03 p makris1a

8/14/2019 03 P MAKRIS1a

1/51

8/14/2019 03 P MAKRIS1a

2/51

8/14/2019 03 P MAKRIS1a

3/51

Mechanisms of CancerMechanisms of Cancer--Induced Thrombosis: The InterfaceInduced Thrombosis: The Interface

Pathogenesis?Pathogenesis?

Biological significance?Biological significance?

Potential importance for cancer therapy?Potential importance for cancer therapy?

8/14/2019 03 P MAKRIS1a

4/51

Pathogenesis of Thrombosis in CancerPathogenesis of Thrombosis in Cancer

A Modification of VirchowA Modification of Virchows Triads Triad

1.1. StasisStasis Prolonged bed restProlonged bed rest

Extrinsic compression of blood vessels by tumorExtrinsic compression of blood vessels by tumor

2.2. Vascular InjuryVascular Injury Direct invasion by tumorDirect invasion by tumor

Prolonged use of central venous cathetersProlonged use of central venous catheters Endothelial damage by chemotherapy drugsEndothelial damage by chemotherapy drugs

Effect of tumor cytokines on vascular endotheliumEffect of tumor cytokines on vascular endothelium

3.3. HypercoagulabilityHypercoagulability TumorTumor--associated procoagulants and cytokines (tissue factor, CP, TNFassociated procoagulants and cytokines (tissue factor, CP, TNF,, ILIL--11,,

VEGF, etc.)VEGF, etc.)

Impaired endothelial cell defense mechanisms (APC resistance; deImpaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT,ficiencies of AT,

Protein C and S)Protein C and S)

Enhanced selectin/integrinEnhanced selectin/integrin--mediated, adhesive interactions between tumormediated, adhesive interactions between tumorcells,vascular endothelial cells, platelets and host macrophagescells,vascular endothelial cells, platelets and host macrophages

Sta

sis

Sta

sis

Hyp

erco

agulability

Hyp

erco

agulability

Vascular InjuryVascular Injury

8/14/2019 03 P MAKRIS1a

5/51

Mechanisms of CancerMechanisms of Cancer--Induced Thrombosis: Clot and Cancer InterfaInduced Thrombosis: Clot and Cancer Interfa

Pathogenesis?Pathogenesis?

Biological signBiological significanificance?ce?

Potential importance for cancer therapy?Potential importance for cancer therapy?

8/14/2019 03 P MAKRIS1a

6/51

TF

VEGF

Angiogenesis

Endothelial cellsEndothelial cells

ILIL--88

Blood CoagulationActivation

FIBRIN

PAR-2

Angiogenesis

FVII/FVIIaFVII/FVIIa

THROMBINTHROMBIN

TumorCell

TF

Falanga and Rickles, New Oncology:Thrombosis, 2005

Interface of Biology and CancerInterface of Biology and Cancer

8/14/2019 03 P MAKRIS1a

7/51

Activation of Blood Coagulation in CancerActivation of Blood Coagulation in CancerBiological Significance?Biological Significance?

EpiphenomenonEpiphenomenon??

Is this a generic secondary eventIs this a generic secondary event(as in inflammation, where clot formation is an incident(as in inflammation, where clot formation is an incidentfinding)finding)

Or, is clotting . . .Or, is clotting . . .

A Primary Event?A Primary Event?

Linked to malignant transformationLinked to malignant transformation

8/14/2019 03 P MAKRIS1a

8/51

Mechanisms of CancerMechanisms of Cancer--Induced Thrombosis: ImplicationsInduced Thrombosis: Implications1.1. Pathogenesis?Pathogenesis?

