Interventions for the management of oral submucous fibrosis

19 Pages·2010·0.22 MB·English

Interventions for the management of oral submucous fibrosis
(Review)
Fedorowicz Z, Chan Shih-Yen E, Dorri M, NasserM, Newton T, ShiL
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2008,Issue4
http://www.thecochranelibrary.com
Interventionsforthemanagementoforalsubmucousfibrosis(Review)
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 16
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Interventionsforthemanagementoforalsubmucousfibrosis(Review) i
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Interventions for the management of oral submucous fibrosis
ZbysFedorowicz1,EdwinChanShih-Yen2,MojtabaDorri3,MonaNasser4,TimNewton5,LumingShi2
1UKCC(BahrainBranch),MinistryofHealth,Bahrain,Awali,Bahrain.2SingaporeBranch,AustralasianCochraneCentre,Clinical
Trials & Epidemiology Research Unit, Singapore, Singapore. 3Department of Epidemiology & Public Health, University College
London(UCL),London,UK.4DepartmentofHealthInformation,InstituteforQualityandEfficiencyinHealthcare,Köln,Germany.
5DepartmentofOralHealthServicesResearch&DentalPublicHealth,GKTDentalInstituteKing’sCollegeHospital,London,UK
Contact address: Zbys Fedorowicz, UKCC (Bahrain Branch), Ministry of Health, Bahrain, Box 25438, Awali, Bahrain.
[email protected].
Editorialgroup:CochraneOralHealthGroup.
Publicationstatusanddate:New,publishedinIssue4,2008.
Reviewcontentassessedasup-to-date: 28July2008.
Citation: FedorowiczZ,ChanShih-YenE,DorriM,NasserM,NewtonT,ShiL.Interventionsforthemanagementoforalsubmucous
fibrosis.CochraneDatabaseofSystematicReviews2008,Issue4.Art.No.:CD007156.DOI:10.1002/14651858.CD007156.pub2.
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Oralsubmucousfibrosis(OSF)isachronicdiseaseoftheoralcavitywhichismorecommonlyfoundinpatientsintheAsiansubcontinent
andtheFarEast.Itischaracterisedbytheprogressivebuildupofconstrictingbandsofcollageninthecheeksandadjacentstructures
ofthemouthwhichcanseverelyrestrictmouthopeningandtonguemovementandcauseproblemswithspeechandswallowing.
Objectives
Toassesstheeffectivenessofinterventionsforthemanagementofpainandrestrictedjawopeningormovementoccurringasaresult
oforalsubmucousfibrosis.
Searchstrategy
We searched the Cochrane Oral Health Group’s Trials Register to July 2008; CENTRAL (The Cochrane Library 2008, Issue 2);
MEDLINE(from1950toJuly2008);EMBASE(from1980toJuly2008)andIndMEDon18thNovember2007.Therewereno
languagerestrictions.
Selectioncriteria
Randomised controlledtrialscomparing surgical interventions, systemicor topical medicinesor otherinterventions tomanage the
symptomsoforalsubmucousfibrosis.
Datacollectionandanalysis
Two authorsindependentlyassessedtrialquality andextractedtrialdata. Disagreementswereresolvedbyconsultation withathird
author.Attemptsweremadetocontactstudyauthorswherenecessaryforclarificationandforadditionalinformation.
Mainresults
Twotrials,involving87participants,evaluatedlycopeneinconjunctionwithintralesionalinjectionsofasteroid,andpentoxifyllinein
combinationwithmouthstretchingexercisesandheat.Onlytwooftheprimarybutnoneofthesecondaryoutcomesofthisreview
wereconsideredinthesetrialsandprovidedalimitedamountofunreliabledata.Thedatainonetrialwerebasedoninadequately
definedevaluationsofoutcomes,andintheothertrialarelikelytobeskewedduetoasubstantialnumberofwithdrawalsandtherefore
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 1
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
werenotenteredintotheRevMananalyses.Therewerenoreportsoftoxicitytotheinterventionsbutsomesideeffects,whichwere
mostlygastricirritationtopentoxifylline,werenoted.
Authors’conclusions
The lack of reliable evidence for the effectiveness of any specific interventions for the management of oral submucous fibrosis is
illustratedbythepaucity,andpoormethodologicalquality,oftrialsretrievedforthisreview.
