Cancer- Associated Thrombosis CAT Academic Day - Medical Oncology Jan 28, 2011

Cancer- Associated Thrombosis

CAT

Academic Day - Medical Oncology

Jan 28, 2011

Armand Trousseau 1801-1867

1865: Association of Cancer and Thrombosis

“…struck by the frequency with which cancerous patients

are affected with painful edema of the…extremities…other

cases, in which the absence of appreciable tumour made

me hesitate as to the nature of a disease of the stomach, my

doubts were removed … I know the disease to be

cancerous when phlegmasia alba dolens appeared in the …

limb. There appears to be cachexiae…a particular condition of

the blood which predisposes to spontaneous coagulation”

Armand Trousseau, New Sydenham Society 1865

“J’ai perdu”“I am lost”

“The phlebitis that has just appeared tonight leaves me no doubt as to

the nature of my illness”

Trousseau 1867

Cancer and Venous Thromboembolism A two way street

CANCER THROMBOSIS

Cancer causes Thrombosis

Thrombosis affects the Biology of Cancer

Cancer and VTE - Introduction

Major complication in 4-20% of pts 6x risk

Leading cause of death

Risk increases with Cancer Therapy

VTE Prophylaxis and Treatment - Complex

Risk of recurrence & bleeding on treatment

VTE in Cancer pts Reduction in Survival

VTE in Cancer Impact and Implications

VTE:

May indicate occult Cancer

May complicate known Cancer

May complicate hospitalization, surgery or

systemic Rx for Cancer

VTE in Cancer Impact and Implications

VTE:

Second leading cause of death

Interrupts/delays needed Ca treatment

Anticoagulant therapy increases bleeding risk

Reduces survival 2-8x likelihood of death

Increases readmission x4 25% for VTE issues

Economic burden: Hospitalization 11 days

$20,000 (U.S. figures - 2002)

Cancer and VTE

Topics for Discussion Pathogenesis of Thrombosis

Epidemiology - Tumour type/stage, ChemoRx

Prognosis of Cancer and VTE

Prophylaxis: Surgery/Medical/Central Catheters

Thalidomide and Myeloma

Treatment of VTE – Failure of LMWHs

Cancer and VTE

Additional Topics New anticoagulants ?? For Cancer

Cancer Survival and Anticoagulants ?

Treatment of Portal/Splenic Vein Thrombosis

Treatment of Central Venous Catheter clots

Treatment of Tumour Thrombi eg Renal Cell Ca

Malignancy Workup in Idiopathic VTE

Cancer and VTE

Pathogenesis

Rudolf Virchow 1821-1902

ENDOTHELIAL INJURY STASIS

DVT

HYPERCOAGULABILITY

VIRCHOW’S TRIAD

Virchow’s Triad & Cancer Venous stasis

Prolonged bedrest Venous compression by tumor or nodes Venous invasion by tumor

Endothelial Injury Direct invasion/adhesion by tumor Surgery Chemotherapy Radiation Venous catheters

Virchow’s Triad & CancerActivation of coagulation Tumour Cell Activities

Procoagulant Fibrinolytic Inflammatory Cytokines Direct cell interactions

- Endothelial - Monocytes/Macrophages

- Platelets

Cancer and Thrombosis

TF

CP

TNFIL-1

↑TF

↓ TM

VEGF

↑TF

↑TF

F X

FXa

TF- FVIIa

Thrombin

Fibrin

Prothrombin

Fibrinogen

↑PAI

FVIIa

TUMOUR CELL

Monocyte

Mitogen

↑TF

Endothelial cell

uPAuPAR

Mitogen

Adhesion

Adhesion

PlateletIL- 8

TC

Plt

Rickles, F. Thrombosis Research 2001

Cancer and Thrombosis - Procoagulant

TF

CP

TNFIL-1

↑TF

↓ TM

VEGF

↑TF

↑TF

F X

FXa

TF- FVIIa

Thrombin

Fibrin

Prothrombin

Fibrinogen

↑PAI

FVIIa

TUMOUR CELL

Monocyte

Mitogen

↑TF

Endothelial cell

uPAuPAR

Mitogen

Adhesion

Adhesion

PlateletIL- 8

TC

Plt


Procoagulant Activity Tissue Factor

– Transmembrane glycoprotein forms complex with VIIa

– Prime activator of Coagulation

– Cancer cells express TF constitutively

– Major role in VEGF/angiogenesis

Cancer Procoagulant– Cysteine proteinase

– Activates factor X directly

– Mostly in malignant tissue

(Acute Promyelocytic Leukemia)

Cancer and Thrombosis - Fibrinolysis

TF

CP

TNFIL-1

↑TF

↓ TM

VEGF

↑TF

↑TF

F X

FXa

TF- FVIIa

Thrombin

Fibrin

Prothrombin

Fibrinogen

↑PAI

FVIIa

TUMOUR CELL

Monocyte

Mitogen

↑TF

Endothelial cell

uPAuPAR

Mitogen

Adhesion

Adhesion

PlateletIL- 8

TC

Plt


Fibrinolytic Properties Most tumor cells can express proteins necessary

for fibrinolysis: u-PA, t-PA and PAI-1, PAI-2

May also express receptors to activate fibrinolysis

– Likely cause of bleeding problems in leukemia

Plasminogen activators/inhibitors may play role in tumor invasion, proliferation, and metastasis

Cancer and Thrombosis - Cytokines

TF

CP

TNFIL-1

↑TF

↓ TM

VEGF

↑TF

↑TF

F X

FXa

TF- FVIIa

Thrombin

Fibrin

Prothrombin

Fibrinogen

↑PAI

FVIIa

TUMOUR CELL

Monocyte

Mitogen

↑TF

Endothelial cell

uPAuPAR

Mitogen

Adhesion

Adhesion

PlateletIL- 8

TC

Plt


Cytokine Release

Tumours release inflammatory cytokines:

