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A Year 2010 Milestone Summit
New Frontiers and Evolving Paradigms
in Cancer and Thrombosis
Optimizing Prevention, Risk Assessment, and
Management of Thrombotic Complications in
Malignancy: What Do the Trials Teach Us?
How Should the Science Guide Us?
Program Chairman
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Program Faculty
Program Chairman
Samuel Z. Goldhaber, MD
Alok A. Khorana, MD, FACP
Craig Kessler, MD
Frederick R. Rickles, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Professor of Medicine
Department of Hematology
Anticoagulation Services
Georgetown University Medical Center
Washington, DC
Vice-Chief, Division of Hematology/Oncology
Associate Professor of Medicine and Oncology
James P. Wilmot Cancer Center
University of Rochester
Rochester, NY
Clinical Professor of Medicine, Pediatrics,
Pharmacology and Physiology
Division of Hematology-Oncology
Department of Medicine
The George Washington University School of
Medicine and Health Sciences
Washington, DC
Program Agenda
8:15 PM — 8:30 PM
Program Chairman’s Concluding Vision Statement:
Current and Near Future Perspectives of VTE
Management in the Setting of Malignancy
Translating Scientific Advances into Clinical Practice
Program Chairman
Samuel Z. Goldhaber, MD
Cardiovascular Division │ Brigham and Women’s Hospital │
Professor of Medicine │ Harvard Medical School
8:30 PM — 8:45 PM
Interactive Q&A and Discussion Session
Disclosures
Research Support
BMS; Boehringer-Ingelheim; Eisai; Johnson
& Johnson, Sanofi-Aventis
Consultant
Boehringer-Ingelheim; BMS; Eisai; EKOS:
Medscape; Merck; Pfizer; Sanofi-Aventis
A Year 2010 Milestone Summit
New Frontiers and Evolving Paradigms
in Cancer And Thrombosis
Epidemiology, Trials, Guidelines
Program Chairman
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Epidemiology
As Number of Cancer Survivors
Increase, VTE Rates Increase
Stein PD, et al. Am J Med 2006; 119: 60-68
Stein PD, et al. Am J Med 2006; 119: 60-68
Bladder
Cervix
Breast
Leukemia
Liver
Ovary
Colon
Kidney
Rectal
Prostate
Esophagus
Lung
Uterus
Lymphoma
Stomach
Myeloprol
Brain
Pancreas
Relative Risk of VTE in
Cancer Patients
VTE Risk and Cancer Type:
“Solid and Liquid”
Relative Risk of VTE Ranged From 1.02 to 4.34
4.5
4
3.5
3
2.5
2
1.5
1
0.5
Rate of PE Diagnosis
is Increasing in the USA
250,000
200,000
150,000
100,000
229,637
Total cohort
Surgical patients
Non-surgical patients
163,096
126,546
90,468
66,541
50,000
36,078
0
1998
CHEST 2009; 136: 983-990
1999 2000 2001 2002 2003 2004 2005
Hospital Costs are Skyrocketing
CHEST 2009; 136: 983-990
DVT: Ominous Sequellae
►
30% recur over 10 years (after anticoagulation is
discontinued)
►
More than ½ of DVTs result in chronic venous
insufficiency
►
Leads to PE, potentially fatal
►
1% to 4% of PEs evolve chronic thromboembolic
pulmonary hypertension (CTEPH)
Recurrent VTE is Common After A First
Episode of Symptomatic DVT
355 patients followed for 8 years
30
25
20
Cumulative
Incidence (%)
15
10
5
0
0
1
2
3
4
Years
Prandoni et al, Ann Intern Med 1996;125:1-7
5
6
7
8
Stages of Chronic Venous
Insufficiency
1.
Varicose veins
2.
Ankle/ leg edema
3.
Stasis dermatitis
4.
Lipodermatosclerosis
5.
Venous stasis ulcer
Progression of
Chronic Venous Insufficiency
From UpToDate 2006
U.S.A.
SURGEON
GENERAL:
CALL TO ACTION
TO PREVENT
DVT AND PE
September 15,
2008
100,000-180,000
Deaths/year in USA
CTEPH
RECURRENT
ACUTE PE
Lang, I. M. NEJM 2004;350:2236-2238
DVT FREE Registry
5,451 patients enrolled prospectively
●
Consecutive acute DVT diagnosed by venous
ultrasonography
No exclusions
●
183 participating sites in the U.S.
●
Goldhaber SZ, Tapson VF. Am J Cardiol 2004;93:259-262.
DVT FREE Registry (N=5,541):
TOP 5 Medical Comorbidities
1.
2.
3.
4.
5.
Hypertension
Immobility
Cancer
Obesity (BMI > 30)
Cigarette Smoking
Am J Cardiol 2004; 93: 259-262
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Pivotal VTE
Primary Prevention Trials
Trials of VTE Prophylaxis in
Hospitalized Medical Patients
► MEDENOX
●
(enoxaparin 40 mg)
Samama MM, et al. N Engl J Med.
1999;341:793-800.
► PREVENT
●
(dalteparin 5000 IU)
Leizorovicz A, et al. Circulation.
2004;110:874-879.
► ARTEMIS
●
(fondaparinux 2.5 mg)
Cohen AT, et al.
●
BMJ 2006; 332: 325.
PREVENT-Dalteparin Trial (N=3,681)
►A
multicenter, randomized, controlled study in
acutely ill medical patients
► Compared
the incidence in the dalteparin and
placebo groups of:
●
●
●
Any symptomatic VTE
Asymptomatic proximal DVT
Sudden death
Circulation 2004; 110: 874-879
Randomization
PREVENT Study Design (N=3,681)
Treatment period
Follow-up period
Dalteparin
No study drug
Placebo
No study drug
Day 14
Day 90
Day 21
Primary endpoint/
Bilateral leg U/S
• Dalteparin 5000 Units SC once daily (12-14 d)
• Placebo SC once daily (12-14 d)
Primary Efficacy Endpoint:
VTE (Day 21)
Dalteparin
N=1518
Placebo
N=1473
42
73
2.77%
4.96%
95% CI
Difference
in Incidence
(%)
-2.19
-3.57 to -0.81
P = 0.0015
Circulation 2004; 110: 874-879
Risk
Ratio
0.55
0.38 to 0.80
Dalteparin Benefit Similar
Across Subgroups
► Age
► Gender
► Cancer
► Obesity
► Previous
DVT
Quality Improvement Initiative to
Improve VTE Prophylaxis
► Randomized
controlled trial to issue or
withhold electronic alerts to MDs whose
high-risk patients were not receiving
VTE prophylaxis
Kucher N et al. NEJM 2005; 352: 969
Computer Program
► We
developed a computer program linked to
the patient database that screened the
system daily to identify high-risk patients.
► We
included consecutive high-risk patients
on medical and surgical services who were
not receiving DVT prophylaxis.
Kucher N et al. NEJM 2005; 352: 969
Definition: “High Risk”
VTE risk score ≥ 4 points:
►
Cancer
3 (ICD codes)
►
Prior VTE
3 (ICD codes)
►
Hypercoagulability
3 (Leiden, ACLA)
►
Major surgery
2 (> 60 minutes)
►
Bed rest
1 (“bed rest” order)
►
Advanced age
1 (> 70 years)
