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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
S. A. C
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LONG-TERM OROPHARYNGEAL AND
LARYNGEAL FUNCTION IN PATIENTS WITH
ADVANCED HEAD AND NECK CANCER
SOPHIE ANNE CHARLOTTE KRAAIJENGA
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
ADVANCED HEAD AND NECK CANCER
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
170 mm
12,7 mm 10 mm
170 mm 60 mm
240
mm
boe
kenl
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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
LO
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RM
OR
OP
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EA
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ND
LA
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PAT
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TS W
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D H
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CA
NC
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SOPHIE ANNE CHARLOTTE KRAAIJENGA
S. A. C
. KR
AA
IJEN
GA
ADVANCED HEAD AND NECK CANCER
CHAPTER 1General introduc.on and outline of thesis
CHAPTER 1General introduction and outline of thesis
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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
LO
NG
-TE
RM
OR
OP
HA
RY
NG
EA
L A
ND
LA
RY
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UN
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ION
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PAT
IEN
TS W
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D H
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NE
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CA
NC
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SOPHIE ANNE CHARLOTTE KRAAIJENGA
S. A. C
. KR
AA
IJEN
GA
ADVANCED HEAD AND NECK CANCER
CHAPTER 1General introduc.on and outline of thesis
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10|Chapter1
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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
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Generalintroductionandoutlineofthesis|13
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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14 | Chapter 1
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
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Generalintroductionandoutlineofthesis|15
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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16 | Chapter 1
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,
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Generalintroductionandoutlineofthesis|17
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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18 | Chapter 1
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.
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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.
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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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79. KahrilasPJ,LogemannJA,KruglerC,FlanaganE.Volitionalaugmentationofupperesophagealsphincter opening during swallowing. Am JPhysiol.1991;260:G450-6.
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180. ShakerR,KernM,BardanE,TaylorA,Stewart
ET, Hoffmann RG, et al. Augmentation ofdeglutitive upper esophageal sphincteropening in the elderly by exercise. Am JPhysiol.1997;272:G1518-22.
81. 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.
82. Logemann JA, Rademaker A, Pauloski BR,Kelly A, Stangl-McBreen C, Antinoja J, et al.A randomized study comparing the Shakerexercisewithtraditionaltherapy:apreliminarystudy.Dysphagia.2009;24:403-11.
83. Easterling C, Grande B, Kern M, Sears K,ShakerR.Attainingandmaintainingisometricand isokinetic goals of the Shaker exercise.Dysphagia.2005;20:133-8.
84. Yoon WL, Khoo JK, Rickard Liow SJ. Chintuck against resistance (CTAR): newmethodfor enhancing suprahyoid muscle activityusing a Shaker-type exercise. Dysphagia.2014;29:243-8.
85. Wada S, Tohara H, Iida T, InoueM, SatoM,UedaK. Jaw-openingexercise for insufficientopeningofupperesophagealsphincter.ArchPhysMedRehabil.2012;93:1995-9.
86. Hara K, Tohara H, Wada S, Iida T, Ueda K,AnsaiT. Jaw-opening force test toscreen forDysphagia:preliminaryresults.ArchPhysMedRehabil.2014;95:867-74.
87. LogemannJA.Theroleofexerciseprogramsfordysphagia patients. Dysphagia. 2005;20:139-40.
88. Steele CM. Exercise-based approaches todysphagia rehabilitation. Nestle Nutr InstWorkshopSer.2012;72:109-17.
89. LangmoreSE,PisegnaJM.Efficacyofexercisesto rehabilitate dysphagia: A critique ofthe literature. Int J Speech Lang Pathol.2015;17:222-9.
90. Robbins J, Butler SG, Daniels SK, Diez GrossR, LangmoreS, LazarusCL, et al. Swallowingand dysphagia rehabilitation: translatingprinciples of neural plasticity into clinicallyoriented evidence. J Speech Lang Hear Res.2008;51:S276-300.
91. Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications forrehabilitation after brain damage. J SpeechLangHearRes.2008;51:S225-39.