TNF, IL-1 acts on vascular endothelial cells

Tissue Factor and PAI

Thrombomodulin ( Protein C activation)

VEGF (Vascular endothelial growth factor)

Tissue Factor by endothel. cells and monocytes

adhesion molecules expression by endothel. cells

- attracts platelets, WBCs, tumour cells

Cancer and Thrombosis – Cell interactions

TF

CP

TNFIL-1

↑TF

↓ TM

VEGF

↑TF

↑TF

F X

FXa

TF- FVIIa

Thrombin

Fibrin

Prothrombin

Fibrinogen

↑PAI

FVIIa

TUMOUR CELL

Monocyte

Mitogen

↑TF

Endothelial cell

uPAuPAR

Mitogen

Adhesion

Adhesion

PlateletIL- 8

TC

Plt


Tumor Cell Interactions with Host Cells Endothelial Cells

Indirect: via cytokines (TNF, IL-1, VEGF)

Direct: Tumour cells have membrane adhesion molecules

These integrins and selectins bind to tumour adhesion molecules receptors on endothelium cells

Initiates local clotting activation & thrombosis

Attracts and activates platelets and WBC’s

Tumor-tumor and tumor-vascular cell adhesion leads to cell migration, cell invasion, angiogenesis

Tumor Cell Interactions with Blood Cells Platelets

Direct Adhesion of platelets to tumor cells and to vascular endothelial cells

Activation by tumor cells in vitro & in vivo

Release of proaggregation factors

(ADP, cathepsin)

Tumor Cell Interactions with Blood Cells Monocyte-Macrophage

Tumors may induce expression of Tissue Factor on mononuclear phagocytes directly or via inflammatory mediators

May be mechanism of localized fibrin deposition within tumor tissue

Cancer and VTE

Epidemiology

Cancer and VTE – Epidemiology

4-20% of Cancer patients will have VTE during the course of their disease

15% Symptomatic, 50% asymptomatic, 50% autopsy

Cancer has 4-7x risk of VTE

Active Cancer accounts for 20% of New VTEs

VTE is second most common cause of death

Cancer and VTE – Epidemiology Annual Incidence

- Small Cohort (Hospital)studies 6-8%

- Epidemiological studies (data bases) 1.1-1.2

- Recent Population studies ~ 1%

Time course of VTE Odds Ratio

Highest Incidence first 3 months 54X

3 -12 months 14X

1 - 3 years 4X

Cancer and Risks of VTE Cancer - related Factors

Treatment - related Factors

Patient - related Factors

Biomarkers

Cancer and Risks of VTE

Cancer-related Factors

Tumour type: pancreas, stomach, gynecologic, renal, lung, primary brain, lymphoma, myeloma

Advanced stage

Initial period after diagnosis (3-6 months)

Histology – adeno Ca >> squamous Ca 2-3x

Cancer and Risks of VTE Treatment-related Factors

Major Surgery RR 2x

Hospitalization RR 2.3x

Cancer Therapy

Chemotherapy RR 2 - 6x

Hormonal therapy RR 1.6x

Anti-angiogenesis drugs RR 1.3 - 2.0 x

Erythropoiesis Stimulating agents RR 1.7x

Transfusions RR 1.6x

Central vein catheters ??? 14%~4% recent data

Cancer and Risks of VTE Patient -related Factors

Older age

Female Sex

Race Black > Caucasian > Asian

Comorbidities: Infection, Renal, Pulmonary, Arterial

Thrombosis, Anemia, Obesity RR ~1.5-2.5

Prothrombotic Mutations – FVL, Prothrombin Gene

Prior VTE RR 6x

Performance status- Immobility RR 2-4x

Cancer and Risks of VTE Candidate Biomarkers Risk Models

Pre-chemo platelets > 350,000

Pre-chemo WBC > 11,000

Hb < 100 gm/l

Elevated Tissue Factor – Hi grade expression in

Tumour cells, ↑Systemic TF levels

↑ D-dimer

↑ Soluble P-selectin (12%) RR 2.6

↑ C-reactive protein

Cancer and Risks of VTE

Cancer-related Factors

Tumour type: pancreas, stomach, gynecologic, renal, lung, primary brain, lymphoma, myeloma

Advanced stage

Initial period after diagnosis (3-6 months)

Histology – adeno Ca>> squamous Ca 2-3x

Cancer and VTE

Cancers most strongly associated with VTE:

– Bone 75 per 1,000/yr

– Ovary 65

– Brain 64

– Pancreas 45

Cancers most common in patients with VTE:

– Breast 26% 371 of 1426 VTE’s

– Colorectal 13% 189

– Prostate 12% 168

– Lung 11% 152Blom J. J Thromb Haemost 2006; 4:529-535

Frequency, Risk Factors and Trends for VTE in Cancer Pts in Hospital

Sites with Highest Risk VTE % Odds Ratio p

Pancreas 8.1% 2.46 <.0001

Kidney 5.6% 1.71

Ovary 5.6% 1.57

Lung 5.1% 1.31

Stomach 4.9%

Brain 4.7% 1.74

Myeloma 5.0%

Non Hodg Lymphoma 4.8%

Hodg Lymphoma 4.6%Khorana et al Cancer 2007;110:2339-46

Cancer and VTE - Metastatic Disease

Metastatic Disease increases VTE risk 4-13X

Incidence of VTE / 100 pt-yr

Pancreas 20.0

Stomach 10.7

Bladder 7.9

Renal 6.0

Lung 5.0

Chew et al. Arch Int Med. 2006;166: 458-64

Cancer and VTE

Cancer Therapy

Cancer Therapy VTE odds ratio. Surgery in Cancer pts 2x

Hospitalization 2.3x

Cancer therapy Chemotherapy 6.5x

Hormonal therapy 1.6xAnti-angiogenesis agents 1.3x

Support Rx- Erythropoiesis agents 1.7x

Transfusions - RBCs/Platelets 1.6x

Central Venous Catheters 28% 4% ???