►
Obesity
1 (BMI > 29 kg/m2)
►
HRT/OC
1 (order entry)
Randomization
VTE risk score > 4
No prophylaxis
N = 2,506
INTERVENTION:
Single alert
N = 1,255
Kucher N, et al. NEJM 2005;352:969-977
CONTROL
No computer alert
N = 1,251
Baseline Characteristics
► Median
age:
► Medical services:
► Surgical services:
62.5 years
83%
17%
► Comorbidities
●
●
●
●
Cancer:
Hypertension:
Infection:
Prior VTE:
Kucher N, et al. NEJM 2005;352:969-977
80%
34%
30%
20%
Primary End Point
%Freedom from DVT/ PE
100
98
Intervention
96
94
Control
92
90
0
Number at risk
Intervention 1255
Control
1251
Kucher N, et al. NEJM 2005;352:969-977
30
60
Time (days)
977
976
900
893
90
853
839
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Pivotal VTE Treatment Trial
in Patients with Cancer
Cancer and VTE
►
3-fold higher recurrence and bleeding, when
treating cancer patients (Prandoni. Blood 2002;
100: 3484)
►
LMWH Monotherapy halves recurrence,
compared with warfarin.
FDA approved May 2007
Lee AYY. NEJM 2003; 349:146
“CLOT Trial”
► Dalteparin
monotherapy for 6 months was
more effective (8.8% vs. 17% recurrence)
than warfarin in 672 cancer patients with
DVT.
► Dalteparin
dose: 200 u/kg daily 1st month,
then 150 u/kg daily.
Agnes Lee, et al. NEJM 2003; 349:146-153)
Dalteparin Reduces VTE Recurrence in
Cancer Patients (N = 676)
CLOT TRIAL
NEJM 2003; 349:146-153
LMWH Monotherapy
►
Cancer patients with DVT/PE
►
Any patient who fails warfarin (has
recurrent DVT/PE) despite target INR
►
Difficulty maintaining target INR
►
Poor GI absorption of meds
►
Alopecia or rash from Coumadin
►
“Bridging”
ACCP VTE Rx in Cancer: Guidelines
8th Edition
1. At least 3 months of LMWH.
2. Then administer LMWH or warfarin as
long as the cancer is active.
3. Indefinite duration anticoagulation after
2nd unprovoked VTE.
CHEST 2008; 133: 454S
Conclusions
1. Cancer and VTE are closely linked.
2. Cancer increases VTE risk and may be
occult when VTE is diagnosed.
3. Cancer patients are at high risk for VTE
but receive less prophylaxis than any
other at-risk group of hospitalized
patients.
4. Dalteparin 5,000 U/d is effective for
VTE prophylaxis in cancer patients.
Conclusions (Continued)
5. Dalteparin 200 U/kg/day is effective
for treatment of acute VTE as
monotherapy without warfarin.
6. NCCN, ASCO, and ACCP guidelines
endorse VTE prevention with LMWH
and VTE treatment of cancer patients
with LMWH alone (monotherapy
without warfarin).
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
The Role of the Coagulation
Cascade in Malignant
Transformation
Can Anticoagulation Affect Cancer Survival?
Frederick R. Rickles, MD
Professor of Medicine, Pediatrics,
Pharmacology and Physiology
The George Washington University
Washington, DC
Disclosures
Consultant
Genmab, Bayer/Ortho‐McNeil/J & J,
Pharmacyclics, Leo
Speaker’s Bureau
Eisai
Interface of Coagulation and Cancer
Tumor cells
Angiogenesis,
Basement matrix
degradation.
Fibrinolytic
activities:
t-PA, u-PA, u-PAR,
PAI-1, PAI-2
Procoagulant Activities
TF-rich MPs
IL-1,
TNF-a,
VEGF
PMN leukocyte
Activation of
coagulation
FIBRIN
Platelets
Monocyte
Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis, 2005; Hematology, ASH Education Book, 2007
Mechanisms of Cancer-Induced
Thrombosis: Clot and Cancer Interface
1. Pathogenesis?
2. Biological significance?
3. Anticoagulation and cancer survival?
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
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; Ruf. J Thromb Haemost
Coagulation Cascade and Tumor Biology
TF
Clottingdependent
VIIa
Clottingindependent
Thrombin
Xa
Clottingindependent
Clottingdependent
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
In Situ Localization of Tissue Factor in Vascular Endothelium
of Human Lung Adenocarcinoma – co-localization with vWF
Shoji et al, Amer J Pathol 1998;152:399-411
In Situ localization of Tissue Factor in Tumor Vascular
Endothelium in Invasive Human Breast Cancer
Contrino et al. Nature Med 1996;2:209-215
In Situ Co-Localization of TF and VEGF
mRNA in Lung Adenocarcinoma
H&E
TF
VEGF
Shoji et al. Amer J Pathol 1998;152:399-411
Human melanoma cell lines grown
as xenogeneic tumors in SCID mice
TF high producer
TF low producer
Abe K et al. PNAS 1999;96:8663-8668
©1999 by The National Academy of Sciences
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, perhaps by
mediating signal transduction
4. Thisa and other data on signaling pathways activated
by TF/VIIa engagement of PAR-2b and/or thrombin
engagement of PAR-1c suggest that clotting
pathways are directly involved in regulating tumor
growth, angiogenesis and metastasis
5. Is this a paradigm shift?
a
Abe et al Proc Nat Acad Sci 1999;96:8663-68
Ruf et al Nature Med 2004;10:502-9
c Karpatkin et al Cancer Res 2009;69:3374-81
b
Activation of Blood Coagulation
in Cancer and Malignant Transformation
Epiphenomenon vs. Malignant Transformation?
Paradigm Shift (2005)
1.
MET oncogene induction produces DIC in human liver
carcinoma (Boccaccio lab)
(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)
(Rong et al Cancer Res 2005;65:1406-1413; Cancer 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 EMTs (Rak lab)
(Yu et al Blood 2005;105:1734-1741; Milson et al Cancer 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
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
phosphatase activity
Loss or inactivation of Pten (70-80% of
glioblastomas) leads to Akt activation and
upregulation of Ras/MEK/ERK signaling cascade
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
“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
“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
Yu et al Blood 2005;105:1734-41
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
Yu et al Blood 2005;105:1734-41
Microparticles
•
Originate directly from membrane surface of activated or
apoptotic cell
•
Express surface antigens derived from parent cell