PLAIN LANGUAGE SUMMARY
Interventionsforthemanagementoforalsubmucousfibrosis
OralsubmucousfibrosisisachronicdiseasewhichiscommonlyfoundinpatientsintheAsiansubcontinentandtheFarEastandis
characterisedbythebuildupofconstrictingbandsofcollageninthecheeksandadjacentstructuresofthemouth.Theprecisecauseis
unknownbutchewingofbetelquidaswellasotherarecanutcontainingproducts,excessiveuseofchilliesandspices,poornutrition
andvitaminandirondeficiencyhavebeensuggested.
Mucosal ulcersmay occur atan earlier stage, whereasfibrous bands in the cheeksand lips, depigmented gums and a rubbery and
deformedsoft palate and blanched, leathery floor of themouth are later developments. These changes can severely restrictmouth
openingandtonguemovementandcauseproblemswithspeechandswallowingwhilstothersymptomsincludeaburningsensation
whilsteatingspicyfood,drymouthandhearingloss.
Treatmentoptions include ironandmultivitamin supplementsincluding lycopene,anextractoftomato, andarange ofmedicines
(e.g.intralesionalinjectionofsteroids,hyaluronidase,humanplacentaextracts,chemotrypsin,pentoxifyllineandcollagenase).Surgery,
includingcuttingofthefibrousbandsandjawmusclesandjoint,hasbeenusedformoreextremecases.
Thereview authorsfound twostudies whichevaluatedtheeffectivenessoflycopene inconjunction with intralesional injections of
asteroid,andpentoxifyllineincombination withmouthstretchingexercisesandheat.Thesestudiesprovidedalimitedamountof
unreliabledatawhichdidnotpermitanyfirmconclusionstobemade.Therewerenoreportsoftoxicitybutsomesideeffects,which
weremostlygastricirritationtopentoxifylline,werenoted.
Futureresearchshouldaimtoprovideevidenceforpeopletomakeinformeddecisionsaboutwhetherthesetreatmentsareeffectiveand
shouldalsoexploretreatmentplanswhichincludepatienteducationaimedatcessationofthechewinghabit.
BACKGROUND
Aetiologyandprevalence
Oral submucous fibrosis (OSF) is a chronic disease of the oral Theaetiologyoforalsubmucousfibrosisisconsideredtobemulti-
cavity.Worldwideestimatesindicatethatasmanyas2.5million factorial:betelquidchewing,excessiveuseofchilliesandspices,
peoplemaybeaffected(Cox1996).Itismorecommonlyfound poor nutrition and vitamin and iron deficiency have been sug-
inpatientsintheAsiansubcontinent andtheFar Eastbut,asa gestedascausativeagents(Ahmad2006).Chewingofbetelquid
resultoftransmigrationofpopulations,anincreasingnumberof (arecacatechu,limeandtobacco)aswellasotherarecanutcon-
casesarebeingseeninothercountries(Reichart2006). taining products(e.g.panmasalaand guthka)for mouth fresh-
ening and the mild euphoric effectis a fairly common practice
Itischaracterisedbytheprogressivebuildupofconstrictingbands
inIndia,PakistanandSriLanka.Othercombinations aswellas
of collagen inthecheeksand adjacent structuresof the mouth,
varietyofpackagedproductsareavailableinpartsoftheFarEast
whichcancauseproblemswithspeechandswallowingandseverely
inparticularlyChina,TaiwanandMalaysia.
restrictmouthopeningandtonguemovement.
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 2
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Epidemiological studies have provided substantial evidence of a extractoftomato,hasrecentlybeenshowntohavesomebeneficial
close correlation betweenbetelquid chewing and theincidence effectinthemanagementofsymptomsofOSF.
of OSF (Lee 2003), as well as highlighting the significant con- Wherethereisrestrictionofmouthopeningsurgicalinterventions
tributionofsmokingandalcoholconsumptiontothemalignant havebeentried.Sectioningofthefibroticbandshasbeenusedin
transformationofOSF(Ho2007). mildcases,whereasbilateraltemporalismyotomyorcoronoidec-
Whilstthe precise mode of action of the various chemical con- tomywithsplit-thicknessskin-graftingtechniqueshavebeenused
stituentsofarecanutonmucosaltissueisstillunclear,ithasbeen inmoreextremecases.
suggested that these constituents interfere with the processes of Inanyevent,alltreatmentplansshouldincludepatienteducation
depositionorofbreakdownofcollagenorboth(Lin2007).There andaimatcessationofthechewinghabit.