92. Powers SK, Howley ET. Exercise Physiology.NewYork:McGraw-Hill;2001.
93. Burkhead LM, Sapienza CM, Rosenbek JC.Strength-training exercise in dysphagiarehabilitation: principles, procedures, anddirections for future research. Dysphagia.2007;22:251-65.
94. Robbins J, Gangnon RE, Theis SM, Kays SA,Hewitt AL, Hind JA. The effects of lingualexerciseon swallowing inolder adults. JAmGeriatrSoc.2005;53:1483-9.
95. SapienzaCM,WheelerK.Respiratorymusclestrengthtraining:functionaloutcomesversusplasticity. Semin Speech Lang. 2006;27:236-44.
96. Zaninotto G, Marchese Ragona R, Briani C,CostantiniM,RizzettoC,PortaleG,etal.Therole of botulinum toxin injection and upperesophageal sphincter myotomy in treatingoropharyngealdysphagia.JGastrointestSurg.2004;8:997-1006.
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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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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LONG-TERM OROPHARYNGEAL AND LARYNGEAL FUNCTION IN PATIENTS WITH
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UITNODIGING
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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
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PARANIMFEN
CAROLINE BAMBACHVERONIQUE KRAAIJENGA
SOPHIE KRAAIJENGA
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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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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
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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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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
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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.
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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
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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
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lusio
n
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3,
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The
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allowingfunctio
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to<55
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tors
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ispromising
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nof
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themost
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ric p
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Interven
tionsfo
reati
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king
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lemsfollowingtreatm
entforHNC
Ther
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ce to
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tionsaim
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swallowingan
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obilityfo
llowingHNC
treatm
ent,bu
tstudiesarelimite
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sizean
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e
Larger,h
ighqu
ality
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ieswhichinclud
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iredforp
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bilitati
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Hutcheson
,20
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Dyspha
giaan
dothe
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aloutcomes
afterche
morad
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yforlaryngealand
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aryngealcan
cers
Growing eviden
cesup
portsthebe
nefitof
preven
tivesw
allowingtherap
ytore
duce
thebu
rden
ofd
ysph
agia
Analysis offu
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
ent regim
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
R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20R21R22R23R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38R39
Systematicreviewof2-yearsdysphagialiteratureinheadandneckcancer|37
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
R10R11R12R13R14R15R16R17R18R19R20R21R22R23R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38R39
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
R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20R21R22R23R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38R39
Systematicreviewof2-yearsdysphagialiteratureinheadandneckcancer|39
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
R10R11R12R13R14R15R16R17R18R19R20R21R22R23R24R25R26R27R28R29R30R31R32R33R34R35R36R37R38R39
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
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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-
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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.
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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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44 | Chapter 2
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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46 | Chapter 2
REFERENCES
Papers of particular interest, published within the annual period of review, have been highlighted as special (*) or outstanding (**) interest.
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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.
13. Carnaby-Mann G, Crary MA, SchmalfussI, Amdur R. “Pharyngocise”: randomizedcontrolled trial of preventative exercisesto maintain muscle structure and swallowing function during head-and-neckchemoradiotherapy. Int J Radiat Oncol BiolPhys.2012;83:210-9.
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.
22. Kotz T, Federman AD, Kao J, Milman L,Packer S, Lopez-Prieto C, et al. Prophylacticswallowing exercises in patients with headandneckcancerundergoingchemoradiation:a randomized trial. Arch Otolaryngol HeadNeckSurg.2012;138:376-82.
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.
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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.
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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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LONG-TERM OROPHARYNGEALAND LARYNGEAL FUNCTION
IN PATIENTS WITH ADVANCEDHEAD AND NECK CANCER
DOOR SOPHIE KRAAIJENGA
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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
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PARANIMFEN
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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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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
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ADVANCED HEAD AND NECK CANCER
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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52|Chapter3
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
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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
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Long-termdysphagiaandtrismusinadvancedheadandneckcancer|55
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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)
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Analyzed(n=22)
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Included survivors not available at
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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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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?”.
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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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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.
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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
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63kg
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*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).
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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.
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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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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.
34. Langmore S, KrisciunasGP,Miloro KV, EvansSR,ChengDM.DoesPEGusecausedysphagiainheadandneckcancerpatients?Dysphagia.2012;27:251-9.