•
Anucleate
•
<1 µm in diameter
•
Procoagulant activity
mediated by TF and/or PS
Burnier L et al. Thromb Haemost 2009;101:439-451
Cumulative incidence of VTE in cancer patients with (--)
/without (  ) circulating TF-bearing microparticles
Zwicker et al. Clin Cancer Res 2009;15:6830-40
Microparticle TF PCA in
Cancer Patients ± VTE
Manly DA, et al. Thromb Res 2010;125:511-512
Activation of Blood Coagulation
in Cancer: Malignant Transformation
►
►
Q: What do these experiments tell us?
A: They suggest two things:
● Tumor cell-derived, TF-rich microparticles
●
(MPs) may be important as a predictive test
for VTE
All patients with oncogene-driven cancer may
need prophylactic anticoagulation
Mechanisms of Cancer-Induced
Thrombosis: Implications
1. Pathogenesis?
2. Biological significance?
3. Anticoagulation and cancer
survival ?
Anticoagulants and Survival
Inconclusive evidence to date
► Experimental data supportive of antitumor
effects but exact mechanisms not established
► Clinical trials provide supportive data for
LMWH but are heterogeneous in design and
methodology:
►
●
●
●
●
●
Tumour types
Stage or course of disease
Treatment history or concurrent cancer therapies
LMWH agents
Doses and regimens of LMWHs
A Lee ICTHIC, 2010
Survival Effect of Anticoagulants
Kuderer N et al. Cancer 2007;110:1149-60.
PROTECHT Study
►
Multicentre, double-blind, placebo-controlled RCT
►
Advanced lung, breast, GI, pancreas, ovary, H+N
►
Nadroparin vs placebo for duration of chemo (up to 4m)
Nadroparin
Placebo
P-value
NNT/H
769
381
1° endpoint: VTE +
ATE
2.0%
3.9%
0.02*
54
Major bleeding
0.7%
0
0.18
154
Death
4.3%
4.2%
1-yr mortality
43%
41%
No. Patients
Agnelli et al. Lancet 2009;10:943-949.
*1-sided
Prophylaxis in Pancreatic Cancer
CONKO 004
no treatment
10%
8%
6%
enoxaparin
FRAGEM
no treatment
40%
P<0.0
1
dalteparin
P<0.02
30%
No survival difference
P=0.6
20%
4%
P=0.03
10%
2%
0%
NS
0%
VTE
bleeding
VTE
fatal PE
Riess et al. ASCO May 2009 and ISTH July 2009. Maraveyas et al. Presented at ESMO 2009.
Gr 3 bleed
Cancer and Thrombosis
Year 2010 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
Year 2010 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 recent, randomized clinical trials of LMWHs in
cancer patients indicate superiority to oral agents in
preventing recurrent VTE; increasing survival (not due to
prevention of VTE) not clear
LMWH in Cancer
Survival Studies
►
INPACT (NSCLC, prostate, pancreatic)
●
►
ABEL (limited SCLC)
●
►
bemiparin + chemo vs. chemo
TILT (nonsmall cell lung cancer)
●
►
nadroparin + chemo vs. chemo
tinzaparin + chemo vs chemo
FRAGMATIC (newly diagnosed lung cancer)
●
dalteparin + chemo vs chemo
Stay tuned !
A Lee ICTHIC, 2010
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Optimizing Risk Assessment and
Management of Cancer Patients at Risk
for Venous Thromboembolism (VTE)
Reducing DVT Recurrence and Related Complications
Craig Kessler, MD
Professor of Medicine
Department of Hematology
Anticoagulation Services
Georgetown University Medical Center
Washington, DC
COI Financial Disclosures
Grant/Research Support:
GlaxoSmithKline, sanofi-aventis, Eisai
Consultant:
sanofi-aventis, Eisai
Outline
► Guidelines
patients
for VTE prevention in cancer
► Opportunities
► Guidelines
►
for improvement
for VTE Treatment
LMWHs—What Do the Trials, NCCN
and ASCO Guidelines Teach Us About
Duration of Therapy and Patients at
Risk?
Recommendations for Venous
Thromboembolism Prophylaxis and
Treatment in Patients with Cancer
ASCO Clinical Practice Guideline
•www.nccn.org
•NCCN Clinical Practice
Guidelines in Oncology™
•Guidelines for supportive
care
•“…the panel of experts
includes a medical and
surgical oncologists,
hematologists,
cardiologists, internists,
radiologists. And a
pharmacist.”
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
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 the presenting sign of occult malignancy
10% with idiopathic VTE develop cancer within 2
years
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
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
Effect of Malignancy on Risk of VTE
53.5
40
30
• 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
28
22.2
20.3
MEGA = Multiple Environmental
and Genetic Assessment casecontrol study
19.8
20
4.9
3.6
2.6
1.1
> 15 years
10
5 to 10 years
14.3
1 to 3 years
Adjusted odds ratio
50
Type of cancer
3 to 12 months
0 to 3 months
Distant
metastases
Breast
Gastrointestinal
Lung
Hematological
0
Time since cancer diagnosis
VTE = venous thromboembolism; CA = cancer; OR = odds ratio. Silver In: The Hematologist - modified from Blom JW, et.
al. JAMA. 2005;293:715-722.
The Importance of DVT Prophylaxis
in Patients With Cancer: ASCO Guidelines
►
VTE is a leading causes of death in CA, occurring in 4% to 20%
patients
►
Hospitalized CA pt and those on chemo tx have greatest VTE
risk
●
●
►
►
►
►
Cancer increased the risk of VTE 4.1-fold
Chemotherapy increased the risk 6.5-fold
Major risk factors: older age, comorbid conditions, recent
surgery or hospitalization, active chemotherapy or hormonal
therapy
All hospitalized CA patients should be considered for prophylaxis
Patients with cancer undergoing surgery should be considered
for prophylaxis
LMWH is the preferred drug
Lyman GH, et al. J Clin Oncol. 2007;25:5490-5505.
Updated ASCO Guidelines
Hospitalized Patients with Cancer
Role of VTE Prophylaxis
Evidence
Patients with cancer should be
considered candidates for VTE
prophylaxis with anticoagulants
(UFH, LMWH, or fondaparinux) in
the absence of bleeding or other
contraindications to anticoagulation
Multiple RCTs of hospitalized
medical patients with subgroups of
patients with cancer. The 8th ACCP
guidelines strongly recommend
(1A) prophylaxis with either lowdose heparin or LMWH for
bedridden patients with active
cancer.
VOLUME 25 NUMBER 34 DECEMBER 1 2007
Prophylaxis in Cancer Patients

