Transcript Slide 1

Oncology Grand Rounds
University of North Carolina
Lineberger Comprehensive Cancer Center
April 21, 2009
An Oncologists Perspective on
Cancer and Thrombosis
Gary H. Lyman, MD, MPH, FRCP(Edin)
Professor of Medicine and Director
Health Services, Effectiveness and Outcomes Research
Duke University School of Medicine and the
Duke Comprehensive Cancer Center
Cancer and Venous Thromboembolism (VTE)
Armand Trousseau
•
Association recognized since
Trousseau’s observation more than
130 years ago1
•
Of all cases of VTE, approximately
20% occur in cancer patients.2
•
VTE affects 4-20% of cancer patients
antemortem but has been reported in
up to 50% on postmortem
examination.3-4
•
Cancer-associated VTE has
important clinical and economic
consequences5-7
Patients with
cancer: 20%
All deep venous
thrombosis and
pulmonary embolism
1. Trousseau, Armand. In Clinique Medicale de l'Hôtel-Dieu de
Paris, 2nd ed. Paris: J.B. Bailliere et Fils; 1865
2. Lee AY. Br J. Haematol. 2005;128:291-302.
3. Gao S et al: Expert Rev Anticncer Ther 2004; 4: 303-320.
4. Lyman GH et al: J Clin Oncol 2007; 25: 5490-5505.
5. Sorensen HT, et al. N Engl J Med. 2000;343:1846-1850.
6. Prandoni P, et al. Blood. 2002;100:3484-3488.
7. Khorana AA, et al. J Clin Oncol. 2006;24:484-490.
Pathogenesis: Virchow’s Triad
Stasis
Blood Components
[Hypercoagulability]
Vessel Damage
Bed rest and immobility,
extrinsic compression of
vessel by mass
Tumors and macrophages
produce procoagulants,
inflammatory cytokines
Direct tumor invasion,
indwelling catheters,
chemotherapy, erythropoietin,
antiangiogenic agents
Growth
Invasion
Metastases
Angiogenesis
Hemostatic
System
Tumor
Cells
Procoagulant Activity
Cytokines
Growth Factors
Fibrinolytic Activity
Kuderer NM et al J Clin Oncol 2009 (in press)
Risk of VTE Varies Over Natural History of Cancer
8
Risk (Odds Ratio)
7
Hospitalization
Chemotherapy
6
5
End of life
Metastasis
Diagnosis
4
Risk of VTE in the cancer population
3
2
1
Remission
Risk of VTE in the general population
0
Time
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.
VTE within Two years of Cancer Diagnosis
Metastatic Disease
Local-Regional Disease
• The California Cancer Registry linked to the California Discharge Data, 1993 - 1995.
• Among 235,149 cancer cases, 3775 (1.6%) were diagnosed with VTE within 2 years
including 463 (12%) at the time cancer and 3312 (88%) subsequently.
Chew, H. K. et al. Arch Intern Med 2006;166:458-464.
Incidence of VTE in US Patients
With and Without Cancer, 1979-1999
National Hospital Discharge Survey
VTE Incidence (%)
4
Cancer
3
No cancer
2
1
0
1979
1981
1983
1985
1987
1989
Years
Stein PD, et al. Am J Med. 2006;119:60-68.
1991
1993
1995
1997
1999
Risk Factors for VTE in Patients with Cancer
Patient-related factors
• Older age
• Gender
• Race (higher in African
Americans, lower in Asians)
• Patient comorbidities
• History of VTE
Cancer-related factors
• Site of cancer
• Advanced stage
• Initial period after diagnosis
Treatment-related factors
•
•
•
•
•
•
Major surgery
Hospitalization
Chemotherapy
Hormonal therapy
Antiangiogenic agents
ESAs, ?Transfusions
Biomarkers
•
•
•
•
Platelet and leukocyte counts
Tissue factor
P-selectin
D-dimer
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.
Risk Factors for VTE in Patients with Cancer
Patient-related factors
• Older age
• Gender
• Race (higher in African
Americans, lower in Asians)
• Patient comorbidities
• History of VTE
Cancer-related factors
• Site of cancer
• Advanced stage
• Initial period after diagnosis
Treatment-related factors
•
•
•
•
•
•
Major surgery
Hospitalization
Chemotherapy
Hormonal therapy
Antiangiogenic agents
ESAs, ?Transfusions
Biomarkers
•
•
•
•
Platelet and leukocyte counts
Tissue factor
P-selectin
D-dimer
Important Consequences of VTE in Cancer Patients
• Increased morbidity
– Hospitalization
– Anticoagulation
– Postphlebitic syndrome
• Increased mortality
• Increased risk of recurrent VTE
• Bleeding complications
• Cancer treatment delays
• Increased healthcare costs
Important Consequences of VTE in Cancer Patients
• Increased morbidity
– Hospitalization
– Anticoagulation
– Postphlebitic syndrome
• Increased mortality
• Increased risk of recurrent VTE
• Bleeding complications
• Cancer treatment delays
• Increased healthcare costs
Effect of VTE on Risk of Death
Stratified by Stage, Adjusted for Age and Race
• CA Cancer Registry linked
to Discharge Data
• Overall Mortality
– HR=3.7 [1.3-14.4]
• Multivariate analysis
– Stratified by stage
– Adjusted for age, race
– VTE is a significant predictor
for 1 year mortality for each
cancer type
Chew, H. K. et al. Arch Intern Med 2006;166:458-464.
VTE in Diffuse Large B-cell Lymphoma
 Retrospective review of patients
with DLBCL treated 1990-2001
 Symptomatic VTE at diagnosis or
during initial treatment.
– 27/211 patients (12.8%).
 Median survival (years)
– Controls: 5.20 [1.80 – 8.60]
– VTE: 1.04 [0.75 – 1.33]
– P = 0.038
 Multivariate Analysis for Mortality*
Variable
HR
P-value
Age
1.02
.014
IPI
1.45
.015
VTE
1.92
.025
* Adjusted for sex, race, and stage
Komorokji RS et al. Leuk Lymph 2006; 47: 1029-1033
Unsuspected PE On Routine Cancer Staging
Impact on Survival
 Retrospective review of 70
patients with unsuspected PE
found on staging CT
– 2003–2006
– VTE, anticoagulation or
multiple cancers excluded
 2:1 matching based on
– Cancer type
– Age
– Stage
 Unsuspected PE:
– Subsegmental: 24.3%
– Proximal: 75.7%
O’Connell CL et al: ASH 2008
HR=1.79 [95% CI: 1.10-2.90; P=0.018]
Unsuspected VTE in Cancer Patients
Results from Autopsy Series
Roswell Park Cancer Institute
 Consecutive autopsies in 506
cancer patients
 Causes of Death, n (%)
– Major
–
–
–
–
Infection 184 (36%)
Hemorrhage 55 (11%)
VTE 35 (7%)
MI 35 (7%)
– Contributing
–
–
–
–
Infection 68 (13%)
Hemorrhage (25%)
VTE 91 (18%)
MI 13 (3%)
Ambrus J et al J Med 1975; 6: 61-64
University of Missouri
 578 consecutive autopsies
 145 cancer patients, n (%)
– PE 24 (17%)
– Fatal PE 20 (14%)
 433 noncancer patients
– PE 55 (13%)
– Fatal PE 343 (8%)
P<.05
 Author’s conclusions:
– 1 in 7 hospitalized cancer pts
died of PE
– 60% of fatal PEs occur in early
or limited metastatic disease
Shen VS et al. South Med J 1980; 73: 841-843
Causes of Early Death in Ambulatory Cancer Patients
Results from Prospective Study of Series
 Patient Population
– Prospective study of 4466 patients starting new chemotherapy
– Consecutive patients accrued at 117 US practices
– Median followup of 75 days, 141 (3.2%) died.
 Causes of Death, n (%)
– All 141 (100)
– Progression of cancer 100 (70.9)
– Thromboembolism 13 (9.2)
–
–
–
–
–
–
–
Breast Cancer
40%
Colon Cancer
14%
Small Cell Lung
5%
Arterial 8 (5.6)
Venous 5 (3.5)
Infection 15 (10.6)
Respiratory failure 5 (3.5)
Bleeding 2 (1.4)
Other 9 (6.4)
Unknown 5 (3.5)
Non-small Cell
Lung
18%
Ovarian
8%
Non-Hodgkin's
Lymphoma
13%
Hodgkin's
Lymphoma
2%
Distribution of Cancer Type
Khorana AA et al. J Thromb Haemost 2007; 5: 632-634
Recommendations for Venous
Thromboembolism Prophylaxis and
Treatment in Patients with Cancer
ASCO Clinical Practice Guideline
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Clinical Questions
1. Should patients with cancer receive anticoagulation for
VTE prophylaxis while hospitalized? √
2. Should ambulatory patients with cancer receive
anticoagulation for VTE prophylaxis during systemic
chemotherapy? √
3. Should patients with cancer undergoing surgery
receive perioperative VTE prophylaxis?