35. HutchesonKA,BhayaniMK,BeadleBM,GoldKA, Shinn EH, Lai SY, et al. Eat and exerciseduring radiotherapy or chemoradiotherapyforpharyngealcancers:useitorloseit.JAMAOtolaryngolHeadNeckSurg.2013;139:1127-34.
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.
39. Chen AM, Li BQ, Lau DH, Farwell DG, LuuQ, Stuart K, et al. Evaluating the role ofprophylactic gastrostomy tube placementprior to definitive chemoradiotherapy forheadandneckcancer.IntJRadiatOncolBiolPhys.2010;78:1026-32.
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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
in advanced head and neck cancer pa.ents
10-‐years+ aSer chemoradiotherapy
S.A.C. Kraaijenga I.M. Oskam
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
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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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MATERIAL AND METHODS
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).
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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.
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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)
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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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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
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Abbreviatio
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=In
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nCo
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50).
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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).
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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.
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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
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[email protected] – 42 07 74 78
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ADVANCED HEAD AND NECK CANCER
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
S.A.C. Kraaijenga L. van der Molen
I. Jacobi O. Hamming-‐Vrieze
F.J.M. Hilgers M.W.M. van den Brekel
Eur Arch Otorhinolaryngol. 2015; 272: 3521-‐3531.
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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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ADVANCED HEAD AND NECK CANCER
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
S.A.C. Kraaijenga L. van der Molen
I. Jacobi O. Hamming-‐Vrieze
F.J.M. Hilgers M.W.M. van den Brekel
Eur Arch Otorhinolaryngol. 2015; 272: 3521-‐3531.
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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
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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.
MATERIAL AND METHODS
Thisstudyconcernsthelong-termfollow-upofalldisease-freeandevaluablepatientsfromanoriginalcohortof55patientswithadvanced(stageIIIandIV),functionally43 or anatomically
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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
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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)
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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.
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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).
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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
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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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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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37. LazarusCL. Effectsof chemoradiotherapyonvoiceandswallowing.CurrOpinOtolaryngolHeadNeckSurg.2009;17:172-8.
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.
42. Rinkel RN, Verdonck-de Leeuw IM, vanden Brakel N, de Bree R, EerensteinSE, Aaronson N, et al. Patient-reportedsymptomquestionnaires in laryngealcancer:voice, speech and swallowing. Oral Oncol.2014;50:759-64.
43. 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.
44. vanderMolenL,vanRossumMA,AckerstaffAH, Smeele LE, Rasch CR, Hilgers FJ.Pretreatmentorganfunctioninpatientswithadvanced head and neck cancer: clinicaloutcomemeasuresandpatients’views.BMCEarNoseThroatDisord.2009;9:10.
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.
46. Rosenbek JC, Robbins JA, Roecker EB, CoyleJL, Wood JL. A penetration-aspiration scale.Dysphagia.1996;11:93-8.
47. Dijkstra PU, Huisman PM, Roodenburg JL.Criteriafortrismusinheadandneckoncology.IntJOralMaxillofacSurg.2006;35:337-42.
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.
53. Logemann JA, Pauloski BR, Rademaker AW,Lazarus CL, Gaziano J, Stachowiak L, et al.Swallowing disorders in the first year afterradiation and chemoradiation. Head Neck.2008;30:148-58.
54. Ackerstaff AH, Rasch CR, Balm AJ, de BoerJP, Wiggenraad R, Rietveld DH, et al. Five-yearqualityof liferesultsof therandomizedclinical phase III (RADPLAT) trial, comparingconcomitant intra-arterial versus intravenous chemoradiotherapy in locally advanced head andneckcancer.HeadNeck.2012;34:974-80.
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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.
56. vanderMolenL,vanRossumMA,JacobiI,vanSonRJ, Smeele LE,RaschCR,et al. Pre- andposttreatmentvoiceandspeechoutcomesinpatientswithadvancedheadandneckcancertreated with chemoradiotherapy: expertlisteners’ and patient’s perception. J Voice.2012;26:664.e25-33.