Radiation ???

Cancer and VTE

Thrombosis and Chemotherapy

VTE and Chemotherapy

Chemotherapy - independent risk for VTE

Pts on Chemotherapy VTE 11% /yr

VTE during Chemo Early Mortality RR 2X

Cancer pts Cancer pts + Chemo

VTE risk 4x 6.5x

Recurrent VTE 2x 4x

Rate of VTE in Breast Cancer

Stage % VTE * Treatment

I 0.1 none 1 tamoxifen 4.5 tamoxifen + CTX

II 0 -1.6 tamoxifen 1.3 -10 CTX 3.1-9.6 tamoxifen + CTX

III/IV 15-17 CTX

*Asymptomatic VTE

Prothrombotic Effects of Chemotherapy

Damage to vascular endothelium

Platelet Activation/Aggregation

Increased Procoagulants

Decreased Anticoagulants (AT III, PC, PS)

Tumour and Endothel. cell Apotosis increase TF

Tumour cell Cytokine Release increases TF

Monocyte/Macrophage Expression of TF

Decrease Fibrinolysis

Haddad T. Thromb Res 2006 118:555-68

VTE and ChemotherapyChemotherapy and VTE 10-20% / yr

Cisplatin 8 - 18%

L-asparaginase 4 - 14%

Fluoruracil 15 - 17%

Thalidomide + Decadron / ChemoRx 20 - 40%

Anti-angiogenesis drugs (Avastin) marginal - 30%?

Supportive Rx: EPO, G-CSF, Steroids 3 - 60%?

Risk Model - ChemoRx associated VTE Khorana Patient Characteristic Odds Ratio Cancer site

Very high risk - stomach, pancreas 4.3

High Risk - lung, lymphoma, gyn, blad. testic. 1.5

Low Risk - breast, colorectal, Head & Neck 1.0

Pre-chemo Platelets >350x109/l 1.8

Hgb <100 g/l or ESAs use 2.4

Prechemo WBC > 11x109/l 2.2

BMI >35 kg/m2 2.5Khorana A. Blood 2008; 111:4902

Risk Model - ChemoRx associated VTE Patient Characteristic Risk Score Cancer site

Very high risk - stomach, pancreas 2

High Risk - lung, lymphoma, gyn, blad. Testic. 1

Pre-chemo Platelets >350x109/l 1

Hgb <100 g/l or ESAs 1

Prechemo WBC > 11x109/l 1

BMI >35kg/m2 1

Khorana A. Blood 2008; 111:4902

Risk Model - ChemoRx associated VTE Results during 4 cycles of ChemoRx

Risk group % of pts Risk of VTE Risk Score

0 Low 27% 0.3 %

1-2 Intermediate 60% 2 %

≥ 3 High 13% 7 %

Median time – ChemoRx to VTE 2.5 months

Khorana A. Blood 2008; 111:4902

Risk Model – Progression/Mortality Results after 4 months of ChemoRx (3%- 38 d)

Risk group VTE Progression Death HR* % HR* % HR*

Group 1 Low 1 5.8 1 1.2 1

Group 2 Intermed 3.1 12.1 2.8 5.9 3.6

Group 3 High 11.7 15.3 4.3 12.7 6.9

* HR- Hazard Ratio p < .0001

Model predicts early VTE, Progression and Mortality

Kuderer Blood 2008;112 ASH abstract 172

Risk Assessment Models

Khorana Model

– Ambulatory patients followed for febrile neutropenia and other complications on new chemo regimen

– VTE not a predefined outcome

Ay Model

– Ambulatory patients with new diagnosis of cancer or progression of cancer followed in the Vienna CATS

– VTE is primary outcome and objectively verified

– Khorana model + D-dimer + sP-selectin

Khorana et al. Blood 2008. Ay et al Blood 2010.

VTE Risk Model - CATS study

Vienna CATS (Cancer and Thrombosis study)

Prospective, Observational Cohort study in Cancer pts

Newly diagnosed or Progression after previous remission

Brain, Breast, Lung, GI, Renal, Prostate, Myeloma, Lymphoma

No ChemoRx > 3months, No surgery or RadioRx >2 weeks

2 year observation: VTE, death

Risk of Symptomatic Objectively confirmed VTE

Ay C et al. Blood 2010;116:5377

VTE Risk Model -CATS Patient Characteristic Risk Score Cancer site

Very high risk - stomach, pancreas 2

High Risk - lung, lymphoma, gyn, blad. Testic. 1

Pre-chemo Platelets > 350x109/l 1

Hgb < 100 g/l or ESAs 1

Prechemo WBC > 11x109/l 1

BMI > 35kg/m2 1

Soluble P- selectin ≥ 53.1 ng/ml 1

D-Dimer ≥ 1.44 ug/ml 1

Ay C et al Blood 2010; 116:5377

Khorana VTE Risk Model - CATS Results after 6 months

Risk Score % of 819 pts Risk of VTE HR

0 33.6% 1.5%

1 28% 3.8% 2.7

2 27% 9.6% 5.5

≥ 3 11.4% 17.7% 9.5

Score ≥ 3 PPV 22.1% NPV 94.9%

Ay C et al Blood 2010; 116:5377

• Prospective follow up of 819 patients

• Median observation time/follow-up: 656 days

6-mo cumulative VTE rates:Patients Events

n %

Score ≥3 93 17.7%

Score 2 221 9.6%

Score 1 229 3.8%

Score 0 276 1.5%

Ay et al Blood 2010.

