Transcript Principles, Challenges, and Solutions New Frontiers and Evolving Paradigms in Cancer and Thrombosis Focus on the Complex Interfaces Among Thrombosis, Anticoagulation, and Malignancy PROFESSOR LORD.

Principles, Challenges, and Solutions
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Focus on the Complex Interfaces Among
Thrombosis, Anticoagulation, and Malignancy
PROFESSOR LORD AJAY KAKKAR, MBBS (Hons) BSc, PhD, FRCS
Program Chairperson
Professor of Surgery
University College London
Director
Thrombosis Research Institute
London
Program Faculty
Program Chairman
PROF. LORD AJAY KAKKAR,
MBBS (Hons) BSc, PhD, FRCS
Professor of Surgery
University College London
Director
Thrombosis Research Institute
London, UK
ALOK A. KHORANA, MD, FACP
Vice-Chief, Division of Hematology/Oncology
Associate Professor of Medicine and Oncology
James P. Wilmot Cancer Center
University of Rochester
Rochester, NY
FREDERICK R. RICKLES, MD
Clinical Professor of Medicine, Pediatrics,
Pharmacology and Physiology
CRAIG M. KESSLER, MD, MACP Division of Hematology-Oncology
Professor of Medicine and Pathology
Department of Medicine
Lombardi Comprehensive Cancer Center The George Washington University School of
Director, Division of Coagulation
Medicine and Health Sciences
Georgetown University Medical Center
Washington, DC
Washington, DC
Principles, Challenges, and Solutions
Understanding the Relationship
Between Anticoagulation,
Thrombosis, and Cancer Biology
A Landscape Assessment
PROFESSOR LORD AJAY KAKKAR, MBBS (Hons) BSc, PhD, FRCS
Program Chairperson
Professor of Surgery
University College London
Director
Thrombosis Research Institute
London
Register of Interests for Ajay Kakkar
Research Support/P.I.
Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim,
Pfizer, Bristol–Myers Squibb, Eisai
Employee
N/A
Consultant
Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim,
Pfizer, Bristol–Myers Squibb, Eisai
Major Stockholder
N/A
Speakers Bureau
N/A
Honoraria
Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim,
Pfizer, Bristol–Myers Squibb, Eisai, GSK
Scientific Advisory Board
Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim,
Pfizer, Bristol–Myers Squibb, Eisai
N/A = not applicable (no conflicts)
Trousseau (1865)
“In other cases, in which the
absence of appreciable
tumour made me hesitate as
to the nature of the disease
of the stomach, my doubts
were removed, and I knew
the disease to be cancerous
when phlegmasia alba
dolens appeared in one of
the limbs.”
(Lectures in Clinical
Medicine, 1865)
Our Symposium Today
►
Is thrombosis a common problem in cancer?
►
Does it influence clinical outcomes?
►
Why does it happen?
►
Can we prevent it?
►
How should it be treated?
►
Can antithrombotic drugs prolong survival?
Cancer and Thrombosis
►
Cancer patients are at increased risk for thrombosis1,2
Active cancer accounts for almost 20% of all new VTE events3
● As many as 50% of patients with cancer have VTE at autopsy4
●
►
Patients with VTE may be at risk for developing cancer5
10% or patients with idiopathic VTE develop cancer within 2 years
● 20% of patients with recurrent idiopathic VTE develop cancer within 2
years
●
►
Two-way association between cancer and VTE
►
Cancer patients are at increased risk for thrombotic episodes, and
VTE maybe a sign of occult malignancy
DVT=deep vein thrombosis; VTE=venous thromboembolism.
1. Kakkar AK et al. Oncologist. 2003;8:381-388.
2. Lee AY et al. Circulation. 2003;107(23 suppl 1):I17-I21.
3. Prandoni P. Cancer Treat Rev. 2002;28:133-136.
4. Geerts WH et al. Chest. 2004;126:338S-400S.
5. (Bura J et al. Thromb Haemost. 2004;2:445-51.
Risk for VTE by Type of Malignancy
Fold increase in risk vs patients without malignancy
ENT=ear, nose, throat; GI=gastrointestinal
Blom JW et al. JAMA. 2005;293:715-722.
VTE in Hospitalized Cancer Patients
7.0
VTE patients on chemotherapy
VTE all patients
DVT all patients
PE all patients
Rate of VTE (%)
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Cancer 2007
1995
1996
1997
1998
1999
Years
2000
2001
2002
2003
Thrombosis and Cancer Death
Probability of death within 183 days of initial hospital admission
Probability of death
1.00
DVT/PE and
malignant disease
0.80
0.60
0.40
Malignant
disease alone
0.20
0.00
0
40
80
120
Number of days
180
Cancer at the Time of VTE is
Associated with Reduced Survival
Sorensen HT et al. N Engl J Med. 2000;343:1846-1850.
Risk for Cancer in Relation to Length of Follow-up
Period in Patients with Primary DVT or PE
Sorensen HT et al. N Engl J Med. 1998;338:1169-1173.
Thrombosis and In-patient Mortality
20
18
Mortality, %
16
14
16.13
14.85
12
16.41
10
10.59
8
6
8.67
7.98
4
2
0
All
(n=66,016)
J Clin Oncol 2006;24:484–90
Non-metastatic cancer
(n=20,591)
Metastatic cancer
(n=17,360)
Mechanism of Thrombosis
in Patients with Cancer
►
The hemostatic system can influence tumor angiogenesis, which is critical to
the growth of solid tumors1
►
Expression of tissue factor (TF) by tumor or stromal cells results in a
generally procoagulant tumor microenvironment 1
►
TF expressed in this way is a procoagulant and can directly activate factor X
►
TF released by monocytes or macrophages can induce activation of factor
VII 2
►
TF also may stimulate angiogenesis: 3
1) Directly, by signaling through cytoplasmic tails
2) Indirectly, through generation of thrombin and interaction with
protease-activated receptors
►
1.
2.
3.
4.
5.
High levels of TF expression have been shown to predict poor prognosis in
patients with ovarian and pancreatic cancer 4,5
Belting M et al. Arterioscler Thromb Vasc Biol 2005; 25: 1545–1550.
Taubman MB. Informa Healthcare, 2007; 35–49.
Khorana AA et al. Clin Cancer Res 2007; 13: 2870–2875.
Han LY et al. J Clin Oncol 2006; 24: 755–761.
Nitori N et al. Clin Cancer Res 2005; 11: 2531–2539.
The Coagulation Cascade
TF
Initiation
VII
VIIa
X
IX
IXa
Xa
Propagation
II
IIa
Clot formation
Fibrinogen
Prothrombin
Thrombin
Fibrin
Tissue Factor Expression and
Grade of Cancer
Normal
Tissue
100% Negative
Tumour
20%
Well
Moderate
50%
Poor
77%
0%
20%
40%
60%
80 %
100%
Activation of Coagulation
in Cancer Patients
Control
Cancer
349
582
0.0006
Factor VIIa
69
100
0.0002
TAT
(g/L)
2.0
8.0
0.0001
PF 1+2 ( ng/ml)
1.0
3.0
0.0001
Factor XIIa
2.0
3.0
0.02
N=72
TF
(pg/ml)
(ng/ml)
(ng/ml)
Kakkar A, et al. Lancet. 1995;346:1004-5.
N=106
P value
VTE Risk Factors in Patients With Cancer
Chemotherapy
Biological therapy
Cytokines
Microparticles
Tissue factor
Cell type
Cancer stage
Thrombosis
Tumor compression
Blood vessel invasion
Central venous line
Surgery
Infection
Supportive
therapy
• EPO
• CSFs
CSFs=colony-stimulating factors; EPO=erythropoietin; GF=growth factor.
Adapted from Bick RL. J Support Oncol. 2006;4:115-120.
Independent Risk Factors for DVT/PE
Risk Factor/Characteristic
Odds
Ratio
Recent surgery with institutionalization
21.72
Trauma
12.69
Institutionalization without recent surgery
7.98
Malignancy with chemotherapy
6.53
Prior CVAD or pacemaker
5.55
Prior superficial vein thrombosis
4.32
Malignancy without chemotherapy
4.05
Neurologic disease with extremity paresis
3.04
Serious liver disease
0.10
CVAD=central venous access device.
Heit JA et al. Thromb Haemost. 2001;86:452-463.
Impact of Cancer Treatment and Type
on Risk of Thrombosis
Incidence
of DVT/PE
Cancer Treatment
Cancer Type
Thalidomide plus chemotherapy
Renal cell carcinoma
43%1
Thalidomide plus chemotherapy
Multiple myeloma
28%1
Surgery
None reported
20%–40%2
L-asparaginase
Hodgkin's or non-Hodgkin's
lymphoma
10%1
Acute lymphoblastic leukemia
4%1
Tamoxifen plus chemotherapy
Node-negative breast cancer
4.2%1
Central venous catheter
None reported
3%–21%2
Tamoxifen
Node-negative breast cancer
0.9%1
1. Lee AY et al. Circulation 2003;107(23 suppl
1):I17-I21. 2. Bick RL. J Support Oncol.
2006;4:115-120.
Effects of Chemotherapy on VTE
Chemotherapy may increase the risk of VTE due
to the following:
1. Release of procoagulants and cytokines from
damaged cancer cells
2. Direct drug toxicity on vascular endothelium
3. Direct induction of monocyte or tumor cell
transcription factors (TFs)
4. Decrease in physiological anticoagulants
• Proteins C and S
Falanga A. Haemostasis. 1998;28(suppl 3):50-60.
