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
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
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
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
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
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
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
Agnelli G - Ann Surg 2006. 243:89-95
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
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
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
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 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
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 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
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
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
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- 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
Thalidomide and Risks of VTE
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%
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 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
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 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
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
• 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
ACCP 2008 Guidelines - VTE in Cancer
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
LMWH for VTE in Cancer Patients
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%
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 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
Carrier M , Lee A. J Thromb Haemost 2009; 7: 760-5
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
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 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
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 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
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