4. What is the best method for treatment of patients with
cancer with established VTE to prevent recurrence? √
5. Should patients with cancer receive anticoagulants in
the absence of established VTE to improve survival? √
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Hospitalized Cancer Patients
• Hospitalized patients with cancer should be
considered candidates for VTE prophylaxis in the
absence of bleeding or other contraindications to
anticoagulation.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Risk of Inpatient VTE
By Site of Cancer – Solid Tumor
Discharge database of the University HealthSystem Consortium
• 115 U.S. academic medical centers
• 66,106 adult neutropenic cancer patients hospitalized 1995 - 2002
Rate (%)
12
10
8
6
4
2
0
Khorana et al, J Clin Oncol 2006; 24: 484-490
Risk of Inpatient VTE
by Type of Cancer – Hematologic Malignancies
Percent (%)
7
6
5
4
3
2
1
0
All
Leukemia
NHL
Hodgkin
Account for one-third of all VTE
NHL=Non-Hodgkin’s lymphoma
Khorana AA, et al. J Clin Oncol. 2006;24:484-490.
Myeloma
Discharge database of the University HealthSystem Consortium
• 133 U.S. academic medical centers
• 1,015,598 adult cancer patients hospitalized 1995 - 2003
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
VTE: 34,357 (3.4%)
PE: 11,515 (1.1%)
20
P<0.0001
Inpatient Mortality (%)
Rate of VTE (%)
VTE Inpatient Risk and Mortality
1995 1996 1997 1998 1999 2000 2001 2002 2003
VTE- patients on chemo
VTE-all patients
DVT-all patients
PE-all patients
Khorana AA et al. Cancer 2007; 110: 2339-2346
18
16
14
12
10
8
6
4
2
0
P<0.0001
1995 1996 1997 1998 1999 2000 2001 2002 2003
VTE
No VTE
Anticoagulant Prophylaxis to Prevent Screen-Detected VTE
High Risk Hospitalized Medical Patients
• 3 large, randomized, placebo-controlled, double-blind
trials in medical patients at high risk including cancer
– MEDENOX (enoxaparin)1 ~ 15%
– PREVENT (dalteparin)2 ~5%
– ARTEMIS (fondaparinux)3 ~15%
• Screening for asymptomatic DVT with venography
or ultrasound
1. Samama MM, et al. N Engl J Med. 1999;341:793-800.
2. Leizorovicz A, et al. Circulation. 2004;110:874-879.
3. Cohen AT, et al. BMJ. 2006;332:325-329.
Anticoagulant Prophylaxis to Prevent Screen-Detected VTE
High Risk Hospitalized Medical Patients: VTE
Study
RRRRRR
MEDENOX1
P < 0.001
63%
PREVENT2
P = 0.0015
45%
Placebo
47%
Enoxaparin 40 mg
5.5
Placebo
5.0
Dalteparin 5,000
units
Fondaparinux 2.5 mg
MM, et al. N Engl J Med. 1999;341:793-800.
Leizorovicz A, et al. Circulation. 2004;110:874-9.
3Cohen AT, et al. BMJ 2006; 332: 325-329.
2
14.9
2.8
10.5
Placebo
ARTEMIS3
1Samama
Thromboprophylaxis Patients with VTE (%)
5.6
Incidence of Major Bleeding (%)
Anticoagulant Prophylaxis to Prevent Screen-Detected VTE
High Risk Hospitalized Medical Patients: Major Bleeding
1.8
1.7%
1.6
1.4
1.2
1.1%
1.0
LMWH
0.8
Placebo
0.49%
0.6
0.4
0.16%
0.2%
0.2
0.0
Medenox
Prevent
Study
Samama MM, et al. N Engl J Med. 1999;341:793-800.
Leizorovicz A, et al. Circulation. 2004;110:874-9.
Cohen AT, et al. BMJ 2006; 332: 325-329..
Artemis
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Ambulatory Cancer Patients
1. Routine prophylaxis with an antithrombotic agent is not
recommended.
2. Patients receiving thalidomide or lenalidomide with
chemotherapy or dexamethasone are at high risk for
thrombosis and warrant prophylaxis. LMWH or adjusted
dose warfarin (INR~1.5) is recommended.
• This recommendation is based on extrapolation from studies
of post-operative prophylaxis in orthopedic surgery and a trial
of adjusted dose warfarin in patients with breast cancer.
3. Randomized clinical trials evaluating antithrombotic agents in pts
with myeloma on thalidomide or lenalidomide are needed.
4. Research is also urgently needed to identify better markers in
ambulatory patients with cancer likely to develop VTE.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Prospective Study of Adult Cancer Patients
Receiving Systemic Chemotherapy
• Prospective observational study
conducted at 117 randomly selected
US practice sites.
Proportion with VTE
• Data obtained on 4,458
consecutive adult patients
initiating a new chemotherapy
regimen between March 2003
and February 2006.
• There were no exclusions for
age, prior history or comorbidities with nearly 40% of
patients age 65 and older.
.04
.03
.02
.01
0.00
Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008).
0
10
20
30
40
50
60
70
80
90
Time (Days)
100 110 120 130 140 150
Reported Cause of Early Mortality
Cancer Patients Starting New Chemotherapy
1.00
[HR=5.48, 95%CI: 2.21-13.61; P<.0001]
Cause of
Death
No VTE
N=4,365
VTE
N=93
All
N=4,458
PD
2.1
2.2
2.1
Infection
0.3
0
0.3
0
5.4
0.1
Pulmonary
0.2
0
0.2
Bleeding
0.1
0
0.1
Other
vascular
0.2
0
0.2
Unknown
0.3
0
0.3
All
3.2
7.6
3.3
.99
.98
.97
.96
PE
.95
.94
No VTE
.93
.92
.91
VTE
.90
0
10
20
30
40
50
60
70
80
90 100 110 120 130 140 150
Time (Days)
Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008)
RCTs of Thromboprophylaxis in Ambulatory Cancer Patients
Warfarin
• Double-blind, placebo-controlled RCT demonstrated the
efficacy of low-intensity warfarin (INR 1.3-1.9) in patients
receiving chemotherapy for metastatic breast cancer
• 311 women with metastatic breast cancer on
1st- or 2nd-line chemotherapy
• Randomized to 1 mg warfarin for 6 weeks, then warfarin
titrated to INR 1.3-1.9 or placebo
• 1 VTE in warfarin group vs 7 in placebo arm
– 85% risk reduction, P = .03, with no increased bleeding
INR=international normalized ratio
Levine M, et al. Lancet. 1994;343:886-889.
RCTs of Thromboprophylaxis in Ambulatory Cancer Patients
Low Molecular Weight Heparin
Trial
N
Treatment
Chemo
Duration
VTE
Major
Bleeding
FAMOUS
385
Dalteparin
Placebo
64%
12 months
2.4%
3.3%
0.5%
0
TOPIC-I
353
Certoparin
Placebo
100%
6 months
4%
4%
1.7%
0
TOPIC-2
547
Certoparin
Placebo
100%
6 months
4.5%†
8.3%
3.7%
2.2%
PRODIGE
186
Dalteparin
Placebo
-
6-12 months
11%
17%
5.1%
1.2%
SIDERAS
141
Dalteparin
Placebo/Control
54%
Indefinitely
5.9%
7.1%
2.9%
7.1%
PROTECHT
1166
Nadroparin
2:1 Placebo
100%
< 4 months
with chemo
1.4%
2.9%
0.7%
0
Solid tumors
(Stage III/IV)
Breast
(Stage IV)
NSCLC
(Stage IV)
Glioma
Solid Tumors
(Stage IV)
Solid Tumors
(Stage III/IV)
1. Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948. 2. Haas SK, et al. J Thromb Haemost. 2005(suppl 1):
abstract OR059. 3. Perry JR et al. Proc ASCO 2007. 2011 4. Sideras K et al. Mayo Clin Proc 2006; 81:758-767. 5. Agnelli
G et al. Am Soc Hemat Sunday December 7, 2008
The PROTECHT Study
RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy
DESIGN
 Placebo-controlled, double blind, multicenter RCT
 Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1
 1150 patients receiving chemotherapy for locally
advanced or metastatic cancer.