Khorana Model Validation

Log-rank test P<0.001)

Expanded VTE Risk Model - CATS

Results after 6 months Risk Score % of 819 pts Risk of VTE HR

0 24.5% 1.0%

1 23.2% 4.4% 3.7

2 26.6% 3.5% 2.9

3 15.9% 10.3% 7.0

4 6.2% 20.3% 15.6

≥ 5 3.7% 35.0% 25.9

Score ≥ 5 PPV 42.9% NPV 94.4%

Ay C et al Blood 2010; 116:5377

6-mo cumulative VTE rates:Patients, n Events, %

Score ≥5 30 35%

Score 4 51 20.3%

Score 3 130 10.3%

Score 2 218 3.5% Score 1 190 4.4%Score 0 200 1.0%

• Addition of D-dimer and soluble P-selectin to Khorana model:

Ay Model for Outpatients

Ay et al Blood 2010.

Cancer and VTE

Prognosis

Levitan - Medicine 1999;78:285

0 20 40 60 80 100 120 140 160 180

0.00

0.20

0.40

1.00

0.80

0.60

DVT/PE and Malignant Disease

Malignant Disease

DVT/PE Only

Nonmalignant Disease

Number of Days

Pro

babi

lity

of D

eath

VTE, Cancer and Survival

94 %

42%

29%

20%

0 5 10 15 20

100

80

60

40

20

Years after Diagnosis

Sur

viva

l, %

of p

atie

nts

VTE, Cancer and Survival

Sorensen - NEJM 2000;343:1846

1- yr survival

Cancer at time of VTE 12%

Cancer without VTE 36%

p< .001

Cancer and VTE

Prophylaxis of VTE

Cancer and VTE- Prophylaxis

Prophylaxis in Surgery for Cancer

Prophylaxis in Medical Pts with Cancer

Prophylaxis for Central Venous Catheters

Cancer Associated ThrombosisCAT

Prophylaxis and Treatment

ASCO 2008 ACCP 2008

Am. Soc of Clin. Oncology Guidelines Recommendations for VenousThromboembolism

Prophylaxis and Treatment in Patients with Cancer

G Lyman, A Khorana, A Falanga et al

Journal of Clinical Oncology

Dec. 1, 2007, 25(34):5490-5505

ACCP GUIDELINES Chest 133; 6 June 2008 supplement

ACCP GuidelinesLevels of evidence/recommendations

Grade Risk/benefit Methodologic Strength Implications

1 A Clear RCTs Ø limitations Strong recommendations

1 B Clear RCTs + limitations Strong recommendations

1 C+ Clear Ø RCTs - extrapolations Strong recommendations

1 C Clear Observational studies Intermediate strength

2 A Unclear RCTs Ø limitations Intermediate strength

2 B Unclear RCTs + limitations Weak recommendations

2 C+ Unclear Ø RCTs - extrapolations Weak recommendations

2 C Unclear Observational studies Very weak

Cancer and VTE- Prophylaxis

Surgical Oncology

VTE and Surgical Oncology

Patients undergoing cancer surgery:

Major risk group – no prophylaxis 10 - 40% VTE

On prophylaxis - at least 2x the risk of DVT

On prophylaxis - more than 3x the risk of fatal PE

Cancer-independent predictor of prophylaxis failure

Prolonged VTE risk 25- 40% VTE Day 21+ post-op

Cause of death in 46% in first 30 days post-op

0

3

6

9

12

15

18

21

Not confirmed(n=42)

Confirmed (n=50)

30-day Symptomatic VTE - 2.1%

DVT=0.4 PE=0.9 Death=0.8

The @ristos Project: A Clinical Outcome-Based Prospective Study of VTE in Cancer Surgery

• 2,373 patients in 31 Italian hospitals

In-hospital prophylaxis: 82%Post-discharge prophylaxis: 31%

Agnelli G - Ann Surg 2006. 243:89-95

0

2

4

6

8

10

12

@ristos: VTE Timing

VTE Event - 40% > 21 days after surgery

No. events

Agnelli G - Ann Surg. 2006 243:89-95

02468

101214161820

VTE

Dis

. Pro

grB

leed

ing

Live

r fa

ilure

Str

oke

Sep

sis

Oth

er

@ristos: 30-day Mortality

Overall at 30 days: 1.7%

General: 2.9%

Urological: 0.6%

Gynecological: 0.2%

No. events


VTE–related: 46%

Variable Effect OR 95%CI

Age 60 years 2.6 1.2 - 5.7

Previous VTE Yes 6.0 2.1 - 16.8

Anesthesia 2 hours 4.5 1.1 - 19.1

Stage Advanced 2.7 1.4 - 5.2

Bed rest post-op 4 days 4.4 2.4 - 7.8

@ristos: Risk Factors for VTE in Cancer Surgery


ENOXACAN II - Duration of Prophylaxis after Cancer Surgery

curative, open surgery for abdo or pelvic cancer double-blind RCT in 37 centers, 8 countries

enoxaparin 40 mg QD

R

placebo

enoxaparin 40 mg QD

surgery Day 6-10 Day 25-31

bilat venography

Bergqvist - NEJM 2002;346:975

Duration of Prophylaxis after Major Abdominal Surgery

unblinded, multicenter RCT (interim report) unspecified proportion had cancer (N=117)

Dalteparin 5000 U od + GCS

RProphylaxis stopped

Dalteparin 5000 U od

surgery Day 7 Day 28

bilat venography

Rasmussen - Cancer Treat Rep 2002; 28:141

Prolonged thromboprophylaxis after cancer operations

0

2

4

6

8

10

12

14

16

18

20

1 week 4 weeks

Inci

denc

e of

tota

l VTE

(%)

4 .8%

12%

p=0.02

20/167

8/165

0

2

4

6

8

10

12

14

16

18

20

1 week 4 weeks

Inci

denc

e of

tota

l VTE

(%)

