www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
A
novel
method
to
evaluate
salivary
flow
rates
of
head
and
neck
cancer
patients
after
radiotherapy:
a
pilot
study
夽
Luiz
Felipe
Palma
a,b,∗,
Fernanda
Aurora
Stabile
Gonnelli
a,
Marcelo
Marcucci
b,
Adelmo
José
Giordani
a,
Rodrigo
Souza
Dias
a,
Roberto
Araújo
Segreto
a,
Helena
Regina
Comodo
Segreto
aaUniversidadeFederaldeSãoPaulo(UNIFESP),DepartamentodeDiagnósticoporImagem,SetordeRadioterapia,SãoPaulo,SP,
Brazil
bHospitalHeliópolis,Servic¸odeEstomatologiaeCirurgiaBucomaxilofacial,SãoPaulo,SP,Brazil
Received8November2016;accepted4March2017 Availableonline25March2017
KEYWORDS
Headandneck neoplasms; Xerostomia; Radiotherapy; Saliva
Abstract
Introduction:The procedureused toevaluate salivary flowrateiscalled sialometry.Itcan be performedthrough severaltechniques, butnoneappears tobe reallyefficient for post-radiotherapypatients.
Objective: Toadequatesialometrytestsforheadandneckcancerpatientssubmittedto radio-therapy.
Methods:22 xerostomic patientspost-radiotherapy(total radiationdose rangingfrom60 to 70Gy)were includedinthisstudy.Tenpatientswereevaluatedusingsialometries originally proposedby theRadiationTherapyOncologyGroup andtwelvewere assessedby our modi-fiedmethods.Unstimulatedandstimulatedsialometrieswereperformedandtheresultswere classifiedaccordingagradingscaleandcomparedbetweenbothgroups.
Results:Therewasnostatisticallysignificantdifferencebetweenthesalivaryevaluationsof bothgroups(p=0.4487andp=0.5615).Also,mostoftheserateswereclassifiedasverylow andlow.
Conclusion: Thisnovelmethodseemstobesuitableforpatientssubmittedtoradiotherapy. © 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
夽 Pleasecitethisarticleas:PalmaLF,GonnelliFA,MarcucciM,GiordaniAJ,DiasRS,SegretoRA,etal.Anovelmethodtoevaluatesalivary flowratesofheadandneckcancerpatientsafterradiotherapy:apilotstudy.BrazJOtorhinolaryngol.2018;84:227---31.
∗Correspondingauthor.
E-mail:luizfelipep@hotmail.com(L.F.Palma).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.
https://doi.org/10.1016/j.bjorl.2017.03.004
1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE
Neoplasiasdecabec¸a epescoc¸o;
Xerostomia; Radioterapia; Saliva
Umnovométodoparaavaliarastaxasdefluxosalivarempacientescomcâncer decabec¸aepescoc¸oapósradioterapia:estudopiloto
Resumo
Introduc¸ão: Oprocedimentoutilizadoparaavaliarataxadefluxosalivarédenominado sialome-tria. Pode ser realizado por meio de várias técnicas, mas nenhuma parece ser realmente eficienteparapacientespós-radioterapia.
Objetivo:Adaptarsialometriasparapacientescomcâncerdecabec¸aepescoc¸osubmetidosà radioterapia.
Método: 22pacientesxerostômicospós-radioterapia(dosederadiac¸ãototal variandode 60-70Gy) foramincluídos neste estudo. Dezpacientes foramavaliados utilizando sialometrias originalmentepropostaspeloRadiationTherapyOncologyGroupedozeforamavaliadospor nossosmétodosmodificados.Sialometriasnãoestimuladaseestimuladasforamconduzidase osresultadosforamclassificadosdeacordocomumaescaladegraduac¸ãoecomparadosentre osdoisgrupos.
Resultados: Nãohouvediferenc¸aestatisticamentesignificanteentreasavaliac¸õessalivaresde ambososgrupos(p=0,4487ep=0,5615).Alémdisso,amaioriadessastaxasfoiclassificada comomuitobaixaebaixa.
