The Role of Hyperbaric Oxygen Therapy (HBOT) in Prevenng ... · § Marx trial (1985) § 74 paents...

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%


4)Peterson,Hovanetal,SupportCareCancer,2010

Controversy:HBOforpost-RTextrac:ons?

For Against



Thisremainstheonly


SystemaDcreviews:1)Peterson,Hovanetal,2010.2)Nabil&Samman,2011.(19studies)

“Basedonweakevidence,prophylacDcHBOiseffecDveinreducingORNdevelopmentaperpost-RTextracDons.”

Protocol ORNIncidence Abx+HBO 4% Abx 6%


15)Nabil&Samman,IntJOralMaxillofacSurg,2011.



For Against



Thisremainstheonly


SystemaDcreviews:1)Peterson,Hovanetal,2010.2)Nabil&Samman,2011.3)Chuang,2011.(14studies)

NostaCsCcallysignificant

difference.


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

The Role of Hyperbaric Oxygen Therapy (HBOT) in Prevenng ... · § Marx trial (1985) § 74 paents...

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