Rate of VTE (%)
Incidence of VTE in Cancer Patients
Receiving Chemotherapy
3.0%
2.5%
2.0%
1.5%
1.0%
0.5%
0.0%
Baseline
Cycle 1
Cycle 2
Cycle 3
VTE/2.4 months
VTE/month
VTE/cycle
Cumulative Rate
(95% CI)
1.93%
0.8%
0.7%
2.2% (1.7-2.8)
Khorana AA et al. Cancer. 2005;104:2822-2829.
Thromboprophylaxis:
Surgical Oncology
►
►
►
332 patients undergoing surgery
for abdominal or pelvic tumours
received enoxaparin (40 mg daily)
for 1 week followed by enoxaparin
or placebo for another 21 days
Venography was performed at 30day and 3-month follow-up
At each follow-up, prolonged TP
was associated with a 60% risk
reduction for DVT
20
RRR, 60%;
P=.02
15
RRR, 60%;
P=.01
13.8%
12.0%
10
5
4.8%
5.5%
0
Day 30
3 month
Follow-up
Enoxaparin
4 weeks
1 week
(n=165)
(n=167)
Bergqvist D, et al, New Engl J Med. 2002;346:975980.
Thromboembolic Event (%)
Thromboprophylaxis: Medical Oncology
Agnelli G. et al. ASH 2008
P= 0.033
RRR = 47.2%
NNT = 53.8
16/769
15/381
Probability of recurrent VTE (%)
Prevention of Recurrent VTE
25
Risk reduction=52%
P=0.0017
20
15
OAC
10
Dalteparin
5
0
0
30
60
90
120
150
Days post-randomisation
180
210
Kaplan–Meier survival distribution
function estimate
Effect of Low Molecular Weight
Heparin on Cancer Survival
1.0
Dalteparin
Placebo
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
No. at risk:
0
12
190
184
85
72
24
36
48
60
72
Time from randomisation (months)
30
15
22
9
12
8
5
5
4
2
84
Dalteparin
Placebo
Antithrombotic Therapy and Survival
LMWH and Prolonged Cancer Survival
Mechanistic explanations
VTE
Coagulation Protease
Direct Heparin
Other
Coagulation Proteases in
Tumour Biology
Coagulation proteases effect
Growth
Invasion
Metastasis
Angiogenesis
Thrombin Signaling in Cancer Cells
AntiPAR1
PAR1
antagonist
Thrombin
PAR2
PAR1
Signalling
PAR2
Signalling
PAR1
Heparins and Tumour Biology
Multiple potential modes of action
Angiogenesis
Apoptosis
Heparanase
Adhesion
The Landscape: 2011
► Thrombosis is common in
cancer patients
► Adversely impacts on
clinical outcomes
► Antithrombotic therapy
validated for the prevention
and treatment of CAT
► Coagulation proteases
implicated in tumour
biology
► LMWH may prolong survival
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Possible Mechanisms by which
Anticoagulants Affect Tumor
Growth
Frederick R. Rickles, MD, FACP
Professor of Medicine, Pediatrics,
Pharmacology and Physiology
The George Washington University
Washington, DC
Veteran Affairs Cooperative Study No. 75
Probability of Survival
Survival in SCLC
warfarin
no warfarin
p=0.026
Weeks Post Randomization
Zacharski et al. JAMA. 1981;245:831-853
FAMOUS Study
Kaplan–Meier survival
distribution function estimate
Post-hoc Survival Analysis
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
-
Dalteparin
Placebo
17
23
29
35
41 47
53
59 65
71
77
83
Time from randomisation (months)
No. at risk:
47 17
55 31
10 9
9
26 22 20
Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
8
13
8
8
5
5
3
5
2
5
0 Placebo
3 Dalteparin
CLOT STUDY
Post-Hoc Survival Analysis
Solid tumor patients Without Metastases: N = 150
12-month mortality
Hazard ratio (95% CI)
Dalteparin
OAC
20%
36%
0.50 (0.27, 0.95); p = 0.03 *
Solid tumor patients With Metastases: N = 452

12-month mortality
Hazard ratio (95% CI)
Dalteparin
OAC
72%
69%
1.09 (0.87,1.36); p = 0.55
The hazard ratios for the 2 patient subgroups are significantly different (p = 0.02);
Hazard ratio = 0.41, p = 0.02 after adjusting for baseline prognostic factors - age, gender,
current smoking, cancer treatment, qualifying episode of VTE, ECOG status, and tumor site
Lee et al. JCO 2005;23:2130-2135
LMWH Effect on Survival in Cancer
Ongoing Randomized Clinical Trials
Study
LMWH
Tumor Type
Principal
Investigator
NIH sponsored
Dalteparin
High Risk VTE Solid Tumor
Patients
C. Francis &
G. Lyman
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
SAVE-ONCO
Semuloparin
Lung, Pancreas, Stomach,
A. G. Turpie
Colon/Rectum, Bladder, Ovary G. Agnelli
Adapted by Dr Anna Falanga
Anticoagulation as Cancer Rx
► Clear association exists between malignancy and
activation of the hemostatic system
► Cancer patients with VTE are at higher risk for mortality,
and cancer progression
► Impact of anticoagulation on cancer mortality remains an
open question:
–
–
–
Intriguing animal and in vitro studies
Promising clinical studies, but they remain inconclusive
Ongoing studies hopefully will answer this key question
► Mechanism ??
Mechanisms of Cancer-Induced
Thrombosis
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer therapy?
Armand Trousseau’s Observations
“There appears in the cachexiae…a
particular condition of the blood that
predisposes it to spontaneous
coagulation.”
Lectures in Clinical Medicine, 1865
Multiple Mechanisms in
Trousseau's Syndrome
Note : heparin actions
Tissue Factor
microparticles (MPs)
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Varki, A. Blood 2007;110:1723-1729
Pathogenesis of Thrombosis in Cancer
A Modification of Virchow’s Triad
1. Stasis


Prolonged bed rest
Extrinsic compression of blood vessels by tumor
2. Vascular Injury




Direct invasion by tumor
Prolonged use of central venous catheters
Endothelial damage by chemotherapy drugs
Effect of tumor cytokines on vascular endothelium
3. Hypercoagulability



Tumor-associated procoagulants and cytokines (tissue factor, CP,
TNF, IL-1, VEGF, etc.)
Impaired endothelial cell defense mechanisms (APC resistance;
deficiencies of AT, Protein C and S)
Enhanced selectin/integrin-mediated, adhesive interactions
between tumor cells,vascular endothelial cells, platelets and host
macrophages
Mechanisms of Cancer-Induced
Thrombosis: Clot and Cancer Interface
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer therapy?
Activation of Blood Coagulation in Cancer
Biological Significance?
►
Epiphenomenon?
Is this a generic secondary event where
thrombosis is an incidental finding
or, is clotting activation . . .
►
A Primary Event?
Linked to malignant transformation
Interface of Clotting Activation and Tumor Biology –
Early Experiments
Tumor
Cell
TF
FVII/FVIIa
Blood Coagulation
Activation
VEGF
THROMBIN
FIBRIN
Angiogenesis
IL-8
PAR-2
Angiogenesis
TF
Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16
Coagulation Cascade and Tumor Biology
TF
Clottingdependent
VIIa
Clottingindependent
Thrombin
Xa
Clottingdependent
Clottingindependent
Fibrin
Clottingdependent
PARs
Angiogenesis, Tumor
Growth and Metastasis
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584
Regulation of Vascular Endothelial Growth Factor Production
and Angiogenesis by the Cytoplasmic Tail of Tissue Factor
1.
TF regulates VEGF expression in human cancer cell
lines
2.
Human cancer cells with increased TF are more
angiogenic (and, therefore, more “metastatic’) in
vivo due to high VEGF production
Abe et al Proc Nat Acad Sci 1999;96:8663-8668; Ruf et al Nature Med 2004;10:502-509
Regulation of Vascular Endothelial Growth Factor Production
and Angiogenesis by the Cytoplasmic Tail of Tissue Factor
3.
The cytoplasmic tail of TF, which contains three
serine residues, appears to play a role in regulating
VEGF expression in human cancer cells, likely by
mediating signal transduction
4.
Data consistent with new mechanism(s) by which
TF signals VEGF synthesis in human cancer cells
may provide insight into the relationship between
clotting and cancer
Abe et al Proc Nat Acad Sci 1999;96:8663-8668; Ruf et.al. Nature Med 2004;10:502-509
Cancer Cell –
TF-VIIa-PAR2 Signaling
Schaffner and Ruf ATVB 2009;29:1999
Activation of Blood Coagulation
in Cancer and Malignant Transformation
►
Epiphenomenon vs. Oncogenesis:
1.
MET oncogene induction produces DIC in human liver
carcinoma (Boccaccio lab – Turin, Italy)
(Boccaccio et al Nature 2005;434:396-400)
2.
Pten loss and EGFR amplification produce TF activation
and pseudopalisading necrosis through JunD/Activator
Protein-1 in human glioblastoma
(Bratt lab – Emory, Atlanta)
(Rong et al Ca Res 2005;65:1406-1413; Ca Res 2009;69:2540-9)
3.