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CHAPTER 6Hyoid bone displacement as parameter for
swallowing impairment in pa.ents treated for
advanced head and neck cancer
S.A.C. Kraaijenga L. van der Molen
W.D. Heemsbergen G.B. Remmerswaal
F.J.M. Hilgers M.W.M. van den Brekel
Eur Arch Otorhinolaryngol. Online 2016 Apr 16.
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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
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RECEPTIE TER PLAATSE
PARANIMFEN
CAROLINE BAMBACHVERONIQUE KRAAIJENGA
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RHIJNVIS FEITHSTRAAT 31-I1054 TV AMSTERDAM
[email protected] – 42 07 74 78
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CHAPTER 6Hyoid bone displacement as parameter for
swallowing impairment in pa.ents treated for
advanced head and neck cancer
S.A.C. Kraaijenga L. van der Molen
W.D. Heemsbergen G.B. Remmerswaal
F.J.M. Hilgers M.W.M. van den Brekel
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.
MATERIAL AND METHODS
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.
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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.
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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.
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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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VAN HET PROEFSCHRIFT
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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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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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LONG-TERM OROPHARYNGEAL AND LARYNGEAL FUNCTION IN PATIENTS WITH
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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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ADVANCED HEAD AND NECK CANCER
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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LONG-TERM OROPHARYNGEAL AND LARYNGEAL FUNCTION IN PATIENTS WITH
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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
S. A. C
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ADVANCED HEAD AND NECK CANCER
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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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
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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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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.
MATERIAL AND METHODS
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
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(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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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.
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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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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).
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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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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
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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
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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).
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Effectsofstrengtheningexercisesonswallowingmusculatureandfunction|149
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.
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Effectsofstrengtheningexercisesonswallowingmusculatureandfunction|151
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
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Effectsofstrengtheningexercisesonswallowingmusculatureandfunction|153
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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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.
12. Chen AM, Li BQ, Lau DH, Farwell DG, LuuQ, Stuart K, et al. Evaluating the role ofprophylactic gastrostomy tube placementprior to definitive chemoradiotherapy forheadandneckcancer.IntJRadiatOncolBiolPhys.2010;78:1026-32.
13. Kulbersh BD, Rosenthal EL, McGrew BM,Duncan RD, McColloch NL, Carroll WR, etal. Pretreatment, preoperative swallowingexercises may improve dysphagia quality oflife.Laryngoscope.2006;116:883-6.
14. Carroll WR, Locher JL, Canon CL, BohannonIA,McCollochNL,MagnusonJS.Pretreatmentswallowing exercises improve swallowfunctionafterchemoradiation.Laryngoscope.2008;118:39-43.
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.
16. Carnaby-Mann G, Crary MA, SchmalfussI, Amdur R. “Pharyngocise”: randomizedcontrolled trial of preventative exercisesto maintain muscle structure and swallowing function during head-and-neckchemoradiotherapy. Int J Radiat Oncol BiolPhys.2012;83:210-9.
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.
20. Hind JA, Nicosia MA, Roecker EB, CarnesML, Robbins J. Comparison of effortful andnoneffortfulswallowsinhealthymiddle-agedand older adults. Arch Phys Med Rehabil.2001;82:1661-5.
21. LazarusC,LogemannJA,SongCW,RademakerAW,KahrilasPJ.Effectsofvoluntarymaneuversontonguebasefunctionforswallowing.FoliaPhoniatrLogop.2002;54:171-6.
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.
25. Logemann JA, Rademaker A, Pauloski BR,Kelly A, Stangl-McBreen C, Antinoja J, et al.A randomized study comparing the Shakerexercisewithtraditionaltherapy:apreliminarystudy.Dysphagia.2009;24:403-11.
26. Easterling C, Grande B, Kern M, Sears K,ShakerR.Attainingandmaintainingisometricand isokinetic goals of the Shaker exercise.Dysphagia.2005;20:133-8.
27. Yoon WL, Khoo JK, Rickard Liow SJ. Chintuck against resistance (CTAR): newmethodfor enhancing suprahyoid muscle activityusing a Shaker-type exercise. Dysphagia.2014;29:243-8.