Conclusão:Essenovométodopareceseradequadoparapacientessubmetidosàradioterapia. © 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
The treatment for head and neck cancer (HNC) is
basedonthreetherapeutic modalities:radiotherapy(RT),
chemotherapy, and surgery.1 The aim of RT is to control
tumourswiththeleastpossibledamagetoadjacentnormal
tissues.2Formostinitialcases,RTasasolemodalityis
con-sideredthe standard treatment;however, advancedcases
mustreceive RT inassociation withchemotherapy and/or
surgery.3
DespiteeffortsonRTplanningtopreservenon-neoplastic
tissues in tumour region, these are inevitably included
into the irradiation fields and suffer consequences as
well.4,5Intensityandextentoftheradiation-inducedeffects
dependsmainlyonfactorsrelatedtotreatmentsuchastotal
radiationdose,radiation doseperfraction,irradiated
vol-ume, dose distribution in tissue volume, association with
chemotherapy,2,6anditsduration.7
Regarding HNC treatment, the major salivary glands
often receive significant radiation doses.8 Although the
cytotoxic mechanisms of the radiation in salivary tissue
are still not elucidated,7,9 atrophy and acinar
degener-ation are histological findings often encountered.10,11 As
consequences,thesubjectiveperception ofdrymouth (or
xerostomia)andtheobjectivereductioninsalivaryflowrate
(SFR)(orhyposalivation)arecommon,7,12dose-dependent,
irreversiblecomplications.9,13Additionally,theyarealmost
alwaysaccompaniedbychangesinthesalivary
characteris-ticssuchaspH values,immunoglobulinlevels,electrolyte
balance,proteinconcentrations,viscosity,andcolour.8,10,12
Itisknownthatthereisnodirectrelationshipbetween
xerostomiaandlowSFR,soeffortsareneededtomeasure
each one independently.14 In order to assess xerostomia
in irradiated patients, some specific scales have been
developed.9,13Likewise,qualityoflifequestionnaireshave
thegoalofevaluatingxerostomiainconjunctionwithother
well-describedsideeffectsoftheHNCtreatment.13,15Thus,
even subjectively, an overview of the patient’s state is
achieved.
Theprocedure usedtoassessobjectivelySFR
(sialome-try)isperformedusingseveraltechniques,eachonehaving
its own advantages, disadvantages, and challenges.16,17 A
poorreproducibility16 andanumberofmethodspresent in
the literature,4,6,10,11,13 however, maylead toinconsistent
resultsandinappropriatedirectcomparisons.Furthermore,
thereisnoreliable,validatedmethodtoevaluateSFRsof
HNCpatientssubmittedtoRT.
Basedonthewidespread97-09protocoloftheRadiation
Therapy Oncology Group (RTOG),18 sialometry tests were
developed and applied in orderto carry out easy, rapid,
accurateassessmentsinHNCpatientspost-RT.
Methods
Patientsandethicalconsiderations
Aprospectivestudywith22patientswasconductedinthe
DivisionofRadiotherapyoftheUniversidadeFederaldeSão
Paulo(UNIFESP).
All the patients reported persistent xerostomia after
megavoltageRT(3Dplanning)forHNC,withradiationfields
encompassing major salivary glands (cervicofacial regions
and supraclavicular fossae) and totalradiation doses
ran-gingfrom50to70Gy.Also,theywereaged≥18yearsand
had receivedthe lastRT sessionin a periodfrom3 to36
monthsbeforethebeginningofthisstudy.
The present study was approved by the
0844/10-32449414.4.0000.5505) and all research subjects
readandsignedtheinformedconsentform.
Groupsandgeneralinstructions
The patientsweredividedintotwogroups. ControlGroup
consistedof10patientsandTestGroupof12patients.
Con-trolGroupwasassessedusingtheRTOG’s97-09protocol18
andTestGroupwasevaluatedbyanadaptedmethod
devel-opedbytheauthors.
Allpatientswereevaluatedatthesamemorningperiod
byadentist andwereadvisedtostay atleast2hwithout
eating,drinking, smoking, andbrushing their teeth.Also,
during saliva collection they remained seated, with their
eyesopened,andheadsslightlybentforward.
Modifiedsialometrytests(salivacollection)
Unstimulatedsialometry:justbeforethesalivacollection,
thepatientsemptiedtheirmouthsofanysalivaormucous.
