fatdepositionsattherightbaseoftongue(patient#5).

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DISCUSSION

In this prospective pilot feasibility study the potential value of autologous adipose tissuetransplantation(lipofilling)forimprovementoforopharyngealswallowingwasassessedinsixHNCpatientswithchronicdysphagiafollowingHNCtreatment,withoneadditionalpatienttakenoffstudybecauseofintercurrentdiseaseandsubsequenttotallaryngectomy.

Regarding feasibility and safety of the procedure, in this small series there were nocomplicationsoradverseeventsat the injectionordonorsite.Allpatientswereadmittedforobservationforonlyonepostoperativenight,andnoneofthepatientsdevelopedpost-operativeproblems such as airwayobstructiondue to edemaor swellingby the injectedadiposetissue.Alsopainwasnotanissue.Basedonthislimitedexperience,wenowassumethathospitaladmissionsmightnotbenecessary.Forfutureperspectivesthistechniquemightevenbeperformedwithoutgeneralanesthesia,especiallyinlightoftheneedformultipleinjections.Itshouldbestressed,though,thatthelipofillinginjectionswereperformedverycarefully,startingwithminimal(4cc)amountsofadiposetissue,toavoidpotentialrespiratoryproblemsduetopost-operativeswellingoroverfillingintheoropharyngealarea.

Theeffectivenessoftheprocedurevariedperpatient.Althoughtherewasonepatientwhonoticednoclearbenefitfromthelipofillinginjectionsanddidnotwanttocompleteallthreeprocedures(#4),therewerefourpatientswithseveredysphagiareportingsignificantlybetterswallowingfunctionaftertheinjections.Atfollow-upVFSassessmentsthesepatientsactuallyshowedimprovementsonsomeoftheFOISandPASscores,andtwoofthemwereevenable todiscontinue theirenteral feeding.However, swallowing functionwasstillnotentirelysafeinallofthesepatients.Onepatient(#6)experiencedimprovementinoralintakebasedontheFOISscores,whiletherewasno‘true’improvementinfunctionbasedonthePASscores.Afterthelipofillingsessionsshehadonemoreepisodeofaspirationpneumoniatreatedconservatively,but thisdidnotchangehermindabouther subjectively improvedswallowing(asunderlinedinherSWAL-QOLresults)andresumingheroralintake.Thisisinlinewiththeliteraturethatpatient-reportedoutcomemeasuresusuallyprovidedistinctbutcomplementaryinformationaboutswallowing[24],andthatpatients’perceivedswallowingfunctionisimportantforqualityoflife.

We cannot easily explain the variability in resultswe observed between the patients.Adding volume is probably not always sufficient in order to restore swallowing function.Obviously, when there is no increase in tissue volume because of insufficient lipofilling,no benefit can be expected. However, despite the fact that a clear volume increase canbe accomplished, the lipofilling injections nevertheless did not improve function in allof our patients. Currently, it is well acknowledged that dysphagia post-surgery and/orchemoradiotherapy is multifactorial in its physiological basis, which indicates that otherfactorssuchasfibrosis,reducedhyolaryngealelevation,pharyngealconstrictoractivityand/



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orinsufficientsphincteropeningmayalsobeanimportantfactorbesidesvolumeloss5,6. This mightexplainwhyimprovingjustoneelementwasnotsufficienttomakesignificantgainsforsomecases,thoughitwasforothers.Hence,furtherresearchwillbenecessarytoimprovethepatientselectionforthisprocedure.

Althoughforallpatientspre-andpost-treatmentMRIswereavailable, thesewerenotspecifically made according to a protocol enabling accurate volume measurements, butmerelytoshowthepersistenceoftheinjectedadiposetissue.Infact,thefatdepositswerevisualizedinallpatients.MRIsenablingvolumemeasurements,however,mightbeinterestingaspartofafuturestudyprotocoltosubstantiatethesuggestedbeneficialeffectsoflipofillinginHNC.

Adiposetissueisextremelysuitableforfillingtissuedefectsbecauseitisautologousandhomogeneousinconsistency,preventingpossiblegraft-versus-hostreactionswithoutrealmofartificialfillersthatmayhavecomplications11-14.Nevertheless,itremainsdifficulttopredicthowmuchfatwillberesorbedandthushowlongatherapeuticeffectwillpersist16. With the Colemantechniqueabsorptionoffatseemstobereducedasmuchaspossible13,17,however,three(ormore)repeatsareprobablynecessaryinordertoachieveandholdatherapeuticeffect.Accordingtotheliterature,thefavorableoutcomesofautologousfatinjectionarenotonlyduetothefillingofsofttissue,butalsotothepotentialregenerativeeffectofadipose-derived mesenchymal stem cells12,16.Possiblythetissuemayalsobecomelessfibrotic,yetthere is no clear evidence for this.

Asisoftenthecaseinclinicalpilotfeasibilitystudies,thesamplesizeofthisstudywaslimitedtoonlysixpatients,andtheseresultsshouldbeinterpretedwithcaution.However,thepositiveclinicaloutcomesofthisstudywarrantfurtherextensiveinvestigationinlargerpatientcohortstostudytheindicationsforlipofillingmoreprecisely.

CONCLUSION

Inthisstudy,wedescribetheuseoflipofillinginsixpatientswithchronicdysphagiafollowingadvancedHNCtreatment.Theprocedureseemsfeasibleandsafe,and– infouroutofsixcases–ofvaluefor improvingoropharyngealdysfunctioninthissmall,otherwisetherapy-refractorypatientcohort.

ACKNOWLEDGEMENTS

Thisstudywasmadepossiblebyagrantsprovidedby“StichtingdeHoop”,ATOSmedical,andtheVerweliusFoundation.

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REFERENCES









9. Carnaby-Mann G, Crary MA, SchmalfussI, Amdur R. “Pharyngocise”: randomizedcontrolled trial of preventative exercises

to maintain muscle structure and swallowing function during head-and-neckchemoradiotherapy. Int J Radiat Oncol BiolPhys.2012;83:210-9.

10. Kraaijenga SA, van der Molen L, Jacobi I,Hamming-VriezeO,HilgersFJ,vandenBrekelMW. Prospective clinical study on long-termswallowing function and voice quality inadvanced head and neck cancer patientstreated with concurrent chemoradiotherapy andpreventiveswallowingexercises.EurArchOtorhinolaryngol.2014.

11. RigottiG,MarchiA,GalieM,BaroniG,BenatiD, Krampera M, et al. Clinical treatment ofradiotherapy tissue damage by lipoaspiratetransplant: a healing process mediatedby adipose-derived adult stem cells. Plast ReconstrSurg.2007;119:1409-22;discussion23-4.

12. HamzaA,LohsiriwatV,RietjensM.Lipofillinginbreastcancersurgery.GlandSurg.2013;2:7-14.

13. MazzolaRF,CantarellaG,TorrettaS,SbarbatiA, Lazzari L, Pignataro L. Autologous fatinjection to face and neck: from soft tissueaugmentationtoregenerativemedicine.ActaOtorhinolaryngolItal.2011;31:59-69.

14. Navach V, Calabrese LS, Zurlo V, Alterio D,Funicelli L, Giugliano G. Functional baseof tongue fat injection in a patient withsevere postradiation Dysphagia. Dysphagia.2011;26:196-9.


16. Tabit CJ, Slack GC, Fan K, Wan DC, BradleyJP. Fat grafting versus adipose-derived stemcell therapy: distinguishing indications,techniques, and outcomes. Aesthetic PlastSurg.2012;36:704-13.

17. Pu LL, Coleman SR, Cui X, Ferguson RE, Jr.,VasconezHC.Autologousfatgraftsharvestedand refined by the Coleman technique: a



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comparative study. Plast Reconstr Surg.2008;122:932-7.


19. Logemann JA. Evaluation and treatment ofswallowing disorders; Pro-ed (2nd edition).Texas,Austin.1998.


21. Bogaardt HC, Speyer R, Baijens LW, FokkensWJ. Cross-cultural adaptation and validationoftheDutchversionofSWAL-QOL.Dysphagia.2009;24:66-70.

22. RinkelRN,Verdonck-deLeeuwIM,LangendijkJA,vanReijEJ,AaronsonNK,LeemansCR.The

psychometric and clinical validity of the SWAL-QOL questionnaire in evaluating swallowingproblems experienced by patients withoral and oropharyngeal cancer. Oral Oncol.2009;45:e67-71.


24. Rinkel RN, Verdonck-de Leeuw IM, de BreeR, Aaronson NK, Leemans CR. Validity ofpatient-reported swallowing and speechoutcomesinrelationtoobjectivelymeasuredoral function among patients treated fororal or oropharyngeal cancer. Dysphagia.2015;30:196-204.

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CHAPTER 10General discussion and future perspec.ves

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GENERAL DISCUSSION

Asextensivelydiscussedintheintroductionandvariouspapersofthisthesis,patientswithheadandneckcancer(HNC)areatrisktodevelopsubstantialfunctionalimpairmentsafterorgan-preservingtreatmentwithradiotherapy(RT)orconcurrentchemoradiotherapy(CRT).Swallowing isoneofthemainfunctions inwhichoral,pharyngealandlaryngealfunctionscooperate,andtumorsinthisareaandtreatmentsequelscanseriously impairswallowingfunction and oral intake. Asmany as two thirds of patients with advanced HNC are leftwith permanent swallowing impairments1-3, and dysphagia can even deteriorate severalyears post-treatment4-7.Givenitsseriousimpactonqualityof life8,9, functionalswallowingassessmentandtreatmenthavebecomestandardofcareinHNCpatients10,andpreventionof dysphagia has becomeamajor focus point inHNC research. Since the radiationfieldsfrequentlyencompassthelarynxand/orthevocaltract,alsosubstantialeffectsonlaryngealfunction(i.e.voicequality,speechintelligibility)havebeennoted.Theeffectsarecorrelatedto the radiation dose to these structures11, 12, and aggravated by the combination withchemotherapy11,13-18.

Inthepastdecade,improvedRTprotocolswithintensity-modulatedradiotherapy(IMRT)havebeenintroducedtoreducetheradiationdosetothemusclesandstructuresimportantforswallowing(i.e.thepharyngealconstrictormuscles)19-22.RTisknowntoaffectswallowingfunctionintheshort-termthroughmucositisandedema,andatlonger-termthroughfibrosiswithscartissueformationwithintheirradiatedstructures23,24.WiththeprogressiontoIMRTtreatmentplanning,therelevantswallowingstructurescanbedefinedas‘organsatrisk’,asalready isdonefor thesalivaryglandsto limitxerostomia,andpost-treatmentswallowingfunctioncanbecomepotentiallylessimpaired19-21.

AlthoughIMRTisrelevantforfunctionpreservationandnotwithouteffect,morerecently,thenotionhasevolvedthatpartoftheswallowingproblemscanbeattributedtothe‘useitorloseit’concept25,26.Overthelastyears,thestrongfocusonpreventionofweightlossbyconfiningpatientstotubefeeding,eitherbyclinicalnecessityoraccordingtoprotocol,andeffectivelyimmobilizingtheswallowingmusculature,hasinevitablyresultedinnon-useatrophyofthesemusclesandstructures.Hence,aftermonthsofnon-use,recoveryoforalintake isextremelydifficultandnot-seldom impossible.Andby that,prolongeddysphagiawasalmostpre-programmed.

Atpresent,thisnotionhas ledtotheso-called ‘eatorexercise’principle27. This means thatoral intakeshouldbemaintainedas longaspossible,andthatpreventiveswallowingrehabilitation should keep the swallowing musculature ‘active’ as much as possible.Preventiveexerciseprogramsstartingbeforetherapyonsetandbeingcontinuedduringandaftertreatment,evenwhentubefeedinghasbecomeunavoidable,seemavalidapproachtolimitthedismalsideeffectsof(C)RT.RecentstudiesintheNetherlandsCancerInstitute

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andelsewherehaveshownthattheseprograms(inparticularintheshort-term)actuallyareassociatedwithbetterpost-treatmentswallowingfunction28-35.Thus,prescribingpreventiveswallowingexercisestoallpatientswithHNCpriortodefinitiveRTorCRTisnowincreasinglyapplied,andhasbecomemoreorlessstandardofcare.

Unfortunately,asbecameclearfromthesystematicreviewofthe2012-2013literature(Chapter 2), the available studies often differ in the methodologies used and outcomesreported.Thereislackofauniformassessmentmethod,andwhetherthetreatmentstrategyappliedisoptimalremainsuncertaintoo,becausetheperformedstudiesaboutpreventiveor rehabilitative strategies are rather limited in size and scope10, 24. This literature review clearlyconfirmedtheincreasingdemandforeffectiveassessmentandtreatmentstrategiesfordysphagia, in linewithmostof theother reviewsdiscussed in thispaper.All stressedtheimportanceoffurtherlongitudinalstudiesinordertoobtainmuchneededprospective,adequatelycontrolled,poweredandrandomizeddataonpreventiveswallowingexercises10. Research to optimize swallowing treatment strategies regarding time, type, duration,frequencyandintensityofexercises,withoptimaladherencetotreatmentandassessmentofpotential long-termbenefits, iscurrentlyunderwayatmultiplecenters10,24,36,37.Furtheroptimizationofpreventiveeffortsmightcomefromearlyidentificationofhigh-riskpatientsthroughsystematicassessmentusinginstrumentalexaminationsandcomplementarypatient-reported outcomes6.