K-ras oncogene, p53 inactivation and TF induction in
human colorectal carcinoma; TF and angiogenesis
regulation in epithelial tumors by EGFR (ErbB1) –
relationship to EMT (Rak lab – McGill, Montreal)
(Yu et al Blood 2005;105:1734-1741; Milson et al Ca Res 2008;68:10068-76)
Activation of Blood Coagulation
in Cancer: Malignant Transformation
“1. MET Oncogene Drives a Genetic Programme
Linking Cancer to Haemostasis”
►
MET encodes a tyrosine kinase receptor for hepatocyte
growth factor/scatter factor (HGF/SF) 


Drives physiological cellular program of “invasive
growth” (tissue morphogenesis, angiogenesis
and repair)
Aberrant execution (e.g. hypoxia-induced
transcription) is associated with neoplastic
transformation, invasion, and metastasis
Boccaccio et al Nature 2005;434:396-400
“MET Oncogene Drives a Genetic
Programme Linking Cancer to Haemostasis”
►
Mouse model of Trousseau’s Syndrome

Targeted activated human MET to the mouse liver
with lentiviral vector and liver-specific promoter 
slowly, progressive hepatocarcinogenesis

Preceded and accompanied by a thrombohemorrhagic syndrome

Thrombosis in tail vein occurrs early and is followed
by fatal internal hemorrhage

Syndrome characterized by  d-dimer and PT and 
platelet count (DIC)
Blood Coagulation Parameters in Mice
Transduced with the MET Oncogene
Time after Transduction (days)
Transgene
Parameter
0
30
90
Platelets (x103)
968
656
800
D-dimer (µg/ml)
<0.05
<0.05
<0.05
PT (s)
12.4
11.6
11.4
_________
________________
_______________________________
MET
Platelets (x103)
974
350
150
D-dimer (µg/ml)
<0.05
0.11
0.22
PT (s)
12.9
11.8
25.1
GFP
“MET Oncogene Drives a Genetic
Programme Linking Cancer to Haemostasis”
►
Mouse model of Trousseau’s Syndrome


Genome-wide expression profiling of hepatocytes
expressing MET - upregulation of PAI-1 and COX-2
genes with 2-3x  circulating protein levels
Using either XR5118 (PAI-1 inhibitor) or Rofecoxib
(Vioxx; COX-2 inhibitor) resulted in inhibition of
clinical and laboratory evidence for DIC in mice
Activation of Blood Coagulation
in Cancer: Malignant Transformation
2. “Pten and Hypoxia Regulate Tissue Factor
Expression and Plasma Coagulation By
Glioblastoma”
►
Pten = tumor suppressor with lipid and protein
►
Loss or inactivation of Pten (70-80% of
glioblastomas) leads to Akt activation and
upregulation of Ras/MEK/ERK signaling cascade
phosphatase activity
Rong et al Ca Res 2005;65:1406-1413
“Pten and Hypoxia Regulate Tissue Factor Expression
and Plasma Coagulation By Glioblastoma”
►
Glioblastomas characterized histologically by
“pseudopalisading necrosis”
►
Thought to be wave of tumor cells migrating away
from a central hypoxic zone, perhaps created by
thrombosis
►
Pseudopalisading cells produce VEGF and IL-8 and
drive angiogenesis and rapid tumor growth
►
TF expressed by >90% of grade 3 and 4 malignant
astrocytomas (but only 10% of grades 1 and 2)
“Pten and Hypoxia Regulate Tissue Factor Expression
and Plasma Coagulation By Glioblastoma”
Results:
1. Hypoxia and PTEN loss  TF (mRNA, Ag and
procoagulant activity); partially reversed with induction
of PTEN
2. Both Akt and Ras pathways modulated TF in
sequentially transformed astrocytes.
3. Ex vivo data:  TF (by IH-chemical staining) in
pseudopalisades of # 7 human glioblastoma specimens
Both Akt and Ras Pathways Modulate TF
Expression By Transformed Astrocytes
N = Normoxia
H = Hypoxia
Similar data
for EGFR –
upregulation
of TF via JunD/
AP-1 transcription
(CA Res 2009;69:2540-9)
“Pten and Hypoxia Regulate Tissue Factor Expression
and Plasma Coagulation By Glioblastoma”
Pseudopalisading necrosis
H&E
Vascular
Endothelium
TF IHC
Activation of Blood Coagulation in
Cancer: Malignant Transformation
3. “Oncogenic Events Regulate Tissue Factor Expression
In Colorectal Cancer Cells: Implications For Tumor
Progression And Angiogenesis”
►
Activation of K-ras oncogene and inactivation of p53 tumor
suppressor  TF expression in human colorectal cancer cells
►
Transforming events dependent on MEK/MAPK and PI3K
►
Cell-associated and MP-associated TF activity linked to genetic
status of cancer cells
►
TF siRNA reduced cell surface TF expression, tumor growth and
angiogenesis
►
TF may be required for K-ras-driven phenotype
Yu et al Blood 2005;105:1734-41
Activation of Blood Coagulation
in Cancer: Malignant Transformation
TF expression in cancer cells parallels genetic tumor progression
with an impact of K-ras and p53 status
TF Activity (U/106 cells)
Mean Channel TF Flourescence
“Oncogenic Events Regulate Tissue Factor Expression
In Colorectal Cancer Cells: Implications For Tumor
Progression And Angiogenesis”
450
400
350
300
250
200
150
100
50
0
HKh-2
HCT116
del/+
+/+
mut/+
+/+
379.2
mut/+
del/del
160
140
120
100
80
60
40
20
0
HKh-2
HCT116
379.2
(NB: Similar data
for TF-rich MPs)
Activation of Blood Coagulation
in Cancer: Malignant Transformation
“Oncogenic Events Regulate Tissue Factor
Expression in Colorectal Cancer Cells: Implications
for Tumor Progression and Angiogenesis”
Effect of TF si mRNA on tumor growth in vitro and in vivo
“Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells”
%VWF-Positive Area
Effect of TF si mRNA on new vessel formation in colon cancer
Activation of Blood Coagulation
in Cancer: Malignant Transformation
“Oncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells: Implications
For Tumor Progression And Angiogenesis”
Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology
Similar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma
and lung cancer cells, accompanied by epithelial-to-mesenchymal transition (EMT)
Milsom et al CA Res 2008;68:10068-76
TF/VIIa Signaling Monoclonal Antibody
Inhibits Breast Cancer Tumor Growth
0.4
MDA-MB-231mfp
500
Tumor weight (g)
Tumor volume (mm3)
600
IgG1
400
300
5G9
200
100
0
10H10
0
10
20
Days after injection
Versteeg et al Blood 2008;111:190
0.3
0.2
0.1
**
0
30
IgG1 10H10 5G9
Mechanisms of Cancer-Induced
Thrombosis: Implications
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer
therapy?
Activation of Blood Coagulation
in Cancer is Related to Malignant Transformation
Q: What do all of these experiments in mice
have to do with real patients with cancer?
A: They suggest several possible
conclusions, including:
1. Tumor cell-derived, TF-rich microparticles (MPs)
may be an important biomarker for VTE
2. Clotting proteins (e.g. TF) may drive tumor growth
via enhanced cell signaling
3. All patients with oncogene-driven cancer may need
prophylactic anticoagulation
4. Mechanism of action of LMWH may be related to its
ability to interfere with TF expression
Phosphorylated Tissue Factor (pTF)
and Survival in Breast Cancer

#172 consecutive
patients:
pTF
correlates
with PAR-2
expression
Similar
TF data
for pancreatic
and hepatocell.
cancer (Clin Ca
Res 2003;9:5339
2005;11:2531)
Ryden et al. Int J Ca 2010;126:2630-40
Cancer and Thrombosis:
State-of-the-Science Update
Key Questions
1. Does activation of blood coagulation affect
the biology of cancer positively or negatively?
2. Can we treat tumors more effectively using
coagulation protein targets?
3. Can anticoagulation alter the biology of
cancer?
Cancer and Thrombosis:
State-of-the-Science Update
Tentative Answers
1. Epidemiologic evidence is suggestive that VTE is a bad
prognostic sign in cancer
2. Experimental evidence is supportive of the use of
antithrombotic strategies for both prevention of
thrombosis and inhibition of tumor growth
3. Results of randomized clinical trials of LMWHs in cancer
patients indicate superiority to oral agents in preventing
recurrent VTE, as well as possibly increasing survival (not
due to prevention of VTE). Awaiting results of SAVEONCO Trial to help answer these questions.