 Start with new CTX; continue for maximum of 4 m
 Mean treatment duration: 90 days
 Primary outcome: clinically detected thrombotic events,
i.e., composite of venous and arterial TE*
 Main safety outcome: Major bleeding
* deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous
thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute
peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin
Agnelli G et al: ASH 2009
The PROTECHT Study
RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy
RESULTS
• Primary Efficacy Outcome: Any TE Event*
–
–
–
–
Nadroparin: 16 of 769 (2.1%)
Placebo: 15 of 381 (3.9%)
Relative risk reduction: 47.2%, (interim-adjusted p=0.033)
Absolute risk decrease: 1.8%; NNT = 53.8
• Venous thromboembolism (VTE):
–
–
Nadroparin: 11 of 769 (1.4%)
Placebo: 11 of 381 (2.9%) NS
• Major Bleeding:
–
–
–
Nadroparin: 5 (0.7%)
Placebo: 0 (p= 0.177)
Absolute risk increase: 0.7%; NNH = 153.8
Agnelli G et al: ASH 2009
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Relative contraindications for anticoagulation
•
•
•
•
•
•
•
•
•
Active, uncontrollable bleeding
Active cerebrovascular hemorrhage
Dissecting or cerebral aneurysm
Bacterial endocarditis
Pericarditis, active peptic or other GI ulceration
Severe, uncontrolled or malignant hypertension
Severe head trauma
Pregnancy (warfarin)
Heparin-induced thrombocytopenia (heparin,
LMWH)
• Epidural catheter placement
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Risk of VTE in Cancer Patients Receiving Thalidomide
Meta-analysis of RCTs [Estimates ± 95% CI]
• Search identified 17 RCTs including 3,977 patients
• Incidence of VTE
– All Studies: 11.7% [8.1% - 16.5%]
• Multiple Myeloma: 17.7% [10.9% - 22.1%]
• Solid Tumors: 5.3% [2.1% - 12.8%]
• Relative Risk for VTE
– All Studies: 2.4 [1.9 – 3.0], P<.001
• Multiple Myeloma: 3.1 [2.1 – 4.4], P<.001
• Solid Tumors: 3.5 [1.1 – 10.6], P=.028
– Prophylaxis (all studies)
• No prophylaxis: 3.5 [2.5 – 4.9], P<.001
• Prophylaxis: 1.9 [1.4 – 2.5], P<.001
Gray KN et al: ASH 2008
Thromboembolism With Bevacizumab
Arterial Thromboembolism
Pooled analysis of 5 clinical trials of bevacizumab in metastatic
colorectal, breast, or non-small cell lung cancer (N=1,745)
Chemotherapy* plus bevacizumab (n=963)
Chemotherapy* alone (n=782)
12
ATE/VTE Rate (%)
10
8
6
HR=2.0 (95% CI, 1.05-3.75)
P=.031
4
2
0
Arterial thromboembolism
(ATE)
VTE
Thromboembolism With Bevacizumab
Venous Thromboembolism: Meta-Analysis of RCTs
Relative Risk = 1.33 [95% CI: 1.13 – 1.56]
Absolute Risk Increase: 2.2% [95% CI: 1.1% - 3.3%]
Nalluri, S. R. et al. JAMA 2008;300:2277-2285.
Thromboembolic Complications in Cancer Patients Receiving ESAs
Hb Stopping
Value
ESA
Cont
RR
95% CI
< 12 g/dL
50
50
(0)
>12 - <13 g/dL
148
141
0.70
0.29, 1.67
>13 - <14 g/dL
1,596
1,290
1.71
1.23, 2.40
>14 - <15 g/dL
1,151
914
1.92
1.22, 3.02
>15 - <16 g/dL
368
303
1.66
1.08, 2.54
(Unclear)
42
39
5.59
0.71, 43.94
Comparative Effectiveness Review # 3
Comparative Effectiveness of Epoetin and Darbepoetin for
Managing Anemia in Patients Undergoing Cancer Treatment
RR TE = 1.67 [1.35 – 2.06]
Bohlius, J. et al. JNCI 2006 98:708-714
Predictors of Venous Thromboembolism
Multivariate Logistic Regression Analysis
 Retrospective cohort study
of cancer pts at 60 US
hospitals: 1995 – 2003.
 Patients: N = 504,208
 RBC trans: 70,542 (14%)
 Platelet trans: 15,237 (3%)
 RBC transfusions
 VTE: 7.2%
 ATE: 5.2%
 Mortality
1.34 [95% CI:1.29-1.38]
Khorana, A. A. et al. Arch Intern Med 2008;168:2377-2381.
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Preventing Recurrence in Cancer Patients with Established VTE
1. LMWH is the preferred approach for the initial 5 to 10 days
of anticoagulant treatment of the patient with cancer with
established VTE.
2. LMWH given for at least 6 months is also the preferred
approach for long-term anticoagulant therapy. Vitamin K
antagonists with a targeted INR of 2-3 are acceptable for
long-term therapy when LMWH is not available.
3. After 6 months, indefinite anticoagulant therapy should be
considered for patients with active cancer.
4. The insertion of a vena cava filter is only indicated for
patients with contraindications to anticoagulant therapy
and in those with recurrent VTE despite adequate longterm therapy with LMWH.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Recurrent VTE and bleeding during anticoagulant treatment
Patients with cancer and venous thrombosis
30
30
Cancer 21%
20
10
No Cancer 7%
Hazard ratio 2.2 [1.2-4.1]
Major Bleeding, %
Recurrent VTE, %
Hazard ratio 3.2 [1.9-5.4]
20
Cancer 12%
10
No Cancer 5%
0
0
0 1 2 3 4 5 6 7 8 9 101112
Time (months)
Prandoni P et al. Blood 2002; 100: 3484-3488.
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
RCTs of Long-term Treatment in Cancer Patients with VTE:
RCTs of LMWH vs. Vitamin K Antagonists in Cancer
Recurrent
VTE, %
Major
Bleed, %
Death,
%
Study
No.
Long-Term Treatment
Meyer1
2002
71
Warfarin
21.1*
22.7
67
Enoxaparin 1.5 mg/kg
10.5*
11.3
Lee2
2003
336
Warfarin
17*
4
41
336
Dalteparin 200/150 IU/kg
9*
6
39
30
Warfarin
10
2.9
8.8
29
Enoxaparin 1.0 mg/kg
6.9
6.5
6.5
32
Enoxaparin 1.5 mg/kg
6.3
11.1
19.4
100
Warfarin
10*
7
19
100
Tinzaparin 175 IU/kg
6*
7
20
Deitcher3
2006
Hull4
2006
* P < .05
1. Meyer G, et al. Arch Intern Med. 2002;162:1729-1735. 2. Lee AY, et al. N Engl J Med. 2003;349:146-153.
3. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12:389-396. 4. Hull RD, et al. Am J Med.
2006;119:1062-1072.
The CLOT Trial
Study Schema
Control Group
Dalteparin 200
IU/kg OD
Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo
Experimental Group
Dalteparin 200 IU/kg OD x 1 mo
5 to 7 days
then ~150 IU/kg OD x 5 mo
1 month
Lee AY, et al. N Engl J Med. 2003;349:146-153.
6 months
CLOT Trial:
Results: Symptomatic Recurrent VTE
risk reduction = 52%
HR 0.48 (95% CI 0.30, 0.77)
log-rank p = 0.002
Probability of Recurrent VTE, %
25
20
VKA, 17%
15
10
dalteparin, 9%
5
0
0
30
60
90
120
150
Days Post Randomization
Lee AY, et al. N Engl J Med. 2003;349:146-153.
180
210
CLOT Trial:
Results: Bleeding
Dalteparin
VKA
N=338
N=335
19 (5.6%)
12 (3.6%)
associated with death
1
0
critical site*
4
3
14
9
Major bleed
pvalue
0.27
transfusion of > 2 units of RBC
or drop in Hb > 20 g/L
Any bleed
46 (13.6%) 62 (18.5%)
*intracranial, intraspinal, pericardial, retroperitoneal, intra-ocular, intraarticular
Lee AY, et al. N Engl J Med. 2003;349:146-153.
0.09
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Improving survival in absence of established VTE
1. Anticoagulants are not recommended to
improve survival in patients with cancer without
VTE.