Long-term evaluationBecause studies evaluating long-term functional outcomes after (C)RT for advancedHNCwerequite scarce and in demandat the start of this researchproject, in Chapter 3andChapter4apatientpopulationwithHNCpreviouslytreatedwithconcurrentCRTwasstudiedforlong-termswallowing,mouthopening,voiceandspeechoutcomesatmorethan10yearspost-treatment.Regardingswallowing function,bothobserver-ratedandpatient-reportedseverefunctionaldisordersandrelatedmorbidityproblemswerecommoninthispatientcohort.Theresultsshowedoccurrenceofprofoundpharyngealresidueinallpatients,and laryngeal penetration and/or aspiration in almost 70% of the 18 evaluated patients.Moreover,fourofthe22long-termHNCsurvivorswerefeedingtubedependentand/orhaddeveloped frequent aspiration pneumonias or other recurring pulmonary problems. Alsofunctionalvoiceandspeechproblemswerecommoninthispatientcohortmorethantenyearsafterorgan-preservationtreatment,asassessedwithperceptualevaluation,automaticspeech recognition,andwithvalidated structuredquestionnaires.Onapositivenote, theimpairmentsweresignificantlylessprofoundinthepatientstreatedwithIMRTascomparedtothepatientstreatedwithconventionalRT.Althoughthepatientpopulationconcernedonly22long-termsurvivors,theresultsfromthisstudyareinlinewithotherstudiesthatfoundcorrelationsbetweenradiationdosetothepharyngealstructuresorglottisandswallowing



10

orvoice/speechimpairments,resultinginbetterfunctionaloutcomesinpatientstreatedwithIMRTcompared to those treatedwith conventionalRT38-40. It isnotexactly clearwhetherthe poor outcomes in this patient cohort weremainly caused by the lack of preventiverehabilitation,thelargerradiationfields,ortheprogressivefibrosisatlong-termfollowingRT.Nexttopreventiverehabilitation,ongoingclinicaltrialsinHNCarecurrentlylookingintotheoptionstooptimizetheIMRTprocesstofurtherimproveoutcomes41.

ForthediscussioninthisthesisthepublisheddatafromChapter3andChapter4werealsocombinedtoadditionallyinvestigateassociationsbetweenswallowingandvoice/speechproblems,which appeared to be significantly correlated in this patient cohortmore than10yearspost-treatment.InTable1thesignificantunivariatePearsoncorrelationsbetweenswallowingfunctionandvoiceandspeechoutcomesareshown.Ascanbeseen,laryngealpenetrationand/oraspiration,asassessedwithPenetrationAspirationScalescoresobtainedfromvideofluoroscopy,wassignificantlycorrelatedwithpatients’perceivedvoiceandspeechhandicap,basedon(sub)totalVoiceHandicapIndex(VHI)andSpeechHandicapIndex(SHI)scores.Alsopatient’sperceivedswallowingimpairment,assessedwith(sub)totalSWAL-QOLscores,wassignificantlyassociatedwithpatients’perceivedvoice/speechparametersonmost(sub)domains.Thoughtheproblemswerepredominantlyrelatedtoradiationtechnique,thephenomenonofneuralplasticitymightalsoapplyhere,meaningthatdisorderedswallowingfunction is associatedwithcentral andperipheral sensorimotordeficits,whichalso causevoice and speech problems42,43.This is in linewithearlierstudiesthathaveexaminedtheassociationbetweenvoicequalityparametersanddysphagia44-46.

InChapter5thepreventiverehabilitationprogramofvanderMolenetal.(2006-2008)wasfurtherstudiedonlong-termprospectivelycollectedobjectiveandsubjectivefunctionalresults after CRT for advanced, anatomical and functional inoperable HNC30, 35. With the findingthatallpatientsof theoriginalpreventivestudypopulationprospectively followedand still alive at 6 years follow-up hadmaintained or regained adequate oral intake, theeffectivenessofthispreventiveapproachwasfurtherunderlined.Alsovoiceproblemswerelimitedinthisrehabilitatedpatientcohort,despitethefactthatthevastmajorityofpatients(20/22)duetopositivelymphnodeshadreceivedaradiationdosetothelarynxof43.5Gyandhigher,accordingtotheliteraturethethresholdvaluefordevelopingchronicedemaorvoice problems39,47.Especiallywhenthefunctionaloutcomesofthispatientcohort(n=22)are compared with the functional swallowing and mouth opening results of the IMRT-treatedpatients(n=10)fromChapter3,withcomparablepatientandtumorcharacteristics,considerablylowerincidenceoflaryngealpenetrationand/oraspiration(4/18versus5/10),pharyngeal residue (14/18 versus 10/10), abnormal oral intake (0/22 versus 4/10), andtrismus(1/22versus3/10)arepresent.Regardingvoicequality,comparisonofbothpatientcohorts is limitedtothepatient-reportedVHIquestionnaire. InChapter4, fourof thetenIMRT-treated patients showed voice problems (VHI >15) in daily life,whereas in Chapter

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5thisconcernedonlyfiveoutof22patients.Therefore, itseems likely thatthefavorableoutcomesinChapter5,atleastinpart,canbeattributedtothepreventiveandcontinuedpost-treatmentrehabilitationprogramthatwasapplied.

Intheoutcomeanalysisindysphagiaresearch,suchasthestudiesdescribedinChapters3 to 5, videofluoroscopy has been considered the gold standard for clinical swallowingassessment.Quantitative assessment of swallowmechanics represents probably the bestmeansavailableforunderstandingdysphagiainvariouspatientpopulations.Hence,oneoftheoutcomeparametersstudiedinthisthesisishyoidboneelevationandanteriorexcursionduring swallowing. The literature suggests that reducedor delayedhyoiddisplacement isan important factor contributing to aspiration and pharyngeal residues in patients withdysphagia. Specifically, reduced vertical excursion of the hyolaryngeal complex may leadtoincompleteairwayclosurewithanassociatedriskoflaryngealaspiration,whilereducedhyoid displacement in the anterior direction will lead to reduced opening of the upperesophageal sphincter, resulting inpyriformsinus residues, thusalso increasing the riskofaspiration48. Contrary to several papers48,49,intheabove-describedrehabilitatedHNCpatientpopulation,nocorrelationsbetweenanteriorand/orsuperiorhyoidexcursionandaspirationorresiduescoreswerefound(Chapter6).Thesignificantassociationfoundbetweenreducedsuperiorhyoidmovementandsubjectiveswallowingimpairmentbasedonfourstudy-specificquestionsregardingswallowingfunctionwasquitesmall.Possibly,othermechanicalvariablesmay have been impaired and accounted for patients’ reported dysphagia. In the currentpatientcohorthyoiddisplacementdidincreaseslightlyinthesuperiordirectionfor5ccthinliquidswallowsinasubgroupofpatientswithatumorattheoropharynxorhypopharynxat10weekspost-treatmentcomparedtobaseline.Thehighervaluesat10weekpost-treatmentmayreflectextraeffortbeingexertedduringtheseswallows,possiblyasresultofotherissuessuch as poor sensation or non-hyoidmechanical impairment. Thismight also reflect thedisappearanceoftheprimarytumor,whichimpairedthemobilityofthehyoidboneatbaselineinthesepatients.Alsothepreventiveandcontinuedpost-treatmentswallowingrehabilitationprogrammightinpartexplainthesefavorable10weekshyoidelevationoutcomes.However,thepatientpopulationwasrathersmall,andotherparameterssuchastumorvolumeand/orradiationdoseeffectsmayalsoplayarole.Hence,hyoidexcursionissubjecttovariabilityfrom a number of sources. It is therefore not surprising thatmany conflicting results ofassociationbetweenhyoidexcursionandaspirationhavebeenpublished49,50.Moreover, ithasbeenacknowledgedintheliteraturethatthemeasurementsofhyoiddisplacementarenotalwayseasyandreproducible,andthusarepronetomeasurementerrors51,52.Therefore,furtherresearchwith largersamplesizeswillbenecessarytoconfirmpossiblecorrelationpatterns.Fornow,thisparameterseemsnotveryvaluableforclinicaluse inHNCpatientswithdysphagia.



10

Tabl

e 1.Overviewofsignifican

tunivaria

tePearson

correlatio

nsbetwee

nsw

allowingan

dvoice/spee

chvariablesin22he

adand

neckcancerpati

ents10

yearsaft

ercon

curren

tche

morad

iotherap

y.

PAS

SWAL

-QOL

Gen

eral

bu

rden

Food

selection

Eatin

gdu

ratio

nEatin

gde

sire

Fearof

eatin

gCo

mmun

icati

onM

enta

l Health

Soci

al

functio

nSy

mpt

om

scor

eSH

Iscore

.43*

.63*

*.52*

.56*

*.48*

.48*

.55*

*.86*

*.50*

.50*

.66*

*Sp

eech

dom

ain

.46*

.63*

*.54*

*.51*

.52*

.55*

*.59*

*.88*

*.4

3.64*

*Ps

ycho

soci

al d

omai

n.57*

*.43*

.57*

*.45*

.74*

*.56*

*.55*

*.61*

*VH

Iscore

.51*

.70*

*.55*

*.59*

*.61*

*.53*

.60*

*.81*

*.51*

.60*

*.67*

*Ph

ysic

al d

omai

n.76*

*.63*

*.53*

.64*

*.58*

*.74*

*.78*

*.50*

.60*

*.69*

*Fu

nctio

naldom

ain

.49*

.57*

*.54*

*.54*

*.46*

.43*

.72*

*.49*

.57*

*Em

otion

aldom

ain

.52*

.53*

.53*

.44*

.69*

*.46*

.52*

.54*

ELISspe

echintelligibility

–.43

*–.47

*G

rade

–.53

*Ro

ughn

ess

–.51

*–.47

*–.57

*N

asal

ity–.44

*

Abbreviatio

ns:P

AS=Pen

etratio

nAspiratio

nScale;SWAL

-QOL=Sw

allowingQua

lityofLife

que

stion

naire

;SHI=

Spe

echHan

dicapInde

x;VHI=

Voice

Han

dicapInde

x;ELIS=Text-aligne

dRu

nningSpee

chIntelligibility.Note:*m

eansp<.05;**meansp<.01.

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210|Chapter10

Despite the promising effects on pharyngeal swallowing function up to (maximum) 5yearsofpreventiverehabilitationpublishedbytheNetherlandsCancerInstituteandothers,persistentorlateonsetdysphagiainHNCsurvivorsstillcandeveloporprogressbeyondthefirst years of treatment4-7.While acute toxicities such asmucositis andedema commonlydisrupt normal swallowing during or shortly after treatment and usually substantiallyimprove in the subsequent months, late-radiation associated dysphagia, now commonlyreferred to as ‘late-RAD’,maydeveloporpersist longafter the completionof treatment4,6.Althoughrare, late-RADmaydevelopaftertreatmentwithCRT,RTalone,andalsoafterIMRT,asresultofneuropathy,progressivefibrosis,and/ornon-useatrophyoftherelevantswallowingmusculature.Itisthoughttodevelopafteraradiationdoseof70Gyorhigher4,especiallytothesuperiorpharyngealconstrictormuscles6.Oftentimestheonsetisprecededby a long interval of adequate functioning. As late-RAD frequently manifests with lowercranialneuropathy(52–83%)6,thelateeffectswillultimatelyaffecttherangeofmotionofkey swallowing structures (i.e. thehyolaryngeal complex,pharyngeal constrictors,baseoftongue).This leadstoasignificantly inefficientswallowwithprofoundpharyngealresidue,likely combinedwithprogressivefibrosis, anda tendency for refractory, silentaspiration4. Hence,novelapproachestopreventandmanagethisprogressive,challengingcomplication,withhighriskofaspirationpneumoniathat is frequentlyrefractorytostandarddysphagiacare,areincreasinglyindemandfor4.

Prospective studiesBased on the above-described insights obtained with the cross-sectional studies, in thefinal sectionof this thesis different treatment strategies for persistent, therapy-refractoryoropharyngeal and laryngealdysfunctionwereprospectivelyexplored.Many studieshaveinvestigatedtheeffectsofexercisetherapyfor improvementofswallowingfunction,oftencarriedoutinapreventivesettingoratlowlevelofintensity53.Assuggestedintheliterature,compliance, i.e.adherencetotreatment, isoneofthemainfactors influencingoutcomes,and poor compliance will clearly impact the validity of clinical trial results54.Consequently,althoughsometimeseffectiveforpreventiverehabilitation,recentstudieshaveshownthatsimple, low intensity ‘home exercise programs’without adequate patientmonitoring arenotenoughtoimproveclinicallyrelevantswallowingparameters(i.e.reductionoflaryngealpenetrationand/oraspiration,orweightgain)inpatientswithchronicorlateonsetdysphagia,ascomplianceinthesesettingsisoftenlow55,56.Instead,oneshouldaimforindividualized,high-intensityexercisesasrecentlyhavebeentrialedindysphagiatherapyprograms53. It is importanttostressthat,becauseoftheirrelevancefortheoutcomesassessmentoftheseprograms,thecollectionofcompliancedata,e.g.withdailyexerciselogsortimelogs,isvital,andthatpatientsshouldbemonitoredfrequentlywithpreferablyweeklyfollow-upcontactstoachieveoptimalcompliance.



10

Currently,theliteratureissuggestingthatrehabilitativeswallowingtherapythataimstostrengthentheswallowingmusculaturecanpossiblycompensatefor‘loss’ofresistiveload,when acute effects of CRT cause patientswithHNC to stop eating27. Based on the same methodsusedinsportsmedicine,repetitiveexercisesthataddressallprinciplesofstrengthorendurancetraining(i.e.specificity,individuality,andprogressiveoverload)areincreasinglyapplied. In this respect, the development of medical devices supporting a therapeuticapproachispromising,aswasalsoshowninourrecentfeasibilitystudy(Chapter7),provingthatseniorhealthysubjectsareableto improveand increasesuprahyoidmusclestrengthandvolumeduringa6-weekperiodofintensiveswallowingtraining.Theexerciseprotocolconsistedofbothswallowandnon-swallowexercises,whichwereperformedwithanewlydeveloped dedicated swallow exercise device: the Swallow Exercise Aid (SEA). Exercisesincluded chin tuck against resistance (CTAR), jaw opening against resistance (JOAR), andeffortfulswallowexercises.Thedeviceallowsadaptationtoindividualsubjects’capacity,andthus for applying progressive overload during the training program. The high compliance(mean86%)foundinthisstudycertainlycontributedtothepositiveresults,whichprobablyalso inpart is attributable to thebiofeedbackandvisual feedbackon the resistance levelprovidedbythedevice.Theseresultsareinconcordancewithotherstudiesamonghealthysubjects that demonstrated improved swallowing outcome parameters such as improvedhyoidboneelevation,amountofupperesophagealsphincteropening,andtimeforpharynxpassageafterapproximatelysixweeksofintensiveswallowingtraining57-61.

