2. Armand Trousseau
(1801-1867)
• 1. First to associate thrombosis and malignancy.
• 2. First to suggest screening for malignancy in
recurrent or idiopathic thromboembolic disease.
• 3. First to suggest that the pathophysiology was not
mechanical obstruction, but a change in the character
in the coagulation system itself.
• 4. First to suggest the association may be integral to
the cancer growth itself.
– Khorana AA. J. Thrombosis & Haemostasis, 2003
3. January 1, 1867
• “Peter, I am lost, the
phlebitis that has just
appeared tonight leaves
me no doubt about the
nature of my illness.”
• He died six months later
of gastric cancer.
4. Risk of DVT and PE in Patients
With Cancer
20% of cancer patients develop VTE at some point
during their illness
20% of VTE occurs in cancer patients
– Heit, 2005; Prandoni et al, 2005; Hillen, 2000.
Pulmonary embolism represents 1/7 of deaths in
hospitalized cancer patients in early studies.
– Pruemer J. Am. J. Health Syst. Pharm. 62:S4-
6, 2005.
4
5. Thrombosis at Time of Cancer Diagnosis
Associated With Worse Prognosis
• 1 year survival rate for patients with advanced cancer:
• Presented with VTE: 12%
• Presented without VTE: 36%
• Sorensen H et al. N Engl J Med, 2000
6. Effect of Malignancy on the Risk of Venous
Thrombosis Depending on the Duration Between
Diagnosis of Cancer and Venous Thrombosis
Redrawn from Blom JW, et al. JAMA 2005;293(6):715-722.
7. Causes of death in 4466 cancer patients
receiving outpatient chemotherapy
Cause of Death N (%)
All 141 (100)
Progression of cancer 100 (70.9)
Thromboembolism 13 (9.2)
Arterial 8 (5.6)
Venous 5 (3.5)
Infection 13 (9.2)
Respiratory failure 5 (3.5)
Bleeding 2 (1.4)
Aspiration pneumonitis 2 (1.4)
Other 9 (6.4)
Unknown 5 (3.5)
Khorana AA et al. JTH 5: 632–634, 2007.
8. Venous Thrombosis Increases Mortality and
Length Of Stay at MSKCC By About 3-Fold.
25 Overall Mortality Rate (%)
Overall mean LOS (Days)
20 Mortality Rate with VTE (%)
Mean LOS With VTE (Days)
15
10
5
0
2002 2003 2004 2005 2006 2007
9. Identification of Malignancy After
Episode of Thrombosis
Study Idiopathic Secondary Odds Ratio
Thrombosis Thrombosis
Meta-Analysis 50/668 19/1100 4.3
of 7 Studies (7.5%) (1.7%)
(1986-1998)
•Likelihood of finding an occult malignancy is
much greater after an unprovoked VTE than a
secondary VTE.
10. Should We Screen For Cancers In
Patients With Idiopathic VTE?
• Idiopathic thrombosis: 7.5% - 10% diagnosed with cancer within
1-2 years.
• 40-60% of patients already have metastatic disease when their
cancer becomes clinically evident,
• Likelihood of finding early, curable cancers that present with
thromboembolic disease when cancer is only detectable by
aggressive work-up is small.
• Recommend appropriate routine cancer screening for age &
sex, i.e. colonoscopy, prostate exam, mammography, pap and
pelvic exam, etc.
• Follow-up work-up indicated only if initial History/Physical and
routine labs suggest specific site.
11. Risk of Venous Thrombosis per
Type of Malignancy
Adjusted Odds Ratio (95% CI)
No Malignancy 1.00
Lung 22.2 (3.6-136.1)
All Hematological Cancer 28.0 (4.0-199.7)
GI 20.3 (4.9-83.0)
Breast 4.9 (2.3-10.5)
Brain 6.7 (1.0-45.4)
Skin 3.8 (1.1-12.9)
ENT 1.6 (0.4-6.4)
Blom JW, et al. JAMA 2005;293(6):715-722.
12. VTE In Cancer
• Virtually all cancers, solid tumor and
hematologic malignancies, are associated
with thrombotic risk.
• The thrombotic risk appears to be related to
the nature of the specific tumor, and not
simply tumor burden or advanced stage of
disease.
