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CancerandVenousThromboembolism

NoDisclosures

BobRichard,MDPhDVAPugetSound

AssocProfUWSchoolofMedicine

Outline

•  1.PathophysiologyandClinicalRelevance

•  2.ScreeningForOccultMalignancyinunprovoked

thrombosis

•  3.Unsuspected/subsegmentalPE

•  4.HowLongtoTreatandwithWhat

•  5.RoleforTarget-specificOralAnScoagulants

•  6.PrimaryThrombosisProphylaxis

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1.PathophysiologyandClinicalRelevance

•  20%ofcancerpaSentsdevelopVTEatsomepointduringtheirillness.

•  20%ofVTEoccursincancerpaSents.–  Heit,2005;Prandonietal,2005;Hillen,2000.

•  Thrombosis(arterialandvenous)issecondleadingcauseofdeathincancer.–  KhoranaAAetal.JTH5:632–634,2007.

•  Thrombosisincancersignifiesaggressivedisease,notsimplymanifestaSonof“latestage.”

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ThrombosisandCancer:ABadCombinaSon

BraekkanSK,etal.AmJEpidemiol.2010;171(10):1109-1115

Exposure Person-years Deaths(n) MRper100Person-years

HR(95%CI)

None 277,713 1,750 0.63(0.60-0.66) 1.0(reference)

VTEonly

1,317 67 5.1(4.0-6.4) 2.6(2.0-3.3)

Canceronly 5,650 721 12.7(11.9-13.7) 7.4(6.8-8.2)

Cancer+VTE 131 72 55.0(43.6-69.3) 31.2(24.6-39.6)

MetastaScDisease=HigherRiskAlcalayetal.JClinOncol2006.24:1112-1118.

MetastaScDisease=HigherRisk

Chewetal.ArchInternMed.2006;166(4):458-464

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TumorTypeandThrombosisRiskHorstedF.PLoSMed.2012;9(7):e1001275.

‘average’overallrisk:13per1,000pt-yrs

Virchow’sTriad:PathophysiologyOfThrombosis

Alteredbloodflow/venousstasis

Alteredbloodvesselwall

IncreaseinbloodcoagulabilityCancer

WhyistheCoagulantPotenSaloftheBloodIncreasedinCancerPaSents?

•  1.TissueFactor:–  TumorcellsdirectlyproduceandreleaseTissueFactor.–  TissueFactorcirculatesinmicroparSclesandmayresultinsystemicthromboScrisk.

–  BypromoSngthrombinformaSon,TFleadstoplateletacSvaSon.

•  2.Platelets:–  Earlyliteraturesuggestedroleofplateletsadhesion/metastasisofmalignantcells.

–  Elevatedplateletcountincreasesthrombosisratesincancer.•  KhoranaAA&ConnollyGC.JCO.27:4839-4847,2009.

•  3.MucinSecreSon(adenocarcinoma):–  MaypromoteplateletacSvaSon.–  MayexplainwhyheparinsaremoreeffecSvethanwarfarin.

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WhyisthePro-ThromboScStateBeneficialtotheCancerCell?

•  FibrindeposiSon–  StabilizesadhesionofmetastaSccelltoendothelium

•  PlateletacSvaSon–  Protectstumorcellfromanackbyhostimmunesystem

Palumboetal.Blood2004;105:178–85.Rufetal.SeminThrombHemost2006;32:61–8.Horowitzetal.Blood2010;116:358–9.

TFExpressionisMarkedlyIncreasedinPancreaScCancer,ComparedWithNormalPancreaSc

Epithelium.

•  NitoriN.etal.Clin.Canc.Res.11,2531-2539,2005

2.ShouldwesearchforOccultMalignancyinunprovokedthrombosis?

~10%ofpaSentswith‘unprovokedVTE’willhavecancerdiagnosedwithin12months

Timeperiod UnprovokedThrombosis ProvokedThrombosis

BaselineTo

6mo.

8.6%

2.4%

6–12mo.

1.4%

0.5%

Carrieretal.AnnInternMed.2008;149:323-333.

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2.ScreeningForOccultMalignancyinUnprovokedVTE

•  ExtensiveevaluaSon(e.g.CTabd/pelvis)increasestheproporSonofpreviouslyundetectedcancers–  49.5%(Limitedscreening)vs.69.5%(Extensivescreening)*

•  Atleast50%ofpaSentsalreadyhavemetastaScdiseasewhentheircancerbecomesclinicallyevident

•  WhethertheearlierdetecSonofthesecancersmeansthatan‘ExtensiveScreening’strategywilltranslatetobenersurvivalisnotknown

*Carrieretal.AnnInternMed.2008;149:323-333.Timpetal.Blood.2013;122:1712-1723.