iscurrentlymuchinterestintheeffectofcumulative betelquid
exposureoncollagen-relatedgenesinthepathogenesisofOSF(
Tilakaratne2006).Researchalsoappearstoconfirmthattheab-
senceof tobacco inthevariety ofareca/betelquid, asisusedin Rationaleforasystematicreview
Taiwan,doesnotsignificantlyreducethelikelihoodofdeveloping
Significantmorbidity,inparticularmalnutrition,isassociatedwith
OSF(Yang2001).
oral submucous fibrosis with restricted mouth opening causing
Prevalencevarieswidelybetweencountriesandevenbetweencom-
eating difficulties. Mortality figures are reflected in the rate of
munitiesandgeographicalregionswithinthosecountries.Anepi-
transformation(<7%)oforalsubmucousfibrosiscasesintooral
demiologicalstudyinIndiareportedOSFinapatientasyoung
cancer(Reichart2003).AsaresultofincreasingprevalenceofOSF
as 11 yearsof age and noted thatthree timesas many malesas
outside of Asia and theFar East, and with an improvedunder-
femaleswereregularusersofguthka(Ahmad2006),althoughthe
standingoftheimmunologicalbasisofthisdisease,asystematic
reverseofthismale-femaleratiohasbeenreportedinPakistan(
reviewisnow requiredtoassesstheeffectivenessofcurrentand
Aziz1997)andSouthAfrica(VanWyk1997).Theprevalenceof
newlyevolvingtherapiesandtomakerecommendationsforfuture
betelquidchewinginChinaisreportedlythehighestintheHu-
research.
nan(64.5%to82.7%)andHainanprovinceswithsignsofOSF
in0.9%to4.7%ofthepopulationandwiththe30to49yearsage
groupbeingthemostcommonlyaffected(Zhang2007).Similar
figureswerereportedinasurveyinTaiwan,withupto69.5%of
thesamplechewingbetel/arecaquidonadailybasis(Yang2001).
OBJECTIVES
Toassesstheeffectivenessofinterventionsinthemanagementof
painandrestrictedjawopeningormovementoccurringasaresult
Symptomsanddiagnosis
oforalsubmucousfibrosis.
Symptomsoforalsubmucousfibrosisvaryandcanincludearange
ofcomplications:progressiveinabilitytoswallowortoopenthe
mouth;painandaburningsensationwhilsteatingspicyfood;dry
METHODS
mouth andhearingloss. Clinical findings are largelydependant
on the severity and staging of the disease with a tendency for
stomatitis, mucosal ulcers and fibrosis of ruptured vesicles and
ulcerstooccuratanearlierstage,whereastheappearanceoffibrous
Criteriaforconsideringstudiesforthisreview
bandsinthecheeksandlips,depigmentedgumsandmucosa, a
rubberyanddeformedsoftpalateandblanched,leatheryfloorof
themouth,aregenerallylaterdevelopments(Pindborg1989).
Diagnosis of OSF should be based on the history and clinical Typesofstudies
examinationandconfirmedbyhistopathologyofthelesion.
Onlyrandomisedcontrolledclinicaltrials(RCTs)wereconsidered
inthisreview.
Treatmentoptions
Typesofparticipants
Theseincludeironandmultivitaminsupplementsandarangeof
medicines(e.g.intralesionalinjectionofsteroids,hyaluronidase, Individualsinanyagegroupwithaconfirmeddiagnosis,byclinical
humanplacentaextracts,chemotrypsin,pentoxifyllineandcolla- examinationandbiopsy,oforalsubmucousfibrosiswithtrismus
genase),mostofwhichhaveshownmixedresults.Lycopene,an orrestrictedjawmovement.
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 3
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Typesofinterventions version(2008revision)asreferencedinChapter6.4.11.1andde-
tailedinbox6.4.coftheCochraneHandbookforSystematicReviews
(1)Surgicalprocedureseitheragainsteachotherornotreatment.
ofInterventions5.0.0(updatedFebruary2008)(Higgins2008).
(2)Systemicortopicaldrugsormedicines,atanydosageandover
anytimeperiod,againsteachotherorplacebo.
(3)Other(e.g.localheattherapy,jawstretchingexercises).
Databasessearched
Thefollowingdatabasesweresearchedonthedatesindicated:
Typesofoutcomemeasures TheCochraneOralHealthGroup’sTrialsRegister(toJuly2008)
TheCochraneCentralRegisterofControlledTrials(CENTRAL)
(TheCochraneLibrary2008,Issue2)
Primaryoutcomes MEDLINE(1950toJuly2008)
EMBASE(from1980toJuly2008).
