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TheRoleofHyperbaricOxygenTherapy(HBOT)inPreven:ngOsteoradionecrosis:
InterimResultsfromaProspec:veClinicalTrial
ISOOParallelSessionSaturday,June30,2018
Vienna,AustriaDr.AllanHovan,DepartmentHead
PrograminOralOncology/DenDstry,BriDshColumbiaCancer(Vancouver)
OutlineofPresenta:on
• TheClinicalProblem(ORN)
• HBOinPrevenDon:DoesitWork?
• DesigningaStudytoFindOut
• InterimResults:EmergingQuesDons
TheClinicalProblem(ORN)
HistoricalDefini:onofORN
Anon-healingmucosalorskinopeningwithunderlyingexposeddevitalizedbone
inareaofprevioushigh-doseradiotherapy
PrevalenceofORN
4)Peterson,Hovanetal,SupportCareCancer,2010
Modality Prevalence
ConvenDonalRT 7.4%
IntensityModulatedRT 5.2%
Chemo-radiotherapy 6.8%
Brachytherapy 5.3%AdaptedfromPeterson,Hovanetal,2010
ConvenDonal IMRT ConvenDonal IMRT
Table1.Weightedprevalencefrom31studies.4
RiskFactorsforORN
• Exposure>6000cGy5,9,10,13• Posteriormandibleexposed11
• PoordenDDonandoralhygiene12• PoornutriDon14
• Smoking6
• Ill-fibngprosthesiscausingchronictrauma11
• Post-RTextrac:on13
11)Kluthetal,JProsthDent,1988.12)Murrayetal,OralSurgOralMedOralPath,1980.13)Schwartz&Kagan,AmJClinOnc,2002.14)Tengetal,CurrentOpinion,OtolaryngHeadNeckSurg,2005.
5) Reuthersetal,IntJOralMaxillofacSurg,2003.6) Freibergeretal,IntJRadiatOncolBiolPhys,2009.9) Katsuraetal,OralSurgOralMedOralPathol,2008.10) Thornetal,JOralMaxillofacSurg,2000.
ThePurportedSolu:on-HBOWhatisHBO?
• PaDentbreathesoxygenatapressure~2.5Xgreaterthannormobaricpressure(1ATA)fora
predeterminedperiodofDme
• Typical“dosing”is2.4ATAX90minutes
• Drug=Oxygen
• DosingApparatus=HyperbaricChamber
ORNTreatmentProtocolDetails
• ProphylaxiswhensurgeryisperformedinradiatedDssuewithoutfrankRN(eg.dentalextracDons,implantplacement,etc.)
20/10
• EstablishedORN(MarxorMiamiprotocol)
30/10
Ra:onaleforHyperbaricOxygenTherapy(HBO)
1)Marx,JOralMaxillofacSurg,1983.7)Marx&Johnson,OralSurgOralMedOralPath,1987.
§ HBOincreaseblood-Dssueoxygengradient§ FibroblastproliferaDon,angiogenesis,collagenformaDon1,7
§ Bactericidal&bacteriostaDc7
VancouverHBUSta:s:cs#Treated2016-2017(23months)
Delayed Radiation Injury 69 Problem Wounds 47 CO Poisoning 36 Decompression Sickness 25 Chronic Refractory Osteomyelitis 13 Sensori-Neural Hearing Loss 9 Gas Embolus 9 Necrotizing Soft Tissue Infections 7 Clostridial Myonecrosis 5 Compromised Flaps / Grafts 2 Severe Blood Loss Anemia 1
PetersonetalSupportCareCancer(2010)18:1089-1098
Recommenda:onsforFutureResearch
1. AretherespecificvalidpredictorsofORNrisk?
2. IsthereasubsetofpaDentsatriskforORNforwhomHBOis/isnoteffecDve?
3. Whatistheroleof“adjuvantpreven:vetherapy”(includingHBO)?
TheControversy:HBOforpost-RTextrac:ons?
For Against
For Against
§ Marxtrial(1985)§ 74paDentsforexo
§ 37abx+HBO§ 37abx(noHBO)
Thisremainstheonly
randomizedtrialto-datetostudythiseffect
SystemaDcreviews:1)Peterson,Hovanetal,2010.
o 1990-2008(excludesMarx)
“UseofprophylacDcHBOtherapyforprevenDonofORNinpost-RTextracDons.”
“LevelofevidenceIII,recommendaDongradeC:noguidelinepossible.”
Protocol ORNIncidence Abx+HBO 5.4% Abx 29.9%
Protocol ORNIncidence Abx+HBO 5.4% Abx 29.9%
4)Peterson,Hovanetal,SupportCareCancer,2010
Controversy:HBOforpost-RTextrac:ons?
