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MechanismsMechanisms ofof CancerCancer--InducedInduced Thrombosis:Thrombosis: TheThe InterfaceInterface

Pathogenesis?Pathogenesis?

BiologicalBiological significance?significance?

PotentialPotential importanceimportance forfor cancercancer therapy?therapy?

PathogenesisPathogenesis ofof ThrombosisThrombosis inin CancerCancer AA ModificationModification ofof VirchowVirchowss TriadTriad

SSttaassiiss HHyyppeerrccooaagguullaabbiilliittyy
SSttaassiiss
HHyyppeerrccooaagguullaabbiilliittyy

VascularVascular InjuryInjury

1.1. StasisStasis

ProlongedProlonged bedbed restrest ExtrinsicExtrinsic compressioncompression ofof bloodblood vesselsvessels byby tumortumor

bedbed restrest ExtrinsicExtrinsic compressioncompression ofof bloodblood vesselsvessels byby tumortumor

2.2. VascularVascular InjuryInjury

DirectDirect invasioninvasion byby tumortumor ProlongedProlonged useuse ofof centralcentral venousvenous catheterscatheters EndothelialEndothelial damagedamage byby chemotherapychemotherapy drugsdrugs EffectEffect ofof tumortumor cytokinescytokines onon vascularvascular endotheliumendothelium

drugsdrugs EffectEffect ofof tumortumor cytokinescytokines onon vascularvascular endotheliumendothelium
drugsdrugs EffectEffect ofof tumortumor cytokinescytokines onon vascularvascular endotheliumendothelium
drugsdrugs EffectEffect ofof tumortumor cytokinescytokines onon vascularvascular endotheliumendothelium

3.3. HypercoagulabilityHypercoagulability

TumorTumor--associatedassociated procoagulantsprocoagulants andand cytokinescytokines (tissue(tissue factor,factor, CP,CP, TNFTNFαα,, ILIL--11ββ,, VEGF,VEGF, etc.)etc.) ImpairedImpaired endothelialendothelial cellcell defensedefense mechanismsmechanisms (APC(APC resistance;resistance; dedeficienciesficiencies ofof AT,AT, ProteinProtein CC andand S)S) EnhancedEnhanced selectin/integrinselectin/integrin--mediated,mediated, adhesiveadhesive interactionsinteractions betweenbetween tumortumor cells,vascularcells,vascular endothelialendothelial cells,cells, plateletsplatelets andand hosthost macrophagesmacrophages

endothelialendothelial cells,cells, plateletsplatelets andand hosthost macrophagesmacrophages
endothelialendothelial cells,cells, plateletsplatelets andand hosthost macrophagesmacrophages

MechanismsMechanisms ofof CancerCancer--InducedInduced Thrombosis:Thrombosis: ClotClot andand CancerCancer InterfaceInterface

Pathogenesis?Pathogenesis?

BiologicalBiological signsignificanificance?ce?

PotentialPotential importanceimportance forfor cancercancer therapy?therapy?

InterfaceInterface ofof BiologyBiology andand CancerCancer

Tumor

Cell

VEGF

PAR-2

TF FVII/FVIIa FVII/FVIIa

TF

FVII/FVIIaFVII/FVIIa

TF FVII/FVIIa FVII/FVIIa

TF

Blood Coagulation Activation

FVII/FVIIa FVII/FVIIa TF Blood Coagulation Activation THROMBIN THROMBIN FIBRIN Angiogenesis ILIL--88 Angiogenesis

THROMBINTHROMBIN

TF Blood Coagulation Activation THROMBIN THROMBIN FIBRIN Angiogenesis ILIL--88 Angiogenesis Endothelial

FIBRIN

Angiogenesis ILIL--88
Angiogenesis
ILIL--88

Angiogenesis

EndothelialEndothelial cellscells

Falanga and Rickles, New Oncology:Thrombosis, 2005

ActivationActivation ofof BloodBlood CoagulationCoagulation inin CancerCancer BiologicalBiological Significance?Significance?

EpiphenomenonEpiphenomenon?? IsIs thisthis aa genericgeneric secondarysecondary eventevent (as(as inin inflammation,inflammation, wherewhere clotclot formationformation isis anan incidentalincidental finding)finding)

Or,Or, isis clottingclotting

AA PrimaryPrimary Event?Event? LinkedLinked toto malignantmalignant transformationtransformation

MechanismsMechanisms ofof CancerCancer--InducedInduced Thrombosis:Thrombosis: ImplicationsImplications

1.1.

Pathogenesis?Pathogenesis?

2.2.

BiologicalBiological significance?significance?

3.3.

PotentialPotential importanceimportance forfor cancercancer therapy?therapy?