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.
33. Burkhead LM, Sapienza CM, Rosenbek JC.Strength-training exercise in dysphagiarehabilitation: principles, procedures, anddirections for future research. Dysphagia.2007;22:251-65.
34. Wada S, Tohara H, Iida T, InoueM, SatoM,UedaK. Jaw-openingexercise for insufficientopeningofupperesophagealsphincter.ArchPhysMedRehabil.2012;93:1995-9.
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.
38. LeonardRJ,KendallKA,McKenzieS,GoncalvesMI, Walker A. Structural displacements innormalswallowing:avideofluoroscopicstudy.Dysphagia.2000;15:146-52.
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39. Kendall KA, McKenzie S, Leonard RJ,GoncalvesMI,WalkerA.Timingofevents innormalswallowing:avideofluoroscopicstudy.Dysphagia.2000;15:74-83.
40. Rosenbek JC, Robbins JA, Roecker EB, CoyleJL, Wood JL. A penetration-aspiration scale.Dysphagia.1996;11:93-8.
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.
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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.)
- Plaats de borststeun op de borst zonder veeldrukuitteoefenen
- Plaatsdekinopdekinsteun
- Duw met de onderkaak de kinsteun naarbeneden,door de mond te openen,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 1
Oefening 2
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Effectsofstrengtheningexercisesonswallowingmusculatureandfunction|159
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Oefening 3 (<1 min.)
- Plaats de borststeun op de borst zonder veeldrukuitteoefenen
- Plaats de kin/onderkaak op de bovenstekinsteun
- Houdtdemond open (tandennietopelkaar)maardelippengesloten
- Slikmetdelippengesloten,tegendeweerstandvan de SEA
Duur en hoeveelheid:
- Herhaaldezeoefening10keer,metongeveereenritmevan1herhalingper2seconden
Oefening 3
170 mm
12,7 mm 10 mm
170 mm 60 mm
240
mm
boe
kenl
egge
r 230
mm
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
LO
NG
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OR
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EA
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ND
LA
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EA
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IN
PAT
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AD
VAN
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ER
SOPHIE ANNE CHARLOTTE KRAAIJENGA
S. A. C
. KR
AA
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ADVANCED HEAD AND NECK CANCER
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.
170 mm
12,7 mm 10 mm
170 mm 60 mm
240
mm
boe
kenl
egge
r 230
mm
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
LO
NG
-TE
RM
OR
OP
HA
RY
NG
EA
L A
ND
LA
RY
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EA
L F
UN
CT
ION
IN
PAT
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TS W
ITH
AD
VAN
CE
D H
EA
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ND
NE
CK
CA
NC
ER
SOPHIE ANNE CHARLOTTE KRAAIJENGA
S. A. C
. KR
AA
IJEN
GA
ADVANCED HEAD AND NECK CANCER
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
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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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164 | Chapter 8
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.
MATERIAL AND METHODS
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).
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Strengtheningexercisesinlong-termheadandneckcancersurvivorswithchronicdysphagia|165
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
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entsin
dicatedbyadot(*
)wereinclud
edatthe
Rad
boud
University
;allothe
rpa
tientswereinclud
edatthe
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rland
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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.
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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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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
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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)
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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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172 | Chapter 8
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
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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.
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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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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.
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Tabl
e 4.VFS,n
utriti
on,and
pati
ent-rep
ortedda
taonsw
allowingfunctio
npe
rpati
entb
eforean
daft
erth
etraining
period.Note:pati
ent#
3,#4,and
#5
werestill(com
pletely)fe
edingtube
dep
ende
ntatthe
post-treatmen
tassessm
entp
oint.H
ence,the
post-treatmen
tSWAL
-QOLresultswereiden
ticalto
th
eir p
revi
ous
resu
lts.
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-QOL
EQ-5D
Patie
ntWeigh
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IS T
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fit?