Extensivevs.Limited:Comparisonof2centersVanDoormaletal.JThrombHaemost.2011;9(1):79-84

3.UnsuspectedPulmonaryEmbolism

•  PulmonaryemboliidenSfiedonCTscansperformedforotherreasons– MostinsStuSonsnowusinghighlysensiSveCTmachinesforrouSneoncologystagingscans

•  Incidence– 3-6%dependingonslicethickness,reader– HigherininpaSents,olderpaSents– 2SmesmorecommonincancerpaSents

Farrell,etal.ClinRadiol2010;65:1-5.Ritchie,etal.Thorax2007;62:470-2.

Dentalietal.ThrombRes.2010Jun;125(6):518-22

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AsymptomaScVTE(DVTorPE)associatedwithapoorprognosis

•  All62paSentswereanS-coagulated– 92%LMWH,8%warfarin

•  45%(28/62)diedwithin6monthsofasymptomaScVTEdiagnosis– 27%mortalityincontrolswithsimilarage,tumortype/stage,chemo,epouse

DentalietalJThrombHaemost.2011May;9(5):1081-3.

UnsuspectedPE=DecreasedSurvivalProbability

O’ConnelletalJTH2011;9:305–11

denExterPLetal.JCO2011;29:2405-2409

CumulaSveRecurrentVTECommonWhetherIndexEventisSymptomaScorNot

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denExterPLetal.JCO2011;29:2405-2409

CumulaSveOverallSurvivalisPoorWhetherPEisSymptomaScorNot

UnsuspectedPE:WhereDoTheyOccur?

Main 7(10%)

Lobar 26(37%)

Segmental 20(29%)

Subsegmental 17(24%)

Browneetal.JThoracicOncol2010;5:798-803

O’ConnellCLetal.JThrombHaemost.2011Feb;9(2):305-11

O’ConnelletalJTH2011;9:305–11

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Sub-segmentalPulmonaryEmbolismMoreCommonwithModernScanners

Single-detectorCT

MulS-detectorCT

(MDCT)

MDCT4detectors

MDCT16detectors

MDCT64detectors

N 1123 1534 461 207 100

%SSPE

4.7 9.4 7.1 6.9 15.0

CarrierM.,etal.JThrombHaemost2010;8:1716–22

Oldervs.NewerCTScanners:NoDifferencein3-monthrateofVTE

CarrierM.,etal.JThrombHaemost2010;8:1716–22

Single-detectorCT

MulS-detectorCT

(MDCT)

MDCT4detectors

MDCT16detectors

MDCT64detectors

N 1943 2982 547 424 239

RateofVTEinf/u

0.9 1.1 1.4 0.6 0.8

4.HowLongShouldweTreataCancerPaSentforVTE,andWithWhatDrug?

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CanWePredictWhichCancerPaSentsAreMostLikelytoHaveRecurrentVTE?

•  +1pointforbeingawoman•  +1pointforhavinglungcancer•  +1pointforpriorVTE.PaXentsreceived•  -1pointforbreastcancer•  -1pointforlocalizedcancer(withoutmetastasis)

•  ≥1HighRisk•  0IntermediateRisk•  ≤-1LowRisk

Louzadaetal.CirculaSon2012;126:448–54.

CumulaSveRiskofRecurrentVTE

denExteretal.JThrombHaemost2013;11:998–1000.

Daltecan:Whataretheconsequencesofextending

dalteparinbeyond6months?

•  Assessconsequencesofextendingdalteparinincancer-associatedVTE

•  MulScentercohortstudy

•  dalteparin200IU/kgdailyX1month•  Then,dalteparin150IU/kgdailyforupto11months

•  50sitesintheUnitedStates,Europe,andCanada

Kakkar,A.etal.AbstractPresentaSon,ISTHConference,Amsterdam2013.

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DaltecanStudy

Kakkar,A.etal.AbstractPresentaSon,ISTHConference,Amsterdam2013.

DaltecanStudy

Kakkar,A.etal.AbstractPresentaSon,ISTHConference,Amsterdam2013.