VTEVTE andand Cancer:Cancer: EpidemiologyEpidemiology

OfOf allall casescases ofof VTE:VTE:

AboutAbout 20%20% occuroccur inin cancercancer patientspatients AnnualAnnual incidenceincidence ofof VTEVTE inin cancercancer patientspatients ≈≈ 1/2501/250

OfOf allall cancercancer patients:patients:

15%15% willwill havehave symptomaticsymptomatic VTEVTE AsAs manymany asas 50%50% havehave VTEVTE atat autopsyautopsy

ComparedCompared toto patientspatients withoutwithout cancer:cancer:

HigherHigher riskrisk ofof firstfirst andand recurrentrecurrent VTEVTE HigherHigher riskrisk ofof bleedingbleeding onon anticoagulantsanticoagulants HigherHigher riskrisk ofof dyingdying

LeeLee AY,AY, LevineLevine MN.MN. CirculationCirculation 2003;107:232003;107:23 SupplSuppl 1:I171:I17--I21I21

ClinicalClinical FeaturesFeatures ofof VTEVTE inin CancerCancer

VTEVTE hashas significantsignificant negativenegative impactimpact onon qualityquality ofof lifelife VTEVTE maymay bebe thethe presentingpresenting signsign ofof occultoccult malignancymalignancy

10%10% withwith idiopathicidiopathic VTEVTE developdevelop cancercancer withinwithin 22 yearsyears 20%20% havehave recurrentrecurrent idiopathicidiopathic VTEVTE 25%25% havehave bilateralbilateral DVTDVT

22 yearsyears 20%20% havehave recurrentrecurrent idiopathicidiopathic VTEVTE 25%25% havehave bilateralbilateral DVTDVT
22 yearsyears 20%20% havehave recurrentrecurrent idiopathicidiopathic VTEVTE 25%25% havehave bilateralbilateral DVTDVT

BuraBura et.et. al.,al., JJ ThrombThromb HaemostHaemost 2004;2:4452004;2:445--5151

Rate of recurrent 3–5% pts in the first 3 months Main causes active cancer AP

Rate of recurrent

3–5% pts in the first 3 months

Main causes

active cancer AP syndrome.

The rate of recurrent venous thromboembolism (VTE) during well-conducted anticoagulation in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) is consistently around 3–5% of patients in the first 3 months following the thrombotic episode. The conditions that have mainly been found to be associated with the risk of recurrent VTE during anticoagulation are active cancer and antiphospholipid syndrome.

VTE during anticoagulation are active cancer and antiphospholipid syndrome. Prandoni et al; J Thromb Haemost 2007

Prandoni et al; J Thromb Haemost 2007

The rate of recurrent VTE during well-conducted anticoagulation in patients with DVT or PE is consistently around 3–5% of patients in the first 3 months following the thrombotic episode.

PE is consistently around 3–5% of patients in the first 3 months following the thrombotic episode.

Rate of recurrent

other causes

other causes

Recurrent VTE during the 3-month course developed in six of the 55 patients (10.9%) with immobility, as compared with 11 of the 322 (3.4%) ambulant patients, leading to a relative risk, adjusted for age, of 2.9 (95% CI: 1.2–7.5).

patients, leading to a relative risk, adjusted for age, of 2.9 (95% CI: 1.2–7.5). immobilization RR

immobilization RR =2,9

10.9%

3–5% pts in the first 3 months

Prandoni et al; J Thromb Haemost 2007

DVTDVT andand PEPE inin CancerCancer Facts,Facts, Findings,Findings, andand NaturalNatural HistoryHistory

VTEVTE isis thethe secondsecond leadingleading causecause ofof deathdeath inin hospitalizedhospitalized cancercancer patientspatients 1,21,2 TheThe riskrisk ofof VTEVTE inin cancercancer patientspatients undergoingundergoing surgerysurgery isis 33-- toto 55--foldfold higherhigher thanthan thosethose withoutwithout cancercancer 22 UpUp toto 50%50% ofof cancercancer patientspatients maymay havehave evidenceevidence ofof asymptomaticasymptomatic DVT/PEDVT/PE 33 CancerCancer patientspatients withwith symptomaticsymptomatic DVTDVT exhibitexhibit aa highhigh riskrisk forfor recurrentrecurrent DVT/PEDVT/PE thatthat persistspersists forfor manymany yearsyears 44

1.1. AmbrusAmbrus JLJL etet al.al. JJ MedMed 1975;6:611975;6:61--6464

2.2. DonatiDonati MB.MB. HaemostasisHaemostasis 1994;24:1281994;24:128--131131

3.3. JohnsonJohnson MJMJ etet al.al. ClinClin LabLab HaemHaem 1999;21:511999;21:51--5454

It has been estimated that 1 in every 7 hospitalized cancer patients who die, do so from pulmonary embolism (PE).