2.2. Biological significance?Biological significance?

3.3. Potential importance for cancer therapy?Potential importance for cancer therapy?

8/14/2019 03 P MAKRIS1a

9/51

VTE and Cancer: EpidemiologyVTE and Cancer: Epidemiology

Of all cases of VTE:Of all cases of VTE: About 20% occur in cancer patientsAbout 20% occur in cancer patients

Annual incidence of VTE in cancerAnnual incidence of VTE in cancerpatientspatients 1/2501/250

Of all cancer patients:Of all cancer patients: 15% will have symptomatic VTE15% will have symptomatic VTE As many as 50% have VTE at autopsyAs many as 50% have VTE at autopsy

Compared to patients without cancer:Compared to patients without cancer: Higher risk of first and recurrent VTEHigher risk of first and recurrent VTE Higher risk of bleeding on anticoagulantsHigher risk of bleeding on anticoagulants

Higher risk of dyingHigher risk of dying

Lee AY, Levine MN.Lee AY, Levine MN. CirculationCirculation. 2003;107:23 Suppl 1:I17. 2003;107:23 Suppl 1:I17--I21I21

8/14/2019 03 P MAKRIS1a

10/51

Clinical Features of VTE in CancerClinical Features of VTE in Cancer

VTE has significant negative impact on quality of lifeVTE has significant negative impact on quality of life

VTE may be the presenting sign of occult malignancyVTE may be the presenting sign of occult malignancy 10% with idiopathic VTE develop cancer within 2 year10% with idiopathic VTE develop cancer within 2 years

20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE 25% have bilateral DVT25% have bilateral DVT

BuraBura et. al.,et. al., J Thromb HaemostJ Thromb Haemost2004;2:4452004;2:445--5151

8/14/2019 03 P MAKRIS1a

11/51

Prandoni et al; J Thromb Haemost 2007

The rate of recurrent venous thromboembolism (VTE) during

well-conducted anticoagulation in patients with deep vein

thrombosis (DVT) or pulmonary embolism (PE) is consistentlyaround 35% 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 duringanticoagulation are active cancer and antiphospholipid

syndrome.

Rate of recurrent

35% pts in the first 3 months

Main causes

active cancer

AP syndrome.

8/14/2019 03 P MAKRIS1a

12/51Prandoni et al; J Thromb Haemost 2007

The rate of recurrent VTE during

well-conducted anticoagulation in patients with DVT or PE isconsistently around 35% of patients in the first 3 monthsfollowing the thrombotic episode.

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: 1.27.5).

Rate of recurrent

35% pts in the first 3 month

other causes

immobilization 10.9%

RR =2,9

8/14/2019 03 P MAKRIS1a

13/51

1.1. Ambrus JL et al.Ambrus JL et al. J MedJ Med. 1975;6:61. 1975;6:61--64642.2. Donati MB.Donati MB. HaemostasisHaemostasis. 1994;24:128. 1994;24:128--131131

3.3. Johnson MJ et al.Johnson MJ et al. Clin Lab HaemClin Lab Haem. 1999;21:51. 1999;21:51--5454

4.4. Prandoni P et al.Prandoni P et al. Ann Intern MedAnn Intern Med. 1996;125:1. 1996;125:1--77

DVT and PE in Cancer Facts, Findings, and Natural HistoryDVT and PE in Cancer Facts, Findings, and Natural History

VTE is the second leading cause ofVTE is the second leading cause ofdeathdeath in hospitalized cancer patientsin hospitalized cancer patients1,21,2

The risk of VTE in cancer patientsThe risk of VTE in cancer patientsundergoing surgery isundergoing surgery is 33-- to 5to 5--fold higherfold higherthan those without cancerthan those without cancer22

Up toUp to 50% of cancer patients50% of cancer patients may havemay haveevidence ofevidence ofasymptomatic DVT/PEasymptomatic DVT/PE33

Cancer patients with symptomatic DVTCancer patients with symptomatic DVT

exhibit aexhibit a high risk for recurrent DVT/PEhigh risk for recurrent DVT/PEthat persists for many yearsthat persists for many years44

It has been estimated

that 1 in every 7

hospitalized cancerpatients who die, do so

from pulmonaryembolism (PE).