Cancer patients undergoing surgical procedures: routine
thromboprophylaxis that is appropriate for the type of surgery
(Grade 1A)

Cancer patients who are bedridden with an acute medical illness:
routine thromboprophylaxis as for other high-risk medical patients
(Grade 1A)

Cancer patients receiving chemotherapy or hormonal therapy:
recommend against the routine use of thromboprophylaxis for the
primary prevention of VTE (Grade 1C)

Cancer patients overall: recommend against the routine use
of primary thromboprophylaxis to try to improve survival
(Grade 1B)
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
Therapeutic Anticoagulation Treatment for
VenousThromboembolism
► The NCCN panel recommends VTE thromboprophylaxis for
all hospitalized patients with cancer who do not have
contraindications to such therapy
► Panel also emphasized that an increased level of clinical
suspicion of VTE should be maintained for cancer patients.
► Following hospital discharge, it is recommended that
patients at high-risk of VTE (e.g. cancer surgery patients)
continue to receive VTE prophylaxis for up to 4 weeks postoperation.
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
Caveats
►
No randomized controlled trials (RCTs) designed
ad hoc for hospitalized medical cancer patients
are available
►
Recommendations are based on RCTs of acutely
ill medical patients, involving a small proportion
of patients with cancer
►
No bleeding data are reported specifically in the
subgroup of patients with cancer
Anticoagulant Prophylaxis to Prevent
Screen-Detected VTE
High Risk Hospitalized Medical Patients
Study
MEDENOX1
P < 0.001
PREVENT2
P = 0.0015
RRRRRR
63%
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
EXCLAIM: Extended-duration Enoxaparin
Prophylaxis in High-risk Medical Patients
(Most benefit seen in Level 1 Disability Patients with
bedrest or sedentary without BRP-some with CA)
Outcome,
extended
prophylaxis,
n=2052 (%)
Outcome,
placebo,
n=2062(%)
0.8%
0.3%
VTE events
2.5
4.0
38%
0.001
Symptomatic
0.3
1.1
73%
0.004
No Sxs
2.5
3.7
34%
0.032
End points
Major bleeding
(Hull RD et al. Ann Intern Med 2010; 153:8)
RR
reduction
(%)
p
PRODIGE: Dalteparin for Primary VTE Prophylaxis in
Newly Diagnosed Malignant Glioma
►
Reduced VTE for dalteparin
5,000 anti-Xa units qd for 6
mos: 11% vs 17% for
placebo
►
Increased ICH: 5.1% vs
1.2% for placebo
►
Both NS significant
Perry JR et al. JTH 2010;8;1959
2009 NCCN Guidelines:
DVT Prophylaxis
Adult
Cancer
Inpatient
Pharmacologic Prophylaxis
UFH
LMWH
Pentasaccharide
Contraindication to
Anticoagulation Treatment
Mechanical Prophylaxis
Sequential Compression Devices
Compression Stockings
NCCN, National Comprehensive Cancer Network.
NCCN. Venous Thromboembolic Disease: Version 1.2006. Available at: http://www.nccn.org/professionals/
physician_gls/PDF/vte.pdf.
Mechanical thromboprophylaxis in critically ill
patients: a systematic review and meta-analysis
RESULTS: 21 relevant studies (5 randomized controlled trials, 13
observational studies, and 3 surveys) were found. A total of 811 patients
were randomized in the 5 randomized controlled trials; 3421 patients
participated in the observational studies.
Trauma patients only were enrolled in 4 randomized controlled trials and
4 observational studies. Meta-analysis of 2 randomized controlled trials
with similar populations and outcomes revealed that use of compression
and pneumatic devices did not reduce the incidence of venous
thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).
A range of methodological issues, including bias and confounding
variables, make meaningful interpretation of the observational studies
difficult.
CONCLUSIONS: The role of mechanical approaches to
thromboprophylaxis for intensive care patients remains uncertain.
The beneficial role for mechanical thromboprophylaxis in cancer
pts is empiric and derived from benefits seen in surgical studies;
No controlled studies in cancer patients
Limbus A et al. Am J Crit Care, 2006;15:402-10
Rate of Appropriate Prophylaxis, %
VTE Prophylaxis Is Underused
in Patients With Cancer
100
90
80
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
70
Cancer:
Surgical
60
52
Major
Surgery2
Major
Abdominothoracic
Surgery (Elderly)3
50
Confirmed DVT
(Inpatients)5
Medical
Inpatients4
40
30
Cancer:
Medical
20
10
5
0
FRONTLINE FRONTLINE:
Surgical
Medical
1. Kakkar AK et al. Oncologist. 2003;8:381-388.
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340.
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912.
Stratton
Bratzler
Rahim
DVT FREE
4. Rahim SA et al. Thromb Res. 2003;111:215-219.
5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262.
Despite Evidence, Medical Patients
at Risk Remain Unprotected
No. of
patients
At risk for
VTE
Receiving
ACCP Tx
ENDORSE1
IMPROVE2
Medical
United
States
Other
Countries
3,410
11,746
37,356
Surgical
30,827
42%
64%
40%
59%
No. of
patients
VTE
prophylaxis
1852 (54%) 5788 (49%)
LMWH
476 (14%) 4657 (40%)
UFH
717 (21%) 1014 (9%)
1. Cohen AT, et al. Presented at: 2007 Congress of the International Society on Thrombosis and
Haemostasis; July 6-12, 2007; Geneva, Switzerland.
2. Tapson VF, et al. Chest. 2007;132(3):936-945.
Electronic Alerts to Prevent VTE in
Hospitalized Patients
100
Freedom From DVT
or PE (%)
98
96
Intervention group
94
92
Control group
90
P<.001
0
0
300
1255
1251
977
976
No. at Risk
Intervention group
Control group
Days
600
90
900
893
853
839
P<.001 by the log-rank test for the comparison of the outcome between groups at 90 days.
Reprinted with permission from Kucher N, et al. N Engl J Med. 2005;352:969-977.
Ambulatory Patients with Cancer Without
VTE Receiving Systemic Chemotherapy
Updated ASCO Guidelines
Role of VTE Prophylaxis
Evidence
Routine prophylaxis with an
antithrombotic agents is not
recommended except as noted below
Routine prophylaxis in ambulatory
patients receiving chemotherapy is not
recommended due to conflicting trials,
potential bleeding, the need for
laboratory monitoring and dose
adjustment, and the relatively low
incidence of VTE.
LMWH or adjusted dose warfarin (INR
~ 1.5) is recommended in myeloma
patients on thalidomide or
lenalidomide plus chemotherapy or
dexamethasone
This recommendation is based on
nonrandomized trial data and
extrapolation from studies of
postoperative prophylaxis in
orthopedic surgery and a trial of
adjusted-dose warfarin in breast
cancer
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.
Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008).
.04
.03
.02
.01
0.00
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]
.99
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
.98
.97
PE
.96
.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.
Low Molecular Weight Heparin in RCTs of
Thromboprophylaxis in Ambulatory Cancer Patients
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 mos