8.8%

19.6%

p=0.03

21/107 8/91

ENOXACAN II enoxaparin

FAME dalteparin

Bergqvist - NEJM 2002;346:975 Rasmussen - ASH (2003)

Cancer Surgery PatientsProphylaxis

1. LDUH and LMWH efficacious in cancer surgery

2. For anticoagulant prophylaxis, greater protection at higher doses UF Heparin tid vs bid

dalteparin 5,000 U vs 2,500 U od

3. Extending prophylaxis for 3 weeks after discharge

60% risk reduction in DVTs (venographic)

ASCO 2008 Guidelines – VTE in Cancer

Prophylaxis: Cancer Surgery

- Prophylactic doses - UFH / LMWH / Fondaparinux

early post-op x 7-10 days

- Mechanical methods if bleeding risk

- LMWH x 4 weeks for Major abdo-pelvic surgery,

residual cancer, DVT risk (previous VTE, obese,

prolonged immobility)

Lyman G et al. J Clin Oncol 2007; 25(34): 5490-5505

ACCP 2008 Guidelines - VTE in Cancer

Prophylaxis: Cancer Surgery

Cancer Patients undergoing major surgery

Prophylaxis – LMWH, LDUH tid, Fondaparinux

x 7-10 days or discharge Grade 1A

Hi Risk Cancer Surgery

Prophylaxis - up to 28 days post-op Grade 2A

Intermission – Spring Break

Cancer and VTE- ProphylaxisMedical OncologyAmbulatory Patients

VTE and Chemotherapy Chemotherapy - independent risk for VTE

Pts on Chemotherapy VTE 11% /yr

Cancer pts Cancer pts +

Chemo

VTE risk 4x 6.5x

Recurrent VTE 2x 4x

Prevention of Thromboembolism in CancerMedical Oncology Pts

Levine 1994 Stage IV Breast – RRR 85%

Hass 2005 TOPIC Breast/Lung -NS

Perry 2007 PRODIGE – Gliomas - NS

Agnelli 2008 PROTECHT Metastatic Ca- RRR 47%

Reiss 2009 CONKO 004 Pancreas – RRR 65%

Maraveyas 2009 FRAGEM Pancreas – RRR 62%

Prevention of Thromboembolism in Cancer

Stage IV breast cancer patients receiving CTX Double-blind RCT x 6 months Very low-dose warfarin: 1 mg x 6 wks INR 1.3-1.9

Placebo Warfarin

No. 159 152

Thromboembolism 4.4 % 0.6 % p = 0.03

Major bleeding 1.3 % 0.6 % NS

All bleeding 3.1 % 5.3 % NS

Levine - Lancet (1994)

Levine - Lancet 1994;343:886

Cumulative Thromboembolism in Patients Treated with Warfarin

20

15

10

5

0

Time from randomization (months)

15120 3 6 9

Pat

ient

s w

ith

thro

mbo

sis

(%)

P=0.031

warfarin

placebo

Risk Reduction – 85%

Prevention of Thromboembolism in CancerTOPIC studies

Advanced Cancer on ChemoRxLMWH vs. placebo x 6 months Dopplers q 4 weeks

TOPIC 1- Breast Ca Placebo LMWH p

VTE 3.9% 4%

Bleeding 0% 1.7%

TOPIC 2 - Lung Ca

Overall VTE 8.3% 4.5% .07

Stage IV VTE 10.1% 3.5% .03

Bleeding 2.2% 3.7%

Haas et al J Throm Haemos 2005; 3 (suppl) OR 059


PRODIGE- ASC0 2007

Malignant Glioma

LMWH vs. placebo x 6 months

RCT double blind

Target 512 pts Only 186 randomized ***

Efficacy outcome: 6 month VTE-free survival

Safety outcome : Bleeding

Perry J. et al J Clin Onc 2007 25:suppl abstract 2011

Prevention of Thromboembolism in CancerPRODIGE - ASC0 2007

Outcomes LMWH Placebo

99 pts 87 pts

VTE 11% (9 ) 17% (12) HR .7 p=.3

Major Bleed 5.1% (5) 1.2% (1) HR 4.0 p= .2

All major bleeds - intracranial

Perry J. et al J Clin Onc 2007 25:suppl abstract 2011

Prevention of Thromboembolism in CancerPROTECHT study – ASH 2008

Metastatic or locally advanced Ca on ChemoRx

RCT double-blind clinical outcome

LMWH vs placebo 2:1 randomization while on ChemoRx

maximum 4 months 1,150 pts LMWH 769: Placebo 381

Primary Efficacy Endpoint: Composite of Venous/Arterial

Thromboembolic events

Safety: Major Bleeding

Agnelli 2008 Blood; 112:abstract 6

Prevention of Thromboembolism in CancerPROTECHT study – ASH 2008

Cancer type %Lung 279 24.3

Colon 235 20.4

Breast 165 14.3

Ovary 143 12.4

Stomach 98 8.5

Rectum 87 7.6

Pancreas 53 4.6

Head/Neck 36 3.1

Other 54 4.7

LMWH Placebo

Study Patients 769 pts 381pts

Treatment duration 90.3 days 94 days

TE events 2.1% (16) 3.9% (15) p=.033

- Lung Ca 4% 8.8%

- GI 1.5% 2.7%

DVT 1.0% 2.1%

PE 0.4% 0.8%

Major Bleed 0.7% 0 p=.177

Minor Bleed 7.4% 7.9%

Relative Risk Reduction - 47.2% NNT 53.8

Prevention of Thromboembolism in CancerPROTECHT study - Results


CONKO 004 study – ASCO 2009

Open Prospective Randomized

312 Advanced Pancreatic Cancer

ChemoRx vs ChemoRx + Enox 1mg/kg od x 3 months

Outcomes: Symptomatic VTE /Bleeding

Reiss et al JCO 2009; 27 LBA 4506


CONKO 004 – ASCO 2009

Outcome Observed Enox 1 mg/kg RRR

152 pts 160 pts

VTE 14.5% 5.0% 65% Major Bleed 9.9% 6.3%

No difference in Time to Progression or Overall Survival

Reiss et al JCO 2009; 27 LBA 4506


FRAGEM study

Prospective Multi-centre

123 Advanced Pancreatic Cancer

Gemcitabine vs Gemcitabine + Fragmin (CLOT protocol) for 3 months

Outcome: Study period VTE, Overall VTE, Death (VTE)