8/14/2019 03 P MAKRIS1a

14/51

Risk Factors for CancerRisk Factors for Cancer--Associated VTEAssociated VTE

CancerCancer TypeType

Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung

Women: breast, ovary, lungWomen: breast, ovary, lung

StageStage TreatmentsTreatments

SurgerySurgery

1010--20% proximal DVT20% proximal DVT 44--10% clinically evident PE10% clinically evident PE

0.20.2--5% fatal PE5% fatal PE

SystemicSystemic

Central venous cathetersCentral venous catheters (~4% generate clinically relevant VTE)(~4% generate clinically relevant VTE)

8/14/2019 03 P MAKRIS1a

15/51

Comorbid Condition and DVT RiskComorbid Condition and DVT Risk

Hospitalization for surgery (24%) and for medical illness (22%)Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similaraccounted for a similarproportion of the cases, while nursing home residence accountedproportion of the cases, while nursing home residence accounted for 13%.for 13%.

The individual attributable risk estimates forThe individual attributable risk estimates formalignant neoplasmmalignant neoplasm, trauma, congestive, trauma, congestiveheart failure, central venous catheter or pacemaker placement, nheart failure, central venous catheter or pacemaker placement, neurological diseaseeurological diseasewith extremity paresis, and superficial vein thrombosis werewith extremity paresis, and superficial vein thrombosis were 18%,18%,

12%, 10%, 9%, 7%,12%, 10%, 9%, 7%,

and 5%, respectively.and 5%, respectively.

Together, the 8 risk factors accounted for 74% of disease occurrTogether, the 8 risk factors accounted for 74% of disease occurrenceenceHeit JAet al Arch Intern Med.Heit JAet al Arch Intern Med. 2002.2002. Relative impact of risk factors for deep veinRelative impact of risk factors for deep vein

thrombosis and pulmonary embolism: a populationthrombosis and pulmonary embolism: a population--based studybased study

Predicted probability for any venthromboembolic events (VTE) based on

factors inpatient treatment, thrombosis in medical history, thrombin family history, chemotherapy, feverC-reactive protein (CRP), showing the

of patients with a given number offactors as calculated from the total o

patients inclu

8/14/2019 03 P MAKRIS1a

16/51

A total of 2119 patients were enrolled, ofwhom 424 (20%) had cancer.

The incidence of bilateral lower limb DVT

was

significantly higher in patients with cancerthan in patients without cancer (8.5% versus

4.6%; p

8/14/2019 03 P MAKRIS1a

17/51

Venous thromboembolism (VTE) is a frequent

complication in cancer patients and represents animportant cause of morbidity and mortality.

consequently

8/14/2019 03 P MAKRIS1a

18/51Prandoni et al; J Thromb Haemost 2007

During the 3-month period,

Major

bleeding complications

developed in twice as many patientswith (four of the 55, 7.3%)

than without (11 of the 322, 3.4%) prior immobilization,

but the adjusted relative risk was not

statistically significant (2.1; 95% CI 0.76.5).

immobilization

Rate of major bleeding

7,3 %

pts in the first 3 month

No immobilization 3.4%

RR =2,1

8/14/2019 03 P MAKRIS1a

19/51

DalteparinDalteparin

N=338N=338

OACOAC

N=335N=335 PP--value*value*

Major bleedMajor bleed 19 ( 5.6%)19 ( 5.6%) 12 ( 3.6%)12 ( 3.6%) 0.270.27

Any bleedAny bleed 46 (13.6%)46 (13.6%) 62 (18.5%)62 (18.5%) 0.0930.093

* Fisher* Fishers exact tests exact test

Bleeding Events in CLOTBleeding Events in CLOT

Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146

8/14/2019 03 P MAKRIS1a

20/51

Treatment of CancerTreatment of Cancer--Associated VTEAssociated VTE

StudyStudy DesignDesign Length ofLength ofTherapyTherapy

(Months)(Months)