Hirudin Reduces Pulmonary Metastases
in Mice Independent of Fibrinogen Level
Palumbo et al. Blood, 2000
Ex Vivo Angiogenesis:
Embryonic Chick Aortic Rings
Control Aortic Ring: Day 5
10U/ml dalteparin-treated
Aortic Ring: Day 5
Fernandez, Patierno and Rickles. Proc AACR 2003;44:698 (Abstr. #3055); Rickles J Path Haem Thromb
2006;35:103-10
Effects of Low-Molecular Weight Heparin on
Lung Cancer Cell Apoptosis
► G1 arrest
► Decrease in S phase
► 3-fold  in p21WAF1 and
p27KIP1 (p <0.01)
►
Reversed apoptosis and G1
arrest with p21 or p27 siRNA
Chen et al Cancer Invest 2008;26:718-24
P<0.05
Tube Length (mm/cm2)
Heparins Inhibit Cytokine–induced
Capillary Tube Formation
500
§
§
400
§
*
*
*
300
*
*
*
*
*
Control
*
200
100
0
VEGF
Cytokine
FGF-2
+UFH
TNF-
+enoxaparin
+dalteparin
§ = p<0.05 vs control, * = p<0.05 vs cytokine
Marchetti et al. Thromb Res 2008;121:637-645
LMWH and VEGF Antisense Oligonucleotides Inhibit
Growth and Metastasis of 3LL Tumors in Mice
40 mice with Lewis Lung Cancer (3LL)
► Rx qod x 15 with:
►





►
Control (saline)
VEGF antisense oligos (ASODN)
VEGF mismatch sense oligo (MSODN)
LMWH (dalteparin)
LMWH + ASODN
RESULTS:



Growth Inhibit*
Lung Mets*
47%
27%
59%
38%
38%
25%
ASODN
LMWH
Combined
* P < 0.05
Zhang YH et al Chinese Med J 2006;86:749-52
Inhibition of Binding of Selectins to
Human Colon Carcinoma by Heparins
Stevenson et al Clin Ca Res 2005;11:7003-11
Heparin Inhibition of B16 Melanoma
Lung Metastasis in Mice
Stevenson et al Clin Ca Res
2005;11:7003-11
Effect of Low-Molecular-Weight Heparin on
Circulating Tissue Factor Levels in APC
FRAGEM Study – Advanced Pancreatic Carcinoma Rx with Gemcitabine +/- Dalteparin (200 IU/kg)
TF Ag (pg/ml)
P = 0.005
(#20)
(#19)
Maraveyas et al. Blood Coag Fibrin 2010;21:452-458
• Patient serum inhibition of
pancreatic carcinoma cell migration
aided significantly by LMWH (P =
0.025)
• ? Mechanism – inhibition of NFκB
stimulation of growth factorstimulated transcription
Coagulation Cascade and Tumor Biology
TF
Clottingdependent
VIIa
Clottingindependent
Thrombin
Xa
Clottingdependent
Clottingindependent
?
Fibrin
Clottingdependent
PARs
Angiogenesis, Tumor
Growth and Metastasis
LMWHs; Non-anticoagulant heparins; siRNAs; mAbs; small
molecule inhibitors of VIIa; ASOs; etc.
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
Principles, Challenges, and Solutions
The Complex Clinical Interface of
Malignancy, Thrombosis, and Clinical End
Points in Cancer
Can Anticoagulation Produce Survival Prolongation:
When? How? Why? In Whom? In What Types of
Malignancies? Key Trials?
Alok A. Khorana, MD, FACP
Vice-Chief, Division of Hematology/Oncology
Associate Professor of Medicine and Oncology
James P. Wilmot Cancer Center
University of Rochester
Rochester, New York
Principles, Challenges, and Solutions
► Interface of hemostasis, angiogenesis
and tumor biology
► Impact of the hypercoagulable state
on mortality
► Anticoagulants and survival in cancer
Hemostasis, Angiogenesis and Cancer
(+) Growth factors
(+) Blood vessels
Angiogenesis
(+) Tissue factor
(+) Platelets
Tumor
(+) Fibrin matrix
(+) Fibrin sheath
Thrombus
Tissue Factor Regulates
Hemostasis and Angiogenesis
VEGF: Vascular endothelial growth factor
Carmeliet P, Science 2001
Tissue Factor in Cancer
► Regulated by mutations in KRAS, P53
and EGFR
► May function as an “effector” of the
angiogenic phenotype1,2
► Upregulated in multiple solid tumors2
1.
2.
Yu et al.Blood 2005
Rickles et al Chest 2003
Effect of Tissue Factor
Gene Silencing
TF-expressing HCT116 induce robust angiogenesis
TF-deficient cells show little angiogenesis
Yu, J. L. et al. Blood 2005;105:1734-1741
TF Is Expressed in Preneoplastic and
Neoplastic Pancreas
Normal islets, TF-
Pancreatic dysplasia, TF+
Khorana AA et al. Clin Cancer Res. 2007; 13(10):2870-5
TF, VEGF and MVD in Resected
Pancreatic Cancer
Characteristic
VEGF Expression
Negative
Positive
Microvessel Density
Median MVD
High TF
Low TF
P value
<0.0001
13 (20%)
53 (80%)
41 (73%)
15 (27%)
0.01
8
Khorana AA et al. Clin Cancer Res. 2007; 13(10):2870-5
5
TF and Survival In Pancreatic Cancer
Proportion surviving
Median Survival in pts with TF MP-PCA >2.5 and </=2.5pg/ml.
10
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median survival was
98.5 days for TF >2.5
pg/mL vs.
231 days for TF </=
2.5 pg/mL
p=< 0.0001
0
100 200
300
TF (pg/mL)
Bharthuar et al ASCO GI 2010
400 500
600
Days on study
<2.5
700
800
>=2.5
900
1000
N=117 patients with
pancreaticobiliary
cancers
Approaches to Inhibiting TF
Mceachron and Mackman, J Throm Hem 2009
Principles, Challenges, and Solutions
►
►
►
Interface of hemostasis, angiogenesis
and tumor biology
Impact of the hypercoagulable state
on mortality
Anticoagulants and survival in cancer
Thromboembolism and Mortality
Bleeding
AspirationOther
1%
1%
6%
Respiratory
failure
4%
Infection
9%
Unknown
4%
2nd leading cause of
death in cancer patients
►
►
Thromboembolism
9%
►
Cancer
progression
71%
1.
2.
Khorana AA et al. J Thromb Haemost 2007
Kuderer NM et al ASCO 2008 # 9521
Accounts for 9% of
deaths 1
Associated with early
mortality during
chemotherapy
(HR=6.98)2
47-fold increased risk of
mortality from VTE1
18
16.3
16
14
P<0.0001
12
10
6.3
8
6
4
2
0
With VTE
Without VTE
Adjusted OR 1.8, P<0.0001
Khorana AA et al. Cancer 2007
Inpatient Mortality (%)
Inpatient Mortality (%)
VTE and Inpatient Mortality
20
18
16
14
12
10
8
6
4
2
0
P<0.0001
199519961997199819992000200120022003
VTE
No VTE
VTE Independent Risk Factor for
Overall Mortality
1.00
HR=3.04* [95% CI: 1.31-7.15; P<0.01]
.99
Overall survival
.98
No VTE
.97
.96
.95
.94
.93
VTE
.92
.91
.90
0
10
20
30
Kuderer et al. ASCO Poster Discussion 2009
40
50
60
70
80
90
100 110 120
Time (days)
*Adjusted for all major confounders: Age, gender, race, cancer type, stage, year of therapy,
chemotherapy type and dose intensity, major laboratory abnormalities, PS, BMI, and comorbid conditions
Risk Model
Patient Characteristic
Site of Cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, GU
excluding prostate)
Score
2
1
Platelet count > 350,000/mm3
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
Progression-Free Survival
by VTE Risk Score Categories
1.00
Progression-Free Survival
Low
Intermediate
.90
P<.001
P<0.001*
High
.80
P<.001
.70
0
10
20
30
40
50
60
70
Time (days)
Kuderer et al. Oral Presentation. ASH 2008
80
90
100 110 120
*Overall test of significance
Risk Score and Short-Term Mortality
by VTE Risk Score Categories
1.00
Low
Overall Survival
.95
.90
Intermediate
P < 0.0001
High
.85
.80
.75
0
10
20
30
40
50
60
70
Time (days)
Kuderer NM et al. ASH 2008
80
90
100 110 120
Principles, Challenges, and Solutions
► Interface of hemostasis, angiogenesis
and tumor biology
► Impact of the hypercoagulable state
on mortality
► Anticoagulants and survival in cancer
Prolongation of Survival with LMWH:
A Systematic Analysis
9 LMWH trials in patients with VTE:
LMWH
UFH
OR
(95% CI)
Patients without
cancer
2.6%
(39/1481)
2.8%
(41/1471)
0.94
(0.60-1.47)
Patients with cancer
15.0%
(46/306)
22.0%
(71/323)
0.61
(0.40-0.93)
3-month
Mortality
Hettiarachchi RJ et al. Thromb Haemost 1999;82:947-52
1.
7
kD
a
a
a
kD
kD
kD
pa
ri
n)
pa
ri
n)
(d
al
te
(ti
nz
a
1.
2
a
a
a
a
kD
kD
kD
FH
(e
no
kD
xa
pa
a
(fo
ri
n)
nd
ap
ar
in
ux
)
4.
5
5
5.
5
3
6
U
2
l
FG
F-
on
tr
o
2.
4
C
Change from FGF-2 (%)
FGF-2
UFH
LMWH
120
100
80
60
40
20
0
Conditions
Khorana et al, ATVB 2003
LMWH and Survival
FAMOUS
385 patients with solid
tumour malignancy
R
Dalteparin
5000 units once daily
for up to 1 year
Placebo
Up to 1 year
SCLC study
Small cell lung
cancer (SCLC)
R
Patients with responsive limited
disease received thoracic
radiotherapy
MALT
302 patients with
solid tumor
malignancy
R
Chemotherapy plus
dalteparin 5000 IU od
18 weeks
Chemotherapy
(cyclophosphamide, epirubicin,
vincristine)
18 weeks
Nadroparin
2 weeks therapeutic dose
4 weeks 1/2 therapeutic dose
Placebo
6 weeks
LMWH and Survival
Median survival, months
Trial
Therapy
FAMOUS1
(2002)
Daltaparin
Placebo
Overall
population
p
Good prognosis
population
10.80
9.14
43.5
24.3
0.03
SCLC study2 Daltaparin
(2003)
Placebo
13.0
8.0
16.0
10.0
0.007
MALT3
(2003)
8.0
6.6 (HR 1.0)
15.4
9.4 (HR 0.64)
0.01
Daltaparin
Placebo
1-year survival, %
CLOT4
(2003)
Dalteparin
OAC
62
61 (HR 1.0)
80
64 (HR 0.5)
0.03
HR = hazard ratio; OAC = oral anticoagulant.