Obviously, thepositiveresults found inourandotherstudies58-61 in healthy individuals hadtobeconfirmedandtestedinpatientswithdysphagia,sinceitneedstobedemonstratedwhether the targeted, often atrophied and/or fibrosed muscle groups in patients withtherapy-refractory dysphagia are also still trainable. And even more important questionwas,whether increased suprahyoidmuscle strength indeed aids in opening of the upperesophagealsphincterbyelevationandanteriorexcursionofthehyolaryngealcomplex,andresultsinlesspost-swallowaspiration.Thiswasreasontoconductaclinicaltrialinpatientswith chronic dysphagia after organ-preservation treatment for HNC (Chapter 8). In thisprospectivephase2clinical trial thefeasibility,compliance,andshort-termefficacyofthesameSEA-basedstrengthtrainingprotocolwasstudiedin18patientswithchronic,therapy-refractorydysphagiaaftertreatmentforadvancedHNC.Similarly,swallowandnon-swallowexerciseswereusedforrehabilitation,includingCTAR,JOAR,andeffortfulswallowexercises.After 6 to 8 weeks of targeted swallowing training, the feasibility and compliance againappearedtobehigh,andsomeobjectiveandsubjectiveeffectsofprogressiveloadonmusclestrengthandswallowingfunctionweredemonstrated,indicatingthattheswallowingmusclesatlong-termare,uptoacertainpoint,stilltrainable.Unfortunately,nomajorimprovementssuchastuberemovalorimprovedPASscoreswereobserved.Anexplanationcouldbethat6to8weeksofstrengthtrainingisnotenoughforachievingclinicallyrelevantimprovements

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inthischallengingpatientpopulationwithchronicorlateonsetdysphagia10yearsaftertheironcologicaltreatment.Anotherreasoncouldbethatothermusclesinvolvedinswallowing,notor less efficiently targetedwith the SEAexercises,mightplay an important role.Alsofibrosisand/ornervedysfunctionatlong-termarelikelytoprohibitfunctionalimprovementat such short notice, in spite of improvedmuscle strength. And although the benefits asperceivedbythepatientsthemselvesdidnotcorrelatewiththeobjectiveimprovementsinmusclestrength,theliteraturesuggeststhatswallowingtraining‘mighthelppatientsadapttoseverelevelsofswallowingdysfunction,tocopeandcompensatebetter,andtolivebetterwiththeirproblem’53.Andasaresult,patients’oralintakemightherebyimproveaswell.Andthechallengeofincreasingordecreasingthe‘resistiveload’ofswallowing,recentlyenvisagedbyLangmoreetal.,asmentionedintheintroduction,hasbeennotbeentooelusiveafterall.

Future perspectivesTo further study the efficacy and effectiveness of rehabilitative exercises inHNC patientswithchronicorlatedysphagia,larger,prospective,well-designedstudiesoflongerdurationensuring adequate numbers of patients (with comparable tumor sites and stages), andstructured treatment protocols (with well-defined numbers of sets and repetitions) areneeded24,36.Basedontheestablishedeffectsizeforimprovedoralintake(Cohen’sd=0.3)obtainedfromChapter8,atleast56patientsshouldideallybeincluded.Further,probablyonlypatientswithbaselinemusclestrengthsof10Newton(N)orhighershouldbeincluded,because the non-responders all showed baselinemuscle strengths below 10 N, and thedeviceappearedtoworkbetterwiththeresistanceminimallyonposition2orhigher.Sincesignificant benefits of preventive exercises during organ-preservation treatment alreadyhave been demonstrated24,31,32,35,startingrehabilitationbeforetreatmentonset,oratleastas soonaspossible in caseofpost-treatment rehabilitation, ispreferable.Therefore, asanextstepinthevalidationprocessoftheSEA-basedexerciseprotocol,aphase3randomizedcontrolledtrialinthepreventiveorearlyrehabilitationsettingofHNCtreatmentisplanned.It cannotbe ruledout, however, that this subsequent trialwill show that therapyeffectsin the field of dysphagia rehabilitation are time dependent. Already after two years, butespeciallymore than tenyears after radiation treatment, swallowing functionmighthavebecomesopoorthateventhebesttherapycannotstoptheprogressivedeterioration4-6. It is thereforenotunlikelythatapossiblecriticalwindowforpost-treatmentrehabilitationexists,withathresholdapproximatelytwoyearsafterradiation4. This is also stated in the principle ‘timematters’ of neural plasticity,meaning that early implementation of interventions ishypothesizedmostlikelytoaccessneuralplasticadaptations42,43.

Many factors contribute to dysphagia, aspiration and even the inability to swallow.In patients with chronic or late dysphagia who are really refractory to therapy, multiple



10

swallowingabnormalitiesarelikelypresent.Often,duetoinsufficientcontactbetweenthebaseof tongueandposteriorpharyngealwall, the foodbolus is swallowed lesspowerful,leading to stagnation of food (‘residue’), with a high risk of aspiration of the residue. Acombinationofdecreased tonguestrength,deficient/reducedhyolaryngealelevation, lackofpharyngealconstrictoractivity,lackoforopharyngealseal,orinsufficientopeningoftheesophagealinletmayalsoplayaroleinaspiration62,63.Toaddressdysphagiabasedonvolumelossornon-usemuscleatrophyofthetongueorpharyngealmusculature,afeasibilitystudyonthepotentialvalueoflipofillingasminimallyinvasivesurgicalmethodforthetreatmentof oropharyngeal dysfunction and dysphagia was carried out in Chapter 9. This study,encompassingpreliminarydataonsevenpatients,showedthattheprocedurewasfeasibleand safe. Regarding effectiveness, promising results were demonstrated, with significantswallowing improvements in four of the seven patients. Two of them were confined tolong-term tube feeding,butafterwardswereback tooral intake, allowing removalof thefeedingtube.Accordingtotheliterature,thefavorableoutcomesofautologousfatinjectionarenotonlyattributabletothefillingeffectofsofttissue,butpossiblyalsotothepotentialregenerativeeffectofadipose-derivedmesenchymestemcells64,65.Asaresult,thetissuealsomaybecomelessfibrotic.Theseexamplesshowthataclosecollaborationbetweentheheadandnecksurgeonandalliedhealthprofessionalsisessentialforprogressinthesefunctionaldeficitareas.Headandnecksurgeonsshouldhaveakeeninterest,notonlyinHNCtreatment,butalsoinHNCrehabilitation,sincetheyhavethearmamentariumtorestoreorcompensatefunctionslosses.Anddysphagiaresearchisonlyatitsinfancyinthisrespect.

Tosumup,overthelastdecadestheincreasinguseoforgan-preservationprotocolshascreatednewchallengesforHNCrehabilitation.Besidesthetraditionalrehabilitationaftertotallaryngectomy,nowalsothefunctionalissuescausedbythecompromisedlarynxandpharynxasresultofRTorconcurrentCRThavetobeaddressed.Multipleswallowingabnormalitiesarelikelypresentinpatientswithchronicorlatedysphagia.TobetterrehabilitatedysphagiainHNCpatients,thefollowingfocuspointsforfutureperspectivesindysphagiarehabilitationarerecommended.First,functionpreservationinorgan-preservationprotocolsshouldbemoreintegrated,notonlythroughevermorecleverRTtreatmentplanning,butalsothroughthe(continued)evaluationoftraditionaltherapytechniques(i.e.chintuck,effortfulswallow),togivespeechlanguagepathologistsandheadandnecksurgeonstheammunitiontoselectandapplythesetechniquesonabest-practicebasisforindividualpatients.Second,incorporationof structural, intensive, daily functional swallow and non-swallow exercises for dysphagiarehabilitationisrequired,asmanyswallowingdifficultiesarerelatedtomuscleweakness,andpotentialeffectsoftheseexercise-basedstrategiesalreadyhavebeendemonstrated.Toolsordevicesthatintensifytheworkloadunderaprogressive-resistancemodelofexercise-basedtherapyareencouraged, inordertoavoidnon-useatrophyandprogressivefibrosisoftherelevantswallowingmusculatureandstructuresatlong-term.Third,novelapproachessuch

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ascompensatingexistingtissuedefectsortissuelossbytransplantationofautologousadiposetissue(lipofilling)cansometimesrestorefunctionaloutcomesinHNCpatientswithchronicdysphagia.Especiallythecombinationofstrategiesmightprovidethebestpossiblecareforpatientswith chronic dysphagiawithhigh risk of aspirationpneumonia that is frequentlyrefractorytostandarddysphagiacare.EspeciallycombiningofSEAexercisesandlipofillingisworthwhilefurtherexploring,sincebothtreatmentmodalitieswereexploredinparallelforthisthesis.Firstsignsofanadditionalbeneficialeffectofthecombinationarepositive.Astheevidenceandclinicians’skillsforvariousstrategiesandtoolsincreases,hopefullytheclinicaloutcomesinHNCpatientswithdysphagiawillimproveaswell66.



10

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22. GutiontovSI,ShinEJ,LokB,LeeNY,CabanillasR.Intensity-modulatedradiotherapyforheadandnecksurgeons.HeadNeck.2015.

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25. Lee WT, Akst LM, Adelstein DJ, Saxton JP,Wood BG, Strome M, et al. Risk factors forhypopharyngeal/upper esophageal strictureformation after concurrent chemoradiation.HeadNeck.2006;28:808-12.








33. Bhayani MK, Hutcheson KA, BarringerDA, Lisec A, Alvarez CP, Roberts DB, et al.Gastrostomy tube placement in patientswith oropharyngeal carcinoma treated withradiotherapy or chemoradiotherapy: factors affecting placement and dependence. HeadNeck.2013;35:1634-40.

34. Ohba S, Yokoyama J, Kojima M, FujimakiM, Anzai T, Komatsu H, et al. Significantpreservation of swallowing function inchemoradiotherapy for advanced head and neck cancer by prophylactic swallowingexercise.HeadNeck.2014.




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38. van Rij CM, Oughlane-Heemsbergen WD,AckerstaffAH,LamersEA,BalmAJ,RaschCR.ParotidglandsparingIMRTforheadandneckcancerimprovesxerostomiarelatedqualityoflife.RadiatOncol.2008;3:41.

39. Nguyen NP, Abraham D, Desai A, Betz M,DavisR,SrokaT,etal.Impactofimage-guidedradiotherapy to reduce laryngeal edemafollowing treatment for non-laryngeal andnon-hypopharyngealheadandneckcancers.OralOncol.2011;47:900-4.

40. Vainshtein JM,GriffithKA,FengFY,VinebergKA,ChepehaDB,EisbruchA.Patient-reportedvoiceandspeechoutcomesafterwhole-neckintensity modulated radiation therapy andchemotherapy for oropharyngeal cancer:prospective longitudinal study. Int J RadiatOncolBiolPhys.2014;89:973-80.

41. Tejpal G, Jaiprakash A, Susovan B, Ghosh-Laskar S, Murthy V, Budrukkar A. IMRT andIGRT in head and neck cancer: Have wedelivered what we promised? Indian J SurgOncol.2010;1:166-85.


43. van derMolen L, van RossumMA, Jacobi I,van SonRJ, Smeele LE, RaschCR, et al. Pre-andposttreatmentvoicespeechoutcomesinpatientswithadvancedheadandneckcancertreated with chemoradiotherapy: expertlisteners’ and patient’s perception. J Voice.2012;26:664.e25-33.

44. Ryu JS, Park SR, Choi KH. Prediction oflaryngeal aspirationusing voice analysis. AmJPhysMedRehabil.2004;83:753-7.

45. Murugappan S, Boyce S, Khosla S, KelchnerL, Gutmark E. Acoustic characteristics ofphonationin“wetvoice”conditions.JAcoustSocAm.2010;127:2578-89.

46. [46] de Bruijn MJ, Rinkel RN, Cnossen IC,Witte BI, Langendijk JA, Leemans CR, etal. Associations between voice quality andswallowing function in patients treated fororal or oropharyngeal cancer. Support CareCancer.2013;21:2025-32.

47. Sanguineti G, Adapala P, Endres EJ, BrackC, Fiorino C, Sormani MP, et al. Dosimetricpredictors of laryngeal edema. Int J RadiatOncolBiolPhys.2007;68:741-9.

48. SteeleCM,BaileyGL,ChauT,MolfenterSM,OshallaM,Waito AA, et al. The relationshipbetween hyoid and laryngeal displacementandswallowingimpairment.ClinOtolaryngol.2011;36:30-6.

49. Molfenter SM, Steele CM. Kinematic andtemporalfactorsassociatedwithpenetration-aspiration in swallowing liquids. Dysphagia.2014;29:269-76.

50. Steele CM, Cichero JA. Physiological factorsrelatedtoaspirationrisk:asystematicreview.Dysphagia.2014;29:295-304.

51. Sia I, Carvajal P, Carnaby-Mann GD, CraryMA. Measurement of hyoid and laryngealdisplacement in video fluoroscopicswallowing studies: variability, reliability, andmeasurementerror.Dysphagia.2012;27:192-7.