RiskRisk FactorsFactors forfor CancerCancer--AssociatedAssociated VTEVTE

CancerCancer

TypeType

Men:Men: prostate,prostate, colon,colon, brain,brain, lunglung Women:Women: breast,breast, ovary,ovary, lunglung

StageStage

TreatmentsTreatments

SurgerySurgery

1010--20%20% proximalproximal DVTDVT 44--10%10% clinicallyclinically evidentevident PEPE 0.20.2--5%5% fatalfatal PEPE

SystemicSystemic

CentralCentral venousvenous catheterscatheters (~4%(~4% generategenerate clinicallyclinically relevantrelevant VTE)VTE)

ComorbidComorbid ConditionCondition andand DVTDVT RiskRisk

HospitalizationHospitalization forfor surgerysurgery (24%(24%)) andand forfor medicalmedical illnessillness (22%)(22%) accountedaccounted forfor aa similarsimilar proportionproportion ofof thethe cases,cases, whilewhile nursingnursing homehome residenceresidence accountedaccounted forfor 13%.13%. TheThe individualindividual attributableattributable riskrisk estimatesestimates forfor malignantmalignant neoplasmneoplasm,, trauma,trauma, congestivecongestive heartheart failure,failure, centralcentral venousvenous cathetercatheter oror pacemakerpacemaker placement,placement, nneurologicaleurological diseasedisease withwith extremityextremity paresis,paresis, andand superficialsuperficial veinvein thrombosisthrombosis werewere 18%,18%, 12%,12%, 10%,10%, 9%,9%, 7%,7%, andand 5%,5%, respectively.respectively. Together,Together, thethe 88 riskrisk factorsfactors accountedaccounted forfor 74%74% ofof diseasedisease occurroccurrenceence

thethe 88 riskrisk factorsfactors accountedaccounted forfor 74%74% ofof diseasedisease occurroccurr enceence
thethe 88 riskrisk factorsfactors accountedaccounted forfor 74%74% ofof diseasedisease occurroccurr enceence

HeitHeit JAetJAet alal ArchArch InternIntern Med.Med. 2002.2002. RelativeRelative impactimpact ofof riskrisk factorsfactors forfor deepdeep veinvein thrombosisthrombosis andand pulmonarypulmonary embolism:embolism: aa populationpopulation--basedbased studystudy

aa populationpopulation -- basedbased studystudy Predicted probability for any venous thromboembolic events

Predicted probability for any venous thromboembolic events (VTE) based on the factors inpatient treatment, prior thrombosis in medical history, thrombosis in family history, chemotherapy, fever and C-reactive protein (CRP), showing the rate of patients with a given number of risk factors as calculated from the total of 507 patients included

Clinical characteristics and management of acute deep vein thrombosis and pulmonary embolism (PE) have been reported to be different in patients with and without cancer. MASTER multicenter registry

A total of 2119 patients were enrolled, of whom 424 (20%) had cancer. The incidence of bilateral lower limb DVT was significantly higher in patients with cancer than in patients without cancer (8.5% versus 4.6%; p<0.01), as were the rates of iliocaval thombosis (22.6% versus 14%; p<0.001), and upper limb deep vein thrombosis (9.9% versus 4.8%;

MASTER multicenter registry

8.5% versus 4.6%;

p<0.01

p<0.001).

Imberti et al 2008

consequently

Venous thromboembolism (VTE) is a frequent complication in cancer patients and represents an important cause of morbidity and mortality.

During the 3-month period, Major bleeding complications developed in twice as many patients immobilization Rate

During the 3-month period, Major bleeding complications developed in twice as many patients

3-month period, Major bleeding complications developed in twice as many patients immobilization Rate of major bleeding

immobilization Rate of major bleeding

with (four of the 55, 7.3%) than without (11 of the 322, 3.4%) prior immobilization,

with (four of the 55, 7.3%) than without (11 of the 322, 3.4%) prior immobilization, No

No immobilization 3.4%

but the adjusted relative risk was not statistically significant (2.1; 95% CI 0.7–6.5).

but the adjusted relative risk was not statistically significant (2.1; 95% CI 0.7–6.5). RR =2,1

RR =2,1

7,3 % pts in the first 3 months

Prandoni et al; J Thromb Haemost 2007

BleedingBleeding EventsEvents inin CLOTCLOT

 

DalteparinDalteparin

OACOAC

PP--value*value*

N=338N=338

N=335N=335

MajorMajor bleedbleed

1919 (( 5.6%)5.6%)

1212 (( 3.6%)3.6%)