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: Lancet 2009;10, 930
The PROTECHT Study
RCT of Thromboprophylaxis in Cancer Patients Receiving
Chemotherapy
►
RESULTS
Primary Efficacy Outcome: Any TE Event*
●
●
●
●
►
Venous thromboembolism (VTE):
●
●
►
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
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
33 patients in the nadroparin group and 16 in the placebo group
had died; 48 of these deaths were due to disease progression.
Agnelli G et al: Lancet 2009;10:930
LMWH “halves” VTE in ambulatory patients with
metastatic or locally advanced cancer who are
receiving chemotherapy

Agnelli G et al. www.thelancet.com/Oncology Oct 2009
2.1% DVT and 0.8% PE
with placebo (N=381
pts)

p=0.02
NNT=53.8

1% DVT and 0.4% PE
with LMWH (N=769 pts)

PROTECHT
All cause thromboembolic events: 2%
LMWH vs 3.9% in
placebo
Major bleeding:
0.7% LMWH vs
none in placebo
(P=0.18)
By the end of study
treatment, 33
LMWH deaths vs 16
in placebo group;
48 of these deaths
due to CA
progression
Benefits most
apparent in
those with lung
or GI CA (not
pancreatic)
VTE Incidence In Various Tumors
Oncology Setting
VTE
Incidence
Breast cancer (Stage I & II) w/o further treatment
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%
Wilms tumor (cavoatrial extension)
4%
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
Arterial Thrombotic Complications
of Myeloma
VAD (n 6, 5.9%)
TAD (n 2, 4.5%)
PAD (n 3, 6.4%)
N=195
ATE=11
5.6%
4 developed thrombosis
while on VKAs;
2 on LMWH
Libourel et al. Blood 2010;116:2
LMWH Warfarin ASA
9
3
9
15-24
14
18
31 (LDW)
3-14
Palumbo A et al. Leukemia 2008;22:414
These VTE
prophylaxis
regimens have not
been assessed in
any prospective,
randomized trial
and are
recommended
based on anecdotal
experience
Palumbo A et al. Leukemia
2008;22:414
VTE Risk with Bevacizumab in Colorectal Cancer
Approaches Risk of Antiangiogenesis in Myeloma
Naluri SR et al. JAMA. 2008;300:2277
Tamoxifen and Chemotherapy
►
705 postmenopeusal women with breast cancer
►
CMF regimen
►
Total thromboembolic events
►
39 of 54 events occurred during chemotherapy
16
14
12
10
8
6
4
2
0
Pritchard , J Clin Onc, 1996
Rate of thrombosis (%)
p=0.0001
9.6%
1.4%
Tamoxifen
(n=352)
Tamoxifen + CT
(n=353)
Treatment of Patients with Established
VTE to Prevent Recurrence (continued)
Role of VTE Prophylaxis
Evidence
In the absence of clinical trials,
benefits and risks of continuing LMWH
Anticoagulation for an indefinite period
beyond 6 months is a clinical
should be considered for patients with
judgment in the individual patient.
active cancer (metastatic disease,
Caution is urged in elderly patients
continuing chemotherapy)
and those with intracranial
malignancy.
Inferior vena cava filters are reserved
for those with contraindications to
anticoagulation or PE despite
adequate long-term LMWH.
Consensus recommendations due to
lack of date in cancer-specific
populations
Treatment of Patients with Established
VTE to Prevent Recurrence
Role of VTE Prophylaxis
LMWH is the preferred approach for the initial
5-10 days in cancer patient with established
VTE.
LMWH for at least 6 months is preferred for
long-term anticoagulant therapy. Vitamin K
antagonists with a targeted INR of 2-3 are
acceptable when LMWH is not available. The
CLOT study demonstrated a relative risk
reduction of 49% with LMWH vs. a vitamin K
antagonist. Dalteparin sodium approved by the
FDA for extended treatment of symptomatic
VTE to reduce the risk of recurrence of VTE in
patients with cancer (FDA 2007)
Evidence
LMWH for 3-6 months is
more effective than vitamin K
antagonists given for a
similar duration for
preventing recurrent VTE.
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
Dalteparin
N=338
VKA
N=335
pvalue
19 (5.6%)
12 (3.6%)
0.27
Associated with death
1
0
Critical site*
4
3
14
9
46 (13.6%)
62 (18.5%)
Results
Major bleed
Transfusion of > 2 units of RBC