2. People with cancer should be encouraged to
participate in clinical trials designed to evaluate
anticoagulant therapy as an adjunct to
standard anticancer therapies.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
Systematic Review of Anticoagulants as Cancer Treatment:
Impact on Survival
1-Year Overall Mortality by Type of Anticoagulation
Treatment
Cancer
Citation
SCLC
Altinbas
Mixed
Rate 1 Rate 2 0.5
2
1
RR
[95% CI]
.696
.476 1.018
.054
P Value
.487
.700
Kakkar
.542
.592
.915
.766 1.093
.327
Mixed
Klerk
.608
.727
.836
.711
.983
.028
Mixed
Sideras
.603
.600
1.005
.766 1.319
.972
.88
.79
.015
.862
.724 1.026
.093
.86
.72 1.03
.095
LMWH
SCLC
Lebeau
.601
.698
UFH
.98
SCLC
Chahinian
.728
.802
.908
.775 1.063
.233
Breast
Levine
.382
.403
.948
.719 1.251
.705
SCLC
Maurer
.242
.278
.869
.608 1.240
.438
NSCLC
Zacharski (1)
.802
.796
1.008
.875 1.161
.915
SCLC
Zacharski (2)
.600
.840
.714
.497 1.027
.059
CRC
Zacharski (3)
.588
.529
1.111
.727 1.697
.625
Prostate
Zacharski (4)
.357
.300
1.190
.366 3.871
.770
HN
Zacharski (5)
.850
.667
1.275
.895 1.817
.172
NSCLC (early) Zacharski (6)
.143
.300
.476
.137 1.651
.224
Warfarin
.94
.85 1.04
.239
Combined
.91
.85
.003
Anticoagulation
Kuderer NM, et al. Cancer. 2007;110:1149-1161
.97
Control
SCLC=small cell lung cancer; NSCLC=non-small cell lung cancer;
HN=head and neck; CRC=colorectal cancer
Systematic Review of Anticoagulants as Cancer Treatment:
Impact on Survival
Major Bleeding Complications by Type of Anticoagulation
Treatment
Rate 1 Rate 2
0.1 0.2
0.5
1
2
5
10
Study
SCLC
Altinbas
.000
.000
1.025
.021
50.418
.990
NSCLC
Haas (2)
.037
.023
1.642
.605
4.453
.325
Mixed
Sideras
.029
.071
.412
.083
2.051
.261
Mixed
Klerk
.034
.006
5.203
.615
44.006
.089
Mixed
Kakkar
.005
.000
2.906
.119
70.874
.492
Breast
Haas (1)
.017
.000
7.120
.370 136.830
.127
1.68
.86
3.27
.128
1.007
.064
15.943
.996
1.01
.06
15.94
.996
LMWH
SCLC
Lebeau
.007
.007
UFH
RR
[95% CI]
P Value
Cancer
SCLC
Zacharski (2)
.400
.080
5.000
1.217
20.549
.008
SCLC
Maurer
.067
.018
3.798
1.091
13.223
.023
SCLC
Chahinian
.068
.000
12.548
.727
216.606
.023
Prostate
Zacharski (4)
.571
.200
2.857
.763
10.695
.069
NSCLC (early)
Zacharski (6)
.524
.250
2.095
.885
4.960
.072
NSCLC
Zacharski (1)
.323
.071
4.521
2.092
9.768
.000
HN
Zacharski (5)
.500
.381
1.312
.652
2.642
.443
CRC
Zacharski (3)
.618
.206
3.000
1.473
6.109
.001
Breast
Levine
.007
.013
.523
.048
5.709
.588
4.16
<.001
3.49
<.001
Warfarin
2.98
Combined
2.59 1.94
Control
Kuderer NM, et al. Cancer. 2007;110:1149-1161
Anticoagulation
2.13
Systematic Review of Anticoagulants as Cancer Treatment:
Impact on Survival
Findings
• Anticoagulation significantly decreased 1-year overall mortality
with a relative risk of 0.905 [95% CI, 0.847-0.967]; P=.003
Conclusions
• Anticoagulants, particularly LMWH, significantly improved
overall survival in cancer patients without VTE while increasing
the risk for bleeding complications
• Improved survival with anticoagulation may be dependent on
tumor type
• However: given the limitations of available data, the use of
anticoagulants as antineoplastic therapy cannot be
recommended until additional RCTs confirm these results
Kuderer NM, et al. Cancer. 2007;110:1149-1161.
Ongoing Randomized Clinical Trials Testing the Effect of LMWH on
Survival in Cancer Patients
Principal
Investigator
Study
LMWH
Tumor Type(s)
INPACT
Nadroparin
Advanced prostate,
non-small cell lung, pancreatic
H. Buller
FOCUS
Dalteparin
Ovarian
A. Lee
FRAGMATIC
Dalteparin
Lung
S. Noble
ABEL
Bemiparin
Small cell lung
R. Lecumberri
TILT
Tinzaparin
Non-small cell lung (I, II, III-A)
G. Meyer &
P. Girard
GASTRANOX
Enoxaparin
Gastric (III/IV)
A. K. Kakkar
INPACT=Improving with Nadroparin the Prognosis in Advanced Cancer Treatment;
FOCUS=Fragmin® in Ovarian Cancer: Utility on Survival; FRAGMATIC=Fragmin® Added to Standard
Therapy in Patients with Lung Cancer; ABEL=Adjuvant Bemiparin in Small Cell Lung Carcinoma;
TILT=Tinzaparin in Lung Tumors.
Courtesy Dr Anna Falanga
Clinical Risk Model for Chemotherapy-associated VTE
Patient Characteristics
Characteristic
Development Cohort
N (%)
Validation Cohort
N (%)
P value
2,701 (100)
1,365 (100)
─
60 (2.2)
28 (2.1)
.72
1,083 (40.1)
2,473 (91.6)
332 (12.3)
515 (37.7)
1,242 (91)
166 (12.2)
.14
.54
.9
Stage IV
Platelet count
≥350,000/mm3
997 (36.9)
604 (22.4)
477 (34.9)
295 (21.6)
.06
.59
ESA
Recent surgery
764 (28.3)
829 (30.7)
358 (26.2)
473 (34.7)
.17
.01
All
All VTE
Age >65 yr
PS 0-1
BMI >35
PS=performance status; BMI=body mass index; ESA=erythropoiesis-stimulating agents.
Khorana AA et al. Blood. 2008; 111:4902-4907
Clinical Risk Model for Chemotherapy-associated VTE
Predictors of VTE: Multivariate Analysis
β
OR*
P-value
1.46
.43
4.3
1.5
.05
Platelet count >350,000/mm3
.6
1.8
.03
Hemoglobin <10 g/dL or use of ESA
.89
2.4
.001
Leukocyte count >11,000/mm3
.77
2.1
.008
BMI >35
.9
2.5
.01
Characteristic
Site of cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic,
genitourinary excluding prostate)
*Odds ratio adjusted for stage
Khorana AA et al. Blood. 2008; 111:4902-4907
Clinical Risk Model for Chemotherapy-associated VTE
Risk Score Based on Pretreatment Risk Factors
Risk Factors
Risk
score
1. Site of cancer
a) Very high risk cancer (stomach, pancreas)
2
b) High risk (lung, lymphoma, gynecologic, bladder, testicular)
1
2. Platelet count >350,000/mm3
1
3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors
1
4. Leukocyte count >11,000 /mm3
1
5. BMI > 35 kg/m2
1
Khorana AA et al. Blood. 2008; 111:4902-4907
Clinical Risk Model for Chemotherapy-associated VTE
Risk Score Based on Pretreatment Risk Factors
Risk Factors
Risk score
1. Site of cancer
a) Very high risk cancer (stomach, pancreas)
2
b) High risk (lung, lymphoma, gynecologic, bladder, testicular)
1
2. Platelet count >350,000/mm3
1
3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors
1
4. Leukocyte count >11,000 /mm3
1
5. BMI > 35 kg/m2
1
Khorana AA et al. Blood. 2008; 111:4902-4907
Clinical Risk Model for Chemotherapy-associated VTE
Risk Score Based on Pretreatment Risk Factors
Risk Factors
Risk score
1. Site of cancer
a) Very high risk cancer (stomach, pancreas)
2
b) High risk (lung, lymphoma, gynecologic, bladder, testicular)
1
2. Platelet count >350,000/mm3
1
3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors
1
4. Leukocyte count >11,000 /mm3
1
5. BMI > 35 kg/m2
1
Khorana AA et al. Blood. 2008; 111:4902-4907
VTE Prediction Risk Score
Chemotherapy – Associated Thrombosis
Rate of VTE (%)
8%
7.1%
7%
Development
cohort
Development
cohort
6%
Validation
Validationcohort
cohort
6.7%
5%
4%
3%
1.8%
2%
1%
2.0%
0.8%
0.3%
0%
n=734 n=374
RISK SCORE:
Low (0)
Khorana AA et al. Blood. 2008; 111:4902-4907
n=1,627 n=842
Intermediate (1-2)
n=340 n=149
High (>3)
Venous Thromboembolism and Overall Survival
by VTE Risk Score Categories
Overall Survival
Venous Thromboembolism
.10
1.00
Low
High
P<.001
.08
Overall Survival
.95
P < 0.001*
.06
.04
Intermediate
P < 0.001*
P<.001
P<.001
.90
High
.85
Mortality
Intermediate
.80
.02
P<.001
Low
Grp
Low
Intermed
High
%
1.2
5.9
12.7
HR
1.0
3.56
[1.91-6.66]
6.89
[3.50-13.57]
.75
0.00
0
10
20
30
*Overall test of significance
40
50
60
70
80
90
100
110
Time (Days)
Kuderer NM et al; Blood 2008 (ASH 2008)
120
0
10
20
30
*Overall test of significance
40
50
60
70
Time (Days)
80
90
100
110
120
LMWH prophylaxis NIH trial in cancer outpatients
Phase III Multicenter Trial of Thromboprophylaxis in High Risk Ambulatory Cancer
Patients Receiving Chemotherapy
Trial Design
 Phase III, multicenter, randomized
controlled trial of primary LMWH
thromboprophylaxis in ambulatory
cancer chemotherapy patients
Patient Population
 400 consenting adult solid tumor or
lymphoma patients starting a new
chemotherapy regimen
 Considered high risk based on the
VTE model, ie, risk score for VTE ≥3
Study Outcomes
 Primary Outcomes: Symptomatic and
asymptomatic VTE
 Secondary Outcomes: Overall
mortality, bleeding complications
Correlative Studies
 Blood for biomarkers and microarray
studies
Fig. 1. Study Schema. (R=randomization, H&P=history and physical
examination, US=ultrasound, CT=computed tomography scan of the chest).
