Clinical trials needed to evaluate compression therapy in breast … · 2011. 1. 14. · Conclusion. This document should inform future research . trials in compression therapy and

442 INTERNATIONALANGIOLOGY October2010

Aim. A mainstay of lymphedema management involves the use of compression therapy. Compression therapy applica-tion is variable at different levels of disease severity. Evi-dence is scant to direct clinicians in best practice regarding compression therapy use. Further, compression clinical tri-als are fragmented and poorly extrapolable to the greater population. An ideal construct for conducting clinical tri-als in regards to compression therapy will promote paral-lel global initiatives based on a standard research agenda. The purpose of this article is to review current evidence in practice regarding compression therapy for BCRL manage-ment and based on this evidence, offer an expert consensus recommendation for a research agenda and prescriptive tri-als. Recommendations herein focus solely on compression interventions.Methods. This document represents the proceedings of a session organized by the International Compression Club (ICC) in June 2009 in Ponzano (Veneto, Italy). The purpose of the meeting was to enable a group of experts to discuss the existing evidence for compression treatment in breast cancer related lymphedema (BCRL) concentrating on areas where randomized controlled trials (RCTs) are lacking.Results. The current body of research suggests efficacy of compression interventions in the treatment and manage-ment of lymphedema. However, studies to date have failed to adequately address various forms of compression therapy and their optimal application in BCRL. We offer recommen-dations for standardized compression research trials for prophylaxis of arm lymphedema and for the management of

Clinical trials needed to evaluate compression therapy in breast cancer related lymphedema (BCRL). Proposals from an expert groupH.PARTSCH1,N.STOUT2,I.FORNER-CORDERO3,M.FLOUR4,C.MOFFATT5,A.SZUBA6,7,D.MILIC8,G.SZOLNOKY9,H.BRORSON10,M.ABEL11,J.SCHUREN12,F.SCHINGALE13,S.VIGNES14,N.PILLER15,W.DÖLLER16

1Dermatology, Medical University of Vienna, Vienna, Austria2Breast Care Department, National Naval Medical Center, Bethesda, MD, USA3Specialist in Physical Medicine and Rehabilitation, Valencia, Spain4Dermatology, University Hospital KU Leuven, Belgium5Glasgow Medical School, Glasgow, UK6Department of Internal Medicine, Wroclaw Medical University, Wroclaw, Poland7Department of Physiotherapy, Wroclaw School of Physical Education, Wroclaw, Poland8Clinic for Vascular Surgery, University Clinical Centre Nis, Nis, Serbia9Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary10Department of Clinical Sciences Malmö, Lund University, Plastic and Reconstructive Surgery, Malmö University Hospital, Malmö, Sweden11Lohmann & Rauscher, Rengsdorf, Germany12Medical Markets Laboratory, Neuss, Germany13Lympho-Opt Clinic, Pommelsbrunn, Germany14Department of Lymphology, Hôpital Cognacq-Jay, Paris, France15Department of Surgery, School of Medicine, Flinders Medical Centre, Bedford Park South, Australia16Center of Lymphology, General Hospital Wolfsberg, Austria

Conflicts of interest.Theauthorsdeclarenoconflictsof in-terest.

Theviewsexpressedaresolelythoseof theauthor(s)anddonotnecessarilyreflecttheopinionsorpolicyoftheDepart-mentoftheNavy,theDepartmentofDefensenortheUnitedStatesGovernment.

Funding.—Travelingcostsofsomeauthorsandthemedicalfacultywerekindlyprovidedby the companies representingtheindustrialboard.

Acknowledgments.—Theauthorswouldliketothankthefol-lowingpersonsfortheiractiveparticipationattheconsensusmeeting:

Medical Faculty.—ArpaiaG (Italy),BrouwerE (Netherlan-ds),CampisiC(Italy),CavezziA(Italy),DamstraR(Netherlan-ds),FrankenvanderWegenK(Netherlands),GardonMollardCh (France), Johansson K (Sweden), Jünger M (Germany),KarlsmarkT (Denmark),),MarianiF (Italy),MillerL (USA),MoBA(Norway),MortimerP(UK),MostiG(Italy),Noerrega-ardS(Denmark),WilliamsA(UK)

Industrial Board members of the ICC.—Karl Otto Braun:Klöppels M (Germany), Huntleigh: Küppers E (Germany),Bauerfeind:ThomäHJ (Germany),Medi:PiscaerT (Nether-lands),MeyerU(Germany),VelasquezN(Spain),BSNJobst:Gassner-OserM(Germany),BenderD(USA),Lohmann-Rau-scher: AbelM(Germany),BechuS(France),FaviniM(Italy),Mazzucci AM (Italy), Activa: Davidson G (UK), Muldoon J(UK),Convatec:BonnefinW(UK),Varitex:BotR(Netherlan-ds), Sigvaris:SchepersH (Switzerland),CartaroN (Switzer-land),RadunerJ(Switzerland),SalzmannMedico:KünzliD(Switzerland),GloriaMed:PeroschiA(Italy),3M:ThomasK(Germany),CizetaMedica:VallarinoE(Italy).