NN RecurrentRecurrentVTE (%)VTE (%)

MajorMajorBleedingBleeding

(%)(%)

DeathDeath

(%)(%)

CLOT TrialCLOT Trial(Lee 2003)(Lee 2003)

DalteparinDalteparinOACOAC

66 336336336336

991717

6644

39394141

CANTHENOXCANTHENOX

(Meyer 2002)(Meyer 2002)

EnoxaparinEnoxaparin

OACOAC

33 6767

7171

1111

2121

77

1616

1111

2323

LITELITE

(Hull ISTH 2003)(Hull ISTH 2003)

TinzaparinTinzaparin

OACOAC

33 8080

8787

66

1111

66

88

2323

2222

ONCENOXONCENOX

(Deitcher ISTH(Deitcher ISTH

2003)2003)

Enox (Low)Enox (Low)

Enox (High)Enox (High)

OACOAC

66 3232

3636

3434

3.43.4

3.13.1

6.76.7

NS

NS0.03

NS

NS0.002

NS

NS

NR

0.09 0.030.09

8/14/2019 03 P MAKRIS1a

21/51

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 morefrequent in patients with cancer, in whom oralanticoagulants were less often used (64.2% versus

82%; p

8/14/2019 03 P MAKRIS1a

22/51

consequently

Major bleedings is a frequent complication in cancer

patients (than in patient without cancer) and representsan important cause of morbidity and mortality.

8/14/2019 03 P MAKRIS1a

23/51

0 20 40 60 80 100 120140 160 1800.00

0.20

0.40

1.00

0.80

0.60

DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease

Malignant DiseaseMalignant Disease

DVT/PE OnlyDVT/PE Only

Nonmalignant DiseaseNonmalignant Disease

Number of Days

Probab

ilityof

Dea

th

Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285

8/14/2019 03 P MAKRIS1a

24/51

As Number Of Cancer Survivors Increases, VTE Rates IncreaseAs Number Of Cancer Survivors Increases, VTE Rates Increase

YEARYEAR

0

0,5

1

1,5

2

2,5

3

3,5

4

79 81 83 85 87 89 91 93 95 97 99

VTEinHospitalizedCance

r

VTEinHospitalizedCance

r

An

dNoncance

rPatients(%

)

An

dNoncance

rPatients(%

)

--

Cancer PatientsCancer Patients

Noncancer PatientsNoncancer Patients

8/14/2019 03 P MAKRIS1a

25/51

VTE Risk And Cancer Type:VTE Risk And Cancer Type: Solid And LiquidSolid And Liquid

Stein PD, et al. Am J Med 2006; 119: 60Stein PD, et al. Am J Med 2006; 119: 60--6868

RelativeRiskofVTE

in

RelativeRiskofVTEin

Can

cerPatients

Can

cerPatients

Pancreas

Pancreas

Brain

Brain

Myelopro

l

Myelopro

l

Stomach

Stomach

Lymphoma

Lymphoma

Uterus

Uterus

Lung

Lung

Esophagus

Esophagus

Prostate

Prostate

Recta

l

Recta

l

Kidney

Kidney

Colon

Colon

Ovary

Ovary

Live

r

Live

r

Leukemia

Leukemia

Breas

t

Breas

t

Cervix

Cervix

Bladde

r

Bladde

r

4.54.5

44

3.53.5

33

2.52.5

22

1.51.5

11

0.50.5

Relative Risk of VTE Ranged From 1.02 to 4.34Relative Risk of VTE Ranged From 1.02 to 4.34

8/14/2019 03 P MAKRIS1a

26/51

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 cancerpatients has been described to be

approximately 15%, with reported

incidence rates ranging from 3.8%to 30.7%.

Does VTE in patients with cancerDoes VTE in patients with cancer

adversely affect outcome?adversely affect outcome?

