Transcript Cancer and Venous Thromboembolism

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 causes Thrombosis
CANCER
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
VIRCHOW’S TRIAD
ENDOTHELIAL INJURY
DVT
HYPERCOAGULABILITY
STASIS
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 & Cancer
Activation of coagulation
Tumour Cell Activities
 Procoagulant
 Fibrinolytic
 Inflammatory Cytokines
 Direct cell interactions
- Endothelial
- Monocytes/Macrophages
- Platelets
Cancer and Thrombosis
FX
TF- FVIIa
Prothrombin
FVIIa
uPAR
uPA
TF
Fibrinogen
FXa
CP
Thrombin
TUMOUR CELL
VEGF
Adhesion
Fibrin
Mitogen
TNF
IL-1
↑TF ↑PAI
Monocyte
↑TF
Adhesion
Mitogen
Platelet
Plt
↑TF
TC
IL- 8
↑TF
↓ TM
Endothelial cell
Rickles, F. Thrombosis Research 2001
Cancer and Thrombosis - Procoagulant
FX
TF- FVIIa
Prothrombin
FVIIa
uPAR
uPA
TF
Fibrinogen
FXa
CP
Thrombin
TUMOUR CELL
VEGF
Adhesion
Fibrin
Mitogen
TNF
IL-1
↑TF ↑PAI
Monocyte
↑TF
Adhesion
Mitogen
Platelet
Plt
↑TF
TC
IL- 8
↑TF
↓ TM
Endothelial cell
Rickles, F. Thrombosis Research 2001
 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
FX
TF- FVIIa
Prothrombin
FVIIa
uPAR
uPA
TF
Fibrinogen
FXa
CP
Thrombin
TUMOUR CELL
VEGF
Adhesion
Fibrin
Mitogen
TNF
IL-1
↑TF ↑PAI
Monocyte
↑TF
Adhesion
Mitogen
Platelet
Plt
↑TF
TC
IL- 8
↑TF
↓ TM
Endothelial cell
Rickles, F. Thrombosis Research 2001
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
FX
TF- FVIIa
Prothrombin
FVIIa
uPAR
uPA
TF
Fibrinogen
FXa
CP
Thrombin
TUMOUR CELL
VEGF
Adhesion
Fibrin
Mitogen
TNF
IL-1
↑TF ↑PAI
Monocyte
↑TF
Adhesion
Mitogen
Platelet
Plt
↑TF
TC
IL- 8
↑TF
↓ TM
Endothelial cell
Rickles, F. Thrombosis Research 2001
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
FX
TF- FVIIa
Prothrombin
FVIIa
uPAR
uPA
TF
Fibrinogen
FXa
CP
Thrombin
TUMOUR CELL
VEGF
Adhesion
Fibrin
Mitogen
TNF
IL-1
↑TF ↑PAI
Monocyte
↑TF
Adhesion
Mitogen
Platelet
Plt
↑TF
TC
IL- 8
↑TF
↓ TM
Endothelial cell
Rickles, F. Thrombosis Research 2001
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
Highest Incidence first 3 months
Odds Ratio
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
Hormonal therapy
Anti-angiogenesis drugs
RR 2 - 6x
RR 1.6x
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%)
 ↑ C-reactive protein
RR 2.6
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%
152
Blom J. J Thromb Haemost 2006; 4:529-535
Frequency, Risk Factors and Trends
for VTE in Cancer Pts in Hospital
Sites with Highest Risk
Pancreas
Kidney
Ovary
Lung
Stomach
Brain
VTE % Odds Ratio
8.1%
2.46
5.6%
1.71
5.6%
1.57
5.1%
1.31
4.9%
4.7%
1.74
Myeloma
Non Hodg Lymphoma
Hodg Lymphoma
5.0%
4.8%
4.6%
p
<.0001
Khorana et al Cancer 2007;110:2339-46
Cancer and VTE - Metastatic Disease
Metastatic Disease increases VTE risk 4-13X
Pancreas
Stomach
Bladder
Renal
Lung
Incidence of VTE / 100 pt-yr
20.0
10.7
7.9
6.0
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
Hormonal therapy
Anti-angiogenesis agents
 Support Rx- Erythropoiesis agents
6.5x
1.6x
1.3x
1.7x
 Transfusions - RBCs/Platelets
1.6x
 Central Venous Catheters
 Radiation
28%  4% ???