All time points are ± 1 week. Baseline CT up to 4 weeks prior to enrollment
will be accepted.
Cancer and Venous Thromboembolism
Conclusions
 VTE is a common complication of cancer and cancer treatment
and is associated with considerable morbidity, mortality and costs.
 The US Surgeon General has recently issued a Call
to Action to Prevent Deep Vein Thrombosis and
Pulmonary Embolism including new research
initiatives to lower the burden of this serious illness.
 Hospitalized medical and surgical cancer patients are at
increased risk for VTE and should be considered for
pharmacologic prophylaxis if no contraindication to
anticoagulation is present.
 Cancer patients treated for documented VTE should be
considered for continued anticoagulation, preferably with LMWH,
for up to six months or longer in patients with active malignancy.
Cancer and Venous Thromboembolism
Conclusions
 Routine thromboprophylaxis of ambulatory cancer patients
is not currently recommended.
 While results from prospective controlled trials are needed,
thromboprophylaxis may be considered in selective high
risk settings such as multiple myeloma patients receiving
thalidomide or lenalidomide along with chemotherapy
and/or dexamethasone.
 Consideration of prophylactic anticoagulation
cancer patients must always balance the
VTE with the increased risk of bleeding.
in
risk of
 Improved methods for the identification of ambulatory
cancer patients at increased risk for VTE and targeted
thromboprophylaxis are needed and under active
investigation.
Acknowledgments
 Duke University
 University of Rochester
– Nicole Kuderer MD
– Alok Khorana MD
– Thomas Ortel MD
– Charles Francis MD
– Jeffrey Crawford MD
– Mark Taubman MD
– Eva Culakova PhD
– Rami Komrokji, MD
– Marek Poniewierski MD
– Debra Wolff, MS PCNP
 ASCO VTE Guideline
Panel Members
– Anna Falanga, Co-Chair
Just Wait Until Next Year………..
Official Duke University Slide for Presentations at the University of North Carolina
Cancer and Thrombosis
What to Look For……..
• Cancer Investigation, 2009
–
Special Issue on Cancer and Thrombosis
• Journal of Clinical Oncology, 2009
–
Special Issue on Cancer and Thrombosis
• ASCO 2009
–
–
Education Session on Cancer and Thrombosis
3 Chapters in the Education Book
• NHLBI Trials on going at Duke/Rochester and UNC
• ISTH 2009: Boston July 11-16
• 5th International Conference on Thrombosis and Hemostasis:
Issues in Cancer, Stresa, Italy, April 23-25, 2010
• Any much more………….
ASCO VTE Guideline Panel Members
Gary H. Lyman, MD, MPH, FRCP
(Edin), Co-Chair
Duke University
Anna Falanga, MD, Co-Chair
Ospedali Riuiniti, Bergamo, Italy
Daniel Clarke-Pearson, MD
University of North Carolina
Christopher Flowers, MD, MS
Emory University
Charles W. Francis, MD
University of Rochester
Leigh Gates, Patient Representative
University of Colorado
Mohammad Jahanzeb, MD
University of Tennessee
Ajay Kakkar, MD, PhD
Barts and The London School of
Medicine
ASCO VTE Guideline Panel Members
Alok A. Khorana, MD
University of Rochester
Nicole M. Kuderer, MD
Duke University
Mark Levine, MD, PhD
McMaster University
Howard A. Liebman, MD
University of Southern California
David S. Mendelson, M.D.
Premiere Oncology
Gary Edward Raskob, PhD
University of Oklahoma
Paul A. Thodiyil, MD
New York Methodist Hospital
David Trent, MD, PhD
Virginia Cancer Center
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Summary
Patient Group
Recommended
Not Recommended
Hospitalized
VTE prophylaxis with anticoagulants
patients with cancer
If bleeding or
contraindication to
anticoagulation
Ambulatory patients
with cancer
receiving
chemotherapy
Myeloma patients receiving thalidomide or
lenalidomide + chemotherapy/
dexamethasone. LMWH or adjusted dose
warfarin.
Otherwise, no routine
prophylaxis
Patients with
cancer undergoing
surgery
Prophylaxis with low-dose UFH or LMWH
Prophylaxis with mechanical methods for
patients with contraindications to
pharmacologic methods
Consider mechanical
methods when
contraindications to
anticoagulation.
Patients with
cancer with
established VTE
Pharmacologic treatment for at least 6
months. Consider continued anticoagulation
beyond 6 months in those with active cancer.
To improve survival
-
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
-
Not recommended
Symptomatic VTE in Hematopoietic Stem Cell Transplantation (HSCT)
Implications for VTE Prevention
●
Retrospective review of 1514
HSCT patients
●
Median F/U: 642 days
●
Symptomatic VTE: 75 (4.6%)
–
●
Catheter-related: 55 (73%)
Clinical bleeding: 230 (15.2%)
–
Fatal bleeding: 55 (3.6%)
–
OR with anticoagulation: 3.1
–
OR with VOD: 2.2
Gerber, D. E. et al. Blood 2008;112:504-510
Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic VTE
Hospitalized Medical Patients
• 9 studies with 19,958 patients
• Anticoagulant prophylaxis:
–
Pulmonary embolism (PE):
•
•
–
RR = 0.38; CI 0.21-0.69
ARD = 0.25%; NNT = 400
Symptomatic DVT:
•
•
–
RR = 0.43; CI 0.26-0.71
ARD = 0.29%; NNT = 345
Fatal PE:
•
•
–
Pulmonary Embolism n=8)
RR = 0.47; CI 0.22-1.00
ARD = 0.43%; NNT = 233
Major bleeding
•
•
RR = 1.32; CI 0.73-2.37
ARD = 0.14%; NNH = 714
Dentali F, et al. Ann Intern Med. 2007;146:278-288.