Probability of death within 183 days of initialProbability of death within 183 days of initialhospital admission in patients with cancer withospital admission in patients with cancer wit

without concurrent VTEwithout concurrent VTE

8/14/2019 03 P MAKRIS1a

27/51

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 duringanticoagulant treatment.

These complications may occur more frequently

if these patients have concomitant cancer.

8/14/2019 03 P MAKRIS1a

28/51

From a prospective follow-up study arise that in

thrombosis patients those with cancer have a

higher risk (was 20.7% or a hazard ratio of 3.2for recurrent venous thromboembolism or

bleeding during anticoagulant treatment than

those without cancer (6.8%).

In the same study, the cumulative incidence ofmajor bleeding was 12.4% in patients with

cancer and 4.9% in patients without cancer, with

a risk ratio of 2.2.

F XIIa

F XIa

F IXa

F Xa

THROMBIN (IIa)

F VII

F IX

F X

F II

F Xa

ANTICOAGULANTS

HEPARIN-AT LMWH WARFAR

PTT Anti Xa levelsPT/INR

ACTION AND MONITORING

Fig 1. Cumulative incidence of recurrent

VTE during anticoagulant therapy.

Prandoni et al 2002

Fig 2. Cumulative

incidence of clinically

important bleeding

during anticoagulant

therapy in DVT

patients with and

without cancer.
http://bloodjournal.hematologylibrary.org/cgi/content/full/100/10/3484/F2http://bloodjournal.hematologylibrary.org/content/vol100/issue10/images/large/h82223419001.jpeg

8/14/2019 03 P MAKRIS1a

29/51

OAC vs LMWH

LMWH vs placebo

8/14/2019 03 P MAKRIS1a

30/51

L d k CLOT C T i lL d k CLOT C T i l

8/14/2019 03 P MAKRIS1a

31/51

Landmark CLOT Cancer TrialLandmark CLOT Cancer TrialReduction in Recurrent VTEReduction in Recurrent VTE

00

55

1010

1515

2020

2525

Days Post RandomizationDays Post Randomization

00 3030 6060 9090 120120 150150 180180 210210

ProbabilityofRecurrentVTE,

%

ProbabilityofRecurrentVTE,

% Risk reduction = 52%Risk reduction = 52%

pp--value = 0.0017value = 0.0017


OACOAC

Recurrent VTERecurrent VTE

Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. NN

Engl J Med,Engl J Med, 2003;349:1462003;349:146

8/14/2019 03 P MAKRIS1a

32/51

KaplanKaplanMeier survival curves for all patients in dalteparin and placeboMeier survival curves for all patients in dalteparin and placebo

groupgroup

Kaplan

KaplanMeiersurvival

Meiersurvival

distributio

nfunction

estimate

distributio

nfunction

estimate

0 12 24 36 48 60 72 84

1.0

0.9

0.8

0.7

0.6

0.5

0.40.3

0.2

0.1

0.0

Time from randomisation (months)Time from randomisation (months)

No. at risk:No. at risk:


PlaceboPlacebo

190190 8585 3030 2222 1212 55 44 DalteparinDalteparin184184 7272 1515 99 88 55 22 PlaceboPlacebo

Kakkar AK, et al. J Clin Oncol. 2004;22:1944Kakkar AK, et al. J Clin Oncol. 2004;22:1944--1948.1948.

The Kaplan-Meier survival estimates at 1, 2, and 3 years after

randomization for patients receiving dalteparin were 46%, 27%,

21%, respectively, compared with 41%, 18%, and 12%, respecti

for patients receiving placebo (P= .19).