0.270.27

AnyAny bleedbleed

4646 (13.6%)(13.6%)

6262 (18.5%)(18.5%)

0.0930.093

** FisherFisher’’ss exactexact testtest

Lee,Lee, Levine,Levine, Kakkar,Kakkar, RicklesRickles et.al.et.al. NN EnglEngl JJ Med,Med, 2003;349:1462003;349:146

TreatmentTreatment ofof CancerCancer--AssociatedAssociated VTEVTE

     

NN

RecurrentRecurrent

 

DeathDeath

 

StudyStudy

DesignDesign

LengthLength ofof

     

MajorMajor

 
 

TherapyTherapy

VTEVTE (%)(%)

BleedingBleeding

 

(%)(%)

(Months)(Months)

 

(%)(%)

CLOTCLOT TrialTrial (Lee(Lee 2003)2003)

DalteparinDalteparin

66

336336

99

0.002

66

NS

3939

NS

OACOAC

336336

1717

44

4141

CANTHENOXCANTHENOX (Meyer(Meyer 2002)2002)

EnoxaparinEnoxaparin

OACOAC

33

6767

7171

1111

2121

0.09

77

1616

0.09

1111

2323

0.03

LITELITE (Hull(Hull ISTHISTH 2003)2003)

TinzaparinTinzaparin

33

8080

66

0.03

66

NS

2323

NS

OACOAC

8787

1111

88

2222

ONCENOXONCENOX (Deitcher(Deitcher ISTHISTH

EnoxEnox (Low)(Low) EnoxEnox (High)(High) OACOAC

66

3232

3.43.4

NS

 

NS

 

NR

3636

3.13.1

   

2003)2003)

3434

6.76.7

MASTER multicenter registry

Major bleeding (3.3% versus 1.1%; p=0.001), in- hospital treatment (73.3% versus 66.6%; p=0.02) and inferior vena cava filter implantation (7.3% versus 4.1%; p=0.005) were significantly more frequent in patients with cancer, in whom oral anticoagulants were less often used (64.2% versus 82%; p<0.0001).

ImbertiImberti etet alal 20082008

consequently

Major bleedings is a frequent complication in cancer patients (than in patient without cancer) and represents an important cause of morbidity and mortality.

1.00 DVT/PEDVT/PE andand MalignantMalignant DiseaseDisease 0.80 0.60 MalignantMalignant DiseaseDisease 0.40
1.00 DVT/PEDVT/PE andand MalignantMalignant DiseaseDisease 0.80 0.60 MalignantMalignant DiseaseDisease 0.40
1.00
DVT/PEDVT/PE andand MalignantMalignant DiseaseDisease
0.80
0.60
MalignantMalignant DiseaseDisease
0.40
DVT/PEDVT/PE OnlyOnly
0.20
NonmalignantNonmalignant DiseaseDisease
0.00
0
20 40
60
80 100 120140 160 180
Probability of
Death

LevitanLevitan N,N, etet alal MedicineMedicine 1999;78:2851999;78:285

Number of Days

(%)And

Patients (%)

CancerVTE

Hospitalized Cancer

Noncancer Patients

in Hospitalized

And Noncancer

VTE in

AsAs NumberNumber OfOf CancerCancer SurvivorsSurvivors Increases,Increases, VTEVTE RatesRates IncreaseIncrease

4 3,5 CancerCancer PatientsPatients 3 2,5 2 1,5 1 NoncancerNoncancer PatientsPatients 0,5 0 79 81
4
3,5
CancerCancer PatientsPatients
3
2,5
2
1,5
1
NoncancerNoncancer PatientsPatients
0,5
0
79 81 83 85 87 89 91 93 95 97 99

YEARYEAR

SteinStein PDPD etet al.al AmAm JJ MedMed 2006;2006; 119:119: 6060--6868

inRelative

VTE in

of VTE

Risk of

Relative Risk

KidneyKidney

BladderBladder

CervixCervix

OvaryOvary

LiverLiver

ProstateProstate

BreastBreast

LymphomaLymphoma

UterusUterus

EsophagusEsophagus

LeukemiaLeukemia

LungLung

BrainBrain

StomachStomach

ColonColon

MyeloprolMyeloprol

RectalRectal

PancreasPancreas

VTEVTE RiskRisk AndAnd CancerCancer Type:Type: SolidSolid AndAnd LiquidLiquid

RelativeRelative RiskRisk ofof VTEVTE RangedRanged FromFrom 1.021.02 toto 4.344.34 4.54.5 44 3.53.5 33 2.52.5 22
RelativeRelative RiskRisk ofof VTEVTE RangedRanged FromFrom 1.021.02 toto 4.344.34
4.54.5
44
3.53.5
33
2.52.5
22
1.51.5
11
0.50.5
PatientsCancer
Cancer Patients

SteinStein PD,PD, etet al.al. AmAm JJ MedMed 2006;2006; 119:119: 6060--6868

60% of cancer patients, have localized cancer or limited metastatic disease that would have allowed for longer survival in the absence of a fatal PE.