1Kakkar AK,
et al. J Clin Oncol. 2004;22:1944-8;
M, et al. J Thromb Haemost. 2004;2:1266-71;
3Klerk CP, et al. J Clin Oncol. 2005;23:2130-5;
4Lee AY, et al. N Engl J Med. 2003;349:146-53.
2Altinbas
Kaplan–Meier survival
distribution function estimate
FAMOUS: Survival for
Good-prognosis Patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
-
Dalteparin
Placebo
17
23
29
35
41 47
53
59 65
71
77
83
Time from randomisation (months)
No. at risk:
47 17
55 31
10 9
9
26 22 20
Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
8
13
8
8
5
5
3
5
2 0 Placebo
5 3 Dalteparin
Anticoagulation Improves Survival
in Small Cell Lung Cancer
Altinbas M et al. JTH, 2004;2:1266-71
MALT: Survival Probability
Probability of Survival
1.0
Nadroparin
Placebo
.8
P = .021
.6
.4
.2
0
0
12
24
36
48
60
72
Months After Randomization
Klerk CP, et al. J Clin Oncol. 2005;23:2130-2135.
84
96
MALT: Patients with Life-expectancy
6 Months or More
1.0
Overall survival (%)
.8
P=.010
.6
.4
Nadroparin
.2
Placebo
0.0
0
12
24
36
48
60
Months after randomization
Klerk CP, et al. J Clin Oncol. 2005;23:2130-2135.
72
84
96
CLOT: Post Hoc Study
Survival Probability (%)
Survival in Patients With Solid Tumors
100
90
80
70
60
50
40
30
20
10
0
Without metastases (n = 150)
Dalteparin
Oral anticoagulant
0
No. at risk:
Without metastases:
Dalteparin
75
OAC
75
With metastases:
Dalteparin 221
OAC
231
60
120
With metastases (n = 452)
180
240
300
360
Days Postrandomization
72
65
70
58
67
56
64
50
59
50
51
44
167
178
132
139
107
116
87
97
74
78
51
64
Lee AYY et al. J Clin Onc (CLOT post hoc study)2005;23:2123-9; Lee AYY et al. N Engl J Med 2003;349:146-53
Anticoagulation and Cancer Mortality
Kuderer et al. Cancer 2007
Prophylaxis in Pancreatic Cancer:
CONKO-004
Observation
15 VTE (9.9%)
9.9% major bleed
Advanced
pancreatic
cancer
N=312
Stratified
by PS,
creat
Gem alone
(57), or
GFFC (255)
Riess et al. ASCO 2009; LBA#4506
R
ITT analysis
RRR =87%
NNT = 12
NNH = 90
Enoxaparin 1mg/kg QD x 3 mo,
then 40 mg QD until PD
2 VTE (1.3%)
6.3% major bleed
Prophylaxis in Pancreatic Cancer:
UK FRAGEM study
Lethal VTE
and sudden
death were
seen in (A)
9%Vs 0% (B)
(p = 0.028)
RR = 0.08
(95% CI =
0.005, 1.45)
RR = 0.38 (95% CI = 0.17, 0.84), p = 0.019
*(<100 days from randomization)
RR = 0.14 (95% CI 0.03, 0.58), p=0.002
Maraveyas, et al. European Journal of Cancer Supplements, Vol 7 No 2, September 2009, Page 362
Early Death
Burden was
11% (A) vs.
7% (B) (p =
0.62).
Ongoing Randomized Studies of
LMWHs in Cancer
►
GASTRANOX (primary gastric cancer):
Enoxaparin in stage III/IV
►
SAVE-ONCO: Semuloparin
►
ABEL (limited SCLC): Bemiparin
►
TILT (NSCLC): Tinzaparin
►
FRAGMATIC (lung cancer)” Dalteparin
Semuloparin (SAVE-ONCO)
►
Indirect inhibitor of factor Xa (mainly) and IIa (residually)
Indirect Fxa Inactivation
Molecular Weight Distribution
Pentasaccharide
AVE5026
EnoxaparinFraxiparin
,
AT-III
Xa
Heparin, Fondaparinux,
O
O
O
O
O
or LMWH
Ratio
AVE5026
Enoxaparin
2000
5000
10000
Low Molecular
Weight Heparin
15000
20000
25000
Molecular
30000
Weight
Unfraction
ated
Heparin
Anti Xa/IIa
Mass—Average
Molecular Mass
Molecular Distribution
>30
2000–3000 Da
40% (<1600 Da)
3.3–5.3
3800–5000 Da
12.2%–20.0% (<2000 Da)
Semuloparin
Potential advantages
► Better risk:benefit ratio
►
100% bioavailability
►
No food/drug interactions
►
Fixed dose, once-daily regimen across
different indications, which simplifies current
VTE prevention strategies
►
Organic compound retains TFPI/TAFI activity
Semuloparin: Comparative Characteristics
Pharmacodynamic/
Potential Benefits
Kinetic Attributes
Oral
Anti-Xa
Enoxaparin Semuloparin
Anti-Xa activity
High anti-Xa activity
Yes
Yes
Yes
Anti-IIa activity
(antithrombin)
Anti-FIIa activity
reinforces
anticoagulation
No
Yes
Yes
Multiple mechanisms of
hemostasis
No
Yes
Yes
Once-daily dosing
4‒9 hours
4‒7 hours
16‒20 hours
Other activity (TFPI,
TAFI)
Half-life
SAVE-ONCO (EFC 6521)
DVT Prophylaxis in Chemotherapy Patients
SAVE-ONCO
►
A multinational, randomized, double-blind, placebo-controlled study to
evaluate the efficacy and safety of semuloparin in the prevention of VTE
in cancer patients at high risk for VTE and who are undergoing
chemotherapy
►
Primary
●
►
To compare the efficacy of 20 mg semuloparin with placebo in the
prevention of VTE in cancer patients at high risk for VTE and who are
undergoing chemotherapy
Secondary
●
●
●
To evaluate the safety of semuloparin as compared to placebo in cancer
patients at high risk for VTE and who are undergoing chemotherapy
To document semuloparin exposures in this population
To identify a metagene predictor of cancer patients at high risk of VTE
Data on file. sanofi-aventis.
EFC6521: VTE Prevention in Cancer Patients
Undergoing Chemotherapy (SAVE-ONCO)
N=3200
Randomization
Dynamic allocation on
• Location of tumor
• Stage of the cancer
• Geographical location
Placebo od
Treatment duration variable: until change of
chemotherapy regimen (initial if >6 months or at
least
3 months and until change of ongoing regimen at
M3)
Semuloparin (20 mg od)
End of study: 7 months after LPI
Metastatic or locally advanced
cancer of lung, pancreas,
stomach, colon/rectum,
bladder, or ovary
initiating chemotherapy
End of treatment
Primary end point
• Symptomatic DVT (LL + UL)
• Nonfatal PE
• VTE-related deaths
Superiority (50% RRR)
event rate 4% in the placebo group
=5%, =10%
Data on file. sanofi-aventis.
FUP visit
1 month
after EOT
SAVE-ONCO (EFC 6521)
DVT Prophylaxis in Chemotherapy Patients
►
Inclusion
●
●
With metastatic or locally advanced solid tumor of the pancreas,
stomach, bladder, lung, ovary, or colon/rectum
Planned to start a course of chemotherapy with a minimum intent of 3
months’ therapy
• Chemotherapy = any conventional cytotoxic treatment. Biological agents
used alone are not considered as chemotherapy but could be associated
with cytotoxic agents
►
Exclusion
●
●
●
●
●
Life expectancy less than 3 months
ECOG performance status of 3 or 4
Calculated creatinine clearance <30 mL/min
Any major surgery within the last 6 weeks or planned during the study
treatment period
Contraindications to anticoagulation
Data on file. sanofi-aventis.
Study Treatment Duration
►
Semuloparin or placebo once-daily injections
●
Until change in the initial chemotherapy regimen
(ie, addition or removal of at least one of the initial
antineoplastic drugs) if after 3 months
or
●
At least 3 months and until the end of a second
chemotherapy regimen if a change in the initial
chemotherapy regimen occurs within the first
3 months and the patient continues on chemotherapy
or
●
Until decision is made to stop definitely chemotherapy if it
occurs within the first 3 months, whichever comes first
Data on file. sanofi-aventis.
SAVE-ONCO: Late Breaking Abstract
DVT Prophylaxis in Chemotherapy Patients
The ultra-low molecular weight heparin (ULMWH)
semuloparin for prevention of venous thromboembolism
(VTE) in patients with cancer receiving chemotherapy:
SAVE ONCO study.