ReceivedonMarch9,2010.AcceptedforpublicationonJuly30,2010.

Anno: 2010Mese: OctoberVolume: 29No: 5Rivista: INTER NA TION AL ANGI OL O GYCod Rivista: Int Angiol

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Vol.29-No.5 INTERNATIONALANGIOLOGY 443

chronic BCRL. Suggestions are also made regarding; inclu-sion and exclusion criteria, measurement methodology and additional variables of interest for researchers to capture.Conclusion. This document should inform future research trials in compression therapy and serve as a guide to clini-cal researchers, industry researchers and lymphologists re-garding the strengths, weaknesses and shortcomings of the current literature. By providing this construct for research trials, the authors aim to support evidence-based therapy interventions, promote a cohesive, standardized and in-formative body of literature to enhance clinical outcomes, improve the quality of future research trials, inform indus-try innovation and guide policy related to BCRL.[IntAngiol2010;29:442-53]

Keywords:Breast neoplasms - Lymphedema - Bandages.

Incidence and risk factors

Breastcancerrelatedlymphedema(BCRL)isadistressingeffectofbreastcancerthatpresentsaschronicswellingofthearmandchestwallac-companiedby;skinchanges,decreasedrangeofmotion,pain,limitedstrengthandrecurrentin-fections. These impairments lead to significantfunctional, psychological and social morbidityandreducedhealth-relatedqualityoflife.1-5

Approximately 33% of patients present withlymphedema after breast cancer treatment. Ofthese, 40% will experience long term chronicswelling and 60% will have transitory symp-toms.3Olderage,higherbodymassindex,moreextensive surgery, axillary node dissection, ra-diation therapy and experiencing one or morepostoperative complications are important riskfactors.6 Sentinel node biopsy may reduce theincidenceratesintheshorttermbutlongertermstudiesareneededtoassessthedegreetowhichpatients remain free from lymphedema.6-8 Re-centdatademonstratethatthetimetoonsetoflymphedemamayonlybedelayedwithsentinelnodeproceduresratherthanprevented.9

Lymphedemaistreatableatanystageofsever-ity. Interventionat theearliestpoint isoptimalasitmaypreventtheprogressiontoamorese-verechronicconditionwithfibrosisand/oradi-posetissuebuildup,whichstartswithinthefirstyearafter lymphedemaonset.10Earlydetectionrequires clinicians to identify patients at highrisk,assesssubjectiveandclinicalsymptomsandintervenebasedonthispresentation.Subjectivesymptomscanbepredictiveoftheonsetofswell-ingandshouldbeproperlyassessed.11Addition-ally, women with mild lymphedema are three

timesmorelikelytodevelopadvancedformsofthecondition,thuswarrantingtreatment.8Evenincasesofsevere,progressedlymphedematreat-mentoptions,althoughmoreintense,areeffec-tive.

Pathophysiology

BCRLisnotsimplyduetolymphaticobstruc-tion.Priortoedemaonsetwomenwholaterde-velopBCRLhavehigherperipherallymphflowsthan those not developing BCRL. Peripherallymphflowsmayalsobeelevatedinthecontral-ateral arm suggesting that there is a subgroupof women with constitutionally higher lymphflows, and by implication higher capillary fil-trationrates,whoarepronetoBCRLafteraxil-larysurgery.Therefore,insomecases,followingbreast cancer treatment, the lymphatic pumpfailsintheipsilateralarmbecauseofthechroni-callyelevatedlymphload.12,13

Compression therapy in BCRL

Compression therapy is an integral part ofcaringforlymphedemaatanystageofseverity.Whenlymphedemaisdetectedatitsearlieston-setconservativecompressiontherapy,andedu-cationforprotectivebehaviorsmaypreventtheprogressionoflymphedematoamoreadvancedandpotentiallydisablingstage.Inmanifeststag-esoflymphedema,compressiontreatmentisaneffectivecomponentofamulti-modaldeconges-tivetherapyintervention.Compressioninterven-tionseffectivlyreducelimbvolumeandmaintainvolumedecongestion.

Pastresearchendeavourshavefocusedonop-timalutilizationofstandardcompressionprod-ucts.14, 15 Compression modalities including;garments, compressive short-stretch bandagesandintermittentpneumaticcompressiondevic-esareefficacious in thecontextofa treatmentprogram.16,18However,theoptimalcompressionpressure,pressuregradient,typeofmaterialandfrequencyandintervalofapplicationaswellascombined compression therapy regimens forboth prophylaxis and treatment need to be as-sessedbytheprinciplesofevidencebasedmedi-cine.