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eral
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rden
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selection
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ratio
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ueCo
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enta
l Health
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al
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nSy
mpt
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eSe
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ted
heal
th 3
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NA
NA
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NA
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16
83
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88N
AN
A75
100
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61
41
338
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5844
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st73
71
41
1‒
3838
6317
380
050
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18
88
810
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AN
A10
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A0
075
7565
NA
70Po
st76
18
88
8+
100
NA
NA
100
NA
00
7575
65N
A60
4Pr
e45
28
88
310
050
7542
7575
8325
4060
7115
Post
422
88
83
++10
050
7542
7575
8325
4060
7025
5Pr
e70
18
88
850
NA
NA
75N
A0
2550
5655
NA
75Po
st70
18
82
8++
50N
AN
A75
NA
025
5056
55N
A75
6Pr
e98
41
21
150
6325
4263
6375
2545
6054
60Po
st98
54
43
1+
5038
3850
6963
5075
5055
5270
7Pr
e72
28
53
110
0N
AN
A50
100
017
055
7054
60Po
st72
25
65
3++
88N
AN
A50
100
250
045
7052
508
Pre
675
78
64
00
017
038
830
020
1175
Post
695
78
74
++25
00
1719
6342
380
030
609
Pre
487
48
51
025
3833
4425
3325
00
3090
Post
487
88
11
+0
063
3344
2525
250
023
9010
Pre
585
77
85
7588
6367
650
4210
090
6546
80Po
st58
67
74
5++
6375
8842
2550
3375
7565
5290
11Pr
e65
58
83
310
075
100
7569
5050
7580
7066
60Po
st65
58
28
1+
8850
8875
5050
5050
9570
5570
12Pr
e62
68
86
238
2563
3356
6367
5035
2557
70Po
st65
67
84
2++
+50
3863
844
6333
5025
2543
8513
Pre
626
18
11
5038
100
8325
2533
385
2539
50Po
st62
75
81
1++
500
7517
4438
7525
060
2175
14Pr
e76
51
81
875
5010
050
5663
5875
7535
6870
Post
755
16
18
++63
6310
042
3875
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3520
5778
15Pr
e76
34
88
875
5063
5063
3850
5050
6527
70Po
st77
31
81
8+
6325
6333
6363
5038
5050
3663
Abbreviatio
ns:FOIS=Fun
ction
alOralIntakeScale;PAS
=Pen
etratio
nAspiratio
nScale;SSQ
=Study-Spe
cificQue
stion
naire
:-meansnobe
nefit,+m
eansa
littleben
efit,++
meansquitesom
ebe
nefit,+++
meansaloto
fben
efit;SW
AL-QOL=Sw
allowingQua
lityofLife
que
stion
naire
;NA=no
tapp
licab
le.
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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.
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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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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.
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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
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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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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.
46. Logemann JA. Evaluation and treatment ofswallowing disorders. Texas, Austin: Pro-ed(2nded);1998.
47. Rosenbek JC, Robbins JA, Roecker EB, CoyleJL, Wood JL. A penetration-aspiration scale.Dysphagia.1996;11:93-8.
48. LeonardRJ,KendallKA.Dysphagiaassessmentand treatment planning: a team approach.SanDiego:SingularPub.Group.;1997.
49. LeonardRJ,KendallKA,McKenzieS,GoncalvesMI, Walker A. Structural displacements innormalswallowing:avideofluoroscopicstudy.Dysphagia.2000;15:146-52.
50. Pauloski BR, Rademaker AW, LogemannJA, Stein D, Beery Q, Newman L, et al.Pretreatmentswallowingfunctioninpatientswith head and neck cancer. Head Neck.2000;22:474-82.
51. Dijkstra PU, Huisman PM, Roodenburg JL.Criteriafortrismusinheadandneckoncology.IntJOralMaxillofacSurg.2006;35:337-42.
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.
55. van der Molen L, van Rossum MA, RaschCR, Smeele LE, Hilgers FJ. Two-year resultsof a prospective preventive swallowingrehabilitation trial in patients treated withchemoradiation for advanced head andneck cancer. Eur Arch Otorhinolaryngol.2014;271:1257-70.
56. Kotz T, Federman AD, Kao J, Milman L,Packer S, Lopez-Prieto C, et al. Prophylacticswallowing exercises in patients with headandneckcancerundergoingchemoradiation:a randomized trial. Arch Otolaryngol HeadNeckSurg.2012;138:376-82.