Famous: Trial DesignFamous: Trial Design

S GS i l A l i G d P i P ti t

8/14/2019 03 P MAKRIS1a

33/51

Survival Analysis: Good Prognosis PatientsSurvival Analysis: Good Prognosis Patients

Kaplan

KaplanMeiersurvival

Meiersurvival

distributionestim

ate

distributionestimate

17 23 29 35 41 47 53 5917 23 29 35 41 47 53 59 6565 71 77 8371 77 83

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.40.30.3

0.20.2

0.00.0

4747 17 10 9 917 10 9 9 8 8 5 3 28 8 5 3 2 00 PlaceboPlacebo

55 31 26 22 20 13 8 5 5 555 31 26 22 20 13 8 5 5 5 3 Dalteparin3 Dalteparin

Time from randomisation (months)Time from randomisation (months)

No. at risk:No. at risk:


PlaceboPlacebo

Kakkar AK, et al. J Clin Oncol. 2004;22:1944Kakkar AK, et al. J Clin Oncol. 2004;22:1944--1948.1948.

In an analysis not specified a priori, surv

was examined in a subgroup of patients

(dalteparin, n = 55; and placebo, n = 47)

had a better prognosis and who were ali

months after randomization. In these

patients, Kaplan-Meier survival estimate

and 3 years from randomization were

significantly improved for patients recei

dalteparin versus placebo (78% v55% a60% v36%, respectively, P= .03). The ra

of symptomatic venous thromboembolis

were 2.4% and 3.3% for dalteparin and

placebo, respectively, with bleeding rate

4.7% and 2.7%, respectively.

S S ( )

8/14/2019 03 P MAKRIS1a

34/51

LMWH and Survival: Further Studies (2003)LMWH and Survival: Further Studies (2003)

Solid tumor malignancy andacute VTE

All patients received dalteparin

200 IU/kg od 57 days

R

Dalteparin1 month 200 IU/kg od5 months 160 IU/kg od

Oral anticoagulant

6 months

Small cell lung cancer(SCLC)

Patients with responsive limited diseasereceived thoracic radiotherapy

Chemotherapy plusdalteparin 5000 IU od

18 weeks

Chemotherapy (cyclophosphamide,epirubicin, vincristine)18 weeks

Solid tumormalignancy

Nadroparin2 weeks therapeutic dose4 weeks 1/2 therapeutic dose

Placebo6 weeks

CLOT

SCLC study

MALT

R

R

Klerk CPW, et al.Klerk CPW, et al. J Clin OncolJ Clin Oncol. 2005;23:2130. 2005;23:2130--2135.2135.

Altinbas M, et al.Altinbas M, et al. J Thromb HaemostJ Thromb Haemost. 2004;2:1. 2004;2:1--6.6.

Lee, et.al.Lee, et.al. N Engl J Med,N Engl J Med, 2003;342003;34

SCLC S d S i l C

8/14/2019 03 P MAKRIS1a

35/51

SCLC Study Survival CurvesSCLC Study Survival Curves

1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 15 20 25 30 35

Months after randomization

Probability

ofsurvival

Good prognosis population

limited disease1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 15 20 25 30 35 40


Probability

ofsurvival

Overall population

p=0.01 p=0.007


Placebo Placebo

Altinbas M, et al. J Thromb Haemost. 2004;2:1Altinbas M, et al. J Thromb Haemost. 2004;2:1--6.6.

MALT S i l C

8/14/2019 03 P MAKRIS1a

36/51

MALT Survival CurvesMALT Survival Curves

Probability

ofSurvival

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60 72 84


Placebo

Nadroparin

p=0.010

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60 72 84 96


Probability

ofSurvival

Placebo

Nadroparin

p=0.021

Overall population Good prognosis population

>6 months survival

Klerk CPW, et al. J Clin Oncol. 2005;23:2130Klerk CPW, et al. J Clin Oncol. 2005;23:2130--2135.2135.

Anti-Tumor Effects of LMWH

8/14/2019 03 P MAKRIS1a

37/51

0

1020

30

40

50

60

70

80

90

100

Days Post Randomization0 30 60 90 120 150 180 240 300 360

ProbabilityofSurvival,%

OAC

Dalteparin

HR = 0.50 P-value = 0.03

Anti-Tumor Effects of LMWHCLOT 12-month Mortality

Lee A, et al. ASCO. 2003

Patients Without Metastases (N=150)

8/14/2019 03 P MAKRIS1a

38/51

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, theoccurrence of asymptomatic thrombotic events could

not be assessed.