Anno: 2010Mese: OctoberVolume: 29No: 5Rivista: INTER NA TION AL ANGI OL O GYCod Rivista: Int Angiol

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Interface pressure measurement is useful togauge the levelofpressureapplied to the limbbythecompressiondevice,itprovidesinforma-tionregardingthegradientofpressurealongthelimb,consistencyofthecompressionlevelsalongthelimbandcanassessthecompressiondevicepressure changes over time.19 These measure-ments can inform investigators and cliniciansabout compressiongarment stiffness andpres-suresbeingapplyingagainstthetissue.Interfacepressure measures are also of great interest toindustry to assure quality and effectiveness ofcompressiongarments.

Aim of the document

Thepurposeofthisdocumentistoprovideareview of the current evidence regarding com-pression use in the treatment of BCRL. Muchofthecurrentdogmasurroundingcompressiontherapy must be challengedbasedonnewandemerging data about lymphatic system func-tion and associated pathophysiology.15 We alsopresentrecommendationsforaresearchagendaand propose constructs for future BCRL com-pression therapy trials that may guide and in-formresearchers,cliniciansandindustryrepre-sentativesworld-wideinanefforttopromoteacohesive,standardizedandinformativebodyofliteratureregardingcompressiontherapyappli-cationsandproducts.

Thisdocument isstructured tohighlightevi-denceandresearchrecommendationsregardingcompressionmodalitiesintotwoseparatepara-digms:

I) Prophylaxis and early intervention duringand after primary breast cancer disease treat-ment

II) Therapy of advanced stage BCRL of theupper extremity (these proposals are specificto extremity lymphedema and do not considerchest-wallorbreastlymphedema)

Prophylaxis and early intervention after BC-treat-ment

Current evidenCe

Historical data leads us to believe that onlyone-thirdofbreastcancersurvivorswilldevelop

armlymphedemaafter treatment.Theonsetoflymphedemarangesfrom6monthsto20+yearsafter treatment. This long and erratic latencyperiodispoorlyunderstood,howeverspeakstotheissuethatlymphedemaisalife-longriskforsurvivors. Based on this data, however, a largegroupofsurvivorswillneverdeveloplymphede-ma,makingatrueprophylacticcompressionap-proachtopreventionunrealisticandevenunnec-essarilyconstrainingforthemajorityofwomen.

Amoreprudentapproachfocusesonearlyde-tection of arm swelling and early intervention.Preliminaryresearchfindingssuggestthatiniti-atingcompression therapyat theearliestonsetof lymphedema may prevent progression andmanifestationofseverelymphedema.20Thecon-cept of early intervention will only be realizedif themedicalcommunityembracesaprospec-tivesurveillanceapproachtomonitoringforandeducatingpatientsaboutlymphedema.Insuchamodel,preoperativeassessmentoflimbvolumeisessentialsothatabaselinemeasureofvolumeandinter-limbvariancecanbeestablished.Thisis followed by a period of interval surveillancewherelimbvolume,alongwithpatientsubjectivereport,ismonitoredforchange.Ifthelimbvol-ume differential exceeds the diagnostic thresh-old, even in the absence of clinically apparentswelling,acompressioninterventionisinitiated.Earlyevidencesupportsthisapproach,howeverlargescalecontrolledtrialsarelacking.

Two prophylactic compression therapy trialconstructsshouldbeconsideredinthisprospec-tivesurveillanceapproach(Figure1):

1)inthecontextofaprospectivesurveillancemodelofcare,randomizepatientstostudy(com-pression) or control (no compression) groupsonly if they surpass a standardized diagnosticthreshold associated with sub-clinical lymph-edemaatoneoftheirintervalfollow-upvisits;

2) preoperatively randomize all patients tostudy(compression)orcontrol(nocompression)groupsregardlessoflimbvolumechangesatanypointalongthestudytimeline.Thestudygroupinthiscasereceivespreventivecompressiongar-mentsforwearthroughouttheirpostoperativeperiod.Ifpatientsinthecontrolgroupdeveloplimbvolumechangesconsistentwiththeonsetoflymphedematheywouldbefurtherrandomizedtoreceiveacompressiontherapyinterventionorreceivenocompression(Figure1).

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Working hypotheses

Thesestudyconstructsexplorethehypothesisthat compression therapy, applied at the earli-est onset of limb volume change, prevents theprogression to manifest, chronic lymphedema.However,eachconstructapproachesthepreven-tivemodeldifferently.ConstructAproposesthatinthecontextofasurveillancemodelofcare,ameaningfullimbvolumechangecanbeclinical-lydetectedandtreated.Thisconstructpromotesearlydetectionandfocusesontreatingameas-urableimpairment;however,itreliesonclinicaltoolsandpractitionerdiagnosticskillsthatmaynotbeeasilyextrapolabletothegreaterpopula-tionofclinicalpractitioners.