or drop in Hb > 20 g/L
Any bleed
*intracranial, intraspinal, pericardial, retroperitoneal, intra-ocular, intraarticular
Lee AY, et al. N Engl J Med. 2003;349:146-153.
0.09
Overall, these meta-analyses and clinical trials do not
conclusively establish the need for prophylaxis of CVCrelated thrombosis in cancer patients
Chaukiyal P et al. Thromb Haemost 2008;99:38
Influence of Thrombophilia on Thrombotic
Complications of CVADs in Cancer
In 10 studies involving more than 1250 cancer patients with
CVADs vs CA controls:
CA + FVL
OR=5.18 (95% confidence interval: 3.0-8.8)
CA + G20210A
OR=3.95 (95% confidence interval: 1.5-10.6)
The attributable risk of catheter associated thrombosis conferred
by:
FVL
13.5%
G20210A
3.6%
CAVD = central venous access devices
Dentali F, et al. JTH. 2007;5(Suppl 2):P-S-564.
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
What the ASCO/NCCN Guidelines
Do Not Tell Us
►
►
►
►
►
►
►
►
What is the role for emerging novel anticoagulant
medications? No comparisons with LMWH
Is there equivalent safety and efficacy between menoxaparin and Lovenox?
Is there a survival advantage to the use of LMWH in cancer
patients?
Is there a role for adjunctive statins with anticoagulation in
cancer patients?
Is there a role for monitoring hypercoagulability markers in
cancer patients?
How does palliative care influence the survival and VTE
incidence data in cancer patients?
How should incidental VTE be anticoagulated?
What is the role for retrievable IVC filters in CA patients
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Risk Stratification Tools to Identify Patients
for Primary and Secondary Prevention of
VTE in the Setting of Malignancy
Screening and VTE Risk Assessment Across the
Complex Spectrum of Malignant Disorders—What
Works? What Doesn’t?
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
Disclosures
Consultant
sanofi‐aventis, Eisai, Leo Pharma
Speaker’s Bureau
sanofi‐aventis, Leo Pharma
Grant/Research Support
sanofi‐aventis
VTE in Cancer Patients




Risk assessment for VTE in cancer
patients
 Clinical risk factors
 Biomarkers
Risk assessment tools
Implications for thromboprophylaxis
studies
Secondary prophylaxis
Risk Factors for VTE
Patient-related factors
 Older age
 Race, gender
 Comorbidities
Cancer-related factors

Site of cancer

Advanced stage

Initial period after
diagnosis
Rao et al., in Cancer-Associated Thrombosis.
(Khorana and Francis, Eds) 2007
Treatment-related factors
 Hospitalization
 Chemotherapy
 Anti-angiogenics
 Major surgery
 Erythropoiesis-stimulating
agents
 Transfusions
VTE and Site of Cancer
Type of cancer
Hematologic
Lung
Adjusted OR
(95% CI)
28 (4-199.7)
22.2 (3.6-136.1)
GI
20.3 (4.9-83)
Breast
4.9 (2.3-10.5)
Prostate
2.2 (0.9-5.4)
Blom JW et al. JAMA 2005
VTE With Bevacizumab
RR=1.29 (95% CI, 1.03-1.63)
Rate of VTE (%)
13%
9.9
%
RR=1.38 (95% CI, 1.121.70)
6.2%
4.2%
Bevacizum
ab
(n=1,196)
Control
(n=1,08
3)
All-Grade VTE
(6 studies)
Bevacizumab Control
(n=3,795)
(n=3,167)
High-Grade VTE
(13 studies)
However, when
corrected for
exposure time,
RR =1.1
(95% CI, 0.89-1.36)
Biomarkers for
Cancer-Associated VTE
►Blood counts



Platelet count
Leukocyte count
Hemoglobin
►D-dimer
►Soluble P-selectin
►Tissue factor
►C-reactive protein
►Factor VIII
Incidence Of VTE Over 2.5 Months(%)
Incidence of VTE By Quartiles Of
Pre-Chemotherapy Platelet Count
6%
5%
4%
3%
2%
•P =0.005
1%
0%
<250
250-300
300-350
Pre-chemotherapy Platelet Counts (x1000)
Khorana AA et al. Cancer 2005
>350
Incidence Of VTE Over 2.4 Months (%)
Incidence of VTE by Pre-Chemotherapy
Leukocyte Count
6%
5%
4%
3%
2%
•P =0.0008
1%
0%
<4.5 (n=342)
4.5-11 (n=3202)
>11 (n=513)
3
Pre-chemotherapy WBC Counts (x1000/mm)
Khorana AA et al. Blood 2008
Incidence of VTE by Type of Leukocyte
Absolute Neutrophil
Count
Absolute Monocyte
Count
Proportion with VTE
P=0.0001
P<0.0001
Connolly et al ISTH 2009 Abs 1573
Effect of Leukocyte and Platelet Counts
on VTE Risk