Major Bleeding (n=7)
Risk Factors for Early Mortality in Patients Receiving Cancer
Chemotherapy
Variables
VTE*
Patient Demographics
Age
ECOG >1
Charlson comorbidity index >1
Body mass index [kg/m2]
Stage IV
Cancer Type
Colorectal
Small cell lung cancer
Non-small cell lung cancer
Ovary
Breast
Lymphoma
Relative Dose Intensity
<85%
Unknown
Year
2003
2004
2005
Baseline Laboratory Values
WBC >11,000/mm3
Creatinine >1.5 mg/dL
Alkaline phosphatase >120 U/L
Protein <5.5 g/dL
Albumin <3.5 g/dL
Kuderer NM, et al. ASCO 2008
Hazard Ratio
P value
95% CI
3.059
1.309
7.153
.010
1.021
1.287
1.338
.959
2.304
1.004
.830
.911
.927
1.509
1.038
1.996
1.966
.992
3.516
1.666
1.530
3.072
1.543
1.059
1.580
.765
.609
1.590
.565
.442
.756
3.626
3.842
5.937
4.211
2.536
3.304
.992
2.071
.617
1.132
1.595
3.789
1.166
.821
.300
.685
.461
.100
1.983
1.464
.898
.017
.260
.137
.016
<.0001
.009
.199
.365
.001
.397
.898
.224
.026
.973
.018
.039
.571
.505
.031
1.976
2.214
1.678
3.194
2.373
1.331
1.223
1.146
1.698
1.594
2.932
4.008
2.455
6.009
3.532
.001
.009
.008
<.0001
<.0001
*Time-dependent covariate
Coagulation Proteases in Tumor Biology
Tissue Factor/FVIIa
Growth
Factor Xa
Invasion
Thrombin
Metastasis
Angiogenesis
Fibrin generation plays additional roles in these processes
Fibrinogen Kinetics in Cancer Patients
 Patients: 25 patients with
known advanced or
active cancer
 Methods: Plasma and
urine fractional fibrinogen
catabolic rates were
estimated
 Findings: Significantly
shortened fibrinogen
survival found in patients
with active cancer
Categories
N
T½
TO*
Controls
6
3.89
.828
All Cancers
25 3.01 1.433
Leukemia
6
3.19
Lymphoma
4
2.88 1.881 <.05
Solid Tumor
15 2.98 1.617 <.05
GI
3
No Chemo
15 3.28
Chemo
10 2.61
.671
<.05
NS
2.52 2.234 <.05
*TO= mean turnover in mg/ml/day
Lyman GH et al. Cancer 1978; 41: 1113-1122
P
NS
Risk of VTE in Cancer Patients by Type of Malignancy
Population-based, case-control study [MEGA] of risk factors for VTE
• 6 clinics in Holland
• 3220 consecutive
patients, 18 to 70
years, with a first DVT
or PE
• 2131 control
participants (partners
of the patients)
Type of Cancer
Adjusted Odds Ratio
(95% CI)
Hematologic
28 (4-199.7)
Lung
22.2 (3.6-136.1)
Gastrointestinal
20.3 (4.9-83)
Breast
4.9 (2.3-10.5)
Prostate
2.2 (0.9-5.4)
Risk was greatest in first few months following diagnosis of cancer
Patients with distant metastases and carriers of
factor V Leiden mutation were are further increased risk.
Blom JW, et al. JAMA. 2005;293:715-722.
The Surgeon General’s Call to Action to Prevent Deep
Vein Thrombosis and Pulmonary Embolism
September 15, 2008
Risk Factors for Inpatient VTE: Multivariate Analysis*
Characteristic
OR
P value
Lung
1.3
<0.001
Stomach
1.6
0.0035
Pancreas
2.8
<0.001
Uterine
2
<0.001
Brain
2.2
<0.001
Age > 65
1.1
0.005
Arterial Thromboembolism
1.4
0.008
Major Comorbidities**
1.3-1.6
<0.001
Site of Cancer
* Adjusted for sex, race, HBP, DM, CHF, hepatic disease (NS)
** lung/renal disease, infection, obesity
Khorana et al, J Clin Oncol 2006; 24: 484-490
VTE Risk and Prevention in Multiple Myeloma
Chemotherapy ± Thalidomide
Zangari et al: Brit J Haematol 2004; 126: 715-721
Ambulatory Cancer Patients:
Prophylaxis in Multiple Myeloma Patients
• Prophylaxis with low-molecular-weight heparin (LMWH) or
adjusted dose warfarin (INR~1.5) is recommended in
multiple myeloma patients receiving thalidomide or
lenalidomide plus chemotherapy or dexamethasone
(high VTE risk)
• However:
– No RCTs available
– Recommendation is based on extrapolation from
nonrandomized trials or randomized studies in other
similar high-risk categories
– Well-designed RCTs are urgently needed
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
VTE Risk and Prevention in Multiple Myeloma
Melphalan + Prednisone ± Thalidomide
VTE
• No anticoagulation
(first two years):
11/65 (17%)
• Enoxaparin 40 mg QD
for four months:
2/65 (3%)
(P=.005)
Palumbo A et al: The Lancet 2006; 367: 825-831
Older Age and History of Arterial Thromboembolism
Chemotherapy* plus bevacizumab
Chemotherapy* alone (control group)
20
ATE Rate (%)
16
12
8
4
0
Total cohort
No risk factors
Age ≥65 yr
ATE history
n=963 bev
n=872 ctrl
n=602 bev
n=490 ctrl
n=339 bev
n=279 ctrl
n=89 bev
n=59 ctrl
ATE history
+ age ≥65 yr
n=67 bev
n=46 ctrl
Reduction in
thrombosis
Increase in
bleeding
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Preventing Recurrence in Cancer Patients with Established VTE
5. In patients with central nervous system
malignancies and in the elderly, anticoagulation is
recommended for established VTE as described for
other patients with cancer .
6. Careful monitoring of anticoagulation is necessary
to limit the risk of hemorrhagic complications.
7. Anticoagulation should be avoided in the presence
of active intracranial bleeding or preexisting
bleeding diathesis such as thrombocytopenia
(platelet count <50,000/mm3) or coagulopathy.
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
The CLOT Trial
• multinational, open-label, randomized study
Cancer patients
with proximal DVT,
PE or both
R
Control Group:
dalteparin + VKA
Experimental Group:
dalteparin alone
• treatment period 6 months (or until death)
• primary endpoint: symptomatic VTE recurrence
• follow-up for survival up to 12 months
Lee AY, et al. N Engl J Med. 2003;349:146-153.
CLOT Trial Results:
Survival in Solid Tumor Patients ± metastatic disease
P = 0.62
HR=0.50[.27 to .95]; P=.03
HR=1.1[.87 to 1.4]; P=.46
For patients without metastatic disease, the hazard ratio was 0.50 (95% CI, 0.27 to 0.95; P = .03) for the overall comparison between the treatment groups.
For patients with metastatic disease, the hazard ratio was 1.1 (95% CI, 0.87 to 1.4; P = .46) for the overall comparison between the treatment groups.
Lee, A. Y.Y. et al. J Clin Oncol; 23:2123-2129 2005
Mortality and PFS in Univariate Analysis
by VTE Risk Score Categories
Outcomes
(at 4 months)
Risk Group
Low
Intermed.
High
N=1,206
N=2,709
1.2%
5.9%
12.7%
5.6%
1.0
3.56 [1.91-6.66]
6.89 [3.50-13.57]
-
93%
82%
72%
84%
1.0
2.77 [1.97-3.87]
4.27 [2.90-6.27]
-
N=543
All
N=4,458
Overall Mortality
Risk (%)
HR [+/- CI]
PFS
Risk (%)
HR [+/- CI]
Kuderer NM et al; Blood 2008 (ASH 2008)
VTE Risk Score Independent Predictor for: PFS
Multivariate Analysis*
Variables
P-value
HR
Lower
VTE Risk Score(1)
Upper
0.001
1.00
<0.001
2.077
1.397
3.086
High Risk Group (III)
<0.001
2.344
1.465
3.751
0.028
2.043
1.079
Patient Characteristics
Progression-Free Survival
Intermed. Risk Group (II)
VTE(2)
Progression-Free Survival
95% CI for HR
3.870
Low
Intermediate
.90
P < 0.001*
Age
0.107
1.008
0.998
ECOG >1
0.001
1.498
1.175
Charlson >1
0.047
1.256
1.003
1.574
BMI [kg/m2]
<0.001
0.962
0.944
0.981
Stage IV(3)
<0.001
1.982
1.567
2.506
<0.001
0.792
0.700
0.896
P<.001
1.017
1.909
.80
High
P<.001
.70
Year
0
10
20
30
40
50
60
70
80
90
100
110
120
Time (Days)
*Overall test of significance
*Adjusted for: Cancer Type, and Relative Dose Intensity
(1) Comparison to low risk group (I)
(3) Comparison to stages I-III
(2) Time-dependent covariate
Kuderer NM et al; Blood 2008 (ASH 2008)
LMWH prophylaxis NIH trial in cancer outpatients
Inclusion Criteria:

Age 18 years or older

A histologic diagnosis of malignancy (not basal cell or squamous cell);

At planned initiation of a new systemic chemotherapy regimen (including patients starting on first
chemotherapy or patients previously treated but starting on a new regimen);

A risk score for VTE ≥3. Any counts meeting criteria drawn within 2 weeks prior to enrollment are
considered acceptable.