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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
M.W.M. van den Brekel
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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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2. Agarwal J, PalweV,DuttaD,Gupta T, LaskarSG,BudrukkarA,etal.Objectiveassessmentof swallowing function after definitiveconcurrent (chemo)radiotherapy in patientswith head and neck cancer. Dysphagia.2011;26:399-406.
3. NguyenNP,Moltz CC, Frank C, Vos P, SmithHJ, Karlsson U, et al. Dysphagia followingchemoradiationforlocallyadvancedheadandneckcancer.AnnOncol.2004;15:383-8.
4. Chen AM, Li BQ, Lau DH, Farwell DG, LuuQ, Stuart K, et al. Evaluating the role ofprophylactic gastrostomy tube placementprior to definitive chemoradiotherapy forheadandneckcancer.IntJRadiatOncolBiolPhys.2010;78:1026-32.
5. KosMP,DavidEF,AaldersIJ,SmitCF,MahieuHF.Long-termresultsoflaryngealsuspensionandupperesophagealsphinctermyotomyastreatmentforlife-threateningaspiration.AnnOtolRhinolLaryngol.2008;117:574-80.
6. Lazarus C, Logemann JA, Pauloski BR,Rademaker AW, Helenowski IB, Vonesh EF,etal.Effectsofradiotherapywithorwithoutchemotherapy on tongue strength andswallowinginpatientswithoralcancer.HeadNeck.2007;29:632-7.
7. Metreau A, Louvel G, Godey B, Le Clech G,JegouxF.Long-termfunctionalandqualityoflife evaluation after treatment for advancedpharyngolaryngeal carcinoma. Head Neck.2014;36:1604-10.
8. Kraaijenga SA, van der Molen L, van denBrekel MW, Hilgers FJ. Current assessmentandtreatmentstrategiesofdysphagiainheadandneckcancerpatients:asystematicreviewofthe2012/13 literature.CurrOpinSupportPalliatCare.2014;8:152-63.
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.
15. 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.
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.
18. Rosenbek JC, Robbins JA, Roecker EB, CoyleJL, Wood JL. A penetration-aspiration scale.Dysphagia.1996;11:93-8.
19. Logemann JA. Evaluation and treatment ofswallowing disorders; Pro-ed (2nd edition).Texas,Austin.1998.
20. Pauloski BR, Rademaker AW, LogemannJA, Stein D, Beery Q, Newman L, et al.Pretreatmentswallowingfunctioninpatientswith head and neck cancer. Head Neck.2000;22:474-82.
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.
23. Rinkel RN, Verdonck-de Leeuw IM, vanden Brakel N, de Bree R, EerensteinSE, Aaronson N, et al. Patient-reportedsymptomquestionnaires in laryngealcancer:voice, speech and swallowing. Oral Oncol.2014;50:759-64.
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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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
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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.
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Tabl
e 1.Overviewofsignifican
tunivaria
tePearson
correlatio
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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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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.
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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
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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.
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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.
57. Wada S, Tohara H, Iida T, InoueM, SatoM,UedaK. Jaw-openingexercise for insufficientopeningofupperesophagealsphincter.ArchPhysMedRehabil.2012;93:1995-9.
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.
62. KosMP,DavidEF,AaldersIJ,SmitCF,MahieuHF.Long-termresultsoflaryngealsuspensionandupperesophagealsphinctermyotomyastreatmentforlife-threateningaspiration.AnnOtolRhinolLaryngol.2008;117:574-80.
63. Lazarus C, Logemann JA, Pauloski BR,Rademaker AW, Helenowski IB, Vonesh EF,etal.Effectsofradiotherapywithorwithoutchemotherapy on tongue strength andswallowinginpatientswithoralcancer.HeadNeck.2007;29:632-7.
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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CHAPTER 11Summary
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Acknowledgement | Dankwoord
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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
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CHAPTER 11Summary
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List of abbrevia.ons
Authors and affilia.ons
PhD porbolio
About the author
Acknowledgement | Dankwoord
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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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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
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
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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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
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