Construct B proposes that by applying com-pression to subjects randomized to the studygroup, therewillbeameaningfuldifference intheonsetoflymphedemaovertimeascomparedtothecontrolgroup.Thisconstructsimplifiesthepostoperativesurveillancemodelanddefinitively

assessestheabilityofcompressiongarmentstopreventtheonsetoflymphedema.However,thisconstructrequiresthatallsubjectsinthestudygroup receive compression regardless of theirknownriskfactorsandpotentialfordevelopinglymphedema.Thismayconstraintheresearcherfromidentifyingconfoundingvariablesthatmaybeimportant instudyingthenaturalhistoryoflymphedema.

study ConstruCts

Bothstudyconstructsrelyonprospectivemul-ticenterrandomizedcontrolledtrials.Allpatientsare seen preoperatively for baseline measure-mentsofarmvolumesandallarefollowedinthepost-operativeperiodatthreemonthintervalstooneyear.20-22RecommendationsformeasurableoutcomevariablesareincludedinTableI.23-53

Theinclusioncriteriashouldenablethebroad-estrepresentationofwomenhavingbreastcan-

Figure1.—Prospectiveprophylaxisandearlyinterventioncompressiontherapytrialrecommendations.

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cer treatment. Therefore, outside of those whohaveevidenceofmetastaticprocesses,allstagesof disease should be included. Additional vari-ablesregardingtreatmentinterventions,patientcharacteristics, demographic information andco-morbidities as well as additional objectiveand self-reportedoutcomescanbe captured inbothof the studymodels.Thesevariablescon-tribute richly to the profile of the patient whodevelopslymphedemaandmayaidinenhancingriskstratification.Furthertheyenableresearch-erstodrawconclusionsaboutthepatients’func-tional,socialandpsychologicaldomainsastheyrelatetolymphedema.23TableIIpresentsrecom-mendationsforpatientcharacteristicdatatobecaptured.

Exclusionfromstudyparticipation isrecom-mended for conditions that may skew results(Table III). Every effort should be made to in-cludesubjectsofvariousracialandethnicback-grounds.Languagebarriersmustbeovercometoenablebroadcaptureofthepatientpopulation.

Standardization of the protocol, regardlessof thechosenstudyconstruct, isparamounttoassuringvalidoutcomes.The inclusioncriteriashouldbestandardizedbasedonthelimbvolumeatinitialevaluation.Wesuggestthatasubclini-callymphedemaisdefinedasanexcessvolumeof3-5%withconsiderationforthecontralaterallimb.20 Excess volume can be described eitheras(1)anabsolutevolumeinml(excessvolume(absolute) = affected arm-non-affected arm) orexpressed as (2) percent (excess volume [%] =

table i.—�Recommended Study Outcome

Variables.Primaryoutcomes–Armvolumechangeovertime–Edemavolumeofaffectedlimb(affected-unaffectedarm

volumeateachtimepoint)–Pittingtest–Moisturemeasuringsystems–Rangeofmotion(ROM)–upperquadrant–Subjectivesymptoms41–GeneralandDiseasespecificqualityoflife(QOL)measures:

42-47

–PsychologyGeneralWell-Beingscale(PGWB)–NottinghamHealthProfile(NHP)–EuropeanOrganisationforResearchandTreatmentof

Cancer(EORTC)–DisabilityofArm,ShoulderandHand(DASH)–ShoulderPainandDisabilityIndex(SPADI)–FunctionalAssessmentofCancerTherapies–Fatigue

(FACT-F)–Healthrelatedqualityoflifechanges:ShortForm-36(SF-

36)(diseasespecificandgeneralisttools)–Interfacepressureofcompressiondevice–Compliancewithcompressiondevices53

–Good≥90%compliantwithrecommendations–Fair=60-89%compliantwithrecommendations–Poor≤60%compliantwithrecommendations

Secondary outcomes –Durometer–Tonometry–Musclestrength(dynamometry)–Bio-impedance–anthropometricmeasures–Skinassessment–skinfolds,skinchange–Cost-benefit–Weightchanges–Comfortofthegarment

table ii.—�patient CharaCteristiCs*

AgeMedicalcomorbidities(hypertension,diabetes,etc.)Labvalues(bloodcounts)BodyMassIndexAffectedarm(Right/Left)Dominantarm(Right/Left)SensoryintegrityPresenceofvenousdiseaseDegreesofrangeofmotion(shoulder,elbow)Timecourseofsymptoms/conditionLymphedemaISL-stage:0-IIISegmentaldeformitiesandedemadistributionBaselineabsolutevolume(mL)foreachlimbBaselinevolumedifferential(mL)(Volumeofaffectedlimb