• Most VTE occur “early” and not as a pre-
morbid event.
13. Virchow’s Triad:
Pathophysiology Of Thrombosis
Altered blood Altered blood
vessel wall flow/venous
stasis
Increase in blood
Cancer coagulability
14. Coagulation And Vascular Factors
Contribute to Cancer Associated
Thrombosis
• 1. Tissue Factor:
– Tumor cells directly produce and release Tissue Factor.
– Tissue Factor circulates in microparticles and may result
in systemic thrombotic risk.
• 2. Platelets:
– Early literature suggested role of platelets
adhesion/metastasis of malignant cells.
• 3. Endothelial cell damage.
– Following endothelial cell damage, blood is exposed to a
thrombogenic surface.
– Antiangiogenic agents target endothelial cells.
15. TF Expression is Markedly Increased in
Pancreatic Cancer, Compared With Normal
Pancreatic Epithelium.
• Nitori N. et al. Clin. Canc. Res. 11, 2531-2539, 2005
17. TF Expression Predicts Poor Survival In
Resected Pancreatic Cancer Patients.
All cancer patients With Lymph
node
involvement
Few deaths related to VTE. Therefore, poor prognosis associated
with increased TF expression is largely independent of
thrombosis.
Nitori N. et al. Clin. Canc. Res. 11, 2531-2539, 2005
18. Tissue Factor/Coagulation And
Cancer Progression
• Activation of oncogene/inactivation of tumor
suppressor gene results in cellular
transformation and TF expression as parallel
pathways.
– MET, RAS, P53, PTEN, HIF-1 have been shown to regulate
the expression of TF and other coagulation- related factors.
– Boccaccio and Comoglio. JCO. 27:4827-4833, 2009
– Coagulation may not directly contribute to tumor growth &
progression.
19. Expression of Tissue Factor By
Fibrosarcoma Cells in Mice
• Palumbo, J et al. Blood 2007 110: 133-141
20. Effects of Coagulation System
on Primary and Metastatic
Tumor Growth
• Serine proteases degrade local extracellular matrix, facilitating
invasion and angiogenesis.
• Locally, cancers produce a fibrin network which protects
against immune surveillance and provides the scaffolding for
invasion and angiogenesis.
• Thrombin and other enzymes activate “Protease-Activated
Receptors” (PARs) which regulate cancer, platelets, and
endothelial cells.
21. Systemic Effects of Tissue Factor?
• Why do patients experience
thrombosis at sites distant from the
underlying cancer?
• If Tissue Factor is cell-surface
associated, how does it influence
cancer growth at distant sites?
22. Tissue Factor Circulates in Cell-
Derived Microparticles.
Boulanger et al. Hypertension, Hugel et al, Physiology 20: 22-27, 2005
2006
24. Predictive Model for Chemotherapy-
Associated VTE
Patient characteristic Risk Score
Site of cancer
Very high risk (stomach, pancreas) 2
High risk (lung, lymphoma, gynecologic, bladder,
testicular) 1
Prechemotherapy platelet count 350 x 109/L or more 1
Hemoglobin level less than 10 g/dL or use of red cell
growth factors 1
Prechemotherapy leukocyte count more than 11 x 109/L 1
BMI 35 kg/m2 or more 1
Khorana AA et al. Blood. 111:4902-4907, 2008.
Khorana AA & Connolly GC. JCO. 27:4839-4847, 2009
25. Rates of VTE according to scores from the risk
model in the derivation and validation cohorts
Khorana, A. A. et al. Blood 2008;111:4902-4907
27. Difficulty Using Warfarin For
Anticoagulation in Cancer Patients
• Unpredictable levels of anticoagulation
– Drug interactions
– Malnutrition/anorexia
– Vomiting
– Liver dysfunction.
• Need for interruption of therapy
– Invasive procedures
– Chemotherapy-induced thrombocytopenia
• Higher thrombosis recurrence rate with warfarin in cancer
patients.
– Prandoni et al Blood 100:3484-3488, 2002
28. CLOT Study
• Patients with cancer and DVT &/or PE.
• LMWH, (Dalteparin) compared with warfarin
(vitamin K antagonist).