ASCO Abstract Released June 4, 2011
Citation: J Clin Oncol 29: 2011 (suppl; abstr LBA9014)
J Clin Oncol 29: 2011 (suppl; abstr LBA9014)
SAVE-ONCO
Thromboembolic Events
Thrombembolic events (%)
HR=0.36, 95% CI,
0.21-0.60, p<0.0001
Treatment effect
was consistent for
DVT and PE, with
a 59% risk
reduction in PE
rate (odds ratio
0.41, 95%CI 0.19–
0.85).
64% Risk
Reduction
Semuloparin
(n=1,608)
J Clin Oncol 29: 2011 (suppl; abstr LBA9014)
Placebo
(n=1,604)
SAVE-ONCO
Major Bleeding
Major bleeding (%)
HR=1.05, 95% CI, 0.55-1.99)
Semuloparin
(n=1,589)
J Clin Oncol 29: 2011 (suppl; abstr LBA9014)
Placebo
(n=1,583)
The rate of
clinically
relevant
bleeding was
2.8% with
semuloparin vs
2.0% with placebo
(HR=1.40, 95%CI
0.89–2.21)
SAVE-ONCO
DVT Prophylaxis in Chemotherapy Patients
► Of 3,212 randomized patients, 68% had metastatic cancer;
the majority had lung (37%) or colon-rectum (29%) cancer.
► Median treatment duration was ~3.5 months.
► No heterogeneity in the benefit was observed for cancer type
or stage.
► Conclusions: Demonstrated benefit of thromboprophylaxis
with semuloparin in patients receiving chemotherapy without
increase in major bleeding.
► Such patients should be considered for thromboprophylaxis.
J Clin Oncol 29: 2011 (suppl; abstr LBA9014)
Conclusions
►The hemostatic system, angiogenesis and tumor
biology are closely interlinked
►The hypercoagulable state has consequences for
cancer patients
 Direct cause of mortality (PE, stroke, MI)
 Worsened cancer outcomes
Conclusions
► Anticoagulants may have 2-fold benefits for
cancer patients
● Reduction in clinical thrombotic events
● Improvement in survival
► Clinical trials data are conflicting, but suggest
potential benefits for LMWHs in specific cancer
subgroups
► Ongoing studies such as SAVE-ONCO will provide
definitive answers
Principles, Challenges, and Solutions
Optimizing Risk Assessment and
Management of Cancer Patients at Risk
for Venous Thromboembolism (VTE)
Reducing Thrombosis Risk and Related
Complications
Craig M. Kessler, MD, MACP
Professor of Medicine and Pathology
Lombardi Comprehensive Cancer Center
Director, Division of Coagulation
Georgetown University Medical Center
Washington, DC
Risk of VTE Varies Over the
Natural History of Cancer
8
Risk (Odds Ratio)
7
Hospitalization
Chemotherapy Metastasis
6
5
End of life
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
Venous Thromboembolism in
Cancer Patients
Of all cases of VTE:
●
20% occur in cancer patients
Of all cancer patients:
●
●
0.5% will have symptomatic VTE
As high as 50% have VTE at autopsy
Compared to patients without cancer:
●
●
●
Higher risk of first and recurrent VTE
Higher risk of bleeding on anticoagulants
Higher risk of dying
VTE may be presenting sign of occult malignancy
●
●
●
10% with idiopathic VTE develop CA within 2 yrs
20% have recurrent idiopathic VTE
25% have bilateral DVT
Lee & Levine. Circulation 2003;107:I17 – I21;
Bura et. al., J Thromb Haemost 2004;2:445-51
Thrombosis and Survival:
Likelihood of Death After Hospitalization
Probability of Death
1.00
0.80
0.60
0.40
0.20
Nonmalignant Disease
0.00
0
20
40
60 70
80
100
120
Number of Days
Levitan N, et al. Medicine 1999;78:285
140
160
180
Goals of VTE Treatment in the CA Patient
Prevent fatal PE
► Prevent recurrent VTE and thrombus extension
► Minimize long term sequelae of VTE, e.g. Postthrombotic syndrome, pulmonary HBP, etc
► Avoid major bleeding complications
► Overcome anticoagulation resistance/hypercoag
► Circumvent drug-drug interactions and dietary
variability
► Treat concurrent arterial thromboses
► Affect survival?
►
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
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
Rao MV, et al. In: Khorana and Francis,
eds. Cancer-Associated Thrombosis; 2007.
Treatment-related factors
Major surgery
Hospitalization
Chemotherapy
Hormonal therapy
Antiangiogenic agents
ESAs, ?Transfusions
•
•
•
•
•
•
Biomarkers
•
•
•
•
•
•
Platelet and leukocyte counts
Tissue factor
sP-selectin
D-dimer
FVIII
Microparticles
Risk Factors for VTE in the Cancer Host
►
Age >65 (OR= 1.1; 2.6 for
surgery)
Predisposing co-morbidities (OR=2.1
for one co-morb to 3.9 for 3)
►
Female (OR=1.1)
►
Infection (OR=1.8)
►
Race:
● African-Americans higher
risk; (OR=1.2)
● Asians/Pacific Islanders lower
risk (OR=0.7)
►
Renal disease
►
Pulmonary disease
►
Obesity (BMI>30)
►
►
Performance status and
immobility (OR=1.4 with surgery)
Prior history VTE
Khorana. JCO. 2009;27:4839
(OR=6)
►
Arterial thromboembolism
(ATE) (OR=1.5)
►
Inherited thrombophilias
Factor V Leiden (OR=2.2)
Prothrombin 20210A
(OR=1.2-6.7)
Factor V Leiden and Prothrombin G20210A
ONCENOX
67 cancer patients with
VTE
BRAZIL
VERMONT
211 unselected cancer
patients studied
prospectively
30% with VTE
70% without
Case control
101 Cases
101 Controls
4% with FVL
1.5% with PGM
FVL: 1.5% with VTE
2.7% without
PGM: 1.5% with VTE
1.3% without
FVL: 5% cases
3% controls
PGM: 5% cases
0% controls
No effect on VTE risk
No effect on VTE risk
FVL: No effect
PGM: ??
Fareed, abs PO848 ISTH 2003
Ramacciotti, abs PO848
ISTH 2003
Kennedy, abs 2018
ASH 2003
Catheter Related Thrombosis and Factor V
Leiden in CA patients
Reference
Patients
Number
of pts
Ratcliffe35
Solid and
heme
84
CVP
10 (11.9%)
3 (30%)
NS
Fijnheer6
Allo SCT
277
Tunneled
Hickman
33 (12%)
7 (21.2%)
7.7 (1.317.9)
300
Port-A-Cath
25 (8.3%)
5 (20%)
6.1 (1.134.3)
75 (30%)
12 (16%)
2.7 (1.9-3.8)
18 (18%)
1 (5.6%)
0.6 (0.1-5.5)
13 (7.6%)
4 (30.8%) 3.3 (1.1-3.9)
Mandalà8
van Rooden9
Tesselaar19
Abdelkefi11
Breast
cancer
Various
patients1
Solid cancer
Heme SCT
252
101
171
Thrombosis Research 2010;125,318-321
Type of
catheter
Different
types2
Arm
ports/chest
ports
Non
tunneled
catheters
Thrombosis F V Leiden
n (%)
n (%)
OR
Tumor Related Risk Factors
► Primary site of cancer (uterine, brain, renal,
pancreas, GI, lung, leukemia/lymphoma)
► Tumor histology
► Tumor SEER stage
► Regional versus local stage
► Time elapsed since cancer diagnosis
Predictors of VTE in
Hospitalized Cancer Patients
Characteristic
OR
P Value
Site of Cancer
Lung
Stomach
Pancreas
Endometrium/cervix
Brain
1.3
1.6
2.8
2
2.2
<0.001
0.0035
<0.001
<0.001
<0.001
Age 65 y
1.1
0.005
Arterial thromboembolism
1.4
0.008
Comorbidities (lung/renal disease,
infection, obesity)
1.3-1.6
<0.001
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
Effect of Malignancy on Risk of VTE
50
30
53.5
28
22.2
20.3
19.8
20
14.3
10
3.6
2.6
1 to 3 years
5 to 10 years
4.9
1.1
> 15 years
3 to 12 months
0 to 3 months
Distant
metastases
Breast
Gastrointestinal
Lung
0
Hematologicall
Adjusted odds ratio
40
Population-based case-control (MEGA)
study
N=3220 consecutive patients with 1st
VTE vs. n=2131 control subjects
CA patients = OR 7x VTE risk vs.
non-CA patients
Time from diagnosis
Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
Metastatic Cancers Have Higher Risk of VTE
versus Node-negative Cancers
References
Study Type
No. of Pts
OR
95% CI
Distant versus no evidence of distant metastasis
Agnelli et al
Prospective
2,373
Multicenter Registry
2.7
1.4-5.2
19.8
2.6-149.1
Blom et al
Population Based
Case Controls
3, 220
cases
2,131
controls
Alcalay et al
California Tumor
Registry
68,142
3.2
2.8-3.8
Rodriguez et al
California Tumor
Registry
13,031
6.9
5.7-8.2
Blom et al
Registry Linkage
Analysis
66,329
1.9
1.3-2.3
J Surg Oncol. 2011;103:n/a
Incidence of Venous Thromboembolism (%)
Kaplan-Meier Plot of Incidence of VTE After
Colorectal Cancer Diagnosis Stratified by Stage
8
6
A strong relationship between the presence of
metastatic disease at the time of diagnosis
and the incidence of VTE
Metastatic
4
Regional
2
Local
0
0
50
100
150
200
250
300
Days After Cancer Diagnosis
Alcalay A et al. JCO. 2006;24:1112
350
400
Kaplan-Meier Plot of Incidence of
Death after VTE Diagnosis
For local stage disease
HR=1.8
Comparative risk of death with VTE (v
no VTE) is increased and inversely
For overall colorectal CA
related
to HR=1.2 stage of disease and
not significantly different among patients
with
disease (HR = 1.1; 95% CI,
For metastatic
regional stage disease
HR=1.5
1.0 to 1.2; P = .26).