For Against
§ Marxtrial(1985)§ 74paDentsforexo
§ 37abx+HBO§ 37abx(noHBO)
Thisremainstheonly
randomizedtrialto-datetostudythiseffect
SystemaDcreviews:1)Peterson,Hovanetal,2010.2)Nabil&Samman,2011.(19studies)
“Basedonweakevidence,prophylacDcHBOiseffecDveinreducingORNdevelopmentaperpost-RTextracDons.”
Protocol ORNIncidence Abx+HBO 4% Abx 6%
Protocol ORNIncidence Abx+HBO 5.4% Abx 29.9%
15)Nabil&Samman,IntJOralMaxillofacSurg,2011.
Controversy:HBOforpost-RTextrac:ons?
Controversy:HBOforpost-RTextrac:ons?
For Against
§ Marxtrial(1985)§ 74paDentsforexo
§ 37abx+HBO§ 37abx(noHBO)
Thisremainstheonly
randomizedtrialto-datetostudythiseffect
SystemaDcreviews:1)Peterson,Hovanetal,2010.2)Nabil&Samman,2011.3)Chuang,2011.(14studies)
NostaCsCcallysignificant
difference.
Protocol ORNIncidence Abx+HBO 5.4% Abx 29.9%
Protocol ORNIncidence Median Abx+HBO 0-11% 4.1% Abx 0-29.9% 7.1%
16)Chuang,JEvidBasedDentPract,2011.
IsThereAnyEvidencetoSupportTheUseofProphylac:cHBOPost-XRT?
StudyQuesCon:
DoesHyperbaricOxygenTherapy(HBOT)reduceosteoradionecrosis(ORN)ratesandimproveQualityofLife(QofL)inpaBentsrequiringoralsurgicalproceduresfollowing
acourseofhigh-doseheadandneckradiaBon?
ObjecCvesofStudy:
1. TodeterminewhetherthereisalowerrateandseverityofORNinheadandneck
radiotherapypaBentswhoreceiveprophylacBcHBOTpriortodentalextracBons.
2.TodeterminewhetherthereisadifferenceinQualityofLifemeasuresinsubjectswhoreceived/didnotreceiveHBOT
REB-ApprovedStudy
• ProspecBvelyenrollallH&Nptswhoreceivedhigh-doseRTwithorwithoutconcurrentchemotherapywhonowrequiredentalextracBonstodeterminetheprevalenceofORNwhentreatedwithorwithout
prophylacBcHBO.
• TheHBO-treatedpaBentswillbefromtheBCCAwhoarerouBnelyreferredtotheVGHHBUforprophylacBcHBO
• Thenon-HBOcontrolpaBentswillbefromtheNortheastCancerCentreinSudburyOntariowhoarenotreferredforprophylacBcHBO
StudyDesign• Baselineassessmentspriortooralsurgery;eachtoothassessedre(a)
difficultyofextracDon(b)effecDvedose
• AllpaDentsgivensamepre-opandpost-opmedicaDons;surgicaltechniquestandardizedbetweencentres
• PaDentsseeninfirstweekpost-extracDons;thenat2w,1m,6m,1yand2yfollow-ups
• Ateachvisit,assessedre+/-ORN;ifpresent,ORNstagedandmanaged
• EORTCQLQ-30andEORTC-43(H&N)quesDonnaireappliedateachvisit
ORNAssessmentScales
CommonTerminologyCriteriaforAdverseEvents(CTCAE)Version3.0
Grade1:AsymptomaDc;RadiographicfindingsonlyGrade2:SymptomaDcandInterferingwithFuncDon;MinimalBoneRemovalIndicatedGrade3:SymptomaDcandInterferingwithDailyLifeAcDviDes;OperaDveorHBO
Grade4:Disabling
ORNStage:Lyonsetal.2014Stage1:<2.5cm;AsymptomaDcStage2:>2.5cm;AsymptomaDcStage3:<2.5cm;SymptomaDc
Stage4:>2.5cm;PathologicFracture
ResultstoDate
Vancouver
• 23paDentsenrolled;22evaluableforQofL
• 17male;6female
• Agerange45-80(62.2)
Sudbury
• 45paDentsenrolledtodate;30evaluableforORN;27evaluableforQofL
• 21male;9female
• Agerange43-83(61.1)
ResultstoDateVancouver
• 52teethextracted(36mandible;16maxilla)
• 1caseofORN(Lyons);Stage3;resolvedwithanDbioDcsandlocal
debridement
• 2casesofORN(CTCAE);OneStage1*;OneStage2**
*=radiographicchangeonly**=fistulatobone;noboneexposure
Sudbury
• 55teethextracted(34mandible;21maxilla)
• 1caseofORN(Lyons);Stage3;resolvedwithdebridementand
Pentocloprotocol
• 3casesofORN(CTCAE);1casesStage1*;2casesStage2**
*=radiographicchangeonly
**=fistulatobone;noboneexposure
QualityofLifeData• Ateachstudyvisit,paDentscompletedEORTCQLQ-C30(general)andEORTCQLQ-H&N43(specific)andaskedaboutanyhealthand/
ormedicaDonchanges
QuesDons29and30(EORTCQLQ-30)1-7LickertScale(1=verypoor;7=excellent)
29. Howwouldyourateyouroverallhealththisweek?
30.Howwouldyourateyouroverallqualityoflifethisweek?