Exclusion Criteria:

Patients will be excluded from the trial if they have any of the following:
–
Active bleeding or at high risk of serious bleeding complication in the opinion of the
investigator
–
Diagnosis of primary brain tumor, multiple myeloma, acute leukemia, chronic myelogenous
leukemia or myelodysplastic syndrome
–
Planned stem cell transplant
–
Life expectancy < 6 months
–
Known allergy to heparin or LMWH
–
Incapable of daily self-injection
–
Acute or chronic renal insufficiency with creatinine clearance < 30 mL/min
–
History of heparin-induced thrombocytopenia
–
Allergy to contrast agents
–
Need for anticoagulant therapy
–
Platelet count < 50,000/mm3
–
Pregnancy
Procoagulant activities
Fibrinolytic activities
Tumor
cells
Cytokines and
factors
Activation of
coagulation
Activation of vascular
blood cells
Falanga A: Cancer Invest 2009; 27: 105-115
growth
Extracellular matrix
remodeling
Angiogenesis
Survival of Cancer Patients Developing VTE
Compared to Matched Controls
 Data from the Danish
National Registry of
Patients, the Danish
Cancer Registry, and the
Danish Mortality Files
 Control patients, who did
not have VTE, were
matched by
– cancer type
– Sex
– Age
– year of diagnosis
Sorensen, H. T. et al. N Engl J Med 2000;343:1846-1850
One-Year Mortality
Cancer with VTE
12%
Cancer w/o VTE
36%
HR = 2.20 [2.05-2.40]
P<.0001
RCTs of Thromboprophylaxis in Ambulatory Cancer Patients
Low Molecular Weight Heparin: Meta-Analysis
Summary Estimates [N=6 RCTs]
• Venous Thromboembolism
– Relative Risk: 0.64 [95% CI: 0.44 – 0.94]
– Absolute Risk Reduction: 1.8% [95% CI:
0.2% - 3.4%]
• Major Bleeding
– Relative Risk: 1.85 [95% CI: 0.93 – 3.68]
– Absolute Risk Increase: 0.9% [95% CI:
0% - 1.8%]
Kuderer NM et al: ASCO 2009
VTE Risk Score Independent Predictor for: Mortality
Multivariate Analysis
Variables
VTE Risk Score(1)
P-value
HR*
95% CI for HR
0.028
Intermed. Risk Group (II)
0.025
2.222
1.106
4.464
High Risk Group (III)
0.008
2.926
1.332
6.428
<0.001
4.472
1.928
10.370
Age
0.026
1.018
1.002
1.035
ECOG >1
0.027
1.613
1.055
2.464
Charlson >1
0.014
1.582
1.096
2.284
BMI [kg/m2]
<0.001
0.941
0.910
0.973
Stage IV(3)
<0.001
2.659
1.755
4.028
0.016
0.771
0.624
0.953
VTE(2)
Patient Characteristics
Year
*Adjusted for: Cancer Type, and Relative Dose Intensity
(1) Comparison to low risk group (I)
(3) Comparison to stages I-III
(2) Time-dependent covariate
Kuderer et al. Oral Presentation ASH 2008
Cancer and Venous Thromboembolism
The Need for Risk Stratification
4.5
Chemotherapy
End of Life
4
3.5
Relative Risk
3
2.5
Hospitalization
Metastasis
Diagnosis
2
1.5
Remission
1
Average Risk
0.5
0
1
2
3
Time
4
5
6
Importance of Guidelines to Clinical Outcomes
“Clinicians armed with appropriate assessments
and the best evidence-based practice guidelines
can reduce some of the unpleasant and frequent
side-effects that often accompany cancer and
chemotherapy treatment, obtain the best possible
clinical outcomes, and avoid unnecessary costs.”
Statement from Centers for Medicare and Medicaid Services, August 2005
Candidate Biomarkers
•
•
•
•
•
Platelet count
Leukocyte count
Tissue factor
P-selectin
Others (D-dimer, C-reactive protein)
Soluble P-Selectin and VTE in Cancer
Ay C, et al. Blood. 2008;112:2703-2708
Mechanisms for ESAs to Increase Thrombosis

Rheological effects of increased or increasing
red cell mass

Young red cells in circulation augment platelet
reactivity (red cell–platelet interaction)

ESAs synergize with TPO to activate platelets
(ESA–TPO interactions)

Direct, receptor-mediated effects on endothelium
that enhance interaction with platelets
(ESA–endothelial interactions)
TPO, thrombopoietin
Lancet 2003;362:1265
Highlights from ASCO 2009
Advances in Supportive Care
Managing Disease and Treatment-Related Complications
Venous Thromboembolism and
Thromboprophylaxis
Low-molecular-weight heparin for venous thromboprophylaxis
in ambulatory cancer patients: A meta-analysis
Nicole M. Kuderer, Alok A. Khorana, Charles W. Francis et al
Duke University, Durham, NC; University of Rochester, Rochester, NY
•
Literature Search:
– Medline, EMBASE, Cochrane
Library, Conference Proceedings,
Hand Searching of References
•
Major Inclusion Criteria:
– RCT of LMWH VTE prophylaxis in
adult ambulatory cancer patients
– Treatment Group: LMWH
– Control Group: placebo or no Rx
•
Major Exclusion Criteria:
– Non-cancer patients
– Non-randomized trials
– Surgery, Catheter trials, or
intraportal heparin infusion
– Combination of anticoagulants
Venous Thromboembolism
Study name
Statistics for each study
Relative Risk [95% CI]
Relative
Risk
Lower
limit
Upper
limit
Z-Value
FAMOUS
0.775
0.211
2.840
-0.385
0.700
TOPIC-1
1.006
0.360
2.808
0.011
0.991
TOPIC-2
0.529
0.251
1.111
-1.681
0.093
PRODIGE
0.659
0.292
1.489
-1.003
0.316
PROTECHT
0.495
0.217
1.132
-1.665
0.096
Sideras
0.824
0.231
2.938
-0.299
0.765
0.642
0.441
0.936
-2.301
0.021
Overall
Overall
p-Value
0.1
0.2
0.5
1
Favors Prophylaxis
2
5
10
Favors Control
Major Bleeding
Study name
Statistics for each study
Relative Lower
Risk
limit
Upper
limit
Relative risk [95% CI]
Z-Value p-Value
FAMOUS
2.906
0.119
70.874
0.655
0.513
TOPIC-1
7.040
0.366 135.290
1.294
0.196
TOPIC-2
1.607
0.534
4.837
0.844
0.399
PRODIGE 4.394
0.523
36.887
1.364
0.173
PROTECHT5.457
0.303
98.434
1.150
0.250
Sideras
0.412
0.083
2.051
-1.083
0.279
Overall
1.846 0.927
3.675 1.744
0.081
0.1
0.2
0.5
Favors Prophylaxis
1
2
5
10
Favors Control
Risk - Benefit Comparison
VTE – Prophylaxis with LMWH
Venous Thromboembolism
Study name
Statistics for each study
Absolute risk difference [95% CI]
Risk
Standard
Lower Upper
difference error Variance limit limit Z-Value p-Value
Benefit
Harm
FAMOUS
-0.006
0.016
0.000
-0.037
0.025
-0.385
0.700
TOPIC-1
0.000
0.021
0.000
-0.040
0.041
0.011
0.991
TOPIC-2
-0.040
0.023
0.001
-0.085
0.006
-1.723
0.085
PRODIGE
-0.047
0.047
0.002
-0.139
0.045
-1.002
0.316
PROTECHT -0.015
0.010
0.000
-0.033
0.004
-1.519
0.129
-0.013
0.042
0.002
-0.095
0.070
-0.300
0.764
-0.018
0.008
0.000 -0.034 -0.002 -2.265
Sideras
Overall
Venous
Thrombosis
ARD*
Major
Bleeding
Events
ARD*
0.023
All
Bleeding
Events
ARD*1
-0.25
-0.13
0.00
Favors Prophylaxis
0.13
0.25
Favors Control
Major Bleeding
Study name
1.8% ↓
1Kuderer
0.9% ↑
et al. Cancer 2007
2.4% ↑↑
Statistics for each study
Relative Lower
Risk
limit
Relative risk [95% CI]
Upper
limit Z-Value p-Value
FAMOUS 2.906
0.119 70.874
0.655
0.513
TOPIC-1
7.040
0.366 135.290
1.294
0.196
TOPIC-2
1.607
0.534
4.837
0.844
0.399
PRODIGE 4.394
0.523 36.887
1.364
0.173
PROTECHT5.457
0.303 98.434
1.150
0.250
-1.083
0.279
Sideras
0.412
0.083
Overall
1.846 0.927
2.051
3.675 1.744 0.081
0.1
*ARD = Absolute Risk Difference
0.2
0.5
Favors Prophylaxis
1
2
5
10
Favors Control
Conclusions
VTE – Prophylaxis with LMWH
• While ambulatory cancer patients experienced a 36%
relative risk reduction in VTE with LMWH, the average
absolute risk reduction for VTE was only 1.8%.