Maraveyas A. Eur J of Cancer Suppl 2009;7:362


FRAGEM study

Outcome Gem Gem+Fragmin RR

64 pts 59 pts

Overall VTE 31% 12% .38 p= .02

Study Period VTE 25% 3.5% .14 p=.002

Death (VTE) 9% 0% .08 p=.028

Maraveyas A. Eur J of Cancer Suppl 2009;7:362


Conflicting results of Prophylaxis studies

Negative effect of prophylactic dose LMWH in some Lung,

Breast, Glioma studies

Positive effect of prophylactic dose LMWH in certain

tumour eg lung, GI (PROTECHT)

Positive effect in “Therapeutic dose” LMWH in Advanced

Pancreatic Ca

Optimal dose, duration, specific tumour type/stage

needs further definition

Cancer and VTE- ProphylaxisMedical Oncology

Thalidomide and Lenalidomide

Thrombotic Complications with VEGF Inhibitors

Both Arterial (~5%) & Venous (~12%) Thrombosis and Bleeding associated with anti-VEGF drugs

16-23% thrombotic events with Bevacizumab – Avastin

VTE RR= 1.38 Nalluri - Meta- analysis 15 RCTs- 8,000 pts

VEGF important for neoangiogenesis and maintenance of normal endothelial cell function and regeneration

Anti-VEGF drugs Endothelial cell apotosis

exposure of basement membrane – thrombosis

decrease platelet inhibitors PGI-2 /NO3 - thrombosis

loss of endothelial vessel lining integrity - bleeding

Thalidomide and VTE

Thalidomide and analogs (Lenalidomide)

VTE risk with Thalidomide in Myeloma Rx <5%

Thalidomide + Decadron 17-26% VTE

+ Anthracyclines 12-28% VTE

Uncontrolled studies: efficacy “Mini dose”

Warfarin, Full Dose Warfarin, LMWH, ASA

Thalidomide and VTEMechanisms of Thalidomide associated VTE

1. Alters Endothelial cell PAR-1 expression after Doxorubicin injury leads to Thrombin binding and Platelet activation

2. Serum Thrombomodulin drops in first month of Rx

3. Acquired APC resistance

4. High levels of vWf and FVIII

Thalidomide and Risks of VTE

Thalidomide Newly dx Relapsed/refractory

alone 3-4% 2-4%

+ Hi dose Dex 14-26% 2-8%

+ Melphalan/Pred 10-20% 11%

+ Doxorubicin 10-27% 58%*

+ Cyclophosphamide 3-11% 4-8%

+ Multiagent Chemo 16-34% 15%

Higher VTE Risk: Newly diagnosed RR 2.5

Doxorubicin regimen RR 4.3

Int Myeloma Working group. Leukemia 2008;22:414


Lenalidomide Newly dx Relapsed/refractory

Alone 0-33%

+ Dexamethasone 8-75% 8-16% RR 3.5

+ Cyclophophamide 14%

+ Bortezomib 0%

Thalidomide + ChemoRx in other Cancers

Prostate: Thal + docetaxel 20%

Renal Cell: Thal + Gemcitibine + 5-Fu 43%

Melanoma /Brain mets: Thal + Temozolamide 25%



Risk Factors Obesity BMI > 30kg/m2

Previous VTE, Central Venous Catheter

Co-morbid conditions: Cardiac, Renal, DM, Sepsis, Immobility

Erythropoietin

Newly diagnosed Myeloma, Hyperviscoisty

Hi dose Dexamethasone

Doxorubicin

Multiagent ChemoRx

Thalidomide and VTE Prophylaxis “Suggestions”

Thalidomide alone No prophylaxis/ASA ?? 0 or 1 risk factor

Thalidomide 2+ risk factors Prophylactic LMWH ***newly diagosed Warfarin INR 2-3

Thalidomide + Hi dose Dex Prophylactic LMWH + Doxorubicin Warfarin INR 2-3 + Multiagents

*** No methodologically sound studies



Prophylaxis: Medical Oncology Pts

- No routine prophylaxis for ambulating pts

- ??? LMWH or Warfarin ~ INR 1.5+ Myeloma pts

on Thalidomide + ChemoRx / Decadron (based on

extrapolations from Ortho surgery and Breast Ca studies)


ACCP 2008 Guidelines - VTE in CancerProphylaxis

Medical Oncology pts

Ambulatory pts on Chemo/hormonal Rx

No routine primary prophylaxis Grade 1C

Cancer and VTE- ProphylaxisMedical Oncology

Cancer Patients in Hospital

VTE Prophylaxis - Cancer Pts in Hospital

Study Pts Ca Pts Placebo Rx RR p VTE% VTE%

MEDENOX 579 12.4% 14.9 5.5 .37 <.001

PREVENT 3706 5.1% 4.96 2.77 .55 .0015

ARTEMIS 849 15.4% 10.5 5.6 .47 .029



Prophylaxis:

Hospitalized Pts:

- Prophylactic doses - UFH / LMWH / Fondaparinux

if no bleeding concerns



Medical Oncology pts

Bedridden with acute medical illness:

Prophylactic doses – UFH / LMWH / Fondaparinux

Grade 1A

Cancer and VTE

Central Venous Catheters & VTE

• Not well established

• Methodologically weak studies & inconsistencies

among the studies:

- differences in study design and study population

- lack of standardized technique of CVC insertion

- inconsistent definition of VTE events

(CVC occlusion vs fibrin sleeve)

- different levels of clinical surveillance

- variable accuracy of diagnostic tests

Incidence of CVC-Related DVT

Incidence of CVC-Related DVT

Rate of thrombosis requiring PICC removal – 3.4%

1.1/1,000 catheter days - no prophylaxis (n=351)

Walshe – J Clin Onc 2002; 20:3276

Symptomatic thrombosis - 4% 0.3 /1,000 device days PICCs, Porta- caths, Hickman

catheters – 444 pts

A. Lee - J Clin Onc 2006; 24:1404

Clinically Important CVC-related DVT 2 - 4%

Central Venous Catheter - DVTRisk Factors

Risk Factor O.R.

More than 1 attempt 5.5

Previous CVC insertion 3.8

Left side CVC 3.5

Tip Position SVC vs RA 2.7

Arm vs Chest ports 8.1

Khorana J Clin Onc 2009; 27:4839

Preventing Central Venous Catheter Thrombosis in Cancer (RCTs)

Warfarin 1 mg/day

DVT sympt DVT

Study Endpoint No. control warf control warf

Bern, 1990 venogram D90 82 38 % * 10 % 25 % 10 %

Couban, 2002 sympt. DVT 255 NR NR 4 % 5 %

Heaton, 2002 sympt. thromb 88 NR NR 12 % 18 %

Preventing Central Venous Catheter Thrombosis in Cancer (RCTs)

LMWH

DVT

Study Endpoint No. control LMWH P

Monreal, 1996 venogram Day 90 29 62 % * 6 % 0.002

Reichardt, 2002 clinical 425 3.4 % 3.7 % 0.9

CVC-related Thrombosis in Cancer Pts

Rate of clinically-important symptomatic DVT appears

to have decreased ~ 4%

Rate of thrombosis requiring PICC removal – 3.4%

Primary prophylaxis with Minidose warfarin or LMWH

appear to NOT be effective nor necessary in general


Prophylaxis: Medical Oncology pts

Bedridden with acute medical illnessProphylaxis - LDUH, LMWH, Fondaparinux Gr 1A

Ambulatory receiving Chemo/hormonal therapy No routine prophylaxis Gr 1C

Central Venous CathetersNo prophylaxis with LMWH or Warfarin Gr 1B

Cancer and VTE

Treatment of VTE

Challenges of Treatment ofCancer-associated VTE

Risk of Recurrence of VTE

Risk of Bleeding on Anticoagulants

Negative impact on Quality of Life

Mortality

Recurrent VTE and Bleeding

Symptomatic DVT - Prospective Follow-up 1 yr

No Cancer Cancer Hazard Ratio p

No. 661 181

Rec VTE 6.8% 20.7% 3.2 0.0001

Major Bleed 4.9% 12.4% 2.2 0.015

Prandoni - Blood (2002)

Recurrent VTE on Oral Anticoagulant Therapy

Cu

mu

lati

ve P

rop

ort

ion

(%

)R

ec

urr

ent

Th

rom

bo

emb

olis

m 30

20

10

0

Hazard ratio 3.2 Cancer (21%)

No Cancer (7%)

0181661

1160631

2 3129602

4 5 692

161

7 8 973

120

10 11 1264

115

Time (months)CancerNo Cancer

Prandoni - Blood 2002;100:3484

Major Bleeding During Anticoagulant Therapy of VTE

Cu

mu

lati

ve P

rop

ort

ion

(%

)M

ajo

r B

lee

din

g

30

20

10

0

Hazard ratio 2.2

Cancer (12%)

No Cancer (5%)

Time (months)CancerNo Cancer

0181661

1170636

2 3141615

4 5 6102170

7 8 981

127

10 11 1268

124

Prandoni - Blood 2002;100:3484

Long-term Anticoagulation - Cancer Pts

Warfarin is problematic:

failure rates - recurrent thrombosis 3x - bleeding 2x

difficult to maintain therapeutic range

Repeated INRs / poor venous access

Repeated interruptions for procedures and thrombocytopenia

Traditional anticoagulation for

venous thromboembolism

in cancer patients is

neither effective nor safe.

Advantages of LMWH over OAC

routine laboratory monitoring not needed

weight-adjusted dosing

few drug interactions

Can easily accommodate invasive procedures and thrombocytopenia

effective in patients with warfarin failure

CLOT in Cancer Trial

Randomized trial of long-term

LMWH vs. oral anticoagulants

in Cancer patients

with Acute VTE

Lee et al - NEJM 2003;349:146

Clot in Cancer: Study Design

Active cancerwith DVT/PE

Initial Long-termtreatment treatmentdalteparin oral anticoagulant

200 U/kg QD INR 2-3

dalteparin dalteparin200 U/kg QD 200 U/kg QD

x 1 mo then 150 U/kg QD

x 5 mos

Lee - NEJM 2003;349:146

R

LMWH

N=336

OAC

N=336 P-value*

Recurrent VTE 9% 17% 0.002

Major bleed 6% 4% 0.27

CLOT in Cancer Study: Events

Lee - NEJM 2003;349:146

Clot in Cancer: Recurrent VTE

0

5

10

15

20

25

Days Post Randomization

0 30 60 90 120 150 180 210

Pro

bab

ility

of

Rec

urr

en

t V

TE

, % risk reduction = 52%

P-value = 0.002

dalteparin

OAC

Lee - NEJM 2003;349:146

Treatment of VTE in Oncology

Randomized trials (LMWH vs warfarin)