5.RoleofNewDirectOralAnScoagulants:

•  ShouldweusetheneworalanScoagulantsforVTEtreatmentincancer?

•  Dabigatran(Pradaxa®):DirectThrombinInhibitor•  Rivaroxaban(Xarelto®):FXainhibitor•  Apixaban(Eliquis®):FXainhibitor

•  All3approvedfornon-valvularatrialfibrillaSon,•  All3appeartobeatleastaseffecSveandsafeasstandardtherapiesfor–  AcuteVTEtreatment–  SecondaryVTEprevenSon

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NewOralAnScoagulantsInCancerPaSents

•  VTEtreatmentstudieswiththenewagentsincludedfewcancerpaSents(<10%).

•  VTEtreatmentstudiesusedwarfarinasthecontrolarm,butwarfarinisnotthepreferredDVT/PEtreatmentstrategyincancerpaSents.

One More Time! If 1. LMWH > warfarin And 2. NOAC ~ warfarin Then you cannot conclude NOAC ~ LMWH !

OtherQuesSonsForNewOralAnScoagulantsInCancerPaSents

•  Noreversalagent.

•  VirtuallynoexperienceinpaSentswiththrombocytopenia.

•  InteracSonswithchemotherapyagentsnottested.

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6.PrimaryThrombosisProphylaxis

■  IstherearoleforthrombosisprophylaxisinoutpaSent,ambulatorycancerpaSentspriortodevelopmentofathrombosis?

PrimaryVTEPrevenSoninOutpaSentswithCancer

•  OverallannualriskinunselectedpopulaSonreceivingchemotherapy:10.9%*

•  Highlyvariable(?2–20%?Annual)–  Tumortype:Pancreas>lung>>breast,prostate–  Chemotherapysignificantlyincreasesrisk

•  Cis-plaSn,anS-angiogenicagentsarenotorious

•  DifficulttodefineVTErisk–  Front-loadedevents–  Differentfollow-upintervals–  Highoverallmortality

*Onen,etal.ArchInternMed2004;164:190–4

Meta-Analysis of VTE LMWH Prophylaxis Studies

Pancreas

Statistics for each study MH risk ratio and 95% CI MH risk Lower Upper

ratio limit limit p-Value FAMOUS 0.77 0.21 2.84 0.70 TOPIC-1 1.01 0.36 2.81 0.99 TOPIC-2 0.53 0.25 1.11 0.09 PRODIGE 0.66 0.29 1.49 0.32 PROTECHT 0.50 0.22 1.13 0.10 SIDERAS 0.82 0.23 2.94 0.76

0.64 0.44 0.94 0.02 CONKO004 0.35 0.16 0.75 0.01 FRAGEM 0.37 0.17 0.81 0.01

0.36 0.20 0.62 <.001

0.1 0.2 0.5 1 2 5 10

LMWH Control

Other Cancers

Kuderer et al ASH 2009

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PrimaryVTEPrevenSoninOutpaSents:ProofofConcept

Study Tumor Comparison DuraSon N

PROTECHT Lung,colon,breast

Low-doseLMWHvs.placebo(2.0%vs.3.9%)

4months 1150

SAVE-ONCO Mostlylung,GI,ovarian

Semuloparinvs.placebo(1.2%vs.3.4%)

Lengthofchemo+1month

3200

*Presentedasabstractonly

CONKO-004* Pancreas FULL-doseLMWHvs.NoRx(1.3%vs.9.9%)

3months+ 312

UKFRAGEM Pancreas FULL-doseLMWHvs.NoRx(3.4%vs.23%)

LethalVTE:(0%vs.8.3%)

3months 123

12-monthsLMWH(vs.not)inCancerPaSentsTreatedwithChemo

Akl,E.NEJM2012.

ConclusionsfromprimaryprevenSonstudiestodate

•  WidevariaSoninVTErisk

•  “Treatment”dosesofanScoagulantsmaybepreferable

•  ThehypothesisthatVTEprevenSonmayresultinsurvivalbenefitremainstantalizingbutunproven

•  NeedtoidenSfyhigh-riskpaSents;riskandcostofprimaryprevenSonnotjusSfiedinlow-riskpaSents

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Conclusions

•  Considerthecancerandconsidertherisk–  (easiersaidthandone)

•  NotreadytorecommendtheNOACs•  Clotsneedtobetreated

•  Newguidelineswillbecoming!

•  Manythankstomyexpert–DavidGarcia