QualityofLifeData
Vancouver
Ques:on29: Baseline=5.1 6Months=5.9Ques:on30: Baseline=5.1 6months=6.0
SudburyQues:on29: Baseline=5.0 6months=4.9Ques:on30: Baseline=4.9 6months=4.8
QualityofLifeData
Vancouver
§ 3/23reportedvisualchanges(onewithcataracts)
§ 4/23reporteddecreasesinhearingacuity(onepaDentrequiringtubesaper1stHBOdive)
Sudbury
§ 1/30reporteddecreasedhearingacuity;novisualchanges
OsteoradionecrosisAReviewofPathophysiology,Preven:onandPharmacologicManagementUsingPentoxifylline,Alpha-
TocopherolandClodronate(Pentoclo)Rivero,ShamjiandKolokythas,OOOOVolume124,No.5,November2017
• ReviewofproposedmechanismsofORN,variousstagingclassificaDonsystems,tradiDonalvsmedicalmanagement
• ConclusionsthatthereisalackofscienDficevidencetoexplainthepathogenesisofORN;therefore,alackof
efficaciousconservaDvemanagementstrategies
• PreliminarystudiesusingPentoclohavebeenpromisingbutaddiDonalresearchneededtoelucidateroleofpharmacologic
therapyinthemanagementofORN
Pentoclo–EarlyPublica:onsDelanianetal;JournalofNeurological
Sciences275(2008):164-66Delanianetal;IntJournalRadOncBiolPhys
80(3),832-39,2011
Pa:entCF2013 2016
2017 2018
CBCTResults
May2016 November2016
Issues–Pa:entCF• WorseningbonelossdespiteconservaDvemanagementand
HB0(70divestotal)
• Surgeonreluctanttoextract48/47forfearofjawfracture;worseningorreiniDaDngORN
• PaDentessenDallyasymptomaDcsincestarDngPentocloprotocoldespitenoobjecDveimprovements;doesn’twantto
beonmedsindefinitely
• Shouldweextracttooth/teeth?BonebiopsyorotherdiagnosDctests?
Pa:entTSAugust2016Pre-HBO
March2017
Post-30divesHBO
TS–ConeBeamCT
March29,2017 March29,2017
Issues–Pa:entTS
• PaDentlivesandworksinBruneiwithlimitedaccesstospecializedcare(Singaporeforoncologiccare)
• Veryminorimprovement(??)sincecompleDng30divesof
HBO;pathologicfractureevidentonMarch2017CBCT
• PaDentremainsasymptomaDcdespiteradiographicchange
• PaDentnowonPentoclo.Othermanagementstrategies?
PentocloProtocol
Medica:on* Dose Frequency Prednisone 20mg Daily Amoxicillin/ClavulinicAcid 2g/500mg Daily Ciprofloxacin 1g Daily Fluconazole 50mg Daily
PENTOCLO Medica:on* Dose Frequency Pentoxifylline 400mg Twicedaily,fivedaysperweek VitaminE 600IU Eachmorning,fivedaysperweek VitaminE 400IU Eachevening,fivedaysperweek Clodronate 1600mg Daily,fivedaysperweek Ciprofloxacin 1g Onremainingtwodaysperweek Prednisone 20mg Onremainingtwodaysperweek
IU-InternaDonalUnitsAllmedicaDonstakenorally.
Conclusions
• UsingclassicdefiniDon,ORNappearstooccuratasimilarrate
(<5%)regardlessofwhetherprophylacDcHBOisusedornot
• QofLscoreshigherat6monthsinHBO-treatedgroup
• VisualchangesmorecommonlyreportedinpaDentstreatedwithHBO
• DoingprospecCveclinicaltrialsinoncologyischallenging!!
2
Thoughts
• Medicalmanagementtopreventperi-extracConandtotreatpost-extracConORNshouldbeconsideredasanalternaCve
toHBO
• BonebiopsiesshouldbeconsideredatCmeofextracConinpost-XRTseXng
• DefiniConofORNshouldbeexpandedtoincluderadiographicchangesw/ofrankboneexposure(ASCO
GuidelineDevelopment)
Ques:ons?Vancouver Sudbury
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