• All got LMWH (Dalteparin 200 IU/kg, SQ, daily
for 5-7 days, then randomized to:
– 6 months of Warfarin (INR target 2.5) or
– 6 months of LMWH:
• 200 IU/kg, SQ, daily for 1 month, then 150
IU/kg for 5 months.
• Lee et al. NEJM 349:146-53, 2003
29. Dalteparin Resulted in Approximately
50% Reduction in Thrombosis
Recurrences
Lee, A. et al. N Engl J Med 2003;349:146-153
30. CLOT Study: Death From All Causes
• While VTE complications were reduced by effective anticoagulation with
LMWH this was not associated with improved survival.
• No evidence of an anti-tumor effect.
• Lee, A. Y.Y. et al. N Engl J Med 2003;349:146-153
31. Enoxaparin vs Warfarin in
Treatment of Thrombosis In Cancer
• Enoxaparin 1.5 mg/kg qd in acute phase, then
randomization to continued Enoxaparin or Warfarin
– Meyer G et al. Arch Int Med. 162: 1729-1735, 2002
32. Is There A Benefit of Anticoagulation In Cancer
Survival Beyond Treatment of Thrombosis?
• 1. Several studies have shown that some anticoagulants,
particularly LMWH, may prolong survival in cancer patients,
specifically in “good” prognosis patients (i.e. those with no
identifiable metastases).
– May be synergistic with chemotherapy.
• 2. Other studies have failed to show any benefit to overall
survival.
• 3. No human study has shown objective benefit of
anticoagulation on tumor burden, (but no study designed to test
this).
• 4. Most studies suffer from heterogeneity of cancer types and
stages.
• 5. Anticoagulants are not currently recommended to improve
survival in patients with cancer without VTE.
33. Characterization of Recurrent VTE In
Cancer
Goal is to identify subgroup of VTE in
cancer who have high or low recurrence
rates, to better stratify needs for
anticoagulation.
1,392 patients, treated for VTE with daily
Dalteparin 200, 2008-2009 at MSKCC.
– Weber C et al. ASH Abstract 2010.
34. Incidence of Recurrent VTE
Variable Recurrent 6 month incidence P value
VTE of recurrent VTE
(frequency) (95% CI)
All patients 34 2.3% (1.7%-3.3%)
Sex Female 23 3.0% (2.0%-4.6%) 0.08
Male 11 1.6% (0.8%-2.9%)
Age Continuous 0.04
Diagnosis Lung 10 5.6% (3.1%-10.3%) 0.03
Breast 4 2.7% (0.8%-8.3%)
Ovarian 2 1.9% (0.5%-7.8%)
Soft tissue 0 0
Lymphoma 0 0
Other 18 2.1% (1.3%-3.3%)
Weber C et al. ASH Abstract 2010.
35. Age of Patients and VTE
Recurrence Rates (%)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
<55 yr 55-64 yr 65-73 yr 74+ yr
Weber C et al. ASH Abstract 2010.
36. Recurrent VTE
The risk of death was 3-fold higher among
patients with recurrent thrombosis.
This result is maintained when sex, age, and
diagnosis are included in a multivariate analysis.
Age, tumor type, and gender may require
different treatment strategies.
Weber C et al. ASH Abstract 2010.
37. Incidental Pulmonary Embolism
Clinical relevance?
Risks of recurrence, need for anticoagulation?
Retrospective cohort study (2004-2010)
Incidental PE (n=51)
Symptomatic PE (n=144)
Observed for 1 year
Den Exter P L et al. JCO 29:2405-2409, 2011.
38. Incidental vs. Symptomatic VTE
Incidental and symptomatic patients did not differ with
respect to mean age, sex, cancer type and
stage, and risk factors for VTE.
As a result from evolving treatment
guidelines, approximately half of the patients in both
groups received long-term treatment with vitamin K
antagonists in stead of currently recommended low-
molecular-weight heparin.
– Den Exter P L et al. JCO 29:2405-2409, 2011.
41. Overall Survival Recurrent Thrombosis-
Free Survival
Font C, et al. Annals of Oncology 22: 2101–2106, 2011
42. Thrombosis Prophylaxis In
Hospitalized Medical Patients
Placebo Treatment
Group Group Events Relative
Trial Agent Events (%) (%) Risk P
Enoxaparin
MEDENOX 40 mg qd 14.9 5.5 0.37 <0.001
MEDENOX Enoxaparin
(Cancer 40 mg qd
Subgroup) 19.5 9.7 0.5
Dalteparin
PREVENT 5000 Un pd 4.96 2.77 0.55 0.0015
Fondaparinux
ARTEMIS 2.5 mg qd 10.5 5.6 0.47 0.029
Lyman G, et al. J Clin Oncol 2007. 25:5490-5505.