In the Vienna CATS registry, platelet count
>443,000 was associated with VTE (HR3.5)
 Simanek et al, J Thromb Hemost 2009

In the REAL-2 study of advanced GEJ/gastric
cancers, leukocytosis was associated with VTE
during chemotherapy (HR 2.0)
 Starling et al, J Clin Oncol 2009
Proportion Died
Mortality by Pre-chemotherapy
Leukocyte Count
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
WBC>11x109/L
WBC<11x109/L
0
14.0% (8.9%-21.6%)
4.4% (3.2%-6.1%)
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Time (Days)
MVA for early mortality: HR 2.0, p = 0.001
Kuderer et al ASH 2008
Connolly et al ISTH 2009, Throm Res 2010
P <0.0001
Tissue Factor in Cancer:
Lack of Standardized Assays
► Immunohistochemistry
of tumor specimens
► TF
ELISA
► TF
MP procoagulant activity assay
► Impedance-based
flow cytometry
Rate of VTE (%)
Tissue Factor Expression and VTE
P = 0.04
Khorana AA, et al. Clin Cancer Res. 2007;13:2870-2875.
Cumulative Incidence of VTE for Cancer Patients
According to TF–bearing Microparticles
Cumulative Incidence of VTE
0.6
Log Rank P=0.002
0.5
0.4
0.3
0.2
0.1
0.0
0
5
Zwicker J I et al. Clin Cancer Res 2009;15:6830-6840
10
15
Months
20
25
FRAGEM and TF Biomarker Data
Boxplot of the percentage change of tissue factor antigen in the sera of
pancreatic cancer patients in both the control and dalteparin groups
250
Control
200
150
100
50
0
-50
Maraveyas, et al. Blood Coagul Fibrinolysis 2010
Dalteparin
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
N=117 patients with
pancreaticobiliary
cancers
1000
D-dimer, F1/2 and VTE in Cancer
Cumulative Risk (probability)
0.25
Elevated D-d + F1/2
0.20
0.15
Elevated F1/2
0.10
Elevated D-dimer
0.05
0
Nonelevated D-dimer
and F1/2
100
200
300
400
500
Observation Time (Days)
Ay, C. et al. J Clin Oncol; 27:4124-4129 2009
600
700
VTE in Cancer Patients




Risk assessment for VTE in cancer
patients
 Clinical risk factors
 Biomarkers
Risk assessment tools
Implications for thromboprophylaxis
studies
Secondary prophylaxis
VTE in Cancer Outpatients
►
►
►
The overwhelming majority of cancer patients
are treated in the outpatient/ambulatory setting
Which patients are most at risk?
Which patients will benefit most from
prophylaxis?
How do you define “high” risk?
►
Level of risk for which prophylaxis is considered
acceptable by both patients and oncologists
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
Rate of VTE over 2.5 mos (%)
Risk Model Validation
8%
7%
Development cohort
6%
7.1%
6.7%
Validation cohort
5%
4%
3%
1.8% 2.0%
2%
1%
0.8%
0%
0.3%
n=734 n=374
Risk
Low (0)
Khorana AA et al. Blood 2008
n=1627 n=842
Intermediate(1-2)
n=340 n=149
High(>3)
Vienna CATS Validation
►
►
Full data available in 839 patients
Median observation time/follow-up: 643 days
Number of
Events
Patients
n
n (%)
17.7%
Score ≥3
Score ≥3
96
16 (17%)
Score 2
Score 2
231
25 (11%)
Score 1
Score 1
233
14 (6%)
Score 0
Score 0
279
7 (3%)
9.4%
3.8%
1.5%
6 months
Ay et al ISTH 2009 Abs
Expanded Risk Score with
D-Dimer and sP-selectin
Score ≥5
Number of
Events
Patients
n
n (%)
30.3%
Score 4
Score 3
1.0%
6 months
Ay et al ISTH 2009 Abs
Score 2
Score 1
Score 0
Score ≥5
31
Score 4
52
Score 3
137
9 (29%)
10
(19%)
15
(11%)
Score 2
226
11 (5%)
Score 1
192
13 (7%)
Score 0
201
4 (2%)
Risk Score and Short-Term Mortality
by VTE Risk Score Categories
1.00
Low
Overall Survival
.95
Intermediate
P < 0.0001
High
.90
.85
.80
.75
0
10
20
30
40
50
60
70
Time (Days)
Kuderer NM et al. ASH 2008
80
90
100
110
120
International Myeloma Working Group
Thromboprophylaxis Recommendations
Individual risk factors: obesity (BMI ≥ 30), prior VTE, central venous catheter
Comorbid risk factors: cardiac disease, chronic renal disease, diabetes, acute
infection, immobilization
Surgery risk factors: trauma, general surgery or any anesthesia
Medications: erythropoietin
Myeloma-related risk factors: diagnosis, hyperviscosity
Myeloma therapy risk factors: multiagent chemotherapy, doxorubicin, high-dose
steroids
Patients with ≤ 1 VTE risk factor: Aspirin (81-325 mg daily)
Patients with ≥ 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose
warfarin, although less existing supporting data for the latter
Patients receiving thalidomide/lenalidomide concurrently with high-dose
dexamethasone or doxorubicin should receive LMWH thromboprophylaxis
Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk
factors are present
Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide associated
thrombosis in myeloma. Leukemia. 2008 Feb;22(2): 414-23.
VTE in Cancer Patients