(1)Resumptionofnormaleating,chewingandspeech.
Detailsofthesearchstrategiesforthedatabasessearchedarepro-
(2)Changeorimprovementinmaximaljawopening,measured
videdinAppendix1;Appendix2;Appendix3andAppendix4.
astheinterincisaldistance.
WesearchedIndMED,abibliographicdatabaseofIndianbiomed-
(3)Improvementinrangeofjawmovementutilisinganyvalidated
ical journals, available at http://indmed.nic.in/, using free text
assessmenttool.
termsappropriateforthisreview(18thNovember2007).
(4) Change in severity of oral/mucosal burning pain using any
Additionalsearchesforongoingtrialswereconductedonhttp://
recognisedvalidatedpainscale.
www.clinicaltrials.gov/(18thNovember2007).
ThelibraryrecordsattheUniversityofColomboMedicalSchool,
SriLankaweresearchedforrelevanttheses,dissertationsandpub-
Secondaryoutcomes
lishedandunpublishedstudies(December2007).
(1)Postoperativediscomfortorpainasaresultoftheintervention:
patient-assessedusinganyvalidatedpainscale.
(2)Hospitaladmission:lengthofstay.
Handsearches
(3)Qualityoflifeasassessedbyanyvalidatedquestionnaire,either
genericororalhealthspecific. Noadditionalhandsearchingwasdoneoverandabovethatcarried
(4)Patientsatisfactionassessedbyvalidatedquestionnaire. outonourbehalfattheUniversityofColomboMedicalSchool
Library.Wewereunsuccessfulinarrangingforthehandsearching
ofanyoftheoralhealthjournalsintheFarEastwhichwecon-
Costs sideredmightbeapotentialsourceofstudiesappropriateforthis
review.
Directcostsofmedication,hospitalbeddaysandanyassociated
Wesearchedthereferencelistsofrelevantarticlesandattempted
in-patientcostsforthesurgicalinterventions.
to contact the investigators of both of the included studies by
electronicmailtoaskforfurthertrialdetailsandforinformation
aboutanyadditionaltrials.
Adverseeffects
Anyspecificadverseeffectsrelatedtoanyclinicallydiagnosedre-
Attemptstocontactseveralexpertsinthisfieldalsoprovedunsuc-
actionstoanyoftheactiveinterventionswerenoted.
cessfuland,otherthanIndMED,wewereunabletoidentifyany
additionaldatabasesfromregionsoftheworldwhichareconsid-
eredtohaveahighincidenceoforalsubmucousfibrosis.
Searchmethodsforidentificationofstudies AsearchoftheInternetwasundertakenforexistingandpoten-
tiallyrelevantmeta-analysesandnon-Cochranesystematicreviews
usingGoogleScholaravailableathttp://scholar.google.com/,and
for online published dissertations using: http://www.thesis.org,
Electronicsearches
http://www.dissonline.de/, http://zippo.vtls.com/cgi-bin/ndltd/
For the identification of studies included or considered for this
chameleon.
review,detailedsearchstrategiesweredevelopedforeachdatabase
tobesearched.Thesewerebasedonthesearchstrategydeveloped
for MEDLINE butrevised appropriately foreach database. For
Language
theMEDLINE(OVID)search,thesubjectsearchwasrunwith
theCochraneHighlySensitiveSearchStrategy(CHSSS)foriden- Althoughtherewerenolanguagerestrictionsonincludedstudies
tifying randomised trials in MEDLINE: sensitivity maximising wedidnotlocateanyrelevantnon-Englishpapers.
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 4
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Datacollectionandanalysis comparedthegradingsanddiscussedandresolvedanyinconsis-
tenciesintheinterpretationofinclusioncriteriaandtheirsignifi-
cancetotheselectedstudies.Thefollowingparametersofmethod-
Assessmentofsearchresults ologicalqualitywereassessedandusedtohelpinevaluatingthe
riskofbiaswithintheincludedstudies.