After that, they accumulated saliva on the floor of the
mouth, without swallowing,for 60s. Then,they
expecto-ratedtheaccumulatedsalivaintoatubegradedinmillilitres
(mL) with the aid of a laboratory glass funnel. It was
repeated4moretimesfor atotalof5min. Next,ametal
spatulaand2.0mLofdistilledwaterwereusedtoremove
thesalivaadheredtothesurfaceofthefunnel.Also,0.33mL
of simethicone (75mg/mL) was added to the solution to
eliminategasbubblesandfoamysaliva.Lastly,thetubewas
wellshaken,thevolumeofsalivawasmeasured,andtheSFR
perminutecouldbecalculated.Somematerialsareshown
inFig.1.
Stimulatedsialometry:firstly,thepatientsemptiedtheir
mouthsofanysalivaormucous.Afterthat,2%citrate
solu-tionwasappliedtothedorsolateralbordersofthetongue,
withacottontippedapplicator,5timesover2min(0,30,
60, 90, and120s). Next, all theretained citrate solution
inthemouthwaseliminated.Thestepsofsalivacollection
andSFRassessmentwerethesameasfortheunstimulated
sialometry.
Figure1 Material.(A)Syringeformeasuringdistilledwater; (B)simethicone;(C)metalspatula; (D)tubegradedin millil-itres;(E)laboratoryglassfunnel.
Dataanalysis
Descriptive analysis was used to summarize data on the
patients, tumours, treatments, and sialometries. In
addi-tion,the unstimulated and stimulated SFRs, respectively,
could be classified as: very low (<0.1 and <0.7mL/min),
low(0.1---0.25and 0.7---1.0mL/min), andnormal(>0.25 to
>1.0mL/min).17
Themeansialometryvalueswerealsosubmittedtothe
Student’st-testforcomparisonsbetweenbothgroups.The
p-valuewassetat≤0.05toreachstatisticalsignificance.
Results
GeneralThe patients’ ageof Control Group ranged from37 to68
years(meanvalue:56.3)andthepatients’ageofTestGroup
ranged from 48 to 73 years (mean value: 61.75).
Addi-tionaldemographicfeaturesofthesamplearesummarized
inTable1.
Featuresofthetumoursandtreatmentsaredescribedin
Table2.
Salivasampling
TheaveragesoftheunstimulatedandstimulatedSFRsare
summarized in Fig.2 and their classifications in Table 3.
Additionally, there wereno statistically significant
differ-encesbetweenbothgroups(p=0.4487andp=0.5615).
Regarding unstimulated sialometries, the salivary flow
rates of both groups ranged from 0 to 0.3mL/min. The
medianofControlGroupwas0.16mL/minandthestandard
error was 0.0296mL/min. The median of Test Group was
0.1mL/minandthestandarderrorwas0.0307mL/min.
Concerningstimulated sialometries, theSFR of Control
Group varied from 0.04 to 0.5mL/min, with the median
Table1 Patients’demographicfeatures.
Demographicfeatures Controlgroup Testgroup Patients % Patients % Gender Male 9 90 7 58.3 Female 1 10 5 41.7 Ethnicgroup White 7 70 9 75 Black 3 30 3 25 Alcoholconsumption Non-existent 2 20 0 0 Previous 7 70 8 66.7 Current 1 10 4 33.3 Tobaccoconsumption Non-existent 1 10 0 0 Previous 7 70 10 83.3 Current 2 20 2 16.7
Table2 Featuresofthetumoursandtreatments. Features Controlgroup Testgroup
Patients % Patients %
Histologicaltypeofthetumour
Squamouscell carcinoma 9 90 12 100 Adenoidcystic carcinoma 1 10 0 0
Primarysiteofthetumour
Oralcavity 0 0 2 16.6
Pharynx 8 80 5 41.7
Larynx 2 20 5 41.7
Stageofthetumour
I 1 10 2 16.7 II 0 0 1 8.3 III 0 0 1 8.3 IV 9 90 8 66.7 Surgery Yes 4 40 6 50 No 6 60 6 50
Totalradiationdose
60---69Gy 3 30 6 50 70Gy 7 70 6 50 Chemotherapy Yes 10 100 10 83.3 No 0 0 2 16.7 Stimulated sialometry
Mean salivary flow rates
Unstimulated sialometry mL/min 0.145 0.112 0.264 0.213 0.3 0.25 0.2 0.15 0.1 0.05 0
Control group Test group
Figure2 Meansalivary flowrates. The meansalivary flow ratesof bothgroups, in millilitresper minute (mL/min).No statistically significant difference was obtained (p=0.4487,
p=0.5615).