???
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
1
4.5
none
tamoxifen
tamoxifen + CTX
II
0 -1.6
1.3 -10
3.1-9.6
tamoxifen
CTX
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 Chemotherapy
Chemotherapy and VTE
10-20% / yr
Cisplatin
8 - 18%
L-asparaginase
4 - 14%
Fluoruracil
15 - 17%
Thalidomide + Decadron / ChemoRx
20 - 40%
Anti-angiogenesis drugs (Avastin)
Supportive Rx: EPO, G-CSF, Steroids
marginal - 30%?
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
2.5
Khorana 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
1-2 Intermediate
≥ 3 High
27%
60%
13%
0.3 %
2%
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
HR*
Group 1 Low
1
5.8
3.1
11.7
Group 2 Intermed
Group 3 High
Progression
% HR*
Death
% HR*
1
1.2
1
12.1
2.8
5.9
3.6
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
High Risk - lung, lymphoma, gyn, blad. Testic.
2
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
17.7%
9.5
≥3
11.4%
Score ≥ 3  PPV 22.1% NPV 94.9%
Ay C et al Blood 2010; 116:5377
Khorana Model Validation
• Prospective follow up of 819 patients
• Median observation time/follow-up: 656 days
Log-rank test
P<0.001)
Ay et al Blood 2010.
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%
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
Ay Model for Outpatients
• Addition of D-dimer and soluble P-selectin to
Khorana model:
6-mo cumulative VTE rates:
Patients, n Events, %
Ay et al Blood 2010.
Score ≥5
30
35%
Score 4
51
20.3%
Score 3
130
10.3%
Score 2
Score 1
Score 0
218
190
200
3.5%
4.4%
1.0%
Cancer and VTE
Prognosis
VTE, Cancer and Survival
1.00
Probability of Death
DVT/PE and Malignant Disease
94 %
0.80
0.60
Malignant Disease
42%
0.40
DVT/PE Only
29%
Nonmalignant Disease
20%
0.20
0.00
0
20
40
60
80
100 120 140 160 180
Number of Days
Levitan - Medicine 1999;78:285
VTE, Cancer and Survival
Survival, % of patients
100
1- yr survival
80
Cancer at time of VTE 12%
60
Cancer without VTE
40
36%
p< .001
20
0
5
10
15
20
Years after Diagnosis
Sorensen - NEJM 2000;343:1846
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 Thrombosis
CAT
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 Guidelines
Levels of evidence/recommendations
Grade Risk/benefit Methodologic Strength
Implications
1A
Clear
RCTs Ø limitations
Strong recommendations
1B
Clear
RCTs + limitations
Strong recommendations
1 C+
Clear
Ø RCTs - extrapolations Strong recommendations
1C
Clear
Observational studies Intermediate strength
2A
Unclear
RCTs Ø limitations
Intermediate strength
2B
Unclear
RCTs + limitations
Weak recommendations
2 C+
Unclear
Ø RCTs - extrapolations
Weak recommendations
2C
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
The @ristos Project: A Clinical Outcome-Based
Prospective Study of VTE in Cancer Surgery
• 2,373 patients in 31 Italian hospitals
30-day Symptomatic VTE - 2.1%
21
In-hospital prophylaxis: 82%
Post-discharge prophylaxis: 31%
18
15
12
Not confirmed
(n=42)
Confirmed (n=50)
9
6
3
0
T
DV
DVT=0.4
PE
PE=0.9
at h
De
Death=0.8
Agnelli G - Ann Surg 2006. 243:89-95
@ristos: VTE Timing
VTE Event - 40% > 21 days after surgery
12
10
8
No. events 6
4
2
gg
30
s
>
0
da
y
s
26
-3
5
da
y
s
21
-2
15
-2
0
da
y
s
da
y
5
da
ys
10
-1
10
6-
1-
5
da
ys
0
Agnelli G - Ann Surg. 2006 243:89-95
@ristos: 30-day Mortality
General: 2.9%
Overall at 30 days: 1.7%
Urological: 0.6%
VTE–related: 46%
er
Ot
h
ps
is
Se
e
St
ro
k
fai
lur
e
g
Liv
er
Bl
ee
din
og
r
Pr
Di
s.