[pendingsurgicalintervention]vs.contralaterallimb)Baselinepaininaffectedlimb–VisualAnalogScale(VAS)Baselineheaviness-VASBaselinenumbness-VASPittingtestPresenceoffibrosisHistoryofinfectionsNumberofpreviousinfectionepisodesTypeofsurgeryTypeofaxillaryprocedureandnumberofnodesremovedPost-operativecomplications(seroma,axillarywebsyn-

drome,infectionetc.)Tumorcharacteristics(TNMclassification)Lymphnodecharacteristics(positivevs.negative)AdjuvantchemotherapyanddrugsdeliveredRadiotherapyandlocationoffieldHormonaltherapyanddrugsdelivered

*AdoptedfromVignesetal.62

table iii.—�Exclusion criteria.

–Bilaterallymphnodedissection*–Priorhistoryoflymphnodedissection*–Priorhistoryofradiationtherapytotheadjacentchest

wall*–Metastaticdisease*–Historyofsevereshoulder/armtraumaorsurgery*–Bilateralarmswelling–Clinicalmanifestationofinfectionatenrollment(cellulitis,

erysipelas)–Acutevenousthrombosisorphlebitis–Flaccidparalysisofthelimb–Decompensatedheartfailure–Severepulmonaryinsufficiency–Activeandclinicallysignificantliverorrenaldisease–Contactallergiesrelevanttocompressionmaterials(latex)–Seriouspsychiatricdisorders(severedepression,schizo-

phrenia)–Significantmentaldelaythatpreventscomprehensionand/

orlearningì

*Primarilyconcerninginprophylacticinterventiontrials.

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[affected arm-non-affected arm]/non-affectedarm]x100)with%volumechangeexpressedas:excessvolumechange=(excessvolumetime0-ex-cessvolumetime1)/excessvolumetime0x100.

Arm volumetry of both arms will be trackedateachvisitalongwithpatientcompliancewithcompression therapy and subjective symptomassessment. Interface pressure measurementswillbeassessedatongoingintervals.Compres-siongarmentsshouldbeofastandardizedcom-pressionlevelandideallyfromthesamemanu-facturer.Thesamegarmentsshouldbegiventoallpatientswithastandardeducationalhandoutaddressing;weartime,washingintervalsandin-tervalofgarmentreplacement.

Cost considerations are of growing concernduetofinitehealthcareresources.Effortsshouldbemadetocapturecostdataspecifictothe in-terventionandcompressiondevice(s)used.Costdataisusefullytranslatedtoenable;costutilityanalyses,thebenefitgainedpercostofinterven-tion,costeffectivenessanalyses,comparingtwoor more interventions for optimal cost benefit.Costanalysesandtheimplicationsofsuchanal-yseswill varyamongnationsdependingon thesocietalperspective,availabilityofresourcesandcurrentreimbursementstructures.Theseimpor-tantdatacanbeextrapolatedgloballytosupportnationalpaymentandreimbursementstructures.

Methodology

Arm volumetry will be the primary outcometoassesseffectivenessofthecompressioninter-vention.Manydifferent techniquesare reliablefor measuring and quantifying limb volume,these include; circumferential measurementsatpredefined incrementsalong the limb toen-able calculation of volume using standardizedgeometricalformulas,24waterdisplacement,op-toelectronicPerometer®andbioelectricalspec-troscopsydevices.25-29Standardizedpositioningof the patient and technique for measurementshouldbeassured.

Interfacepressureshouldbemeasuredatthedorsal(lateral)aspectofthearm,afterapplica-tion and before removing the compression de-vice.30, 31 The exact position of the measuringprobewillbestandardizedatthreepointsalongthelimb;distallowerarm,largestpartoflowerarmandmidupperarm,assuggestedbytheGer-

maninstituteforqualitycontrolofcompressiongarments.32Changeininterfacepressureduringexercise(e.g.,fistclosures)assessesthestiffnessof the compression product.33 Standardizationmust be assured and it is advisable to use thesamepressuremeasuringdeviceforallpatientsinthetrial.

Additionaltestsandmeasuresinclude;testsofpittingedema,34watercontentinthetissuethatmay be measured by bioimpedance,35-38 highfrequencyultrasound36ormoisturemeters,39,40durometry(tonometry)canbeperformed41andmusclestrengthmaybeanotherparameterofin-terest.42

Subjective sensory changes should be moni-tored at each follow-up visit using a standard-izedmeasurementtoolsuchasthatdescribedbyArmeret al.43Qualityof lifeassessment instru-mentscanbe integratedaswell.44-51Additionalsubjectiveassessmentmayinclude;thenumberof infections (“dermato-lymphangio-adenitisDLA 52”), the comfort of the compression gar-ment and the subjects compliance with com-pressionwear.