52. Baijens L, Barikroo A, Pilz W. Intrarater andinterrater reliability for measurements in videofluoroscopyofswallowing.EurJRadiol.2013;82:1683-95.

53. HutchesonKA,KellyS,BarrowMP,BarringerDA, Perez DP, Little LG, et al. OfferingMorefor Persistent Dysphagia after Head andNeck Cancer: The Evolution of Boot CampSwallowingTherapy.Downloadedonlineat8thNovember 2015 at: http://researchposters.com/Posters/COSM/COSM2015/C058pdf.

54. Langmore SE, McCulloch TM, Krisciunas GP,Lazarus CL, VanDaeleDJ, Pauloski BR, et al.Efficacyofelectrical stimulationandexercisefordysphagiainpatientswithheadandneckcancer:Arandomizedclinicaltrial.HeadNeck.2015.

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55. Ahlberg A, Engstrom T, Nikolaidis P,Gunnarsson K, Johansson H, Sharp L, et al.Early self-care rehabilitation of head andneck cancer patients. Acta Otolaryngol.2011;131:552-61.

56. Mortensen HR, Jensen K, Aksglaede K,LambertsenK,EriksenE,GrauC.ProphylacticSwallowingExercisesinHeadandNeckCancerRadiotherapy.Dysphagia.2015;30:304-14.


58. Watts CR. Measurement of hyolaryngealmuscle activation using surfaceelectromyography for comparison of tworehabilitative dysphagia exercises. Arch PhysMedRehabil.2013;94:2542-8.

59. Hughes T, Watts CR. Effects of 2 ResistiveExercises on Electrophysiological Measuresof SubmandibularMuscleActivity.ArchPhysMedRehabil.2015.

60. Mishra A, Rajappa A, Tipton E, MalandrakiGA. The Recline Exercise: Comparisons withthe Head Lift Exercise in Healthy Adults.Dysphagia.2015;30:730-7.

61. Sze WP, YoonWL, Escoffier N, Rickard LiowSJ. Evaluating the Training Effects of TwoSwallowing Rehabilitation Therapies UsingSurface Electromyography-Chin Tuck AgainstResistance (CTAR) Exercise and the ShakerExercise.Dysphagia.2016.



64. Tabit CJ, Slack GC, Fan K, Wan DC, BradleyJP. Fat grafting versus adipose-derived stemcell therapy: distinguishing indications,techniques, and outcomes. Aesthetic PlastSurg.2012;36:704-13.

65. HamzaA,LohsiriwatV,RietjensM.Lipofillinginbreastcancersurgery.GlandSurg.2013;2:7-14.

66. Groher ME, Crary MA. Dysphagia: clinicalmanagementinadultsandchildren.St.Louis,Missouri:Elsevier;2016.

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SUMMARY

Thisthesisdescribesanddiscussesoropharyngealandlaryngealfunctionfollowing(organ-preservation) treatment for advanced head and neck cancer (HNC), including long-termresultsofcross-sectionalcohortstudies,andprospectivelystudiedtreatmentstrategiesforchronic,therapy-refractorydysfunction.

Radiotherapy (RT) or combined chemoradiotherapy (CRT) regimens are increasinglyusedasprimary treatment forpatientswith (locally) advancedHNC.Unfortunately, theseorgan-preserving protocols are associated with substantial adverse functional events,notablydysphagia. The result canbe reduced food intake,weight loss andultimately theneed for nasogastric or percutaneous tube feeding,which negatively influences patients’qualityoflife.Chapter 1providesageneralintroductionintotheepidemiology,treatment,andtreatment-inducedtoxicitiesfollowingorgan-preservationtreatmentforadvancedHNC.Preventiveandrehabilitativestrengthtrainingstrategiesbasedonthesamemethodsappliedin sports medicine are discussed. Chapter 2 concerns a systematic review,which aims tosummarizethecurrentassessmentandtreatmentstrategies fordysphagia followingHNC,andtogivedirectionsforthefuture.StudieswereidentifiedbyacomprehensiveelectronicdatabasesearchusingMedlineandEmbase,andallretrievedarticleswerescreenedontitleandabstract,methodologicalquality, and riskofbias.Dysphagiaassessment isaddressedwithemphasisontimingandonthevarioustoolsused.Further,optimaltreatmentstrategiesarediscussedwithspecialfocusontreatmentgoalsandoptions.Intotal11studiesorreviewsthat describe dysphagia assessment, and 10 studies or reviews that report on dysphagiatreatment are reviewed. It became clear that there is still no uniform ‘gold-standard’ foreither assessment or treatment strategies, despite the fact that functional swallowingassessmentandtreatmenthavebecomestandardofcareinHNCpatients,giventheseriousimpactofdysphagiaonqualityoflifeduringHNCsurvivorship.Hence,thissystematicreviewrecommends more high quality data, adequately controlled, powered and randomized,on prophylactic and therapeutic swallowing exercises, with longer follow-up and optimaladherencetotreatment,inordertobetterreducetoxicityofchemo-andradiotherapy,andtopossiblymodifysurgicalresectionsandreconstructions.Inaddition,frequency,timinganddurationofexercisetherapyneedfurtherinvestigationtoimproveswallowingfunctionandoptimizequalityoflife.

Long-term evaluationAlso substantial effects on laryngeal function (i.e. voice quality and speech intelligibility)arereportedintheliteraturefollowingorgan-preservationtreatmentfor(locally)advancedHNC. Part 1 of this thesis focuses on oropharyngeal and laryngeal function at long-term.

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In Chapter 3 and Chapter 4 aHNCpatientpopulationpreviously treatedwithconcurrentCRT is studied on functional swallowing, and voice and speech outcomes at more than10 years post-treatment. Twenty-two disease-free survivors, treated with cisplatin-basedCRT for inoperable HNC (1999–2004), were evaluated to assess long-term morbidity.The prospective assessment protocol consisted of videofluoroscopy (VFS) for obtainingPenetrationAspirationScale (PAS), andpresenceof residuescores. FunctionalOral IntakeScale (FOIS) scores,maximummouthopeningmeasurements,and (SWAL-QOLandstudy-specific) questionnaires were also assessed. A standard Dutch text was recorded, andperceptualanalysisofvoice,speech,andarticulationwasconductedbytwoexpertlisteners.Additionally, an experimental expert system based on automatic speech recognition wasused.Patients’perceptionofvoiceandspeechandrelatedqualityoflifewasassessedwiththeVoiceHandicapIndex(VHI)andSpeechHandicapIndex(SHI)questionnaires.Regardingoropharyngeal functional outcomes, 10 patients (45%) were able to consume a normaloral dietwithout restrictions (FOIS score 7),whereas 12patients (55%)hadmoderate toseriousswallowingissues,ofwhom3(14%)werefeedingtubedependent.VFSevaluationshowed15/22patients(68%)withpenetrationand/oraspiration(PAS≥3).Fifty-fivepercentofpatients(12/22)haddevelopedtrismus(mouthopening≤35mm),whichwassignificantlyassociatedwithaspiration(p=.011).Subjectiveswallowingfunction(SWAL-QOLscore)wasimpairedacrossalmostallqualityoflifedomainsinthemajorityofpatients.Patientstreatedwith IMRT showed significantly less aspiration (p =.011), less trismus (p =.035), and lesssubjectiveswallowingproblemsthanthosetreatedwithconventionalRT.Voicequalityandspeech intelligibilitywerealsoaffected.Perceptualevaluationshowedabnormal scores inupto64%ofcases,dependingontheoutcomeparameteranalysed.Automaticassessmentofvoiceandspeechparameterscorrelatedmoderatelytostronglywithperceptualoutcomescores.Patient-reportedproblemswithvoice(VHI>15)andspeech(SHI>6)indailylifewerepresentin68%and77%ofpatients,respectively.Again,patientstreatedwithIMRTshowedsignificantlylessimpairmentcomparedtothosetreatedwithconventionalRT.

The aim of Chapter 5 was to report the long-term functional outcomes >5 yearsafter concurrentCRT inapatient cohort thatwaspreviouslyalso treatedwithpreventiverehabilitation. Primary endpoints were swallowing function, mouth opening and voicequality. The original trial involved 55 patientswith advancedHNCwho received CRT andwererandomizedtooneoftwopreventiverehabilitationprogrammesfor1year:standardlogopaedic swallowing exercises or an experimental swallowing rehabilitation program.Since the results were generally similar in the two treatment groups, this analysis usedcombineddata fromall 22participantswhoweredisease-free andevaluable at >5 yearspost-treatment.Swallowingfunctionwasassessedbyinvestigatinglaryngealpenetrationandaspiration,oralintakeandnutritionalstatus,mouthopening,painandqualityoflife.Voicequalitywasassessedusingacousticvoiceparameters.Atameanfollow-upperiodof6years,


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thefrequencyofmostswallowingproblemsremainedlowandwassimilartothatobservedatbaselineor after2 yearsof follow-up. Theexceptionswere increases in the frequencyof xerostomia from18%at baseline to 68%at 6 years (p =.003), andofmild pain in theheadandneckregion,from9%at2yearsto32%(p=.06).Inthe7patientswithtumourslocatedbelowthehyoidbone,acousticvoiceanalysisshowedtheyhad lessvoicedness,ahigherfundamentalfrequency,andincreasedvocaleffortat6yearsthanthosewithtumoursabovethehyoidbone.Overall,thepatients’subjectiveperceptionsoftheirvocalfunctionat6yearsweregood,although50%perceivedtheirvoiceasdifferentfromthatatbaseline.Inconclusion,fewsurvivingpatientswithadvancedHNCwhoreceivedconcurrentCRTandtookpart in apreventive rehabilitationprogramhadproblemswitheither swallowingor voicequalityat6yearspost-treatment.

Chapter 6 provides quantitative data pertinent to one of themechanical features offluoroscopicswallowstudies,i.e.anteriorandsuperiorhyoidbonedisplacement.Thisstudyreportsontemporalandkinematicmeasuresofhyoiddisplacement,withtheadditionalgoaltoinvestigatecorrelationswithpersisting(clinical)swallowingimpairmentintherehabilitatedpatientpopulation.Asingle-blindanalysisofdatacollectedaspartoftheabove-describedlargerprospectivestudy (Chapter5)wasperformedat threetimepointsbeforeandafterCRT. Twenty-five HNC patients are evaluated. Patients had undergone clinical swallowingassessmentsatbaseline,at10weeks,andat1yearpost-treatment.VFSanalysiswasdoneondifferentswallowingconsistenciesofvaryingamounts.TheVFSstudieswereindependentlyreviewedframe-byframebytwoclinicalresearcherstoassesstemporal(onsetandduration)andkinematic(anteriorandsuperiormovement)measuresofhyoiddisplacement(ImageJ),PASscores,andpresenceofmorethannormalvalleculaorpyriformsinusresidues.Patient-reported FOIS scores and swallowing function (study-specific questionnaire) were alsoevaluated.Resultsshowthatthemeanmaximumhyoiddisplacementrangedfrom9.4mm(23%ofC2-4distance)to12.6mm(27%)anteriorly,andfrom18.9mm(41%)to24.9mm(54%)superiorly,dependingonbolusvolumeandconsistency.Hyoidelevationstarttimeandmaximumhyoidelevationtimedidnotdiffersignificantlyovertime.Inaccordancewiththeliterature,hyoidbonedisplacementseemssubjecttovariabilityfromanumberofsources.Furtherresearchwithlargersamplesizeswillbenecessarytoconfirmpossiblecorrelationpatterns.

Prospective studiesPart 2 of this thesis describes prospective studies on non-surgical or minimal invasivetreatment strategies for oropharyngeal and laryngeal dysfunction, based on the insightsobtainedwith the cross-sectional studies in Part 1. Since dysphagia inHNC patientsmaydevelopduetomuscleweakness(asresultoffibrosisoratrophy)followingCRT,strengtheningoftheswallowingmusclesthroughtherapeuticexerciseispotentiallyeffectiveforimproving

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swallowingfunction.InChapter 7thefeasibilityandeffectivenessofstrengtheningexerciseswith adedicated swallowingexercise aid (SEA) is studiedon suprahyoidmusculature andfunctioninseniorhealthysubjects.Itwashypothesizedthatthistool,developedforisometricandisokineticstrengtheningexercisesagainstresistance,canhelptofunctionallystrengthenthe suprahyoid musculature (i.e. the mylohyoid, geniohyoid, and digastric muscles),which in turn can improve swallowing function. Ten senior healthy volunteers performedchin tuck against resistance (CTAR), jaw opening against resistance (JOAR), and effortfulswallowexercises3timesperday for6weeks.Multidimensionalassessmentconsistedofmeasurementsofmaximumchintuckandjawopeningstrength,maximumtonguestrength/endurance, suprahyoid muscle volume, hyoid bone displacement, swallowing transporttimes, occurrence of laryngeal penetration/aspiration and/or contrast residue, maximummouth opening, feasibility and compliance (questionnaires), and subjective swallowingcomplaints (SWAL-QOL questionnaire). After 6 weeks exercise, mean chin tuck strength,jawopeningstrength,anteriortonguestrength,suprahyoidmusclevolume,andmaximummouth opening significantly increased (p <.05). Feasibility and compliance (median 86%,range48–100%)oftheSEAexercisesweregood.Tosummarize,thisprospectivefeasibilityandeffectivenessstudyontheeffectsofCTAR/JOARisometricandisokineticstrengtheningexercisesonswallowingmusculatureandfunctionshowedthatseniorhealthysubjectsareabletosignificantlyincreasesuprahyoidmusclestrengthandvolumeaftera6-weektrainingperiod.