The incidence of VTE in cancer patients has been described to be approximately 15%, with reported incidence rates ranging from 3.8% to 30.7%.

DoesDoes VTEVTE inin patientspatients withwith cancercancer adverselyadversely affectaffect outcome?outcome?

adversely adversely affect affect outcome? outcome? ProbabilityProbability ofof deathdeath withinwithin 183183

ProbabilityProbability ofof deathdeath withinwithin 183183 daysdays ofof initialinitial hospitalhospital admissionadmission inin patienpatientsts withwith cancercancer withwith oror withoutwithout concurrentconcurrent VTEVTE

However, it is likely to be much higher, because VTE is often asymptomatic or minimally

However, it is likely to be much higher, because VTE is often asymptomatic or minimally symptomatic and, even when symptoms are present; they are often nonspecific or mistakenly attributed to the underlying malignancy.

Especially in patients who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment.

Some patients with DVT develop recurrent VTE or bleeding complications mainly during anticoagulant treatment.

These complications may occur more frequently if these patients have concomitant cancer.

From a prospective follow-up study arise that in thrombosis patients those with cancer have a

higher risk (was 20.7%

for recurrent venous thromboembolism or bleeding during anticoagulant treatment than

those without cancer (6.8%).

In the same study, the cumulative incidence of major bleeding was 12.4% in patients with cancer and 4.9% in patients without cancer, with a risk ratio of 2.2.

or a hazard ratio of 3.2

ANTICOAGULANTS

ACTION AND MONITORING

HEPARIN-AT

F

XIIa

F

XIa

F

IXa

F

Xa

THROMBIN (IIa) PTT

LMWH

F Xa

Anti Xa levels

WARFARIN

F VII F IX F X F II
F
VII
F
IX
F
X
F
II

PT/INR

Fig 1. Cumulative incidence of recurrent VTE during anticoagulant therapy.

incidence of recurrent VTE during anticoagulant therapy. Prandoni et al 2002 Fig 2. Cumulative inci dence

Prandoni et al 2002

of clinically imp ortant bleeding duri ng anticoagulant ther apy in DVT pati ents with and
OAC vs LMWH LMWH vs placebo
OAC vs LMWH LMWH vs placebo
OAC vs LMWH
LMWH vs placebo
OAC vs LMWH LMWH vs placebo

CLOTCLOT SurvivalSurvival CurvesCurves

Overall population

Good prognosis population

100 90 80 p=0.62 70 60 Dalteparin 50 OAC 40 30 20 10 0 0
100
90
80
p=0.62
70
60
Dalteparin
50
OAC
40
30
20
10
0
0 30
60
90
120 150 180 210 240 270 300 330 360 390
Probability of survival (%)
Probability of survival (%)

100

90

80

70

60

50

40

30

20

10

0

without metastases Dalteparin OAC p=0.03 0 30 60 90 120 150 180 210 240 270
without metastases
Dalteparin
OAC
p=0.03
0 30
60
90
120 150 180 210 240 270 300 330 360 390

Days after randomization

Days after randomization

Lee,Lee, et.al.et.al. NN EnglEngl JJ Med,Med, 2003;349:1462003;349:146

LandmarkLandmark CLOTCLOT CancerCancer TrialTrial

ReductionReduction inin RecurrentRecurrent VTEVTE

%Probability

VTE, %

Recurrent VTE,

of Recurrent

Probability of

2525

2020

1515

1010

55

00

o f 2525 2020 1515 1010 55 00 Recurrent Recurrent VTE VTE Risk Risk reduction

RecurrentRecurrent VTEVTE

Recurrent Recurrent VTE VTE Risk Risk reduction reduction = = 52% 52% pp -- valuevalue ==

RiskRisk reductionreduction == 52%52%

pp--valuevalue == 0.00170.0017

OACOAC

DalteparinDalteparin

VTE Risk Risk reduction reduction = = 52% 52% pp -- valuevalue == 0.00170.0017 OAC OAC
VTE Risk Risk reduction reduction = = 52% 52% pp -- valuevalue == 0.00170.0017 OAC OAC
VTE Risk Risk reduction reduction = = 52% 52% pp -- valuevalue == 0.00170.0017 OAC OAC

00

3030

Lee,Lee, Levine,Levine, Kakkar,Kakkar, RicklesRickles et.al.et.al. NN EnglEngl JJ Med,Med, 2003;349:1462003;349:146