E
20
18
16
14
12
10
8
6
4
2
0
VT
No. events
Gynecological: 0.2%
Agnelli G - Ann Surg 2006. 243:89-95
@ristos: Risk Factors for VTE in Cancer Surgery
Variable
Effect
OR
95%CI
Age
 60 years
2.6
1.2 - 5.7
Previous VTE
Yes
6.0
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
2.1 - 16.8
Agnelli G - Ann Surg 2006. 243:89-95
ENOXACAN II - Duration of Prophylaxis
after Cancer Surgery
 curative, open surgery for abdo or pelvic cancer
 double-blind RCT in 37 centers, 8 countries
placebo
enoxaparin 40 mg
QD
surgery
R
enoxaparin 40 mg QD
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
surgery
Prophylaxis stopped
R
Dalteparin 5000 U od
Day 7
Day 28
bilat venography
Rasmussen - Cancer Treat Rep 2002; 28:141
Prolonged thromboprophylaxis
after cancer operations
ENOXACAN II
enoxaparin
FAME
dalteparin
20
18
16
14
12
10
8
6
4
2
0
p=0.03
20
12%
4 .8%
20/167
8/165
1 week
4 weeks
Incidence of total VTE (%)
Incidence of total VTE (%)
p=0.02
19.6%
18
16
14
12
8.8%
10
8
6
4
2
21/107
8/91
0
Bergqvist - NEJM 2002;346:975
1 week
4 weeks
Rasmussen - ASH (2003)
Cancer Surgery Patients
Prophylaxis
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- Prophylaxis
Medical Oncology
Ambulatory Patients
VTE and Chemotherapy
Chemotherapy - independent risk for VTE
Pts on Chemotherapy
Cancer pts

VTE
11% /yr
Cancer pts + Chemo
VTE risk
4x
6.5x
Recurrent VTE
2x
4x
Prevention of Thromboembolism in Cancer
Medical 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
No.
159
Warfarin
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)
Cumulative Thromboembolism
in Patients Treated with Warfarin
Patients with
thrombosis (%)
Risk Reduction – 85%
20
warfarin
15
placebo
10
P=0.031
5
0
0
3
6
9
12
15
Time from randomization (months)
Levine - Lancet 1994;343:886
Prevention of Thromboembolism in Cancer
TOPIC studies
Advanced Cancer on ChemoRx
LMWH vs. placebo x 6 months Dopplers q 4 weeks
TOPIC 1- Breast Ca
Placebo LMWH
p
VTE
3.9%
4%
Bleeding
0%
1.7%
VTE
8.3%
4.5%
.07
Stage IV VTE
10.1%
3.5%
.03
2.2%
3.7%
TOPIC 2 - Lung Ca
Overall
Bleeding
Haas et al J Throm Haemos 2005; 3 (suppl) OR 059
Prevention of Thromboembolism in Cancer
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 Cancer
PRODIGE - 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 Cancer
PROTECHT 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 Cancer
PROTECHT 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
Prevention of Thromboembolism in Cancer
PROTECHT study - Results
Study Patients
Treatment duration
TE events
LMWH
Placebo
769 pts
381pts
90.3 days
2.1% (16)
- Lung Ca
94 days
3.9% (15)
4%
8.8%
- GI
1.5%
2.7%
DVT
1.0%
2.1%
PE
0.4%
0.8%
Major Bleed
0.7%
0
Minor Bleed
7.4%
7.9%
Relative Risk Reduction - 47.2% NNT 53.8
p=.033
p=.177
Prevention of Thromboembolism in Cancer
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
Prevention of Thromboembolism in Cancer
CONKO 004 – ASCO 2009
Outcome
VTE
Major Bleed
Observed
Enox 1 mg/kg
152 pts
160 pts
14.5%
5.0%
9.9%
6.3%
RRR
65%
No difference in Time to Progression or Overall Survival