0.2750mL/min and the standard error 0.0494mL/min.
The SFR of Test Group ranged from 0 to 0.8mL/min,
with the median 0.1650mL/min and the standard error
0.0665mL/min.
Table3 Classificationsystemofthesalivaryflowrates. Salivaryflowrate Controlgroup Testgroup
Patients % Patients % Unstimulated Verylow (<0.1mL/min) 3 30 5 41.7 Low (0.1---0.25mL/min) 6 60 5 41.7 Normal (>0.25mL/min) 1 10 2 16.6 Stimulated Verylow (<0.7mL/min) 10 100 11 91.7 Low (0.7---1.0mL/min) 0 0 1 8.3 Normal (>1mL/min) 0 0 0 0
Discussion
Sialometriesareperformedbydrainage,expectoration,or weighing cotton wool balls soaked with saliva. Some of these techniques aim toselectively collect the secretion ofeach salivarygland,butwithlittleclinicalapplicability (e.g.catheterizationofsalivaryducts).Ontheotherhand, techniqueswhichtakeintoaccountthewholesalivavolume collectedoveraperiodoftimearethemostusedsincethey arefaster,easier,andcheaper.16
The well-known RTOG’s protocol has been developed
toevaluatethe mitigatingeffectof pilocarpine on
hypos-alivation and mucositis in patients undergoing RT.18 So,
from our experience in using this protocol for irradiated
patients withnomethod ofprevention andtreatment for
hyposalivation,19,20 weconsidered necessaryadaptingitto
post-RTpatients.Theunstimulatedsialometry,inparticular,
couldbesubstantiallyimprovedbyourmethods,sinceitis
basedonthecollectionofextremelysmallamountofsaliva.
Duringthe procedures,the glassfunnel facilitated the
salivacollectionandalsopreventedapossiblevolumeloss
duetothelargerareaforexpectoration.Thehighlyviscous
saliva that adhered to the funnel surface could be easily
removed with the aid of the metal spatula and distilled
water. Anotherimportant pointwas theadditionof
sime-thiconetothesolutiontodecreasethesurface tensionof
gasbubblesandtodispersefoam.Thus,wecouldmeasure
thetotalsalivavolumeimmediately,avoidingfurtherlosses
relatedtotheneedofleavingthesalivasamplestorest.
Concerningthepresenceofstimulationinsialometries,
gustatory (citric acid) and mechanical agents (paraffin,
silicone, unflavoured chewing gum) are used to simulate
patients’ conditions throughout the day (e.g. eating and
chewing). It is believed that the absence of stimulation
reflects thephysiologicalstatusofthesublingualand
sub-mandibular glands, as these are responsible for baseline
salivarysecretion.Ontheotherhand,mechanicalstimulants
promotemarkedresponseoftheparotidglandsand
gusta-tory stimulants activate the threepairs of major salivary
From our standpoint, clinicians should carry out both
sialometries for a thorough evaluation of irradiated
patients.Forthestimulatedsialometry,theuseof2%citrate
solutionseemstobemoreadvantageousbecausethethree
pairsofmajorsalivaryglands(responsiblefor90%ofsaliva
output)areevaluatedatthesametime.7,12Also,edentulous
patientscannotbeassessedusingmechanicalstimulations.
Ourdatashowedthemarked,persistent,well-recognised
radiation-inducedreduction inSFR.7,9,12,13,19,20 The lack of
statisticallysignificantdifferencebetweenbothgroupsand
thequitesimilarresultsobtainedsuggestthatour
modifica-tionsin RTOG’sprotocol weresatisfactoryandapplicable.
Ingeneral,theresultsfromthenovelsialometriescouldbe
obtained morequicklythan thoseof RTOG. Moreover,our
methodwaseasierthantheothersanddidnotrequirecostly
materials, factorsreallyimportantfor theroutineclinical
use.
Conclusion
Thispaperencouragesfurtherresearcheswithbigger
sam-ples to apply these novel sialometries in post-irradiated
patients. Likewise, it would be interesting toinvestigate
whetherthismethodissuitableforotherdiseasesand
patho-logicalconditionswhichalsoresultinlowSFR(e.g.Sjögren’s
Syndrome).
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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