Othervariablesofinterestincluding;jointmo-bility,pain,activityparticipation,andfatigueareinformative to compression therapy trials.53-56Optimally a trial will consider incorporatingseveral measures to further demonstrate andcompare sensitivity and specificity of the vari-oustechniquesfordetectingearly limbvolumechanges.

Ofprofoundimportanceisthefollowupproto-colforongoingassessment.Preoperativeassess-mentandenrollmentwillbefollowedbypostop-erativefollow-upatonemonthandthenatthreemonth intervals thereafter forat least thefirstyear.57,58Samplesizeshouldbeestimatedbasedonfollowupdataaftersurgicaltherapyandshallbecalculateddependingonthepredefinedout-come parameters. Risk reduction by compres-siontherapyandnumberneededtotreat(NNT)areadditionaloutcomesofimportance.

Therapy of advanced stage BCRL

Current evidenCe

ChroniclymphedemaisoptimallytreatedwithDecongestiveLymphaticTherapy (DLT);amul-timodalinterventionthatincludes;manuallym-

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phatic drainage, compression bandaging, exer-cise,skincareinstruction,compressiongarmentsand may also include intermittent pneumaticcompression therapy.Compression therapy isamainstay in the treatment and ongoing care ofalymphedematouslimb.Initialdecongestionofthelimbrequiresastutecompressionapplicationofshortstretchbandages.17,59UponlimbvolumereductionwithDLT,compressiongarmentswillmaintain limb volume provided that they areappropriatelymeasured forandprescribed.16,59Compression bandaging is utilized to managethelimbiftheswellingexacerbates,assuringop-timal limbvolume for compressiongarmentfitandeffectiveness.17Additionally,pneumaticcom-pressiondevicesplayaroleinthecomprehensiveapproachtolymphedemamanagementtoaidindecongestion and limb volume maintenance.60Non-complianceconcerningtheuseofcompres-sion is themost important risk factor for reap-pearanceofarmswelling.61,62

Optimal parameters for the use of compres-siondevicesatallphasesoftreatmentandman-agement are unclear. Many purport compres-siontherapytobeasuccessfuladjuncttoothertherapeutic modalities, however in the absenceofothermodalities,wedonotknowwhichcom-pressionmodeisoptimalandunderwhatclinicalcircumstancesitwillpromotethebestoutcomes.

study ConstruCts

Studyconstructsaimedatexploringtheeffec-tivenessofcompressioninterventionsduringandafter intensive therapy are necessary. Durationof compression application as well as optimalpressures and mode of compression should beexplored through well designed and controlledtrials. Additional studies should be conductedinvestigating a comparison of the effectivenessofdifferentcompressionmodalities.

TwoprimarystudyconstructsarehighlightedinFigure2:

1) comparisonoftwodifferentmodesofcom-pression interventionduringthe intensive ther-apyphasetodetermineifoneissuperiortotheother;

2) comparisonofvariouscompressiondevicesduringthemaintenancephaseoftreatment.

Both study constructs rely on prospectivemulticenterrandomizedcontrolledtrials.Allpa-tients are enrolled at the inception of their in-tensivetherapyregimen(ConstructA)orastheyareentering themaintenancephaseof therapy(ConstructB)illustratedinFigure2.Eachofthestudieswillrandomizepatientstoacompressiongroupusingoneoftheselecteddevicesandwillappropriately standardize frequency and dura-tionofcompressionwear.Recommendationsfor

Figure2.—Decongestivecompressiontherapytrialrecommendationsforchroniclymphedema.

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specificcomparativestudiesaresummarizedintheAppendix1tothisarticle.

Theinclusioncriteriashouldbestandardizedbased on the limb volume at initial evaluationalongwithconsiderationforthepatient’sphysi-cal status and comorbid conditions. Patientsshowing greater than 5-10% interlimb discrep-ancyinexcessvolumeprovideasoundcohortforwhich meaningful change can be documentedovertime.Inlargercohortstudiesstratificationbasedonseveritycanbeconsideredinexamin-ingvolumeoutcomes.

Table II contains a list of recommended pa-tient characteristics. Exclusion should be con-sideredforco-morbidconditionsthatmayskewoutcomes(TableIII).Also,patientswhohaveex-periencedintensivedecongestivetherapywithinthelastsixmonthsmaynotbeoptimalsubjectsforinclusionintointerventionalprotocolsunderConstructA,astheirgreatestvolumedecrementmayhavealreadybeenachieved.Optimally,pa-tients included in Construct B studies shouldhaveveryrecentlycompleteddecongestivether-apyandtransitionedtoamaintenanceselfcarephaseoftreatment.