ThesepositiveresultswarrantedfurtherinvestigationofefficacyandeffectivenessoftheseSEAexercisesinHNCpatientswithchronicdysphagia.Therefore,inChapter 8 this dedicated treatmentregimenisexploredinaphase-2clinicaltrialamongpatientswithchronic,therapy-resistant dysphagia. A prospective clinical studywas carried out in 18HNC patientswithchronicdysphagia,whoperformedswallowandnon-swallowexercises3timesdailyfor6-8weeks.TheexerciseswereperformedwiththeSEAallowingforprogressivemuscleoverload,including chin tuck and jaw opening against resistance, and effortful swallow exercises.Outcomeparameterswerefeasibility,compliance,andshort-termeffectparameters.After6to8weeksofintensiveswallowingtraining,theoverallandspecificcomplianceintermsofthe3dailysessionswere89%and97%,respectively.Attheendofthetrainingperiod,medianchintuckandjawopeningstrengthhadsubstantiallyimproved.Ninety-fourpercentofpatientsreportedtobenefitfromtheexercises.Inconclusion,feasibilityandcompliancewerehigh.Someobjectiveandsubjectiveeffectsofprogressiveloadonsuprahyoidmusclestrengthandswallowingfunctionweredemonstrated.

In Chapter 9,thefeasibilityandpotentialvalueofanexperimentaltreatment(lipofilling)is prospectively studied in patients with post-treatment oropharyngeal dysfunction, toaddresschronicdysphagiaandaspirationinHNCpatientswhoarereallytherapy-refractory.Itwashypothesizedthat,ifintensiveswallowingtherapyoffersnofurtherimprovement,and


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the functional problems persist, transplantation of autologous adipose tissue (lipofilling)mightrestorefunctionaloutcomesbycompensatingtheexistingtissuedefectsortissueloss.In total sevenpatientswith chronic dysphagiawere included. Theprocedurewas carriedoutundergeneralanesthesiainseveralsessionsusingtheColemantechnique.SwallowingoutcomeswereevaluatedwithstandardVFSforobtainingobjectivePASandresiduescores.SubjectiveFOISscoresandSWAL-QOLquestionnaireswerealsocompleted.MRIwasusedto evaluate the post-treatment injected fat. Five patients completed the intended threelipofillingsessions,whiletwocompletedtwoinjections.Onepatientdroppedoutofthestudyaftertwoinjectionsbecauseofprogressivedysphagiarequiringtotallaryngectomy.FourofthesixremainingpatientsshowedimprovedPASscoresonpost-treatmentVFSassessments,withtwopatientsnolongershowingaspirationforaspecificconsistency.Twopatientswerenolongerfeedingtubedependent.Patient-reportedswallowingandoralintakeimprovedinfouroutofsixpatients.Basedontheresults,thelipofillingtechniqueseemssafeand–inselectedcases–ofpotentialvalueforimprovingswallowingfunctioninthissmalltherapy-refractoryHNCpatientcohort.

Finally,inChapter 10,theresultsobtainedinthecurrentthesisarediscussed,andfutureperspectivesareoutlined.

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SAMENVATTING

Ditproefschriftrichtzichoporofaryngealeenlaryngealefunctieszoalsslikken,mondopeningenstem/spraakna(orgaan-sparende)behandelingvoorvergevorderdehoofd-halskanker.Inheteerstedeelvanditproefschriftkomenenkelecross-sectionelestudiesnaardefunctionelegevolgen op de lange termijn aan de orde. In het tweede deel wordt in prospectievestudieopzetgezochtnaarniet-chirurgischeofminimaalinvasievebehandelmodaliteitenvoorchronische/persisterendefunctioneleproblemen.

Vergevorderde hoofd-halskanker wordt veelal orgaan-sparend behandeld middelsradiotherapie(RT)ofdoorradiotherapietecombinerenmetchemotherapie(CRT).Metdezebehandelmodaliteitenwordenregelmatiggoederesultatenbereikt,echterhelaasnogaleenstenkostevanaanzienlijke functionelebijwerkingen,zoalshetoptredenvanslikproblemen(dysfagie).Dysfagiekanleidentotverminderdeoraleintake,gewichtsverliesenzelfstothetpermanentviaeenvoedingssondegevoedmoetenworden.Alsgevolghiervanisdekwaliteitvanlevenvaakernstiggestoord.Hoofdstuk 1 vanditproefschriftgeefteenoverzichtvandeepidemiologie, behandelingen functionelebijwerkingennaorgaan-sparendebehandelingvoorvergevorderdetumoreninhethoofd-halsgebied.Ookwordtaandachtbesteedaandemogelijke rol van preventieve slikrevalidatie en intensieve krachtrevalidatie gebaseerd opprincipesuitdesportgeneeskunde.InHoofdstuk 2wordteensystematischliteratuuroverzichtgegeven over de huidige diagnostische en therapeutische mogelijkheden voor dysfagiena behandeling voor hoofd-halskanker. Met behulp van een uitgebreide zoekactie in deelektronischedatabasesMedlineenEmbase zijn alle artikelenuit 2012en2013opbasisvantitelensamenvattinggescreendoprelevantie,methodologischekwaliteitenhetrisicoopbias. Intotaalkonden11studiesofreviewsgeselecteerdworden,waarinverschillendediagnostische testen voor dysfagie worden beschreven. Eveneens worden 10 studies ofreviewsbesprokenwaarinwordtgerapporteerdoververschillendebehandelmogelijkhedenvoordysfagie.Dit literatuuroverzichtheeftduidelijkgemaaktdatergeenevidentegoudenstandaardbestaatvoordiagnostischeen/oftherapeutischestrategieën.Ondanksdatdysfagiebij hoofd-halskanker patiënten, gezien de zeer negatieve impact van slikklachten op dekwaliteitvanleven,standaardwordtgeëvalueerdenbehandeld,ishetnogsteedsonduidelijkwelkebehandeling(metnamemetbetrekkingtottype,frequentie,duurenintensiteitvanoefeningen)moetwordentoegepast.Ditsystematischeliteratuurreviewmaakthetmogelijkenkele aanbevelingen te doen voor het uitvoeren van prospectieve, gerandomiseerd engecontroleerde studies. Daarbij is het essentieel dat er gestreefd wordt naar optimaletherapietrouw (compliance), lange termijn follow-up en doelgerichtere therapieënomdeslikproblementeverminderen,omdaarmeedekwaliteitvanleventeverbeteren.

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Lange-termijn evaluatieNaastslikproblemenwordenindeliteratuureveneensaanzienlijkestem-enspraakproblemenbeschrevennaorgaan-sparendebehandelingvoorvergevorderdehoofd-halskanker.Deel1vanditproefschriftrichtzichopdefunctionelegevolgenopdelangetermijn.InHoofdstuk 3 en Hoofdstuk 4wordenfunctioneleuitkomstenzoalsslikfunctie,mondopeningenstem/spraak beschreven in een populatie hoofd-halskanker patiënten na eerdere behandelingmetgecombineerdeCRT (1999–2004).Ruim10 jaarnabehandelingwerden22patiëntengeëvalueerd om de lange termijn morbiditeit vast te stellen. Alle patiënten hadden eenprimairetumoruitgaandevandemond-ofkeelholte(mondholte,orofarynxofhypofarynx).Depatiëntenwerdenonderzocht aandehandvaneengestructureerdmultidimensionaalprotocol, te weten: röntgenslikvideo’s, stemopnames, lichaamsgewicht, maximalemondopening en gestructureerde vragenlijsten met betrekking tot de slikfunctie, oraleintake,stem-enspraakfunctieenalgemenekwaliteitvanleven.Devragenlijstenbetroffende gevalideerde ‘Swallowing Quality of Life Questionnaire’ (SWAL-QoL) en een studie-specifieke vragenlijst. Op basis van de röntgenslikvideo’s werden de Penetratie AspiratieSchaal(PAS)encontrastresiduscoresbepaald.DaarnaastwerddeFunctioneleOraleIntakeSchaal (FOIS) toegepast. Perceptieve stemanalyseswerden uitgevoerd door twee ervarenluisteraars (logopedisten) en met behulp van een geavanceerd computerprogramma(ASISTO), gebaseerd op automatische spraakherkenning. Dit onderzoek liet zien dat 10patiënten(45%)eennormaleoraleintakehadden(FOISscore7)ruim10jaarnabehandeling,terwijl 12patiënten (55%)matig toternstige slikproblemenhadden,waarvan3patiënten(14%) zelfs sondevoeding afhankelijk waren. De röntgenslikvideo’s toonden laryngealepenetratie of aspiratie (PAS ≥3) in 15 patiënten (68%). Twaalf patiënten (55%) haddentrismus ontwikkeld (mondopening ≤35 mm), wat geassocieerd was met het optredenvan aspiratie (p=0.011). Het merendeel van de patiënten rapporteerde (op basis van deSWAL-QoL scores) een aande slikproblemen gerelateerde, gestoorde kwaliteit van leven.DepatiëntendiebehandeldwarenmetIMRTlietensignificantminderaspiratie(p=0.011),mindertrismus(p=0.035)enmindersubjectiefervarenslikproblemenziendandepatiëntendie behandeldwarenmet conventionele RT. De stemkwaliteit en spraakverstaanbaarheidwaren eveneens vaker aangedaan in de conventioneel bestraalde patiëntengroep.Perceptieve stem- en spraakanalyses lieten abnormale scores zien oplopend tot 64%,afhankelijk vandegeanalyseerdeuitkomstparameter.Deuitkomstenvandeautomatischestem-enspraakanalysecorreleerdematigtotsterkmetdeperceptievebeoordelingenvandeervarenluisteraars.Depatiëntenrapporteerdendagelijksestem-(VHI>15)enspraak-(SHI>6)stoornissenin68%en77%vandegevallen,respectievelijk.OokhierbijgolddatdedoorIMRTbehandeldepatiëntenminderstoornissenrapporteerden.

HetdoelvanHoofdstuk 5 wasomdelangetermijnfunctioneleuitkomstenterapporterenruim5jaarnabehandelingmetgecombineerdeCRTineencohorthoofd-halskankerpatiënten



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dat had meegedaan aan een gerandomiseerd klinisch onderzoek naar de effecten vanpreventieveslikrevalidatie.Deprimaireuitkomstmatenwarenslikfunctie,mondopeningenstemkwaliteit.Initieelwarener55patiëntenmeteenvergevorderdetumorindemondholte,orofarynx,hypofarynx,nasofarynxoflarynxindezepreventieverevalidatiestudiegeïncludeerd.De patiënten waren behandeld met IMRT en (gelijktijdige) intraveneuze chemotherapie(cisplatin). Voorafgaandaandebehandelingwerdendepatiënten gerandomiseerd in eenstandaard logopedische oefengroep of een experimentele oefengroep. Alle patiëntenhadden tijdens de behandeling preventieve slikoefeningen uitgevoerd, die zij haddengecontinueerdtot1jaarnabehandeling.Doordatderesultateninbeideoefengroepenopdekortetermijngelijkwaren,werdendegegevensgecombineerdvooranalyseopdelangetermijn.Deslikfunctiewerdvastgesteldaandehandvanlaryngealepenetratieofaspiratie(PAS scores), contrast residu scores, orale intakeen voedingsstatus (FOIS scores, gewicht,BMI),maximalemondopening,pijnenkwaliteitvanleven.Destemkwaliteitwerdgemetenaandehandvanverschillendeakoestischestemparameters.Naeenmedianefollow-upvan6jaarblekende22overlevendepatiëntenslechtsweinigslikproblementehebben.Demeestefunctioneleenkwaliteitvanlevenaspectenwarennietsignificantveranderdtenopzichtevandeuitgangssituatieofvandesituatiena2jaarfollow-up.Uitzonderingenwarenxerostomie,diesignificantwastoegenomenvan18%vóórdebehandelingtot68%na6jaar(p=0.003)enmildepijninhethoofd-halsgebied,diewastoegenomenvan9%na2jaartot32%na6jaar(p=0.06).Inde7patiëntenmeteentumordistaalvanhettongbeen(larynx,hypofarynx)lietendeakoestische stemanalysesminder stemhebbendheid,eenhogere toonhoogteenmeervocaleinspanningzienvergelekenmetdepatiëntenmeteentumorcraniaalvanhettongbeen(mondholte,orofarynx,nasofarynx).Depatiëntenervoerenweinigstemklachten6 jaarnabehandeling,ondanksdat50%vandepatiëntenaangafdatde stemveranderdwastenopzichtevandeuitgangssituatie.Concluderendzijnerbeperktefunctioneleslik-enstemproblemeninditpatiëntencohort6jaarnabehandelingmetCRT,mogelijkvanwegedepreventieveslikrevalidatieprogramma’sdietijdensennadebehandelingzijntoegepast.