Two review authors (Mojtaba Dorri (MD) and Zbys Fedorow-
(1)Sequencegeneration.
icz(ZF))independentlyassessedtheabstractsofstudiesresulting
Thiscriterionwasgradedasadequate(A),orunclear(B).Adequate
fromthesearches.Fullcopiesofallrelevantandpotentiallyrele-
(A)includedanyoneofthefollowingmethodsofrandomisation:
vantstudies,thoseappearingtomeettheinclusioncriteria,orfor
computergeneratedortableofrandomnumbers,drawingoflots,
whichtherewereinsufficientdatainthetitleandabstracttomake
coin-toss,shufflingcardsorthrowofadice.
acleardecisionwereobtained.Thefulltextpaperswereassessed
(2)Allocationconcealment.
independentlybythetwoauthorsandany disagreementonthe
Thereviewauthorsgradedthiscriterionasadequate(A),unclear
eligibility of potentially included studies were resolved through
(B),inadequate(C).Adequate(A)methodsofallocationconceal-
discussion with a third author (Mona Nasser (MN)). After as-
mentincludedeithercentralrandomisationorsequentiallynum-
sessmentbytheauthorsanyduplicatepublicationsorremaining
beredsealedopaqueenvelopes.Thiscriterionwasconsideredin-
studies that did not match the inclusion criteria were excluded
adequate (C) if there was an open allocation sequence and the
fromfurtherreviewandthereasonsfortheirexclusionnotedin
participantsandtrialistscouldforeseetheupcomingassignment.
theCharacteristicsofexcludedstudiestable.
(3) Blinding of investigators, participants and outcomes assess-
ment.
Dataextraction Albeitblindingoftheinvestigatorstosurgicalinterventionsmay
notbepossible,thefollowingcriteriawereassessediffeasible(de-
Studydetailsandoutcomesdatawerecollectedbytworeviewau-
tectionandperformancebias):
thors(MDandZF)independentlyusing apredeterminedform
(a)blindingofparticipants(yes/no/unclear)
designed for this purpose. Study details were entered into the
(b)blindingofinvestigators(yes/no/unclear)
Characteristicsofincludedstudiestable.Datawouldonlybein-
(c)blindingofoutcomesassessment(yes/no/unclear)
cludediftherewasanindependentlyreachedconsensus.Anydis-
(d)notfeasible.
agreementwouldbediscussedandifrequiredathirdreviewau-
(4)Handlingofwithdrawalsandlosses.
thorwouldbeconsulted.
Thereviewauthorsgradedthiscriterionasyes(A),unclear(B)and
Thefollowingdetailswereextracted.
no(C)accordingtowhethertherewasacleardescriptiongiven
(1)Studymethods:methodofallocation,maskingofparticipants
of the difference betweenthetwo groups of lossesto follow up
andinvestigators(iffeasible),exclusionofparticipantsafterran-
(attritionbias).
domisationandproportionoffollow-uplosses.
Afterassessmenttheincludedstudiesweregroupedaccordingly.
(2)Participants:countryoforigin,samplesize,age,sex,inclusion
(A)Lowriskofbias(plausiblebiasunlikelytoseriouslyalterthe
andexclusioncriteria.
results):ifallcriteriaweremet.
(3)Intervention:typeofsurgicalprocedure,ifmedicalorpharma-
(B)Moderate riskof bias (plausible bias thatraisessome doubt
cological:modeofadministration,dose,frequency,andduration
abouttheresults):ifallcriteriawereatleastpartlymet.
ofusage.
(C)Highriskofbias(plausiblebiasthatseriouslyweakensconfi-
(4) Control: type, dose and frequency of any comparison or
denceintheresults):ifoneormorecriteriawerenotmet.
placebo.
(5)Outcomes:primaryandsecondaryoutcomes.
(6)Anyadverseevents.
Datasynthesis
Ifstated,thesourcesoffundingofanyoftheincludedstudieswere
recorded. Forfutureupdates,whenstudiesareidentifiedforinclusioninthis
Thisinformationwasusedtoassesstheclinicalhomogeneityand reviewwithsufficientandappropriatedata,thefollowingmethods
theexternalvalidityofthetrials. willbeapplied.
TheCochraneCollaborationstatisticalguidelineswillbefollowed
fordatasynthesis.ThedatawillbeanalysedbyMN,LumingShi
Assessmentofmethodologicalquality
(LS)andZFusingRevMan5andreportedaccordingtoCochrane
Eachreviewauthorthengradedtheselectedstudiesindependently Collaborationcriteria.
and assessed every trial reporting a randomised controlled trial In general, for continuous data, we will calculate themean dif-
(RCT)accordingtothecriteriongradingsystemdescribedinthe ferenceand95%confidenceintervals.Riskratiosandtheir95%
Cochrane Handbook for Systematic Reviews of Interventions 5.0.0 confidenceintervalswillbecalculatedforalldichotomousdata.