Limbvolumechangeover time is theprima-ry outcomevariable.Subjective symptomsandqualityoflifeassessmenttoolsshouldbeincorpo-rated43-51alongwithmeasuresofjointmobility,frequencyofrecurrentinfectionsandtolerabilityof and compliance to compression therapy.53-59Joint range of motion (ROM) is an importantvariableinterrelatedbothwithedemaformationbutalsowithsomelimitationsthatmaybetem-porarily causedbycompressionbandaging.53-56ROMshouldbedocumentedfortheelbowandshoulderjointstocharacterizetheinitialstatusand to assess changes during the trajectory oftreatment. Shoulder strength and stabilizationcorrelatetooverallfunctionalstatusafterbreastcancerandimpairmentsintheshouldershouldbe captured.55 Risk factors closely associatedwithbreastcancerrelatedlymphedemaandout-comevariablesofinterestarenumerous63-65andlistedinTableI.Allmeasureswillfollowstand-ardprotocolforpre-andpost-treatment.

Methodology

Arm-volumetrymeasuredwithareliabletoolis a prerequisite for including a patient into a

compressiontrial.Previouslydiscussedmethodsforvolumetricassessmentcanbeappliedtothispatientcohortaswell.Theseinterventionalstud-iesemployapre-andpostinterventionmeasure-mentstrategy.Controlsmustberigoroustoas-sure consistency of DLT treatment modalities,patienteducationandcompressionapplication.Ideallymeasurementsaretakenatrepeatedin-tervalsbythesameraterandtreatmentinterven-tionsarecompletedbyaseparateratertoblindtheresults.

Severityassessmentmaybeutilizedbasedonsimple inter-limb volume differences assessedasminimal(<20%increase),moderate(20-40%increase), or severe (>40% increase).66 Thisstratificationenablesastandardizedmeasureofincrementalchangeovertimeaswellascatego-rizationoftreatmentresponsebasedonseverity.Thisalsoenablestheresearchertodrawconclu-sionsabouttheintensity,durationandfrequen-cyoftreatmentforsubjectswithvariouslevelsofdiseaseseverity.

Measurement of interface pressure, as dis-cussedinpartI,shouldbepartofanytrialdeal-ingwithcompressiontherapyregardlessofthemodeofcompression.Interfacepressuremeas-ures should be standardized along the limb toprovidecomparabledatawithineachcohort.In-terandintraraterreliabilitywithuseofthepres-

table iv.—�CharaCteristiCs of CoMpression deviCes and Materials .

–Sleeves–Differentiationbetweencustommadeorready-made–CompressionClass(GermanRALregulations)32

–I:15-21mmHg(Low)–II:23-32mmHg(Medium)–III:34-46mmHg(High)

–Sleevestyle–Methodofapplication

–Bandages–Materialsapplied(foampadding,short-stretch)–Numberoflayers–Applicationmethod79

–Intermittentpneumaticcompression:80,81

–Singlechambersleevepumps–Multichambersleevenon-gradientpumps–4-orlesschambers–5andmorechambers–multichambergradientpressurepumpswithpressure

regulation–4orlesschambers–5-9chambers–10ormorechambers–multichamberextremitysleeveandtrunkgarment

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suremonitorshouldbeassessedbeforethetrialbeginstoassurestandardization.

Documentation of compression materials,bandaging technique, intervals of application,initial interface pressure, level of intervention,compliance, follow-up intervals, and prescrip-tionofnewsleevesorbandagesshallbenoted.Thecompressionclassofgarments for theup-perextremityshouldbespecifiedasshouldsomepracticalspecificationsof thecharacteristicsofthecompressionmodalityandmaterials (TableIV).66-81

Additional methods may be used to assesslymphdrainagecapacityincluding;lymphoscin-tigraphy, fluorescence-microlymphangiography,indirectlymphography,MRI-lymphography,andIndocyanine-green test.67-72 These tests provideanadditionalobjectivemeasuretofurthersub-stantiatetheimpactofcompressiontherapyonthelymphaticsystem.

Endpointsforeachoftheseconstructsaredif-ferent(Figure2).InConstructA,favorableout-comeswillbeevidencedbylimbvolumedecon-gestion and improvements in the physical andfunctional domains. In Construct B, favorableoutcomeswillbeevidencedbyhowthecompres-sion modality supports the limb and preventsreaccumulation of fluid in the limb. Recogniz-ingthatsubjectsinConstructBwillbeinaself-carephaseof treatment,mucheducationmustbe done regarding study protocols to controlfor variables that may confound. Standardizedmonitoring througha journalor logwill assistinassessingcompliance,compressionweartimeandactivitylevels.