CANTHANOX (enoxaparin) – Meyer 2002

CLOT (dalteparin) – A Lee et al 2003

Subgroup of LITE (tinzaparin) – Hull et al 2006

ONCENOX (enoxaparin) – Deitcher 2006

Cohort study (LMWH)

Monreal - et al (dalteparin)

LMWH for VTE in Cancer Patients

1. Enoxaparin x 3 months

Meyer – Arch Intern Med 2002;162:1729

Canthenox - 20021 stopped - poor accrual

Warfarin LMWH

Study pts 75 pts 71 pts

Recurrent VTE 4% 3% NS

Major Bleed 16% 7% p=.09

Lee – NEJM 2003;349:146Hull – Am J Med 2006;1062


2. Dalteparin x 6 months3. Tinzaparin x 3 months

Warfarin LMWH RR p

CLOT - 20032

Recurrent VTE 17% 9% 52% <.002

Major bleed 4% 6%

LITE - 20063

Recurrent VTE 16% 7% 44% .044

Major Bleed 7% 7%


Summary of Treatment Studies for CAT

1029 pts: CANTHENOX / CLOT / LITE

Risk Reduction - VTE .56

Risk Reduction - Major Bleeding 1.01

Risk Reduction - Mortality .92

Chest. 133; 6:June 2008 suppl 493S

Treatment of Cancer Associated Thrombosis

Cochrane Meta-analysis 2008 – Akl 11 RCTs Initial Rx of VTE: LMWH vs IV UFH

Cancer pts with LMWH

Mortality Reduction Relative Risk = .71

Cochrane Review 2008 Akl 6 RCTs

Long term Rx of VTE in Cancer LMWH vs VKAs

Bleeding RR = .91 Survival RR = .96

Reduction VTE recurrence - LMWH RR = .47

Cancer and VTE

Treatment of Recurrent VTE

Failure of Anticoagulants

Cancer and Recurrent VTE Failure of Anticoagulation

Cancer Pts

4-6 x risk of VTE

3x risk of recurrent VTE on VKAs

3-6x risk of major bleed on VKAs

CLOT study 9-17% recurrence on LMWH/VKAs

IVC filters 32% VTE recurrence rate

Cancer and Recurrent VTEDose escalation of LMWH study - Carrier and Lee Retrosp. Cohort: Ca pts recurrent VTE on LMWH or VKAs Management - Anticoagulant escalation:

VKA Therapeutic LMWH x 4wks Maintenance LMWH (75%)

Low dose LMWH Therapeutic LMWH for 4wks

Maintenance LMWH

Maintenance LMWH Therapeutic LMWH > 6-12 wks

Therapeutic LMWH 20-25% increase wt-adj dose > 4 wks

Carrier M , Lee A. J Thromb Haemost 2009; 7: 760-5

Cancer and Recurrent VTE

Dose escalation of LMWH study - Carrier and Lee

Baseline Results: 70 Cancer pts with Recurrent VTE

Most common – lung, Met. Ca - 63%

Initial VTE: 56% leg DVT,

17% arm DVT (5 of 12 CVC related)

20% PE 7% DVT+ PE

Initial Anticoag. 67% LMWH: Th -32%, Mn - 51%, LD-17%

33% VKAs: 48% INR>2, 30% INR <2

***No anti-FXa levels at time of recurrence


Cancer and Recurrent VTEDose escalation of LMWH study - Carrier and Lee

Study Results: 70 Recurrent VTE

- 57% Leg DVT

- 19% arm DVT (5/13 – CVC)

- 21% PE

- 3% IVC

67% of recurrent VTE at new site

29% in the first 4 weeks of Rx (median 3.5 months)

Dose escalation: 55 pts Therapeutic LMWH 15 pts 120% Therapeutic LMWH



Dose escalation of LMWH study - Carrier and Lee

Results: Follow-up 3+ months

6 pts(8.6%) had second recurrence: 3 pts on therap LMWH

3 pts on 120% LMWH

5 of 6 had metastatic disease, 4 of 6 – Lung Ca

All 6 treated by increasing LMWH dose by 20-25%

no further symptomatic VTE during 3 month follow-up


Cancer and Recurrent VTEDose escalation of LMWH study - Carrier and Lee

Results: Follow-up 3+ months

Recurrent VTE Event rate - 9.9%/yr

Bleeding - 3 pts:1 ICH (brain Ca), 2 minor 4.8%/yr

Median time to second recurrence: 1.9 months

Median time - first recurrence to death: 11.4 months

Median survival after second recurrence: 4.3 months


Dose Escalation of LMWH Study - Carrier and Lee

Summary:

Cancer pts with recurrent VTE poor prognosis - Median survival 11.4 months

4.3 months if second recurrence

Escalating LMWH dose effective in treating Ca pts with “resistance” to standard LMWH or VKAs

Central Catheter Thrombosis

Treatment

NCCN Practice Guidelines

Catheter Associated Thrombosis:

If Catheter not required (no Anticoag. Contraindications) Remove catheter when clinically appropriate Anticoagulate

Recommended duration of therapy - at least 3 months Massive catheter related DVT consider thrombolysis

NCCN Practice Guidelines

Catheter Associated Thrombosis:

If Catheter still required (no Anticoag. contraindications)

Anticoagulate as long as catheter in place

Recommended duration of therapy - at least 3 months Consider catheter removal if symptoms persists Massive catheter related DVT consider thrombolysis

Cancer and VTESelected references

Lyman, Khorana et al. JCO 2009; 29: 4821-4918 (Oct 10, 2009)

NCCN Practice Guidelines 2010

Lyman et al. JCO 2007; 25:5490-5505

Ay et al. Blood 2010; 116:5377-82

Khorana et al. Blood 2008; 111:4902-07

THANK YOU

Documents

Cancer- Associated Thrombosis CAT Academic Day - Medical Oncology Jan 28, 2011