Reiss et al JCO 2009; 27 LBA 4506
Prevention of Thromboembolism in Cancer
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
Prevention of Thromboembolism in Cancer
FRAGEM study
Outcome
Gem
Gem+Fragmin
RR
64 pts
59 pts
31%
12%
.38
Study Period VTE 25%
3.5%
.14 p=.002
0%
.08 p=.028
Overall VTE
Death (VTE)
9%
p= .02
Maraveyas A. Eur J of Cancer Suppl 2009;7:362
Prevention of Thromboembolism in Cancer
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- Prophylaxis
Medical 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 VTE
Mechanisms 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
alone
Relapsed/refractory
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
Doxorubicin regimen
RR 2.5
RR 4.3
Int Myeloma Working group. Leukemia 2008;22:414
Thalidomide and Risks of VTE
Lenalidomide
Newly dx Relapsed/refractory
Alone
0-33%
+ Dexamethasone
8-75%
8-16%
+ Cyclophophamide
+ Bortezomib
RR 3.5
14%
0%
Thalidomide + ChemoRx in other Cancers
Prostate:
Thal + docetaxel
20%
Renal Cell:
Thal + Gemcitibine + 5-Fu
43%
Melanoma /Brain mets: Thal + Temozolamide
25%
Int Myeloma Working group. Leukemia 2008;22:414
Thalidomide and Risks of VTE
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
0 or 1 risk factor
No prophylaxis/ASA ??
 Thalidomide 2+ risk factors
***newly diagosed
Prophylactic LMWH
Warfarin INR 2-3
 Thalidomide + Hi dose Dex
+ Doxorubicin
+ Multiagents
Prophylactic LMWH
Warfarin INR 2-3
*** No methodologically sound studies
Int Myeloma Working group. Leukemia 2008;22:414
ASCO 2008 Guidelines – VTE in Cancer
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)
Lyman G et al. J Clin Oncol 2007; 25(34): 5490-5505
ACCP 2008 Guidelines - VTE in Cancer
Prophylaxis
Medical Oncology pts
Ambulatory pts on Chemo/hormonal Rx
No routine primary prophylaxis Grade 1C
Cancer and VTE- Prophylaxis
Medical Oncology
Cancer Patients in Hospital
VTE Prophylaxis - Cancer Pts in Hospital
Study
MEDENOX
Pts Ca Pts Placebo
579
12.4%
PREVENT 3706
5.1%
ARTEMIS
849
15.4%
Rx
RR
p
VTE%
VTE%
14.9
5.5
.37
<.001
2.77
.55
.0015
.47
.029
4.96
10.5
5.6
Lyman G et al. J Clin Oncol 2007; 25(34): 5490-5505
ASCO 2008 Guidelines – VTE in Cancer
Prophylaxis:
Hospitalized Pts:
- Prophylactic doses - UFH / LMWH / Fondaparinux
if no bleeding concerns
Lyman G et al. J Clin Oncol 2007; 25(34): 5490-5505
ACCP 2008 Guidelines - VTE in Cancer
Medical Oncology pts
Bedridden with acute medical illness:
Prophylactic doses – UFH / LMWH / Fondaparinux
Grade 1A
Cancer and VTE
Central Venous Catheters & VTE
Incidence of CVC-Related DVT
• 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
 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 - DVT
Risk 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
Study
Bern, 1990
Endpoint
venogram D90
sympt DVT
No. control warf control warf
82
38 % * 10 %
Couban, 2002 sympt. DVT
255
NR
NR
Heaton, 2002
88
NR
NR
sympt. thromb
25 % 10 %
4%
5%
12 % 18 %
Preventing Central Venous Catheter
Thrombosis in Cancer (RCTs)
LMWH
DVT
Study
Monreal, 1996
Endpoint
No. control