Hoofdstuk 6 verschaft kwantitatieve gegevens over de slikfunctie aan de hand vantemporeleenspatielevariabelendiebetrekkinghebbenopdeverplaatsingvanhettongbeen(alsmaatvoorlarynxheffing)tijdenshetslikken.Hetdoelvandestudiewaseenbeterinzichtte verkrijgen in de pathofysiologie van het slikken in de gerevalideerde hoofd-halskankerpatiëntenpopulatieenomcorrelatiesteonderzoekenmetobjectieveensubjectieveklinischeslikproblemen. De gegevens werden geanalyseerd aan de hand van eerder verzamelderöntgenslikvideo’sinhetkadervandehierbovenbeschrevenprospectievestudie(Hoofdstuk5).Eengestandaardiseerdvideofluoroscopieprotocolwastoegepastin25hoofd-halskankerpatiëntendie röntgenslikvideo’shaddenondergaanopdrie verschillendemeetmomentenvóórennaCRT(uitgangssituatie,10wekenen1jaarnabehandeling).Deanalyseswerdenverrichtopverschillende(dunendikvloeibare)consistentiescontrastmiddelvanverschillende

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hoeveelheden. De slikstudies werden onafhankelijk, frame per frame door twee klinischonderzoekersbeoordeeld.Informatiewerdverkregenovertransporttijden,deverplaatsingvan het tongbeen in zowel de anterieure als de craniale richting (met behulp van hetbeeldanalyseprogrammaImageJ),PASscoresencontrastresiduscores.DeeerderverzameldeFOISscoresengegevensoverdesubjectiefervarenslikfunctie(studie-specifiekevragenlijst)werdeneveneensindeanalysemeegenomen.Degemiddeldemaximaleverplaatsingvanhettongbeenvarieerdevan9.4mm(23%vandeafstandtussendecervicalenekwervelsC2-C4)tot12.6mm(27%)indeanterieurerichtingenvan18.9mm(41%)tot24.9mm(54%)indecranialerichting,afhankelijkvanbolusvolumeenconsistentie.Detransporttijdentijdenshetslikkenverschildennietsignificantoverdetijd.Zoalsverondersteldindeliteratuur,werddoormiddelvanditonderzoekduidelijkdatermeerdereoorzakenlijkentezijnvoordevariabeleverplaatsing van het tongbeen. Verder onderzoekmet een grotere patiëntenpopulatie isaldusgewenstommogelijkecorrelatiestebevestigen.

Prospectieve studiesDeel2vanditproefschriftbeschrijftprospectievestudiesoverniet-chirurgischeofminimaalinvasievebehandelstrategieënvoororofaryngealeenlaryngealedysfunctie,medeopbasisvandeinzichtenverkregenmethetliteratuurreviewendecross-sectionelestudiesuitDeel1. Aangezien hoofd-halskanker patiënten dysfagie kunnen ontwikkelen door spierzwakte(als gevolg vanfibroseen spieratrofie)naCRT, kanversterking vande slikspierenmiddelstherapeutische krachtoefeningen mogelijk effectief zijn voor het verbeteren van deslikfunctie. In Hoofdstuk 7 wordt de haalbaarheid en effectiviteit van spierversterkende(slik-)oefeningen gericht op de suprahyoidale spiergroep bestudeerd in oudere, gezondeproefpersonen. De oefeningenwerden uitgevoerdmet een speciaal daarvoor ontwikkeldhulpmiddel; de zgn. ‘Swallow Exercise Aid’ (SEA). Met dit apparaat is het mogelijk omprogressieve spierbelasting te realiseren doordat de weerstand tijdens de oefeningenkan worden opgehoogd. Verondersteld werd dat dit instrument, ontwikkeld voor zowelisometrische als isokinetische krachtoefeningen, kanhelpenomde suprahyoidale spierenteversterkenendaarmeehetslikkenfunctioneelkanverbeteren.Tiengezondevrijwilligershebbengedurende6weken3keerperdagverschillendeoefeningenuitgevoerd,teweten:‘chin tuck against resistance’ (CTAR; kin op de borst), ‘jaw opening against resistance’(JOAR; mond opening) en ‘effortful swallow’ (krachtig slikken) oefeningen. Met behulpvan eenmultidimensionaal evaluatieprotocol werden de volgende uitkomstmaten voorafen achteraf geëvalueerd: maximale ‘chin tuck’ en maximale ‘jaw opening’ kracht (metbehulp van een speciaal ontwikkelde testopstelling met een dynamometer), maximaletongkrachtenuithoudingsvermogengemetenmetde‘IowaOralPerformanceInstrument’(IOPI), suprahyoidale spiervolume (d.w.z. het volume van demusculusmylohyoideus, demusculusgeniohyoideusendemusculusdigastricustezamen,gemetenmetbehulpvanMRI



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opnames),anterieureencraniale tongbeenverplaatsing (opbasis van röntgenslikvideo’s),maximalemondopening(inmm),haalbaarheid/therapietrouw(doormiddelvaneenstudie-specifiekevragenlijst)ensubjectiefervarenslikklachtengebaseerdopSWAL-QoLscores.Nade6-weekseoefenperiodemetdeSEAlietenderesultatensignificanteverbeteringenzieninmaximale‘chintuck’enmaximale‘jawopening’kracht,maximaletongkracht,suprahyoidalespiervolume en maximale mondopening (p <0.05). De haalbaarheid en therapietrouw(mediaan86%;range48-100%)vandeSEAoefeningenwarengoed.Samenvattendtoontdezeprospectievehaalbaarheids-eneffectiviteitsstudieaandatdeisometrischeenisokinetischespierversterkendeoefeningenmetdeSEAslikspiervolumeenspierkrachtbijouderegezondeproefpersonenaanzienlijkkanverhogennaeenoefenperiodevan6weken.

DezepositieveresultatenrechtvaardigdenverderonderzoeknaardewerkzaamheideneffectiviteitvandezeSEAoefeningenbijhoofd-halskankerpatiëntenmetchronischedysfagie.Daaromwerd inHoofdstuk 8 dezebehandeling ineen fase2 klinische studieprospectiefonderzocht bij patiëntenmet chronische, therapieresistente dysfagie. Gedurende 6 tot 8wekenhebben18hoofd-halskankerpatiëntenmetchronischeslikklachten3keerperdaggeoefendmetdeSEA.Deprimaireuitkomstmatenwarenhaalbaarheid, therapietrouwenkortetermijneffectparameters.Na6tot8wekenintensievesliktrainingwasersprakevaneenalgemeneenspecifieke(opbasisvande3dagelijkseoefensessies)therapietrouwvan89%en97%,respectievelijk.Aanheteindvandeoefenperiodewaserwederomsprakevaneensignificanteverbeteringinmedianemaximale‘chintuck’en‘jawopening’kracht,metuitzonderingvaneendrietalpatiëntenmeteenuitgangskrachtvanminderdan10Newton.Bijnaallepatiënten(94%)haddenhetgevoelbetertekunnenslikkennadeoefenperiode.Concluderendwasersprakevaneenhogehaalbaarheidentherapietrouwenwerdenereenaantalobjectieveensubjectieveeffectenvanprogressievespierbelastingopdeslikspierkrachtenfunctieaangetoond.

In Hoofdstuk 9 wordt de haalbaarheid en potentiële waarde van een experimentelebehandeling (lipofilling) prospectief onderzocht bij patiënten met chronische, ernstiginvaliderendeorofaryngealedysfunctie,waarbijeerderereguliereofintensieve(logopedische)sliktherapieonvoldoenderesultaatheeftgeboden.Lipofillingwerdtoegepastbijfunctioneleslikproblemenalsgevolgvanvolumeverliesofatrofievandetongbasisoffarynxachterwandnaeerderechirurgischeof(chemo-)radiatiebehandelingvoorvergevorderdehoofd-halskanker.De hypothese was dat transplantatie van autoloog vetweefsel uit de buikwand mogelijkde klachten van dysfagie en aspiratie kan verminderen door compensatie van de langerbestaandeweefseldefecten/volumeverlies.Intotaalwerdenzevenpatiëntenmetlangdurigbestaande slikproblemengeïncludeerd voordeelnameaande studie.Deprocedurewerduitgevoerdonderalgehelenarcoseineendrietalsessies.Deuitkomstenwerdengeëvalueerdmiddelsröntgenslikvideo’svoorhetverkrijgenvanobjectievePASencontrastresiduscores.SubjectieveFOISscoresenSWAL-QoLscoreswerdenookmeegenomenindeanalyse.MRI

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opnameswerdengebruiktomdepostoperatievehoeveelheidgeïnjecteerdvetteevalueren.Vijfpatiëntenhaddendegeplandeprocedurevan3lipofillingsessiesvoltooid,terwijltweepatiëntenslechtstweevetinjectieshaddenondergaan.Eénpatiëntvieluitdestudienatweevetinjectiesvanwegeprogressievedysfagiewaardooreentotalelaryngectomienoodzakelijkwerd.Viervandezesoverigepatiënten lietennabehandelingverbeterdePASscoreszientijdens videofluoroscopie, waarbij twee patiënten niet langer aspireerden bij het slikkenvan een specifieke dun of dik vloeibare consistentie. Twee patiënten waren niet langersondevoeding afhankelijk. De subjectief ervaren (patiënt-gerapporteerde) slikfunctie enorale intakeverbeterde inviervandezespatiënten.Opbasisvandeze resultaten lijktdelipofillingtechniekdusveiligen–ingeselecteerdegevallen–ookvanpotentiëlewaardevoorverbeteringvandeslikfunctieenoraleintakebijhoofd-halskankerpatiëntenmetchronische,therapieresistentedysfagie.

TotslotwordenderesultatenvanditproefschriftinHoofdstuk 10besprokenenwordenenkeletoekomstperspectievengeschetst.


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LIST OF ABBREVIATIONS

1RM 1-RepetitionMaximum3D 3-DimensionalASISTO: AutomaticSpeechanalysisInSpeechTherapyforOncologyAVQI: AutomaticVoiceQualityIndexBMI: BodyMassIndexCRT: ChemoradiotherapyCT: ChemotherapyCTAR: ChinTuckAgainstResistanceFEES: FiberopticEndoscopicExaminationofSwallowingFOIS: FunctionalOralIntakeScaleHNC: HeadandNeckCancerICC: IntraclassCorrelationCoefficientIA: Intra-ArterialIMRT: Intensity-ModulatedRadiationTherapyIV: IntravenousJOAR: JawOpeningAgainstResistanceMIO: MaximumInterincisorOpeningMRI: MagneticResonanceImagingNMES: NeuroMuscularElectricalStimulationNPO: NothingPerOralOS: Overall SurvivalPES: Pharyngo-EsophagealSphincterPAS: PenetrationAspirationScaleRT: RadiotherapySD: StandardDeviationSEA: SwallowExerciseAidSHI: SpeechHandicapIndexSLP: SpeechLanguagePathologistSPSS: StatisticalPackageforSocialSciencesSWAL-QOL: SwallowingQualityofLifeQuestionnaireTL: TotalLaryngectomyTNM: Tumor Node MetastasisUES: UpperEsophagealSphincterVAS: VisualAnalogScaleVFS: VideofluoroscopyofSwallowingVHI: VoiceHandicapIndexQOL: QualityofLife

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Authorsandaffiliations|235

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AUTHORS AND AFFILIATIONS

A. Al-Mamgani, MD, PhD. Department of Radiation Oncology, The Netherlands CancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

M.W.M. van den Brekel,MD,PhD.DepartmentofHeadandNeckOncologyandSurgery,TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands;Institute of Phonetic Sciences, University of Amsterdam, Amsterdam, The Netherlands;DepartmentofOral andMaxillofacial Surgery,AcademicMedicalCenter,Amsterdam,TheNetherlands.

W.D. Heemsbergen, PhD. Department of Radiation Oncology, The Netherlands CancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

F.J.M. Hilgers, MD, PhD. Department of Head and Neck Oncology and Surgery, TheNetherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, The Netherlands;InstituteofPhoneticSciences,UniversityofAmsterdam,Amsterdam,TheNetherlands

O. Hamming-Vrieze, MD. Department of Radiation Oncology, The Netherlands CancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

I. Jacobi,PhD.DepartmentofHeadandNeckOncologyandSurgery,TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

O. Lapid, MD, PhD. Department of Plastic Reconstructive and Hand Surgery, AcademicMedicalCenter,Amsterdam,TheNetherlands.

L. van der Molen, SLP, PhD. Department of Head and Neck Oncology and Surgery, TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

I.M. Oskam,MD.DepartmentofHeadandNeckOncology andSurgery, TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

G.B. Remmerswaal, MD. Department of Head and Neck Oncology and Surgery, TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

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L.E. Smeele,MD,PhD.DepartmentofHeadandNeckOncologyandSurgery,TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands;DepartmentofOralandMaxillofacialSurgery,AcademicMedicalCenter,Amsterdam,TheNetherlands.

R.J.J.H. van Son,PhD.DepartmentofHeadandNeckOncologyandSurgery,TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.

M.M. Stuiver,PT,PhD.DepartmentofPhysicalTherapy,TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands;DepartmentofClinicalEpidemiologyBiostatisticsandBioinformatics,UniversityofAmsterdam,TheNetherlands.

R.P. Takes,MD,PhD.DepartmentofOtorhinolaryngology-HeadandNeckSurgery,RadboudUniversityMedicalCenter,Nijmegen,TheNetherlands.

H.J. Teertstra,MD.DepartmentofRadiology,TheNetherlandsCancerInstitute–AntonivanLeeuwenhoek,Amsterdam,TheNetherlands.