General study recommendations

Good clinical practice

Theformalrequirements fromGoodClinicalPractice recommendations, based on the Hel-sinki declaration, must be fulfilled. This alsoincludes the agreement of a local Ethics Com-mittee.73,74Patientshavetobe includedwithintheintentiontotreatanalysisandthestatusofthe patient needs to be defined at the point ofleaving the trial. Trial registration in the Inter-nationalStandardRandomisedControlledTrial(ISRCTN) register 75 or with the United States

NationalInstitutesofHealthClinicalTrialregis-try76isrecommended.

Drop-out and adverse events

Areportofinformedconsentisnecessaryandalltrialsarevoluntaryforpatients.Thereasonforadiscontinuationofthestudyshallbespecified.Adverseeventsofparticularinteresttopatientswith lymphedema include; acute inflammatoryepisodes,erysipelas,rapidvolumeincrease,skinbreakdown (rashes), blood clots and recurrentcancer.77,78Eventsneed tobedocumentedandeachinvestigatorwillmakeindividualdecisionsaboutwhetherthesubjectcontinuesinthetrial

Interventions/examples and proposals

Asaprimaryoutcomeof thisarticle, theau-thorsofferspecificrecommendationsforfuturestudies involving compression therapy trials.These recommendationsareoutlinedas “PRO-POSALS1-16”intheAppendix.Thisisintendedto guide researchers towards cohesive effortstoremedycurrentdeficitsintheliterature.Col-laborativeglobaleffortsshouldbemadeinun-dertakingthesetrialstoenableresultsthattran-scend national boarders. Study results shouldaimtoinformclinicalbestpractice,butwillalsobeusefulincontributingtopolicyandpaymentstructures.Largestudiesdemonstratingnotonlyefficacyandeffectivenessofcompression inter-ventions,butalsocost-effectivenesscandirectlyimprovedeliveryofservices,accesstomaterialsandinterventionsandpromotebestpractice.

Conclusions

Thisdocumentrepresentstheculminationofanexpertpaneldiscussionregardingthecurrentstateofthescienceofcompressionuseinbreastcancerrelatedlymphedematreatment.Weiden-tify gaps in the current evidence as for earlystage and manifest lymphedema and providerecommendationstodrivefutureresearchtrials.Werecommendthatthisdocumentbetakenintoadvisement by researchers undertaking futurecompressiontherapytrialsandencourageinter-nationalcollaborationinundertakinglarge-scaletrialstosupportcompressioninterventions.

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Appendix 1

Proposed compression trials

I) Prophylaxis of arm lymphedema PROPOSAL1.ProspectivemulticenterRCTmeasuringarmvolumebe-foreandmonitoringaftersurgery*• Group A: compression sleeves, e.g., Class I (15-21mmHg)• GroupB:nocompression,nootherspecifictreatment*SuchastudycanfollowconstructsinFigure1eithera)Patientspresentingpostsurgicalarm-swellingbetween3–5%comparedtothecontralateralsideormodelb)allpatientsafterbreastcancersurgery.

II a) Initial treatment phasePROPOSAL2.Sleeveshigherpressure(ClassIIorIII)vs.lowpressure(ClassI)3.Sleeveshigher stiffnessvs. lower stiffnessexerting thesamepressure4.Sleevesvs.bandages5.Sleevesvs.velcrodevice6.Bandagesvs.velcrodevice7.Bandagesvs.bandages(differenttypesandpressures)8.IPCandsleeves(orbandages)vs.samesleeves(orband-ages)alone9.IPCandbasiccompressionvs.IPCandsamebasiccom-pression(differenttypesandpressuresofIPC,e.g.,30-50mmHgvs.120-150mmHgProposal concerning sleeves for the initial treatment phase:Duetothevolumereductionofthelimbtobeexpectedespeciallyinthefirstdaysoftreatmentasortimentofreadymadestockingswithdifferentsizesshouldbeavailable(stayinginthepropertyoftheinvestigatinginstitution).

II b) Maintenance phasePROPOSAL10. Sleeves custom-made (flat knitted) vs. ready made(roundknitted),samepressure11.Sleevesready-made(flatknitted)vs.readymade(roundknitted),samepressure12. Sleeves high pressure (e.g., Class II) vs. low pressure(ClassI)13.Sleevesvs.velcrodevice14.IPCandsleevesvs.samesleevesalone15. IPC and sleeves vs. IPC and same sleeves (differenttypesandpressuresofIPC)16.IPC3-4chambernon-gradientpumpvs.10andmulti-chamberpumpwithpossibilitytoaddatrunkgarmentincaseoftrunkedema

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Corresponding author: N. Stout, Breast Care Department,National Naval Medical Center, 8901 Wisconsin Avenue,20889Bethesda,MD,USA.E-mail:[email protected]

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Clinical trials needed to evaluate compression therapy in breast … · 2011. 1. 14. · Conclusion. This document should inform future research . trials in compression therapy and