(updatedFebruary 2008) (Higgins 2008).Thesereviewauthors
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 5
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Weplantoassessclinicalheterogeneitybyexaminingthecharac- onKumar2007,wereobtainedandsubjectedtofurtherevalua-
teristicsofthestudies:thesimilaritybetweenthetypesofpartici- tion. Thebibliographical referencesof thesestudieswere exam-
pants,theinterventionsandtheoutcomesasspecifiedinthecri- ined but did not provide any additional citations to potentially
teriaforincludedstudies.Statisticalheterogeneitywillbeassessed eligiblestudies.
usingaChi2testandtheI2testwhereI2valuesover50%indicate Our search of the IndMED database retrieved six references to
moderatetohighheterogeneity(Higgins2003).Whilstrecognis- publications,thetitlesandabstractsofwhichwereexaminedand
ingitslimitations,ifasufficientnumberofRCTsareidentified, fulltextpaperswereobtainedwhereappropriatebutnoadditional
anattemptwillbemadetoassesspublicationbiasusingafunnel eligible trials were found. The search of the Internet for non-
plot(Egger1997). Cochrane systematic reviews and online published dissertations
Results of clinically and statistically homogeneous trials will be providednofurthertrialsandnoongoingclinicaltrialswerere-
pooled to provide estimates of the efficacy of the interventions trievedinoursearchoftheClinicalTrials.govdatabase.
only if the included studies have similar interventions received Afterfurtherevaluationweexcludedthreestudies(Gupta1988;
bysimilarparticipants. Eitherthefixed-effector random-effects Kakar1985;Tai2001)andnotedthereasonsfortheirexclusion
modelswillbeusedbutifthereissignificantheterogeneitybetween (seeCharacteristicsofexcludedstudies).Wealsoexcludedanab-
thestudieswewillusetherandom-effectsmodel. stracttoconferenceproceedingswhichwewereunabletoobtain
Intheeventthatthereareinsufficientclinicallyhomogeneoustrials (Jain2000).
foranyspecificinterventionorinsufficientstudydatathatcanbe After discussion between the review authors any remaining un-
pooled,anarrativesynthesiswillbepresented. certaintiesontheeligibilityofanyofthestudieswereresolvedby
Wewillconductthefollowingsubgroupanalysesifsufficientdata consensusandsubsequentlytwotrials,involving87participants,
areavailable:categorisingandsubsequentanalysisofparticipants metmostofourinclusioncriteriaandwereincludedinthisreview
bystageanddegreeofrestrictioninjawopeningandmovement,at (Kumar2007;Rajendran2006).
thecommencementofadministrationofanyoftheinterventions.
Characteristicsofthetrialsettingandinvestigators
Sensitivityanalyses BothofthetrialswereconductedinIndia,andwhilstneitherre-
port provided detailed information about the setting it may be
Iftherearesufficientincludedstudiesweplantoconductsensitiv-
assumedthattheywereconductedinauniversityoracademicin-
ityanalysestoassesstherobustnessofourreviewresultsbyrepeat-
stitute.Equally,noinformationwasmadeavailablebytheinves-
ingtheanalysiswiththefollowingadjustments:exclusionofstud-
tigators inboth trialsabout theirsourcesoffunding or anypo-
ieswithunclearorinadequateallocationconcealment,unclearor
tentialconflictsofinterestand,althoughnotexplicitlystated,the
inadequateblindingofoutcomesassessmentandcompletenessof
providersandassessorsofthetreatmentsappearedtoberesearch
followup.
stafffromauniversityoracademicinstitute.
Characteristicsoftheparticipants
RESULTS Onlyadultswererecruitedforbothofthesetrials,oneofwhich
excludedparticipantswithsignificantsystemicmedicalproblems
i.e. cardiac disease, diabetes or gastric ulcers (Rajendran 2006).
ParticipantswereonlyenrolledinKumar2007iftheysatisfiedtwo
Descriptionofstudies
outofthreecriteria:theyhaddifficultyinchewing;hadrestricted
See:Characteristicsofincludedstudies;Characteristicsofexcluded mouth opening with the presence of fibrous bands and had a
studies. diagnosis oforal submucous fibrosiswhichhadbeenconfirmed
by biopsy. This reportwas also unclear, and we were unable to
ascertainfromtheinvestigators,whetheralloftheparticipantswho
Findingthetrials
wereenrolledinthisstudywererandomisedtotheinterventions.