For metastatic
disease HR=1.1
Alcalay A et al. JCO. 2006;24:1112
VTE Associated with Accelerated Death in Breast Cancer
Does Symptomatic VTE Reflect Presence or Emergence
of Metastatic, Aggressive Cancer?
-VTE
+VTE
-VTE
+VTE
White, et al. Thromb Res,120 suppl. 2 (2007)
Treatment Related Risk Factors for
VTE in Cancer Patients
►
Major recent surgery/long duration anesthesia
►
Active chemotherapy
►
Active hormonal therapy
►
Active antiangiogenic therapies
►
Use of erythropoietin stimulating agents
►
Transfusion therapies
►
Central venous access devices
Treatment Factors: Cancer Surgery
RISTOS Prospective Registry Study
31 Departments of Surgery in Italy, n = 2,373 pts
Treatment Factors
OR
95% CI
Prior VTE
6.0
21-16.8
Anaesthesia > 2 hr
4.5
1.1-19.0
Bedrest > 72 hr
4.4
2.5-7.8
Advanced disease
2.7
1.4-5.2
Age > 60 years
2.6
1.2-5.7
Agnelli, Ann Surg 2006; 243: 89-95
Natural History of VTE in Cancer Surgery:
The @RISTOS Registry
►
Web-Based Registry of Cancer Surgery
Tracked 30-day incidence of VTE in 2373 patients
82% received in-hospital thromboprophylaxis
31% received post-discharge thromboprophylaxis
Findings
►
2.1% incidence of clinically overt VTE (0.8% fatal)
►
Most events occur after hospital discharge (40% > postop day 21)
►
Most common cause of 30-day post-op death
►
46.3% of perioperative deaths were due to VTE
Agnelli, Ann Surg 2006; 243: 89-95
Incidence of Venous Thromboembolism (%)
Incidence of VTE after major surgery within 2 mos
of CA diagnosis is lower compared to no surgery
5
4
60% Risk
reduction
3
2
►
Inoperable CA precluded surgery?
►
Significant comorbidities precluded
surgery?
►
Curability/palliation of CA by surgery?
1
0 0
50
100
150
200
Days After Surgery
Alcalay A et al. JCO. 2006;24:1112
250
300
350
400
Independent Risk Factors for DVT/PE
Risk Factor/Characteristic
Odds Ratio
Recent surgery w/ institutionalization
21.72
Trauma
12.69
Institutionalization without recent surgery
7.98
Malignancy with chemotherapy
6.53
Prior CVAD or pacemaker
5.55
Prior superficial vein thrombosis
4.32
Malignancy without chemotherapy
4.05
Neurologic disease w/ extremity paresis
3.04
Serious liver disease
0.10
Heit JA, et al. Thromb Haemost. 2001;86:452-463.
Independent Risk Factors for
Chemotherapy-associated VTE
►
Patient Safety in Surgery Studya revealed the
following independent predictors for VTE:
Disseminated CA
OR= 1.873
Chemotherapy in last 30d
Transfusion > 4 U PRBCs in 72 h pre-op
OR=1.829
OR= 1.609
►
Chemotherapy associated with a 2.2-fold increase
in VTE compared to no chemotxb
►
Rates of VTE rose faster in CA pts on chemotx vs
no chemotx (47% increase vs 26%)
aRogers
SO et al. JAmCollSurg.2007;204:1211;
bBlom
et al. JTH. 2006;4:529
Why the increased risk of VTE with
systemic chemotherapy?
►
75% of VTE occur in first 2 cycles of chemotx
►
Highest VTE rate seen in chemo/neutropenic pts
►
Platinum (cisplatin<oxaliplatins)and anthracyclinebased regimens are associated with especially high
risk for VTE
►
Adjuvant and multidrug regimens with SERMS,
antiangiogenic agents, etc. are thrombogenic
►
Erythropoietin therapy assoc with VTE
►
Gemcitabine and HUS
Khorana AA et al. Blood.2008;111:4902
Prothrombotic Effects of Chemotherapy
► Postulated
●
●
●
●
prothrombotic effects:
Release of procoagulants and cytokines
from damaged cancer cells
Direct drug toxicity on vascular endothelium by
chemotherapy or CVAD
Direct induction of monocyte or tumor cell TF
mRNA
Decrease in physiologic anticoagulants (proteins C
& S ) by MTX, Cytoxan, 5-FU
Falanga A. Haemostasis. 1998;28(suppl 3):50-60.
Candidate Biomarkers for VTE Risk in CA
► Platelet
count
► Leukocyte
► Tissue
count
factor
► P-selectin
► Others
(D-dimer, FVIII, C-reactive protein)
► Thrombin
generation
► Microparticle
production
Survival in metastatic breast cancer
correlates with D-dimer levels
►Breast
cancer patients:
● 23 pre-operative
● 84 metastatic disease
DDmed
75
% Survival
Similar correlations existed with
inflammatory and angiogenic
cytokine expression
DDmed
100
50
Median=87
3 ng/mL
25
0
0
250
500
Days
Dirix LY et al. Br J Cancer 2002;86:389–95.
750
1000
Elevated levels of D-dimer are predictive
of survival in NSC lung cancer
Pre-treatment plasma levels of Ddimer predicted survival
independent of stage,
tumor size, performance status or
histology
100
Survival (%)
80
Low DD group (n=35)
60
(<150 ng/ml)
40
High DD group (n=35)
20
(>150 ng/ml)
0
0
10
20
30
40
Months
Taguchi O. et al. Thorax 1997;52:563–5.
50
60
70
Chemotherapy Induced Changes in Thrombin Antithrombin Complexes in Lung and Breast CA
C1 = Breast Ca
C3 = Non-small Cell
Lung Ca
Weitz IC et al. Thromb Haemost 2002; 88: 213-30
Cumulative probability of venous thromboembolism in
cancer patients (n=840): CATS Study (Symptomatic or Autopsy)
FVIII>232% (N=194; 23%) HR for VTE=2.8
14% vs 4% VTE at 6
mos, P=0.001
FVIII<232%
per FVIII increase of 20%, VTE risk 120%
high FVIII conferred an especially high
risk in younger patients.
Vormittag, R. et al. Arterioscler Thromb Vasc Biol 2009;29:2176-2181
Factor VIII Levels Differ According to the
Tumor Site (P<0.001)
FVIII higher in solid
and Metastatic
(P<0.001)
and Progressive
Disease (P=0.003)
Vormittag, R. et al. Arterioscler Thromb Vasc Biol 2009;29:2176-2181
Copyright ©2009 American Heart Association
Soluble P-Selectin and VTE in Cancer:
CAT Database with a Variety of Malignancies
Kaplan-Meier plot for VTE risk vs sP-Selectin
concentrations ( >53 ng/mL): Newly Dx’d or
Recurrent CA
HR= 2.6
P=0.002
(1l.9% vs 3.7% VTE at 6 mos)
Ay C, et al. Blood. 2008;112:2703-2708
Thrombin Generation in Cancer
Fluorescence units (FU)
Faster rate of
thrombin
generation
More thrombin
generated
Cancer patient
50000
45000
40000
35000
30000
Normal
25000
20000
15000
Hemophiliac
10000
5000
Faster initial
thrombin
generation
0
-10
10
30
50
70
Time (minutes)
Adapted from J Francis
Cumulative Probability of Venous
Thromboembolism (VTE) in all Patients (n = 1,033)
CAT study includes CA pts with new dx CA or CA
progression post CR or PR but no recent chemotx
(within 3 mos), radiotherapy, or surgery (within 2 wks)
At 6 mos, 11% v 4 % VTE, P=0.002
Ay C et al. JCO 2011;29:2099-2103
VTE Incidence In Various Tumors
Oncology Setting
VTE Incidence
Breast cancer (Stage I & II) w/o further tx
0.2%
Breast cancer (Stage I & II) w/chemo
2%
Breast cancer (Stage IV) w/chemo
8%
Non-Hodgkin’s lymphomas w/chemo
3%
Hodgkin’s disease w/chemo
6%
Advanced cancer (1-year survival = 12%)
9%
High-grade glioma
26%
Multiple myeloma (thalidomide + chemo)
28%
Renal cell carcinoma
43%
Solid tumors (anti-VEGF + chemo)
47%
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17).
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)
ATE/VTE Rate (%)
Chemotherapy* plus bevacizumab (n=963)
HR=2.0 (95% CI, 1.05-3.75)
P=.031
Chemotherapy* alone (n=782)
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
Prevention of Initial and Recurrent VTE in
Cancer Patients
► Hospitalized CA patients with medical illness
► Surgical patients: immediate and long term
post-op convalescent periods
► Outpatients with CA and active
chemotherapy
Anticoagulant Prophylaxis to
Prevent Screen-Detected VTE
High Risk Hospitalized Medical Patients
►
3 large, randomized, placebo-controlled, doubleblind trials in medical patients at high risk
including cancer
●
●
●
►
1.