venogram Day 90 29
Reichardt, 2002 clinical
425
LMWH
P
62 % * 6 %
0.002
3.4 %
0.9
3.7 %
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
ACCP 2008 Guidelines - VTE in Cancer
Prophylaxis: Medical Oncology pts
 Bedridden with acute medical illness
Prophylaxis - LDUH, LMWH, Fondaparinux Gr 1A
 Ambulatory receiving Chemo/hormonal therapy
No routine prophylaxis Gr 1C
 Central Venous Catheters
No prophylaxis with LMWH or Warfarin Gr 1B
Cancer and VTE
Treatment of VTE
Challenges of Treatment of
Cancer-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)
Cumulative Proportion (%)
Recurrent Thromboembolism
Recurrent VTE on
Oral Anticoagulant Therapy
30
Hazard ratio 3.2
Cancer (21%)
20
10
No Cancer (7%)
0
0
181
661
1
160
631
2
3
129
602
4
5
6
92
161
7
8
9
73
120
10
11
12 Time (months)
64 Cancer
115 No Cancer
Prandoni - Blood 2002;100:3484
Major Bleeding During
Anticoagulant Therapy of VTE
Cumulative Proportion (%)
Major Bleeding
30
Hazard ratio 2.2
20
Cancer (12%)
10
No Cancer (5%)
0
0
1
181 170
661 636
2
3
141
615
4
5
6
102
170
7
8
9
81
127
10
11
12 Time (months)
68 Cancer
124 No Cancer
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
Initial
treatment
Active cancer
with DVT/PE
Long-term
treatment
dalteparin
200 U/kg QD
oral anticoagulant
INR 2-3
dalteparin
200 U/kg QD
dalteparin
200 U/kg QD
x 1 mo
then 150 U/kg QD
x 5 mos
R
Lee - NEJM 2003;349:146
CLOT in Cancer Study:
Events
LMWH
N=336
OAC
N=336
P-value*
Recurrent
VTE
9%
17%
0.002
Major bleed
6%
4%
0.27
Lee - NEJM 2003;349:146
Probability of Recurrent VTE, %
Clot in Cancer: Recurrent VTE
25
risk reduction = 52%
P-value = 0.002
20
OAC
15
10
dalteparin
5
0
0
Lee - NEJM 2003;349:146
30
60
90
120
150
180
Days Post Randomization
210
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
Canthenox - 20021 stopped - poor accrual
Study pts
Warfarin
LMWH
75 pts
71 pts
Recurrent VTE
4%
3%
NS
Major Bleed
16%
7%
p=.09
1. Enoxaparin x 3 months
Meyer – Arch Intern Med 2002;162:1729
LMWH for VTE in Cancer Patients
Warfarin
LMWH RR
p
CLOT - 20032
Recurrent VTE
Major bleed
17%
4%
9%
6%
52% <.002
16%
7%
7%
7%
44%
LITE - 20063
Recurrent VTE
Major Bleed
2. Dalteparin x 6 months
3. Tinzaparin x 3 months
.044
Lee – NEJM 2003;349:146
Hull – Am J Med 2006;1062
LMWH for VTE in Cancer Patients
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 VTE
Dose 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
Carrier M , Lee A. J Thromb Haemost 2009; 7: 760-5
Cancer and Recurrent VTE
Dose 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
Carrier M , Lee A. J Thromb Haemost 2009; 7: 760-5
Cancer and Recurrent VTE
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
Carrier M , Lee A. J Thromb Haemost 2009; 7: 760-5
Cancer and Recurrent VTE
Dose 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
Cancer and Recurrent VTE
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 VTE
Selected references
 Lyman, Khorana et al. JCO 2009; 29: 48214918 (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
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