6060

9090

120120

150150

180180

210210

DaysDays PostPost RandomizationRandomization

estimatedistribution

function estimate

KaplanMeier survival survivalKaplanMeier

distribution function

Famous:Famous: TrialTrial DesignDesign KaplanKaplanMeierMeier survivalsurvival curvescurves forfor allall patipatientsents inin dalteparindalteparin andand placeboplacebo groupsgroups

1.0 0.9 DalteparinDalteparin PlaceboPlacebo 0.8 The Kaplan-Meier survival estimates at 1, 2, and 3 years
1.0
0.9
DalteparinDalteparin
PlaceboPlacebo
0.8
The Kaplan-Meier survival estimates at 1, 2, and 3 years after
randomization for patients receiving dalteparin were 46%, 27%, and
21%, respectively, compared with 41%, 18%, and 12%, respectively,
for patients receiving placebo (P = .19).
0.7
0.6
0.5
0.4
0.3
0.2
0.1

0.0

 

0

12

24

36

48

60

72

84

 

TimeTime fromfrom randomisationrandomisation (months)(months)

 

No.No. atat risk:risk:

190190

8585

3030

2222

1212

55

44

DalteparinDalteparin

184184

7272

1515

99

88

55

22

PlaceboPlacebo

KakkarKakkar AK,AK, etet al.al. JJ ClinClin Oncol.Oncol. 2004;22:19442004;22:1944--1948.1948.

KaplanMeier survival survivalKaplanMeier

estimatedistribution

distribution estimate

SurvivalSurvival Analysis:Analysis: GoodGood PrognosisPrognosis PatientsPatients

In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P = .03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively.

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.00.0

DalteparinDalteparin PlaceboPlacebo
DalteparinDalteparin
PlaceboPlacebo
0.30.3 0.20.2 0.00.0 DalteparinDalteparin PlaceboPlacebo 1717 2323 2929 3535 4141 4747 5353 5959
0.30.3 0.20.2 0.00.0 DalteparinDalteparin PlaceboPlacebo 1717 2323 2929 3535 4141 4747 5353 5959

1717

2323

2929

3535

4141

4747

5353

5959

6565

7171

7777

8383

 

TimeTime fromfrom randomisationrandomisation (months)(months)

4747

1717

1010

99

99

88

88

55

33

22

00

PlaceboPlacebo

5555

3131

2626

2222

2020

1313

88

55

55

55

33

DalteparinDalteparin

No.No. atat risk:risk:

KakkarKakkar AK,AK, etet al.al. JJ ClinClin Oncol.Oncol. 2004;22:19442004;22:1944--1948.1948.

LMWHLMWH andand Survival:Survival: FurtherFurther StudiesStudies (2003)(2003)

CLOT

Solid tumor malignancy and acute VTE

All patients received dalteparin 200 IU/kg od 5–7 days

R
R

SCLC study

R
R

Small cell lung cancer (SCLC)

Patients with responsive limited disease received thoracic radiotherapy

MALT

Solid tumor malignancy

R
R

AltinbasAltinbas M,M, etet al.al. JJ ThrombThromb HaemostHaemost 2004;2:12004;2:1--6.6. KlerkKlerk CPW,CPW, etet al.al. JJ ClinClin OncolOncol 2005;23:21302005;23:2130--2135.2135.

Dalteparin

1

month 200 IU/kg od

5

months 160 IU/kg od

Oral anticoagulant

6 months

Chemotherapy plus dalteparin 5000 IU od

18 weeks

Chemotherapy (cyclophosphamide, epirubicin, vincristine)

18 weeks

Nadroparin

2

weeks therapeutic dose

4

weeks 1/2 therapeutic dose

Placebo

6 weeks

Lee,Lee, et.al.et.al. NN EnglEngl JJ Med,Med, 2003;349:1462003;349:146

SCLCSCLC StudyStudy SurvivalSurvival CurvesCurves

Overall population

Good prognosis population

1.0 0.8 p=0.01 0.6 0.4 Dalteparin 0.2 Placebo 0.0 0 5 10 15 20 25
1.0
0.8
p=0.01
0.6
0.4
Dalteparin
0.2
Placebo
0.0
0
5
10
15
20
25
30
35
40
Probability of survival
Probability of survival

1.0

0.8

0.6

0.4

0.2

0.0

limited disease p=0.007 Dalteparin Placebo 0 5 10 15 20 25 30 35 40
limited disease
p=0.007
Dalteparin
Placebo
0
5
10
15
20
25
30
35
40

Months after randomization

Months after randomization

AltinbasAltinbas M,M, etet al.al. JJ ThrombThromb Haemost.Haemost. 2004;2:12004;2:1--6.6.