Thesearchstrategyretrieved81(10CochraneOralHealthGroup’s Theinclusioncriteriawerelessclearintheotherstudyinwhich
TrialsRegister,10CENTRAL,41MEDLINE,20EMBASE)ref- theparticipantswereof“comparablediseaseprogression”andonly
erencestostudies,whichafterde-duplicationresultedin41po- recruitediftheyhadclinicallyadvancedoralsubmucousfibrosis
tentially eligible studies. Afterexamination of thetitlesand ab- which were stated to have been judged by “clinico-pathological
stracts of these references, all but six studies (Gupta 1988; Jain parameters” but these were not clearly defined in the reports (
2000;Kakar1985;Kumar2007;Rajendran2006;Tai2001)were Rajendran2006).
eliminatedandexcludedfromfurtherreview.Fulltextcopiesof AlloftheparticipantsinKumar2007hadchewedarecanutasa
theseremainingstudies,andKerr2007whichwasacommentary quid,gutkhaorpanmasala(1to20chewsperday,median6.5)
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 6
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
foraperiodof1to25years(median7years).IntheRajendran Characteristicsofoutcomemeasures
2006studytheinvestigatorsreportednofurtherdetailsotherthan Two of our primary outcomes were reportedin both of thein-
thattheparticipantswerehabitualchewersofarecaquid. cludedtrials.
Theparticipantsinonetrial(Kumar2007)wereactivelyencour- Clinical assessments of maximal jaw opening were carried out
agedbytheinvestigatorstodiscontinue theirarecanutchewing weeklyinKumar2007andmonthlyinRajendran2006andout-
habitduringthecourseofthestudyandalsoatenrolmentreceived comeswereexpressedbymeasuredchangeintheinterincisaldis-
a cleaning to remove tooth staining which it was stated would tance.Themethodusedtomeasurethesechangeswasnotclear
enableclosermonitoringofanyresumptionofthechewinghabit. in Rajendran 2006 but was more comprehensively reported in
No such instructions on habit cessation or its monitoring were Kumar2007.
reportedintheothertrial(Rajendran2006). Neitherofthetrialscarriedoutanyassessmentofimprovement
intherangeofjawmovement.
Changes in severity of burning sensation were reported, but in
Characteristicsoftheinterventions
bothstudiestheseparameterswerepoorlydefinednotbasedon
Theinterventionsinonetrialconsistedoforallycopene,anatural
any recognised and validatedpainscale andthereportsdidnot
pigment(carotenoid)occurringinfruitsandvegetableswhichit
provide any reliable information on how the assessments were
isclaimedhasantioxidant properties;orlycopenetogetherwith
madeorhowthescoreswerecalculated.
twiceweeklyintralesionalsteroidinjections;oraplacebo,which
Oneofthetrials(Rajendran2006)assessed“relieffromdifficulty
were administered over a 2-month period (Kumar 2007). The
ofspeech”andwhilstitincludeddataforbothinterventiongroups
reportdidnotspecifypreciselywhichandhowmanyoftheoral
thereportcontainednoinformationonhowthesespeechevalua-
lesionshadreceivedthesteroidinjectionsateachofthevisits,nor
tionswerecarriedout.
ifthetimewhentheinjectionswereadministeredcoincidedwith
Noneofoursecondaryoutcomeswereconsideredbytheinvesti-
thatoftheoutcomesassessment.
gatorsineitheroftheincludedtrials.
The second trial, which was conducted over a 7-month period,
compared oral pentoxifylline (Trental) taken 3 times per day
against a single daily multivitamin tablet. Participants in both Costs
groups also received local heat therapy and underwent forceful
Nodatawereavailable.
mouthstretchingexercises(Rajendran2006).Itissuggestedthat
thevasodilatorpropertiesofpentoxifyllineinadditiontoitseffect
inreducingplateletaggregation mayleadtoanincreasedvascu- Adverseevents
larityoftheaffectedoraltissues.