MEDENOX (enoxaparin)1 ~ 15%
PREVENT (dalteparin)2 ~5%
ARTEMIS (fondaparinux)3 ~15%
Screening for asymptomatic DVT with
venography or ultrasound
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
1.7%
1.1%
0.49%
0.16%
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..
0.2%
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
Standard Treatment of VTE
Can We Do Better Than This?
Initial treatment
5 to 7 days
LMWH or UFH
Long-term therapy
Vitamin K antagonist (INR 2.0 - 3.0)
> 3 months
Recurrent VTE and Bleeding During
Anticoagulant Treatment
Patients with cancer and venous thrombosis
30
30
Cancer 21%
20
10
No Cancer 7%
Major Bleeding, %
Recurrent VTE, %
Hazard ratio 3.2 [1.9-5.4]
Hazard ratio 2.2 [1.2-4.1]
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 45
6 7 8 9 10 11 12
Time (months)
(months)
Time
Oral Anticoagulant Therapy
in Cancer Patients: Problematic
►
Warfarin therapy is complicated by:
●
●
●
●
►
Difficulty maintaining tight therapeutic control, due
to anorexia, vomiting, drug interactions, etc.
Frequent interruptions for thrombocytopenia and
procedures
Difficulty in venous access for monitoring
Increased risk of both recurrence and bleeding
Is it reasonable to substitute long-term LMWH
for warfarin ? When? How? Why?
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
Lee AY, et al. N Engl J Med. 2003;349:146-153.
then ~150 IU/kg OD x 5 mo
1 month
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
Bleeding
Dalteparin
N=338
VKA
N=335
pvalue
Major bleed
19 (5.6%)
12 (3.6%)
0.27
associated with death
1
0
critical site*
4
3
transfusion of > 2 units of RBC
or drop in Hb > 20 g/L
14
9
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
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
LMWH and Survival Data (1)
Type of
patients
LMWH
n
Dose and duration
FAMOUS1
(2002)
Advanced
malignancy
Dalteparin
374
5,000 IU OD for 1 y
SCLC study2
(2003)
Small cell lung
Dalteparin
cancer
84
5,000 IU OD for 10 weeks of
chemotherapy
MALT3
(2003)
Advanced
malignancy
without VTE
Nadroparin
302
< 50 kg 3,800 IU, 50 – 70 kg 5,700 IU,
> 70 kg 7,600 IU BID for 2 weeks then
OD for 4 weeks
CLOT4
(2003)
Solid tumours
and VTE
Dalteparin
602
200 IU/kg OD for 1 mo. followed by
150 IU/kg OD for 5 mo.
1Kakkar
AK, et al. J Clin Oncol. 2004;22:1944-1948.
M, et al. J Thromb Haemost. 2004;2:1266-1271.
3Klerk CP, et al. J Clin Oncol. 2005;23:2119-2120.
4Lee AY, et al. N Engl J Med. 2003;349:146-153.
2Altinbas
LMWH and Survival Data (2)
Therapy
Median survival, mo.
Overall pop.
P
Good prognosis pop.
FAMOUS1
(2002)
Dalteparin
Placebo
10.80
9.14
43.5
24.3
0.03
SCLC
study2
(2003)
Dalteparin
Placebo
13.0
8.0
16.0
10.0
0.007
MALT3
(2003)
Dalteparin
Placebo
15.4
9.4 (HR 0.64)
0.01
8.0
6.6 (HR 1.0)
1-y survival, %
CLOT4
(2003)
Dalteparin
OAC
62
61 (HR 1.0)
80
64 (HR 0.5)
0.03
1Kakkar
AK, et al. J Clin Oncol. 2004;22:1944-1948.
M, et al. J Thromb Haemost. 2004;2:1266-1271.
3Klerk CP, et al. J Clin Oncol. 2005;23:2119-2120.
4Lee AY, et al. N Engl J Med. 2003;349:146-153.
2Altinbas
HR = hazard ratio; OAC = oral anticoagulant.
ENOXACAN: Study Design
UFH
5,000 IU SC
Surgery
UFH
5,000 IU
SC TID
Venography
Day 10 ± 2
3-month
follow-up
Surgery
Enoxaparin
40 mg
SC OD
Venography
Day 10 ± 2
3-month
follow-up
Randomization
Enoxaparin
40 mg SC
2 h before
surgery
Br J Surg. 1997;84:1099-1103.
VTE in Evaluable Patients
Patients (%)
Odds ratio 0.78 (95% CI, 0.51 – 1.19)
(n = 312)
Br J Surg. 1997;84:1099-1103.
(n = 319)
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
RCTs of Thromboprophylaxis in Ambulatory Cancer
Patients: Low Molecular Weight Heparin
Trial
FAMOUS
Solid tumors
(Stage III/IV)
TOPIC-I
Breast
(Stage IV)
TOPIC-2
NSCLC
(Stage IV)
PRODIGE
Glioma
SIDERAS
Solid Tumors
(Stage IV)
PROTECHT
Solid Tumors
(Stage III/IV)
N
Treatment
Chemo
Duration
VTE
Major
Bleeding
385
Dalteparin
Placebo
64%
12 months
2.4%
3.3%
0.5%
0
353
Certoparin
Placebo
100%
6 months
4%
4%
1.7%
0
547
Certoparin
Placebo
100%
6 months
4.5%†
8.3%
3.7%
2.2%
186
Dalteparin
Placebo
-
6-12 months
11%
17%
5.1%
1.2%
141
Dalteparin
Placebo/Control
54%
Indefinitely
5.9%
7.1%
2.9%
7.1%
1166
Nadroparin
2:1 Placebo
100%
< 4 months
with chemo
1.4%
2.9%
0.7%
0
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 , 2008
RCTs of Thromboprophylaxis in Ambulatory Cancer Patients
Low Molecular Weight Heparin
Trial
CONKO-04
Pancreatic CA
FRAGEM
Pancreatic CA
SAVE-ONCO
PHACS
Duke and
Uof R
MicroTEC
N
Treatment
Chemo
Duration
VTE
100%
30 weeks
14.5%
312
Enoxaparin 1
mg/kg/d X3mos
and then 40
mg/d
Observation
NNT=12
87%Reduced
symptonatic
VTE
5%
123
Dalteparin
Control
12%
31%
Major
Bleeding
6.3%
9.9%
P=0.6
100%
3 months
100%
3-7 months
locally adv
lung, bladder,
229
Dalteparin
Standard of
care
All nonheme
CA
3 months
VTE risk ≥3
(No brainCA)
NA
NA
227
Enoxaparin
Standard of
Care
Lung,
colon,
6mos
TF MP
NA
NA
Semuloparin 20
3200 mg/d X3-7 mos
Placebo
pancreas
NA
GI, GU
NA
NA
Sideras K, et al.Mayo Clin Proc. 2006;81(6):758-767; Reiss H, et al. J Clin Oncol. 2010;28(suppl):15s.
Abstract 4033; Maraveyas A, et al. Joint ECCO Congress;September 20-24,2009;Berlin, Germany.
Abstract O-6503.1
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
Principles, Challenges, and Solutions
Implications of SAVE-ONCO Trial
If the results of the SAVE-ONCO trial
demonstrate a significant benefit of primary VTE
prophylaxis, as seen in the PROTECHT and
CONKO-004 trials, a change in the guidelines
supporting primary VTE prophylaxis in appropriate patients with cancer may be warranted.
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%
4%
Low
0.00
0
3%
10
20
30
*Overall test of significance
0%
RISK SCORE:
50
60
70
80
90
100
110
120
Time (Days)
1.8%
2%
1%
40
2.0%
0.8%
0.3%
n=734 n=374
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)
Principles, Challenges, and Solutions
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Summary and Conclusions
PROFESSOR LORD AJAY KAKKAR, MBBS (Hons) BSc, PhD, FRCS
Program Chairperson
Professor of Surgery
University College London
Director
Thrombosis Research Institute
London
The Landscape: 2011
► Thrombosis is common in
cancer patients
► Adversely impacts on clinical
outcomes
► Antithrombotic therapy
validated for the prevention
and treatment of CAT
► Coagulation proteases
implicated in tumour biology
► LMWH may prolong survival
Recurrent VTE and Mortality in Incidental vs
Symptomatic PE in Cancer Patients
•
•
•
Symptomatic PE, n = 144
Incidental PE, n = 51
Observed for 12 months
Recurrent VTE
p = 0.77
Survival
p = 0.70
den Exter PL, et al. J Clin Oncol. 2011 May 9. [Epub ahead of print].
SAVE-ONCO
Thromboembolic Events
Thrombembolic events (%)
HR=0.36, 95% CI, 0.210.60, p<0.0001
64% Risk
Reduction
Semuloparin
(n=1,608)
J Clin Oncol 29: 2011 (suppl; abstr LBA9014)
Placebo
(n=1,604)
Cancer Cell –
TF-VIIa-PAR2 Signaling
Schaffner and Ruf ATVB 2009;29:1999
Improving clinical outcomes
► Do we underestimate the
burden of VTE in the cancer
patient?
► Do we understand the impact
of VTE on clinical outcome?
► What additional evidence is
required to improve
thromboprophylaxis?
► Can we manipulate
coagulation biology to
influence the natural history of
cancer?