8/14/2019 03 P MAKRIS1a

39/51

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 prophylacticanticoagulation.

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% ofpatients 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.

8/14/2019 03 P MAKRIS1a

40/51

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.

8/14/2019 03 P MAKRIS1a

41/51

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 becareful in generalizing the results to patients with a

poor performance status and patients with these less

prevalent malignancies, as other predictive modelsmay more closely fit those cases.

Khorana et al 2008

8/14/2019 03 P MAKRIS1a

42/51

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.

8/14/2019 03 P MAKRIS1a

43/51

SilverSilver In:In:The HematologistThe Hematologist -- modified from Blom et. al.modified from Blom et. al. JAMAJAMA 2005;293:7152005;293:715

Population-based case-control (MEGA)study

N=3220 consecutive patients with 1st

VTE vs. n=2131 control subjects CA patients = 7x OR for VTE vs. non-CA

patients

Effect of Malignancy on Risk of Venous Thromboembolism (VEffect of Malignancy on Risk of Venous Thromboembolism (V

0

10

20

30

40

50

Hematological

Lu

ng

G

astrointestinal

Breast

Distant

metastas

es

0to3months

3to12months

1to3years

5to10years

>15years

Ad

justedodds

ratio

Type of cancer Time since cancer diagnosis

2828

22.222.220.320.3

4.94.9

19.819.8

53.553.5

14.314.3

2.62.61.11.13.63.6

8/14/2019 03 P MAKRIS1a

44/51

Falanga et all 2008

VTE is a major cause of morbidity and mortality in patients with cancer.Hence, it is essential that oncologists and other health providers areable to diagnose DVT and PE accurately and administer effective

treatment for these common vascular complications

8/14/2019 03 P MAKRIS1a

45/51

Cancer patients with venous thrombosisare more likely to develop recurrent

thromboembolic complications andmajor bleeding during anticoagulanttreatment than those withoutmalignancy.

These risks correlatewith the extent of

cancer.

8/14/2019 03 P MAKRIS1a

46/51

Imberti et al 2008

The most commonsituations that increasethe thromboembolic risk

in cancer patientsinclude immobilization,surgery, chemotherapywith or without adjuvant

hormone therapy, andthe insertion of centralvenous catheters

The clinical presentation

of acute VTE

is different

and often more extensivein 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 forimplantation of inferior

vena cava filters.

8/14/2019 03 P MAKRIS1a

47/51

During anticoagulant therapy,cancer patients have a 2-

to 4-

fold higher risk of recurrentVTE and major bleedingcomplications when comparedwith non cancer patients

Possibilities for improvementusing the current paradigms of

anticoagulation seem limitedand new treatment strategiesshould be developed.

8/14/2019 03 P MAKRIS1a

48/51

The long-term administration of LMWH should be considered as analternative to anti-vitamin K drugs 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 and raises the distinct possibility thatcancer and thrombosis share common mechanisms.

8/14/2019 03 P MAKRIS1a

49/51

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

8/14/2019 03 P MAKRIS1a

50/51

I f f Bi l d CI t f f Bi l d C

8/14/2019 03 P MAKRIS1a

51/51

Fibrinolytic activities:t-PA, u-PA, u-PAR,PAI-1, PAI-2

Procoagulant Activities

FIBRIN

Endothelial cells

IL-1,

TNF-,VEGF

Tumor cells

Monocyte

PMN leukocyte

Activation ofcoagulation

Platelets

Angiogenesis,Basement matrixdegradation.

FalangaFalanga andand RicklesRickles NewNew Oncology:ThrombosisOncology:Thrombosis 20052005

Interface of Biology and CancerInterface of Biology and Cancer

03 p makris1a

Documents