Both studies took note of adverse eventsbut only one reported
Assessmentofparticipants’compliancewasreportedas100%in
anysideeffects(Rajendran2006).
onetrial(Rajendran2006)butitwasunclearwhetherthisreferred
ForfurtherdetailsseeCharacteristicsofincludedstudiestable.
onlytomedicationusageorincludedtheself-administeredmouth
stretchingexercisesand/ortheheattherapy.Althoughtherewere
substantiallossestofollowupintheotherstudytheinvestigators
Riskofbiasinincludedstudies
providednoinformationontheextentoftheparticipants’com-
pliancewiththestudyprotocol. SeeAdditionalTable1.
Table1. Qualityofincludedstudies
StudyID Randomisation Allocation conceal- Blinding Intention-to-treat Attrition
ment
Kumar2007 Unclear(B) Unclear(B) (a)blindingofpartic- No. Only 58 out of 30% drop outs. Un-
ipants(notfeasible) 83 participants were clear(B)
(b)blindingofinves- analysedandthedata
tigators(notfeasible) from an unspecified
(c) number of partici-
blindingofoutcomes pants were excluded
assessment(no) from the analysis of
improvement of jaw
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 7
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Table1. Qualityofincludedstudies (Continued)
opening.
Rajendran2006 Unclear(B) Unclear(B) (a)blindingofpartic- No. All of the par- Nillosses.Yes(A)
ipants(unclear) ticipantswerenotin-
(b)blindingofinves- cludedintheanalysis.
tigators(unclear)
(c)
blindingofoutcomes
assessment(no)
Sequencegenerationandallocationconcealment
TheKumar2007study
Participants were stated to have been “randomly selected”, and
Kumar2007. as therewas no description of the methodsused to conceal the
allocation sequence fromthetrialistsboth ofthesecriteriawere
ratedasunclear(B).
Sequencegenerationandallocationconcealment
Theparticipantswere“randomlycategorizedbytwoinvestigators Blindingofparticipants,investigatorsandoutcomes
intooneofthreegroups”,andthereforethiscriterionwasgraded assessment
unclear(B).Thetrialistsdidnotindicatewhatmethodswereused
Althoughthereportwasuncleariftheinterventionsweresimilar
toconcealtheallocationsequencefromeitherparticipantsortri-
intasteandpackagingofthedosageregimenwasclearlydifferent
alistsandthereforethiscriterionwasalsogradedasunclear(B).
betweentheinterventiongroup(3timesperday)andthesingle
dailydoseforthecontrolgroup,thereforeblindingofbothpar-
ticipantsandinvestigatorswasgradedasunclear.Asmostofthe
Blindingofparticipants,investigatorsandoutcomes outcomesassessmentswerecarriedoutbytheinvestigatorsinthis
assessment trialthiscriterionwasgradedasno.
Inviewofthenatureoftheinterventionsblindingoftheinves-
tigatorswasnotpossibleandforsimilarreasonseventhoughthe
Handlingofwithdrawalsandlosses
oralmedicationswereidenticallypackagedadequateblindingof
Allparticipantswerestatedtohavecompletedthetrial,butdata
theparticipantswouldalsonotbefeasibleinthisstudy.Mostof
weremissingforanumberofoutcomesalthoughsomebutnotall
theoutcomeswereevaluatedbytheinvestigators,whowerelikely
ofthesewereinoutcomessoughtinthisreview.Itwasalsonotclear
tobeawarewhichofthepatientshadreceivedwhichintervention,
fromthereportthat,althoughalltheparticipantshadattended
andthereforethiscriterionwasgradedasno.
forallfollow-upappointments,thislackofdatawasbecausethese
assessmentswerenotmadeforallparticipantsateachvisit.
The data were complete for one of our primary outcomes: the
Handlingofwithdrawalsandlosses change in maximal jaw opening. One participant was excluded
Althoughthelossestofollowupduringthestudywerereported, fromtheanalysisintheevaluationofchangesinseverityoforal
theinvestigatorsfailedtoprovidesufficientdetailontheprecise burningpain,buttheinvestigatorsindicatedthatthisindividual
losses within individual groups and therefore this criterion was wasasymptomaticatenrolment.Thusthehandlingofwithdrawals
gradedasunclear(B). forouroutcomesofinterestwasgradedasyes(A).
Assessmentofriskofbias
TheRajendran2006study
Thevalidityofeachstudywasassessedasatlow,moderateorhigh
Rajendran2006. riskofbias.Bothoftheincludedstudieswereratedasathighrisk
Interventionsforthemanagementoforalsubmucousfibrosis(Review) 8
Copyright©2008TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.