43. Extended Thromboprophylaxis
In Surgical Oncology Patients
Thrombosis “Short” “Extended” P
Prophylaxis Prophylaxis
(7-10 days) (4-5 weeks)
DVT (%) 15 6.5 <0.005
Proximal DVT (%) 5 1 <0.01
Symptomatic DVT (%) 1 0.3 0.27
Pooled data from 4 studies of surgical patients with Low
Molecular Weight Heparin.
Data on mortality not significant.
Kakkar AK. JCO 27:4881-4884, 2009
44. Rates of VTE in Recent Primary
Prophylaxis Studies (Ambulatory)
Solid PancreasPancreas
Tumor Ca Ca
Agnelli et al, 2009; Palumbo et al, 2009; Riess et al, 2009;
Maraveyas et al, 2009.
45. Recent Studies Of Extended Prophylaxis
In High Risk Medical Patients
Study Primary Major
Efficacy Bleeding (%)
Endpoint (%)
EXCLAIM Placebo (after open- 4.0 0.3
(2010)4 label enoxaparin run-
in)
Extended enoxaparin 2.5 0.8
MAGELLA Enoxaparin/placebo 5.7 0.4
N
Extended rivaroxaban 4.4 1.1
1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et
al, 2006; 4. Hull et al, 2010
45
46. SAVE-ONCO
Semuloparin placebo Hazard Ratio
N=1,608 N= 1,604
Thrombosis 20 (1.2%) 55 (3.4%) 0.36 p<0.0001
(95% CI: 0.21–0.60)
Major 19 (1.2%) 18 (1.1%) 1.05
Bleeding (95%CI 0.55 to 1.99)
clinically 2.8% 2.0% HR=1.40
relevant (95%CI 0.89–2.21).
bleeding
59% risk reduction in PE rate (odds ratio 0.41,
95%CI 0.19–0.85).
47.
48. The Question Everyone Is Asking!
Should we use the new oral
anticoagulants for VTE treatment in
cancer?
Dabigatran (Pradaxa): Direct Thrombin
Inhibitor
Rivaroxaban (Xarelto): FXa inhibitor
Apixaban: FXa inhibitor
49. Use In Cancer Patients
• Studies of the new agents did not have adequate
cancer population for subgroup analysis.
• VTE treatment studies used warfarin as the control
arm, but warfarin has already been shown to be unsafe
and ineffective for DVT treatment in cancer patients.
– Warfarin is not the standard of care in cancer.
• No reversal agent,
• No established assay to monitor dose/effect
• Specific studies will need to be conducted in cancer
patients, with LMWH control.
50. Questions To Answer
• Does anticoagulation reduce primary or metastatic
tumor growth?
• Is there a survival benefit from anticoagulation, separate
from thrombosis prophylaxis?
• Is there a role for anti-platelet agents?
• In cancer setting, what is optimal anticoagulation
therapy for indications besides venous thrombosis? (i.e.
mechanical valves, atrial fibrillation)?
• Interaction of Thrombophilia in Patient and Tumor
Progression?
51.
52. Effect of Malignancy on the Risk of Venous
Thrombosis Depending on the Duration Between
Diagnosis of Cancer and Venous Thrombosis
Duration Between Malignancy Adjusted Odds Ratio
and Venous Thrombosis (95% CI)
No Malignancy 1.00
All Malignancies 4.3 (3.3-5.6)
Time after index date (diagnosis)
0 to <3 mo 53.5 (8.6-334.3)
>3 mo to <1 y 14.3 (5.8-35.2)
>1 to <3 y 3.6 (2.0-6.5)
>3 to <5 y 3.0 (1.5-5.7)
>5 to <10 y 2.6 (1.4-4.7)
>10 to <15 y 2.3 (0.9-5.8)
>15 y 1.1 (0.6-2.2)
Redrawn from Blom JW, et al. JAMA 2005;293(6):715-722.