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PhD PORTFOLIO

NamePhDstudent: SophieAnneCharlotteKraaijengaPhDperiod: September2012–March2016NamePhDsupervisors: Prof.dr.M.W.M.vandenBrekel Prof.dr.F.J.M.Hilgers

Courses2010 GlobalHealthCourse,UniversityMedicalCenter,Utrecht2012 ClinicalEpidemiology,AMCgraduateschool,Amsterdam2012 GPRAPost-LaryngectomyRehabilitationCourse,NKI-AVL,Amsterdam2013 DysphagiaDiagnosisandPrevention,UniversityHospital,Antwerp2013 Multidisciplinary treatment in Head and Neck Cancer, Free University, Brussels2013 ‘BasisRegelgevingenOrganisatievoorKlinischonderzoekers’(BROK),AMC graduateschool,Amsterdam2013 DevelopingaSystematicReview,AMCgraduateschool,Amsterdam2013 PracticalBiostatistics,AMCgraduateschool,Amsterdam2014 OralPresentationinEnglish,AMCgraduateschool,Amsterdam2014 Scientific Writing in English for Publication, AMC graduate school, Amsterdam2015 Fundamental Critical Care Support (FCCS), Society of Critical Medicine, Bilthoven

Seminars, workshops, and master classes2012–2016 Monthly‘WerkgroepHoofd-HalsTumoren’(WHHT),NKI-AVL,Amsterdam2012–2016 Monthly‘HeelkundigeOncologischeDisciplines’(HOD)seminars,NKI-AVL, Amsterdam2013–2014 YearlyHeadandNeckCancerDysphagiaWorkshop,NKI-AVL,Amsterdam2014 Three-day Medical Business Masterclass, Masterclass Foundation, Amsterdam

(Inter)national conferences attended2012–2016 KNO-ledenvergadering(Nieuwegein,MaastrichtUMC)2013–2016 NWHHTJongeOnderzoekersdag(UMCUtrecht,NKI-AVL,Radboudumc)2013–2014 NWHHTResearchdag(ErasmusMC,NKI-AVL)2013 NVMKAnajaarsvergadering(Assen)2014 NVPCregionalerefereeravond(Amsterdam)

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2014 IFHNOS5th worldcongress(NewYork)2015 DuitseVerenigingvoorDysfagievergadering(München)2015 DysphagiaResearchSociety(Chicago)2015 NVMKAnajaarsvergadering(Amersfoort)2015 IAOOworldcongress(SaoPaulo)2015 EuropeanSocietyforSwallowingDisorders(Barcelona)

Supervising2014 G.B.Remmerswaal(medicalstudent),scientificinternship2015 S.Verheijen(diagnosticradiographicstudent),scientificinternship

Oral presentations‘13-‘14 Kraaijenga SA, van den Brekel MW. Surgical treatments for oropharyngeal

dysphagia in advanced head and neck cancer. Annual Head and Neck CancerDysphagiaRehabilitationCourse.AntonivanLeeuwenhoek,Amsterdam,26april2013;4oktober2013;25april2014

Nov‘13 Kraaijenga SA,vanderMolenL,vanTinterenH,HilgersFJ,SmeeleLE.Behandelingvan myogene temporomandibulaire dysfunctie; een gerandomiseerd klinischonderzoek met de TheraBite en standaard fysiotherapie. Mond-, kaak- enaangezichtschirurgie(NVMKA)57enajaarsvergadering.Assen,8november2013

Juni‘14 Kraaijenga SA,SmeeleLE,vandenBrekelMW,LapidO.Lipofillinginjectiesindekeelholtebij hoofd-hals kankerpatiëntenvanwegeernstige therapie- resistenteslik-ofstemklachten.PlastischeChirurgieAMC&VUmcregionalerefereeravond.Amsterdam,11juni2014

Juli‘14 Kraaijenga SA, vanderMolenL,JacobiI,vandenBrekelMW,HilgersFJ.Longtermswallowingfunctionandvoicequalityinadvancedheadandneckcancerpatientstreated with chemoradiotherapy and preventive swallowing rehabilitation. Int. FederationHeadNeckOncologySociety(IFHNOS)5thworldcongress.NewYork,30juli2014

Nov‘14 Kraaijenga SA,vanderMolenL,JacobiI,vandenBrekelMW,HilgersFJ.Prospectiefklinischonderzoeknaardelangetermijn(5-jaar+)slik-enstemfunctiebijhoofd-halskankerpatiëntenbehandeldmetchemoradiatieenpreventieveslikrevalidatie.225eKNO-ledenvergadering.Nieuwegein,21november2014


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Mrt‘15 Kraaijenga SA, van derMolen L, StuiverMM, Teertstra HJ, Hilgers FJ, van denBrekel MW. Effects of strengthening exercises on swallowing musculature andfunction in senior healthy subjects; a prospective effectiveness and feasibilitystudy.DysphagiaResearchSociety(DRS)annualmeeting.Chicago,12maart2015

Mrt‘15 Kraaijenga SA, van derMolen L, StuiverMM, Teertstra HJ, Hilgers FJ, van denBrekelMW.Het effect van spierversterkende oefeningen op volume en functievanslikspierenbijgezondeproefpersonen.5eNederlandseWerkgroepHoofd-HalsTumoren(NWHHT)jongeonderzoekersdags.Nijmegen,24maart2015

Mrt‘15 Kraaijenga SA, van der Molen L. Prevention and rehabilitation of swallowingfunctioninheadandneckcancerpatients;resultsofarandomizedcontrolledtrial.DeutscheGesellschaftfürDysphagie,jahrestagung.München,27maart2015

April’15 Kraaijenga SA, vanderMolenL,StuiverMM,TeertstraHJ,HilgersFJ,vdBrekelMW.Een prospectieve effectiviteits- en haalbaarheidsstudie naar spierversterkendeoefeningen op slikspiervolume en -functie in gezonde proefpersonen(posterpresentatie).226eKNO-ledenvergadering.Nieuwegein,24april2015

Juli’15 Kraaijenga SA,OskamIM,vanderMolenL,HilgersFJ,vdBrekelMW.Evaluationoflong-term(10-years+)dysphagiaandtrismusinpatientstreatedwithconcurrentchemo-radiotherapyforlocallyadvancedheadandneckcancer.Int.AcademyofOralOncology(IAOO)5thworldcongress.SaoPaulo,10juli2015

Sept’15 Kraaijenga SA,vanderMolenL,HilgersFJ,vdBrekelMW.Long-termoutcomesof swallowing, voice and speech following organ-preservation treatment foradvancedhead andneck cancer. ChirurgischeOncologie (sectie XI) bespreking.AntonivanLeeuwenhoek,Amsterdam,16september2015

Okt’15 Kraaijenga SA,vanderMolenL,HeemsbergenWD,RemmerswaalG,HilgersFJ,vdBrekelMW.Hyoidbonedisplacementasparameterforswallowingimpairmentin patients treated for advanced head and neck cancer. European Society forSwallowingDisorders(ESSD).Barcelona,3oktober2015

Okt’15 Kraaijenga SA,OskamIM,vanderMolenL,HilgersFJ,vdBrekelMW.Evaluationoflong-term(10-years+)dysphagiaandtrismusinpatientstreatedwithconcurrentchemo-radiotherapyforlocallyadvancedheadandneckcancer.EuropeanSocietyforSwallowingDisorders(ESSD).Barcelona,3oktober2015

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Nov’15 Kraaijenga SA, LapidO,vanderMolenL,HilgersFJ,SmeeleLE,vandenBrekelMW. Hertel van slikfunctie en orale intake met behulp van lipofilling in demond- of keelholte na behandeling voor hoofd-halskanker. Mond-, kaak- enaangezichtschirurgie (NVMKA) 59e najaarsvergadering.Amersfoort, 5 november2015

Nov’15 Kraaijenga SA, van der Molen L, Stuiver MM, Hilgers FJ, vd Brekel MW.Chronischeslikproblemenbijhoofd-halskankerpatiënten:nieuwe(oefentherapie)mogelijkheden? Symposium Logopedische & Audiologische Wetenschappen.Leuven,14november2015

Nov’15 Kraaijenga SA, LapidO,vanderMolenL,HilgersFJ,SmeeleLE,vandenBrekelMW.Hertelvanslikfunctieenoraleintakemetbehulpvanlipofillingindemond-ofkeelholtenabehandelingvoorhoofd-halskanker.227eKNO-ledenvergadering.Nieuwegein,19november2015

Jan’16 Kraaijenga SA, van der Molen L, Hilgers FJ, van den Brekel MW. Chronischeslikproblemen bij hoofd-halskanker patiënten: nieuwe (oefentherapie)mogelijkheden? Jaarvergadering Logopedie landelijke werkgroep Hoofd-Halstumoren.Nijmegen,15januari2016

List of publications

Kraaijenga SA,vanderMolenL,StuiverMM,TakesRJ,Al-MamganiA,vandenBrekelMW,HilgersFJ.Efficacyofanovelswallowingexerciseprogramforchronicdysphagiainlong-termheadandneckcancersurvivors.Submitted.

Kraaijenga SA,vanderMolenL,HeemsbergenWD,RemmerswaalGB,HilgersFJ,vandenBrekelMW.Hyoidbonedisplacementasparameterforswallowing impairment inpatientstreatedforadvancedheadandneckcancer.EurArchOtorhinolaryngol.Online2016Apr16.

Kraaijenga SA,LapidO,vanderMolenL,HilgersFJ,SmeeleLE,vandenBrekelMW.Feasibilityandpotentialvalueoflipofillinginpost-treatmentoropharyngealdysfunction.Laryngoscope.Online2016Apr14.

Kraaijenga SA,OskamIM,vanSonRJJH,Hamming-VriezeO,HilgersFJ,vandenBrekelMW,vanderMolenL.Assessmentofvoice,speech,andrelatedqualityoflifeinadvancedheadandneckcancerpatients10-years+afterchemoradiotherapy.OralOncol.2016Apr;55:24-30.


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Kraaijenga SA,Oskam IM, vanderMolen L,Hilgers FJ, vandenBrekelMW.Evaluationoflong-term (10-years+) dysphagia and trismus in patients treatedwith concurrent chemo-radiotherapyforlocallyadvancedheadandneckcancer.OralOncol.2015Aug;51(8):787-94.

Kraaijenga SA,vanderMolenL,StuiverMM,TeertstraHJ,HilgersFJ,vandenBrekelMW.Effectsofstrengtheningexercisesonswallowingmusculatureandfunctioninseniorhealthysubjects;aprospectiveeffectivenessandfeasibilitystudy.Dysphagia.2015Aug;30(4):392-403.

Kraaijenga SA,vanderMolenL,JacobiI,vandenBrekelMW,HilgersFJ.Prospectiveclinicalstudyonlong-termswallowingfunctionandvoicequalityinadvancedheadandneckcancerpatientstreatedwithconcurrentchemoradiotherapyandpreventiveswallowingexercises.EurArchOtorhinolaryngol.2015Nov;272(11):3521-31.

Kraaijenga SA, Smeele LE, van den BrekelMW, LapidO. Herstel van slik- en stemfunctiemetbehulpvanlipofillingindemond-ofkeelholtenabehandelingvoorhoofd-halskanker.NederlandsTijdschrvoorPlastischeChirurgie.2015Jan;6(1):33-38.

Kraaijenga SA, vanderMolen L, vandenBrekelMW,Hilgers FJ. CurrentAssessment andtreatmentstrategiesofdysphagiainheadandneckcancerpatients:asystematicreviewofthe2012/13literature.CurrOpinSupportPalliatCare.2014Jun;8(2):152-63.

HeresDiddensH,Kraaijenga SA,vanderMolenL,HilgersFJ,SmeeleLE,RetèlVP.Acost-effectivenessanalysisofusingtheTheraBitecomparedtostandardphysicaltherapyexerciseinaprospectiverandomizedclinicaltrialfortreatingmyogenictemporomandibulardisorder.Submitted.

Kraaijenga S, van der Molen L, van Tinteren H, Hilgers FJ, Smeele LE. Treatment ofmyogenic temporomandibulardisorder:aprospectiverandomizedclinical trial,comparingamechanicalstretchingdevice(TheraBite)withstandardphysicaltherapyexercise.Cranio.2014Jul;32(3):208-16.

WintersSM,KlisSFL,Kraaijenga SA,KoolACM,TangeRA,GrolmanW.Peri-operativebone-conducted Vestibular EvokedMyogenic Potentials in otosclerosis patients. Otol Neurotol.2013Aug;34(6):1109-14.

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About the author | 243

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ABOUT THE AUTHOR

SophieKraaijengawasbornonOctober3th,1986 inUtrecht, theNetherlands. She grew up with her parents and three sisters inGeldrop (Noord-Brabant). In 2005 she graduated from secondaryschool and started her medical study at the University of Utrecht.DuringthattimesheworkedasamedicalstudentatthedepartmentofOncologyandHaematology,wasanactivememberof her students’ union (U.V.S.V./N.V.V.S.U), and became chairmenof themasters’medicaleducationcommittee.Shespentaperiodof 3months (2010) in India and 2months (2011) at Curacao forclinicalinternships.Afterobtaininghermedicaldegreeattheendof2012,shestartedherPhDprojectatthedepartmentofHeadandNeckOncologyandSurgeryoftheNetherlandsCancerInstitute,underthesupervisingofprof.dr.F.J.M.Hilgersandprof.dr.M.W.M.vandenBrekel.Duringthisperiodsheworkedattheoutpatientclinicfortwoyears,sheorganizeda2-dayannualmeetingoftheDutchHeadandNeckSociety,andsheparticipatedwith99colleaguesatthenationalcyclingevent‘Alped’HuZes’toraisemoneyforcancerresearch.InAugust2015shestartedworkingasasurgicalresidentattheNetherlandsCancerInstitute,whilefinishingherPhDproject.Theresultsaredescribedinthisthesis.

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Acknowledgement|Dankwoord|245

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ACKNOWLEDGEMENT | DANKWOORD

Eenhalf jaarvoormijnafstuderen,tijdensmijnkeuzeco-schapopdeafdelinghoofd-halsoncologieenchirurgievanhetAntonivanLeeuwenhoek,stondikopdeOKteassisterentoterineenswerdgebeld.Ofdeco-assistentevennaarMichielwildekomen?NietsvermoedendliepiknaarhettoenmaligeH-gebouw,waariknietalleenMichiel,maarookFransenLisettein enigszins formele setting aantrof,met de vraag of ik fulltimewilde gaan promoveren.“Ietsmetslikken”washetenigedatikonthoudenhad..OndanksdatMichielzeidatikhiereigenlijkeenweekovermoestnadenken,zeiikmeteenja.Hetwashetbeginvaneennieuwavontuur,watachterafgezienveeltesnelvoorbij isgegaan.HetAntonivanLeeuwenhoekiseenfantastischinstituutenikkijkmetheelveelplezierterugopdeafgelopenjarendatikdeelhebmogenuitmakenvandehoofd-halsafdeling.Uiteraardhebikgedurendedezejarenvanvelenbegeleidingenondersteuninggehad.Iedereendieeenbijdrageheeftgeleverdaande totstandkomingvanditproefschriftben ikdanookveeldankverschuldigd.Eenaantalpersonenzouikhiergraaginhetbijzondernoemen.