MALTMALT SurvivalSurvival CurvesCurves

Overall population

Good prognosis population

1.0 0.8 p=0.021 0.6 0.4 Nadroparin 0.2 Placebo 0.0 0 12 24 36 48 60
1.0
0.8
p=0.021
0.6
0.4
Nadroparin
0.2
Placebo
0.0
0
12
24
36
48
60
72
84
96
Probability of Survival
Probability of Survival

1.0

0.8

0.6

0.4

0.2

0.0

>6 months survival p=0.010 Nadroparin Placebo 0 12 24 36 48 60 72 84 96
>6 months survival
p=0.010
Nadroparin
Placebo
0
12
24
36
48
60
72
84
96

Months after randomization

Months after randomization

KlerkKlerk CPW,CPW, etet al.al. JJ ClinClin Oncol.Oncol. 2005;23:21302005;23:2130--2135.2135.

Anti-Tumor Effects of LMWH CLOT 12-month Mortality

Patients Without Metastases (N=150)

100 Dalteparin 90 80 70 OAC 60 50 40 30 20 10 HR = 0.50
100
Dalteparin
90
80
70
OAC
60
50
40
30
20
10
HR = 0.50 P-value = 0.03
0
0
30
60
90
120 150 180
240
300
360
Probability of Survival, %

Lee A, et al. ASCO. 2003

Days Post Randomization

A model for the prediction of symptomatic venous thrombosis after the initia tion of chemotherapy,

A model for the prediction of symptomatic venous thrombosis after the initiation of chemotherapy, among outpatients with different types of malignancies schedulated by Khorana et al in 2008. Primary site of cancer, platelet count, leukocyte count, hemoglobin level, use of erythropoiesis-stimulating agents, and body mass index were found to be predictive factors. Symptomatic venous thrombotic events were recorded when reported by physicians. Due to this design, the occurrence of asymptomatic thrombotic events could not be assessed.

Based on the predictive factors, patients were classified into low-risk (27%), intermediate-risk (61%), and high-risk (12%) groups.

Most thrombotic events (75%) occurred during the first 2 cycles of chemotherapy. In the low-risk group, only 0.6% developed symptomatic venous thrombosis, compared with 1.9% in the intermediate-risk group. These findings suggest that the 88% of the patients in the low- and intermediate-risk groups are unlikely to benefit from prophylactic anticoagulation. Patients in the high-risk group had a nearly 7% risk of developing venous thrombosis during a median follow-up period of 73 days. One may argue whether a 7% risk warrants thromboprophylaxis; 93% of patients in this high-risk group would be treated without any apparent benefit, and moreover, patients with a malignancy have an increased risk of major bleeding during thromboprophylaxis.

To make a balanced decision, the risks and benefits need to be assessed. Unfortunately, data regarding bleeding risk were unavailable in the study by Khorana et al. Similarly, data on prophylactic anticoagulation use was lacking. If one of the investigated factors instigated the use of anticoagulation, and thereby indirectly decreased the risk of venous thrombosis, this would influence the model.

This was a very large study consisting of more than 4000 patients with different types

This was a very large study consisting of more than 4000 patients with different types of malignancies. Most patients had an excellent performance status. Only a few patients with less prevalent malignancies strongly associated with venous thrombotic events, such as brain tumors, were included. One has to be careful in generalizing the results to patients with a poor performance status and patients with these less prevalent malignancies, as other predictive models may more closely fit those cases.

Khorana et al 2008

Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first

Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation.

So, patients with DVT who also have cancer seem to be at a higher risk for recurrent venous thromboembolic complications during anticoagulation.

Adjusted odds ratio

3 to 12 months

0 to 3 months

Gastrointestinal

5 to 10 years

metastases

1 to 3 years

> 15 years

Hematological

Distant

Breast

Lung

EffectEffect ofof MalignancyMalignancy onon RiskRisk ofof VenousVenous ThromboembolismThromboembolism (VTE)(VTE)

50

40

30

20

10

0

53.553.5

• Population-based case-control (MEGA) study • N=3220 consecutive patients with 1 st VTE vs. n=2131
Population-based case-control (MEGA)
study
N=3220 consecutive patients with 1 st
VTE vs. n=2131 control subjects
CA patients = 7x OR for VTE vs. non-CA
patients
2828
22.222.2
20.320.3
19.819.8
4.94.9
= 7x OR for VTE vs. non-CA patients 2828 22.222.2 20.320.3 19.819.8 4.94.9 14.314.3 3.63.6 2

14.314.3

= 7x OR for VTE vs. non-CA patients 2828 22.222.2 20.320.3 19.819.8 4.94.9 14.314.3 3.63.6 2