• Concern remains about the potential increase in major
bleeding with an absolute risk increase in major bleeding of
0.9%.
• Major bleeding was not a primary outcome in any of the
studies and were not powered to adequately assess major
bleeding.
• Weighing risks and benefits, routine VTE prophylaxis in the
general outpatient cancer population cannot be
recommended at this time.
• Studies are ongoing to better identify cancer outpatients at
increased risk for VTE, in whom prophylaxis may have a
more favorable risk-benefit ratio.
ASCO Guidelines for Thromboprophylaxis
Hospitalized cancer patients
 Should be considered candidates for VTE prophylaxis in the
absence of contraindications
Surgical cancer patients
 All patients undergoing major surgical intervention for
malignant disease should be considered for prophylaxis
 Prophylaxis should be continued for at least 7-10 days
postoperatively and may be extended into the post discharge
period for selected high-risk patients
Ambulatory cancer patients
 Routine prophylaxis not recommended
 Exception: Patients receiving thalidomide or lenalidomide with
chemotherapy or dexamethasone
Lyman et al. JCO 2007
ASCO Guidelines for Thromboprophylaxis
Hospitalized cancer patients
 Should be considered candidates for VTE
prophylaxis in the absence of contraindications
Surgical cancer patients
 All patients undergoing major surgical intervention
for malignant disease should be considered for
prophylaxis
 Prophylaxis should be continued for at least 7-10
days postoperatively and may be extended into the
post discharge period for selected high-risk patients
Ambulatory cancer patients
 Routine prophylaxis not recommended
 Exception: Patients receiving thalidomide or
lenalidomide with chemotherapy or dexamethasone
Risk Model
Patient Characteristic
Score
Site of Cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, GU
excluding prostate)
Platelet count > 350,000/mm3
2
1
1
Hb < 10g/dL or use of ESA
1
Leukocyte count > 11,000/mm3
1
BMI > 35 kg/m2
1
Khorana AA et al. Blood 2008
VTE Prediction Risk Score
Chemotherapy – Associated Thrombosis
Development cohort
Validation cohort
8%
.10
Rate of VTE (%)
6%
5%
7.1%
High
Venous Thromboembolism
7%
.08
6.7%
P < 0.001*
.06
P<.001
.04
Intermediate
.02
P<.001
4%
Low
0.00
0
3%
10
20
40
*Overall test of significance
50
60
70
80
90
100
110
120
Time (Days)
1.8%
2%
1%
30
2.0%
0.8%
0.3%
0%
n=734 n=374
RISK SCORE:
Low (0)
n=1,627 n=842
Intermediate (1-2)
n=340 n=149
High (>3)
Khorana AA et al. Blood. 2008; 111:4902-4907
Mortality and PFS
By VTE Risk Score
Outcomes
Low
Risk
Intermediate
Risk
High
Risk
All
N=1,206
N=2,709
N=543
N=4,458
1.2%
5.9%
12.7%
5.6%
Mortality
Risk (%)
HR [+/- CI]
1.0
3.6 [1.9-6.7] 6.9 [3.5-13.6]
-
Progression-free survival
Risk (%)
HR [+/- CI]
93%
82%
72%
84%
1.0
2.8 [2-3.9]
4.3 [2.9-6.3]
-
Kuderer NM et al. ASH 2008
PHACS Study
LMWH prophylaxis x 12 weeks
with 4-weekly screening US and
start/end CT chest
Patients starting
chemotherapy
Risk score ≥3
R
Observe x 12 weeks
with 4-weekly screening US and
start/end CT chest
Sites: Duke, Duke Oncology Network, Univ of Rochester
R01 HL095109-01
A prospective, randomized trial of chemotherapy with or without the
low molecular weight heparin enoxaparin in patients with advanced
pancreatic cancer: Results of the CONKO 004 trial
H. Riess, U. Pelzer, G. Deutschinoff, B. Opitz, M. Stauch, P. Reitzig, S. Hahnfeld,
A. Hilbig, J. Stieler, H. Oettle
Randomization
Chemotherapy
Chemotherapy + Enoxaparin
Treatment for 3 months: VTE, Bleeding, RR, PFS, OS
Chemotherapy
Chemotherapy + Enoxaparin
E 1 mg/kg/d
Primary endpoint
E 40 mg/kg/d
until PD
Response evaluation at least every 12 weeks:
VTE, Bleeding, RR, PFS, OS
A prospective, randomized trial of chemotherapy with or without the
low molecular weight heparin enoxaparin in patients with advanced
pancreatic cancer: Results of the CONKO 004 trial
H. Riess, U. Pelzer, G. Deutschinoff, B. Opitz, M. Stauch, P. Reitzig, S. Hahnfeld,
A. Hilbig, J. Stieler, H. Oettle
Randomization
Chemotherapy
Chemotherapy + Enoxaparin
Treatment for 3 months:
Chemotherapy
VTE , Bleeding, RR, PFS, OS
Chemotherapy + Enoxaparin
E 1 mg/kg/d
Primary endpoint
E 40 mg/kg/d
until PD
Response evaluation at least every 12 weeks:
VTE, Bleeding, RR, PFS, OS
CONKO-004: Chemotherapy


Favorable results in randomized phase II/III in patients with good PS:
with Gem/CDDP or Gem/FA/5-FU and Gem/Cap
Gem/CDDP/5-FU and Gem/FA/5-FU/CDDP with remarkable RR and 1year OS
Patient allocation according to Karnofsky-PS (KPS) and plasma
creatinine level
KPS ≥ 80% + creatinine ≤ ULN
KPS 60-70% or creatinine > ULN
Gemcitabine (1000 mg/m2)
Gemcitabine (1000 mg/m2)
Folinic acid (100 mg/m2)
d1, 8, 15; 29
5-FU (750 mg/m2 24 h CI)
CDDP (30 mg/m2)
d1, 8; 22
Results:
VTE and Major Bleeding
Observation
Enoxaparin
Patients (N)
152
160
VTE (at 3 months)*
Major Bleeding (at 3 months)
9.9%
2.6%
1.2%
3.8%
VTE (at 30.4 months)**
15.5%
5%
Major Bleeding (at 30.4 months)
9.9%
6.3%
29 weeks
31 weeks
Median survival
*p<0.01; **p<0.05
Results:
VTE and Major Bleeding
Observation
Enoxaparin
Patients (N)
152
160
VTE (at 3 months)*
Major Bleeding (at 3 months)
9.9%
2.6%
1.2%
3.8%
VTE (at 30.4 months)**
15.5%
5%
Major Bleeding (at 30.4 months)
9.9%
6.3%
29 weeks
31 weeks
Median survival
*p<0.01; **p<0.05
Results:
VTE at 3 Months
Venous thromboembolic events
Observation
N= 162
Enoxaparin
N= 150
All
Pulmonary embolism
2
0
2
Proximal leg DVT
9
2
11
Distal leg DVT only
2
0
2
Upper extremity DVT
3
0
3
All (VTE)
16
2
18
All (Patients)*
15
2
17
Event
Results:
Relative VTE rates
■ Gem
■ GFFC
16
n=5
Percent (%)
14
Δ=12.4%;RRR=79%;P=.300
12
10
8
n=10
6
4
n=1
2
n=1
0
Observation
Enoxaparin
Δ=6.6%;RRR=90%;P=.025
CONKO-004: Summary
•
•
•
•
•
•
Major Limitations
Unusual study design
Non-standard chemotherapy
Chemo allocated by
PS/creat.
Small study: trial stopped
early
Paradoxical major bleeding
results
No information on catheters
•
•
•
•
•
Conclusions
Enoxaparin (1mg/kg/day)
significantly reduces VTE
No OS improvement
High overall major bleeding
Unusual study design
Clinical relevance of data?
– Reducing non-PE VTE
– Setting of high major bleeding
• ? Long-term complications:
– Osteoporosis
– HIT