Mijn promotor prof. dr. M.W.M. van den Brekel. Beste Michiel, ik heb ontzettend veelbewonderingvoordehoeveelheidenergieen interessedie jijhebtenhoe jealtijdzoveelverschillendeklinische,wetenschappelijkeenoverigezakenmetelkaarweettecombineren.Jegafmedevrijheidomzelfstandig tewerk tegaan,maarwasookkritischwanneerdatnodig was. Ook wil ik je enorm bedanken voor het mogelijk maken van verschillendecongresbezoekennaaro.a.NewYork,ChicagoenSaoPaulo.Zolang jede trapnaarde5everdiepingopblijftsprintenenMarionofHenny jeagendaenafsprakenbeheert,weet ikzekerdathetgoedmetjezalgaan.Ikwensjehetallerbestevoordetoekomst!

Mijnpromotor,prof.dr.F.J.M.Hilgers.BesteFrans,hetismegelukt;ikben(tochnog)totéénvanjouwpromovendigaanhoren!Desnelheidvandetotstandkomingvanditproefschriftisdeelstedankenaanjouwsnelleenzorgvuldigebegeleiding,metaltijdzeerlaagdrempelig(whatsapp)contact.Waarjejeookterwereldbevond,jijreageerdealtijdbinnenenkeleurenenhettijdsverschilzorgdeervaakvoordatwedesteefficiënterkondensamenwerken.Ikwiljeenormbedankenvoorjeenthousiasmeenbetrokkenheidenvoorallemogelijkhedendiejemijgebodenhebt.

Mijnco-promotor,dr.L.vanderMolen.LieveLisette,jijwasvanafheteerstemomentmijndirecte begeleider en ik denk dat we zo goed konden samenwerken doordat ik mezelfvaak in jou herkende. Jouwproefschriftwas de basis voor hetmijne enmet nameop aldieinternationalecongressen,waarwerkelijkiedereenjoukende,wasikenormtrotsjouwopvolgertemogenzijn.Develeurendiewesamenachterdecomputerhebbendoorgebracht

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omalle slikvideo’s tebeoordelen zal ik niet snel vergeten, evenalsonzeweekendjesnaarMalmö,Brussel/AntwerpenenLeuven.Ikhebveelbewonderingvoorhoejealjeverschillendewerkzaamhedenweettecombinerenmetooknogeendrukprivéleven.IkwensjenogeenhelefijnetijdinhetAVLtoe!

Deledenvanmijnpromotiecommissie,prof.dr.A.J.M.Balm,prof.dr.J.J.deLange,prof.dr.C.R.N.Rasch,prof.dr.H.A.M.Marresendr.L.W.JBaijens,ikwiluallenhartelijkdankenvoordetijddieuheeftvrijgemaaktommijnmanuscripttebeoordelenenomzittingtenemenindeoppositietijdensdeverdedigingvanmijnproefschrift.Ikhoopuallenteblijventegenkomenin de (steeds veranderende)medischewereld, waarin de vraag naar kritische blikken eninnovatieveoplossingenvangrootbelangis.

Profdr.L.E.Smeele,besteLudi,mijnallereersteprojectovertemporomandibulairedysfunctiewasdeelsonderjouwbegeleiding,gevolgddooronsgezamenlijkelipofillingproject.Ikkijkmet plezier terug op deze samenwerking, maar misschien nog wel meer op het samenopererenopzaterdagofoponzevelewielertochten inzowelbinnen-alsbuitenland.Hoesneljijdebergopfietstisuniekenikhoopooitweersameneenrondjetemaken!

Dr.W.M.Klop,besteMartin,hartelijkbedanktvoorhetbegeleidenvanmijalsco-assistent,arts-assistentenzelfsopdetennisbaan.Naastaljehumorengezelligheidkenikmaarweinigmensendiezodidactischzijnalsjij.Gaanwesnelweereenpotjetennissen?

(Oud) hoofd-hals chirurgen uit het Antoni van Leeuwenhoek, Bing Tan, Fons Balm, LotjeZuur,BarisKarakullukçuenPeterLohuis, ikbenzeertrotsdat ikdeelmochtuitmakenvanjulliefantastischeteamenikwil jullieenormbedankenvoordefijnesamenwerkingopdepolikliniek,afdeling,operatiekamerofU-gebouw.

Alle co-auteurs die hebben meegeschreven aan een of meerdere hoofdstukken uit ditproefschrift,veeldankvoorjullietijdenpositievefeedback.Inhetbijzonderdr.M.M.Stuiver,besteMartijn,enormbedanktvooralleinhoudelijkeopmerkingenoverderolvanintensievekrachtrevalidatieendenodigestatistiekuitleg!Dr.R.P.Takes,besteRobert,veeldankvoordeprettigesamenwerkingmetNijmegen.EnGawein,heelveeldankvooralhet(saaie!)werkdatjijverzethebt!

Allegezondeproefpersonendieruim6wekenhebbengeoefendmetdeSwallowExerciseAidinhetkadervanmijnstudieoverintensieveslikspiertraining,Peter,Wim,Rob,Rien,George,Govert,Cees,Bing,MichielenFrans,enormbedanktvoorjullieinzet!Wim,heelveeldankvoorhetvervaardigenvandeapparaten.EnCees,watfijndatjijhetmogelijkmaakteomopzaterdagMRI’steverrichten.



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MarionvanZuilenenHennyBuis,heelveeldankvoorhetregelen,versturen,boeken,mailen,bellenofdeclarerenvanallerleizaken.

De AVL logopedisten, Anne,Merel en Klaske, bedankt voor de fijne samenwerking in deklinieken rondommijnonderzoek. Ik kanmevoorstellendathetnietaltijduit kwamomonverwachtseenslikvideo‘volgensSEAprotocol’temoetenuitvoeren,maarvoormijwasheelfijndatjulliezoflexibelwaren.Julliezijneengoudenteamenonmisbaarvoordeafdeling!

Alleoverigemensenmetwieikalsarts-onderzoekerof-assistenthebsamengewerkt,zoalsdemedewerkersvandehoofd-halspoli,desecretaressenenverpleegkundigenvande5eetage, de radiotherapeuten, chirurgen, tandartsen en hoofd-hals internisten. Dr. J.P. deBoer en dr.M.E.T. Tesselaar, veel dank voor alle consulten over nierfunctiestoornissenbijRADPLATpatiënten.PeterSeerden, jijwasnooitteberoerdomlangstekomenopzaalenaltijdzogeïnteresseerd,veeldankdaarvoor!Dr.JvanderHage,hartelijkbedanktvoorhetbegeleidenvanmijopzaal,maarbovenalvoorhetvelelachenopdefiets,opdepisteofopdeschaatsbaan.Ikwensjehetallerbestevoordetoekomst.

DeAVLfellowsFLEUS,RDIRVenookX-BEM,veeldankvoorallegezelligheidopdepisteentijdensdeborrelsenvooralookveeldankvooralleonderwijsmomentenopdeOKofafdeling.

DeSaoPaulocongresgroep,Hester,Caro,Simone,Charlotte,Ellen,Saar,Steven,BarisenPim,wateenfantastischeweekhebbenwijgehad!Gaanwesnelweersamenergensheen!?

(Oud-)arts-onderzoekersuithetO-,U-enhoofdgebouw,veeldankvooralleleukelunches,wintersporten(4x!),festivals,squashavondenenvrijdagmiddagborrels.Rosa,hetwasheelfijnomafen toeweerhelemaalbij te kletsen.Marieke,dankvoorde leukewintersport!Matthijs,TjeerdenRoel,deAlped’Huezwasonzeeersteervaringindebergenendaarnavolgdensteedsmeerbergtochten.Ikvindhetheelbijzonderdatwenogsteedsregelmatigsamenfietsen. LieveHannah, Liset,Marije, JosenAnn-Jean, ikwens jullieveel succesenplezierverderinhetU-gebouw!

(Oud-) arts-assistenten chirurgie en KNO, lieve Anne, Bas, Caro, Danique, Gawein, Jacq,Jantien,Jasper,Martijn,Michel,Nick,NielsNoor,Pep,Piet&Piet,Rens,Roos,Tessa,ThijsenSteef,hetwasaltijdeendolleboelopdeafdeling,tijdenswintersport,opdeborrel,opdeschaatsbaanenopderacefiets.Dankvoordefijnesamenwerking!MetpijninmijnharthebikonsweekendRenessemoetenmissen.Maarikhoopbinnenkortopeenherkansing!?

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Almijn lievevriendinnetjesuitEindhoven,Utrecht,Amsterdamofelders, inhetbijzonderWen,Janna,Emma,Cres,Kaar,Wil,Griet,Mayo,Yvette,Siets,Saar,Ell,NynenGeer,heelveeldankvoorallegezelligheid,sportiviteit,borrels,dinersengesprekkenbuitenhetwerkom.Ikbenblijdatwezo’nhechtebandhebben!LieveWen,wekennenelkaarnoggeen5jaarmaarhetvoeltzoveellangerenaltijdzovertrouwd!LieveJanna,watbeniktrotsdatjijzo’ngrotecarrièreswitchhebtdurvenmaken.LieveEmma,sommigevriendinnetjeshoefjenietdagelijkstespreken:)LieveRoenNaad,ikbenstiekemheelergblijdatjullievoorlopignoginNederlandblijven!EnGrietenMayo,gaanwesnelweerzeilen,schaatsen,skiën(hauteroute!)oflekkereten?

Mijnschoonfamilie.LieveBen,MargreetenBente,watbof ikmet jullieals schoonoudersen schoonzus. Veel dank voor jullie interesse, steun en gezelligheid. Ik kijk uit naar allegezamenlijkedinersenvakantiesdienogzullenvolgen!

Mijnparanimfenlievevriendin,CarolineBambach.LieveCaro,watbenikblijdatwijelkaarinAmsterdamweerhelemaalgevondenhebben!Doornietalleenvriendinnetjesmaarookcollega’stezijn,isonzebandalleenmaarversterkt.Endoorhetveletennissenzijnnuzelfsonzevriendjesgoedevriendengeworden. Ikbenenormtrotsop jouwpositieve instelling,kritischeblikendoorzettingsvermogen.Zodraerietsisstajevoormeklaar.Ikbendaaromergblijdatjevandaagnaastmestaat!EnlieveJel,watfantastischdatjijvanavonddeDJwiltzijn.Devoetjesgaanvandevloer!

MijnparanimfenkleinezusjeVeronique.LieveVeer,onzebandwasvanjongsafaanalijzersterkdoordatweenormveelopelkaarlijkenenopdezelfdemanierinhetlevenstaan.DooronzegedeeldeinteressevoordeKNO-heelkundeisdezebandvoormijngevoelalleenmaarsterkergeworden.Ikwasvroegerjouwgrotevoorbeeldmaarstrakszaljijmijvermoedelijkvoorgaan.Ikbensupertrotsopje!EnYannick,watsuperfijndatjijbijonsindefamiliebentgekomen!

Mijnanderelievezus,Charlotte.LieveChar,gelukkigzorgjijervoordatnietallezusjesexacthetzelfdezijn.Waarwijalwateerderopzoekwarennaarenigestructuurenhouvast,wasjijnogweleenszoekendenaarwat jenuprecieswilt. Inmiddelsben jeookbijnaaanhetwerkendeleventoeenikheberallevertrouwenindathetjegoedafzalgaan.Erismaareenzusdiezogoedkaninschattenhoehetmetmegaatenmetwieikzogoedkanpraten,dusikweetzekerdatelkkindstraksontzettendblijzalzijnmetjouwbehandelingenbegeleiding!EnPieter,welkomindefamilie-app;-)



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Mijngrotezus,Juliette,LieveJuul,alseriemandisdiealtijdvoormeklaarstaat,danbenjijhetwel.Ikzoumegeenbeterezusenvoorbeeldkunnenwensendanjij.SamenmetRogierbenjeinmiddelsdetrotseoudervanBoele,dienumet6maandenalvolopgenietvanjouwonvoorwaardelijke liefdeenzorgzaamheid.Alsdiekleinelachtdansmelt ikgewoon!LieveRogier,ook jijbentnabijna10 jaarnietmeerwegtedenkenuitonze familie. Ikvindhetenormbijzonderomstraksopjulliehuwelijkalsgetuigetemogenoptreden.Ikkijkuitnaaronzetoekomstsamenmethopelijkveelgelukensamenzijn.Ikhouvanjullie!

Mijnouders,lievepapaenmama,watbenikblijmetjullieonvoorwaardelijkesteun,liefdeenvertrouwen.DoorjulliewashetmogelijkomeenhuistekopeninAmsterdam,ietswaarikenormdankbaarvoorben.Frank,onzegedeeldeliefdevoorsportbrachtonsdichtbijelkaarenikhoopnogvaaksamenopdefietstestappen.Karien,wijdeleneenpassievoorlekkerengezondkokenenikhoopnogveledinertjessamenteorganiseren.Papa,dankvoorallemogelijkhedendie jemegegevenhebt. IkhoopnogveelsameninFrieslandtezijnomtegenietenvanhetzeilen.Mama,bedanktdatjealtijdvoormeklaarstaat–nomatterwhat.Ikhouzoveelvanjullie!

Totslot..mijnliefdevooraltijd.LieveWiebe,watbenikgelukkigmetjou.Ikbenzoblijdatwijelkaarhebbenontmoet.Onzegedeeltepassieseninteresseszorgenervoordatwijonsnooitvervelen.Waariknogweleenstwijfel,helpjijmeomdejuistekeuzetemaken.Ikhouheelergveelvanjouenverheugmeenormoponzetoekomstsamen!

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