3.63.6 2.62.6

= 7x OR for VTE vs. non-CA patients 2828 22.222.2 20.320.3 19.819.8 4.94.9 14.314.3 3.63.6 2

1.11.1

= 7x OR for VTE vs. non-CA patients 2828 22.222.2 20.320.3 19.819.8 4.94.9 14.314.3 3.63.6 2
4.94.9 14.314.3 3.63.6 2 . 6 2 . 6 1.11.1 T y p e o f

Type of cancer

6 2 . 6 1.11.1 T y p e o f c a n c e

Time since cancer diagnosis

SilverSilver In:In: TheThe HematologistHematologist -- modifiedmodified fromfrom BlomBlom et.et. al.al. JAMAJAMA 2005;293:7152005;293:715

VTE is a major cause of morbidity a nd mortality in patients with cancer. Hence,

VTE is a major cause of morbidity and mortality in patients with cancer. Hence, it is essential that oncologists and other health providers are able to diagnose DVT and PE accurately and administer effective treatment for these common vascular complications

Falanga et all 2008

Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major

Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy.

These risks correlate with the extent of cancer.

The most common situations that increase the thromboembolic risk in cancer patients include immobilization, surgery, chemotherapy with or without adjuvant hormone therapy, and the insertion of central venous catheters

Imberti et al 2008

The clinical presentation of acute VTE is different and often more extensive in cancer patients than in patients free from malignancy. Moreover, the management of the acute phase of VTE is more problematic in cancer patients, especially because of a higher rate of major bleeding and the need for implantation of inferior vena cava filters.

especially because of a higher rate of major bleeding and the need for implantation of inferior
During anticoagulant therapy, cancer patients have a 2- to 4- fold higher risk of recurrent

During anticoagulant therapy, cancer patients have a 2- to 4- fold higher risk of recurrent VTE and major bleeding complications when compared with non cancer patients

Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed.

The long-term administration of LM WH should be considered as an alternative to anti-vitamin K

The long-term administration of LMWH should be considered as an

alternative to anti-vitamin K drugs in patients with advanced disease and in those with condit ions limiting the use ugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants.

Prolongation of anticoagulation should be considered for as long as the malignant disorder is active.

The evidence of lowered cancer mortality in patients on LMWH has stimulated renewed interest in these agents as antineoplastic drugs rtality in patients on LMWH has stimulated renewed interest in these agents as antineoplastic drugs and raises the distinct possibility that cancer and thrombosis share common mechanisms.

Thromboprophylaxis may prevent the oc currence of venous thrombosis, an important cause of morbidity and

Thromboprophylaxis may prevent the occurrence of venous thrombosis, an important cause of morbidity and mortality among patients with cancer, especially those on active antitumor therapy. Identifying cancer patients at high risk for thrombosis who might benefit from prophylaxis is still a major challenge.

The only well-defined high-risk group for which thromboprophylaxis appears to be effective and relatively safe is surgical patients, although prophylaxis is also recommended for acutely ill medical patients. However, a high-risk group of outpatients with cancer remains to be determined, and is a necessary piece of information to obtain before the appropriateness of thromboprophylaxis can be assessed.

Doggen 2008

InterfaceInterface ofof BiologyBiology andand CancerCancer

Tumor cells

IL-1, Activation of TNF-α, coagulation VEGF FIBRIN
IL-1,
Activation of
TNF-α,
coagulation
VEGF
FIBRIN
IL-1, Activation of TNF-α, coagulation VEGF FIBRIN Angiogenesis, Basement matrix degradation. Fibrinolytic
IL-1, Activation of TNF-α, coagulation VEGF FIBRIN Angiogenesis, Basement matrix degradation. Fibrinolytic

Angiogenesis, Basement matrix degradation.

Fibrinolytic activities:

t-PA, u-PA, u-PAR, PAI-1, PAI-2

Procoagulant Activities

: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities PMN leukocyte Platelets Monocyte Endothelial cells
: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities PMN leukocyte Platelets Monocyte Endothelial cells
: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities PMN leukocyte Platelets Monocyte Endothelial cells
: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities PMN leukocyte Platelets Monocyte Endothelial cells

PMN leukocyte

u-PAR, PAI-1, PAI-2 Procoagulant Activities PMN leukocyte Platelets Monocyte Endothelial cells FalangaFalanga andand

Platelets

PAI-1, PAI-2 Procoagulant Activities PMN leukocyte Platelets Monocyte Endothelial cells FalangaFalanga andand

Monocyte

Endothelial cells

FalangaFalanga andand RicklesRickles,, NewNew Oncology:ThrombosisOncology:Thrombosis,, 20052005