Risk assessment for VTE in cancer
patients
 Clinical risk factors
 Biomarkers
Risk assessment tools
Implications for thromboprophylaxis
studies
Secondary prophylaxis
Rates of VTE in Recent
Prophylaxis Studies
N=1165
Agnelli et al Lancet Onc 2009
Palumbo et al ASH 2009
Riess et al ISTH 2009
Maraveyas et al ESMO 2009
N=930
N=312
N=123
VTE in Lung Cancer:
PROTECHT and TOPIC studies
sVTE LMWH
sVTE
Placebo
All VTE
LMWH
All VTE
Placebo
3.5%
5%
4%
6.2%
3%
5.7%
4.5%
8.3%
3.2%
5.5%
4.3%
7.8%
PROTECHT
TOPIC-2
All
Major
Bleeding
LMWH
Major
Bleeding
Placebo
1%
0%
TOPIC-2
3.7%
2.2%
All
2.5%
1.7%
PROTECHT
Verso et al. JTH 2010 online
NNT=50 (sVTE)
NNT=28 (allVTE)
RRR=46%
NNH=125
Ongoing Clinical Trials
Study (Agent)
Criteria for
inclusion*
N
Endpoints
PHACS
-Risk score >=3
(dalteparin x 12 wks)
404
Asymptomatic
and symptomatic
VTE
SAVE-ONCO
(semuloparin up
to 4 mos)
3200
DVT, PE, VTErelated death
227
VTE
-Lung, bladder, GI, ovary
-Metastatic or locally
advanced
-Lung, colon, pancreas
MicroTEC
-Metastatic or
(enoxaparin x 6 mos) unresectable
-Elevated TF MPs
* All studies enroll patients initiating a new chemotherapy regimen
VTE in Cancer Patients




Risk assessment for VTE in cancer
patients
 Clinical risk factors
 Biomarkers
Risk assessment tools
Implications for thromboprophylaxis
studies
Secondary prophylaxis
Predictors of Recurrent VTE: Findings
from the RIETE Registry
►
Recurrent PE
●
●
●
►
Recurrent DVT
●
●
►
Age < 65 (OR 3.0)
PE at entry (OR 1.9)
< 3 months from diagnosis of cancer (OR 2.0)
Age < 65 (OR 1.6)
< 3 months from diagnosis of cancer (OR 2.4)
Patients with leukocytosis had increased risk of
recurrent VTE and death (OR 2.7)
Trujillo-Santos et al Thromb Haem 2008
CLOT Study:
Reduction in Recurrent VTE
Probability of Recurrent VTE, %
25
Risk reduction = 52%
p-value = 0.0017
Recurrent VTE
20
OAC
15
10
Dalteparin
5
0
0
Lee et.al. N Engl J Med, 2003;349:146
30
60
90
120
150
Days Post Randomization
180
210
Treatment of
Cancer-Associated VTE
Study
Design
Length
of
Therapy
N
Recurrent
VTE (%)
Major
Bleeding
(%)
(Months)
CLOT Trial
(Lee 2003)
CANTHENOX
(Meyer 2002)
LITE
(Hull ISTH 2003)
ONCENOX
(Deitcher ISTH
2003)
Dalteparin
6
336
9
336
17
67
11
71
21
80
6
87
11
32
3.4
Enox (High)
36
3.1
OAC
34
6.7
OAC
Enoxaparin
3
OAC
Tinzaparin
3
OAC
Enox (Low)
6
0.002
0.0
9
6
4
7
16
6
0.03 8
N
S
NS
0.0
9
N
S
N
S
Death
(%)
39
41
11
23
23
22
NS
0.03
N
S
NR
Conclusions
► Cancer
patients are clearly at increased risk for
VTE but risk varies widely
► Yet,
53% of cancer patients are unaware that
they are at high risk for VTE
Sousou et al, Ca Inv 2010
► High-risk
subgroups can be identified based on
clinical risk factors and biomarkers
►A
recently validated risk model can predict risk
of VTE (and mortality) using 5 simple clinical
and laboratory variables
Conclusions
►LMWH-based prophylaxis is safe and effective in
certain high-risk settings
●
●
Hospitalized and surgical patients
Highly selected cancer outpatients (myeloma,
?pancreas, ?? lung)
►Ongoing studies are adopting novel approaches
to selecting patients for prophylaxis
►Clinicians need to conduct baseline and ongoing
risk assessment for VTE in cancer patients
receiving chemotherapy
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
VISION STATEMENT
VTE in the Setting of Malignancy
Samuel Z. Goldhaber, MD
Cardiovascular Division
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Disclosures
Research Support:
BMS; Boehringer-Ingelheim; Eisai; Johnson
& Johnson, Sanofi-Aventis
Consultant:
Boehringer-Ingelheim; BMS; Eisai; EKOS:
Medscape; Merck; Pfizer; Sanofi-Aventis
New Frontiers and Evolving Paradigms in
Cancer and Thrombosis
Toward Eradication of InHospital VTE:
The Promise of
Prophylaxis
“VITAE” Studies
VTE Prophylaxis in 19,958 Medical
Patients/9 Studies (Meta-analysis)
► 62%
reduction in fatal PE
► 57%
reduction in fatal or nonfatal PE
► 53%
reduction in DVT
Dentali F, et al. Ann Intern Med 2007; 146: 278-288
VITAE I
► VITAE I uses a Federal database to model
Hospitalized Medical Patients with VTE.
► 2 of every 100 hospitalized Medical Service
patients suffer VTE.
With universal in-hospital prophylaxis, the VTE
rate would be cut by 58%.
Thromb Haemost 2009; 102: 505-510
58% Reduction in VTE with Universal
Prophylaxis in Hospitalized Medical Patients
Thromb Haemostas 2009; 102: 505-510
VITAE II
► VITAE II models the 5-year aftermath of initial
VTE among these same Hospitalized Medical
Patients who were initially stricken.
► If universal prophylaxis had been utilized
initially, the 5-year VTE complication rates of
death, recurrence, PTS, and CTEPH would
have been reduced by 60%.
Thromb Haemost 2009; 102: 688-693
VITAE II
Status Quo
Thromb Haemost 2009; 102: 688-693
100% VTE Prophylaxis
Conclusions
1.
Electronic alerts can identify hospitalized
cancer patients at risk for VTE.
2.
Optimal prophylaxis for hospitalized
cancer patients is LMWH.
3.
When VTE is diagnosed in cancer
patients, the only FDA-approved LMWH
for Rx as monotherapy without warfarin
is dalteparin.
Conclusions (Continued)
4.
ACCP guidelines state that “every hospital
should develop a formal strategy to
prevent VTE.”
5.
As cancer therapies improve, quality lifeyears will be extended.
6.
DVT and PE will be mostly prevented in
cancer patients, and when necessary to
treat, will be managed will LMWH
monotherapy.