1. An Oncologists Perspective on Cancer and Thrombosis
Oncology Grand Rounds University of North Carolina Lineberger Comprehensive Cancer Center April 21, 2009
An Oncologists Perspective on Cancer and Thrombosis
Gary H. Lyman, MD, MPH, FRCP(Edin)
Professor of Medicine and Director
Health Services, Effectiveness and Outcomes Research
Duke University School of Medicine and the
Duke Comprehensive Cancer Center

2. Cancer and Venous Thromboembolism (VTE)
Armand Trousseau
Association recognized since Trousseau’s observation more than 130 years ago1
Of all cases of VTE, approximately 20% occur in cancer patients.2
VTE affects 4-20% of cancer patients antemortem but has been reported in up to 50% on postmortem examination.3-4
Cancer-associated VTE has important clinical and economic consequences5-7
Patients with cancer: 20%
On January 1, 1867, Trousseau told his student Peter: “I am lost; the phlebitis that has appeared tonight leaves me no doubt about the nature of my illness” Six months later, Armand Trousseau died of gastric cancer
Bariety M. Trousseau, in: Medecins Celebres,
Venous Thromboembolism (VTE)
A leading cause of morbidity and mortality in patients with cancer
Affects 4-20% of patients with cancer
Appears to be increasing
Burden
Mortality
Morbidity
Other health outcomes
Use of health care resources
All deep venous thrombosis and pulmonary embolism
1. Trousseau, Armand. In Clinique Medicale de l'Hôtel-Dieu de Paris, 2nd ed. Paris: J.B. Bailliere et Fils; Lee AY. Br J. Haematol. 2005;128: Gao S et al: Expert Rev Anticncer Ther 2004; 4:
4. Lyman GH et al: J Clin Oncol 2007; 25: Sorensen HT, et al. N Engl J Med. 2000;343: Prandoni P, et al. Blood. 2002;100: Khorana AA, et al. J Clin Oncol. 2006;24:

3. Pathogenesis: Virchow’s Triad
Stasis
Bed rest and immobility, extrinsic compression of vessel by mass
Blood Components
[Hypercoagulability]
Tumors and macrophages produce procoagulants, inflammatory cytokines
Vessel Damage
Direct tumor invasion, indwelling catheters, chemotherapy, erythropoietin, antiangiogenic agents
Stasis
Prolonged bed rest
Extrinsic compression of blood vessels by tumor
Vascular Injury
Direct invasion by tumor
Prolonged use of central venous catheters
Endothelial damage by chemotherapy drugs
Effect of tumor cytokines on vascular endothelium
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

4. Hemostatic Tumor System Cells Growth Invasion Metastases Angiogenesis
Procoagulant Activity
Cytokines
Growth Factors
Fibrinolytic Activity
Kuderer NM et al J Clin Oncol 2009 (in press)

5. Risk of VTE Varies Over Natural History of Cancer8 7 6 5 4 3 2 1
Hospitalization
End of life
Chemotherapy
Metastasis
Diagnosis
Risk (Odds Ratio)
Risk of VTE in the cancer population
Remission
Risk of VTE in the general population
Time
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

6. VTE within Two years of Cancer Diagnosis
Metastatic Disease Local-Regional Disease
The California Cancer Registry linked to the California Discharge Data,
Among 235,149 cancer cases, 3775 (1.6%) were diagnosed with VTE within 2 years including 463 (12%) at the time cancer and 3312 (88%) subsequently.
Chew, H. K. et al. Arch Intern Med 2006;166:

7. Incidence of VTE in US Patients With and Without Cancer, 1979-1999
National Hospital Discharge Survey
[Stein.AmJMed. Jan.2006/ p62/c2/Figure 1] 4
Cancer 3
No cancer
VTE Incidence (%) 2 1
This graph shows clearly that since the late 1980s, the incidence of deep vein thrombosis/pulmonary embolism (DVT/PE) in patients with cancer has risen dramatically, from approximately 1.5% to greater than 3.5%, even as the incidence of cancer overall has remained relatively steady1
The graph is based on an analysis of the National Hospital Discharge Survey data of numbers of patients discharged with diagnostic codes for 19 types of malignancies, PE, or DVT from 1979 through 19991
Overall, in patients with any of the 19 malignancies covered, 827,000 of 40,787,000 (2.0%) had DVT or PE, which was twice the incidence in patients without these malignancies, 6,854,000 of 662,309,000 (1.0%)1
The highest incidence of DVT/PE was in patients with carcinoma of the pancreas (4.3%), and the lowest incidences were in patients with carcinoma of the bladder and carcinoma of the lip, oral cavity, or pharynx1
The overall incidences of PE and DVT in patients with cancer were double the rates in patients without cancer and were not age dependent1
[1/Stein.AmJMed. Jan.2006/ p62/c2/Figure 1]
[1/Stein/p61/c1/ line 45-55, c2/line 15-50; p62/c1/line 1-6, Table; p63/c1/line 4-9]
[1/Stein/ p63/c1/line 3-20]
[1/Stein/ p64/c2/line 22-27; p63/c1/line 1-6]
[1/Stein/ p60/line A15-A18]
1979
1981
1983
1985
1987
1989
1991
1993
1995
1997
1999
Years
Stein PD, et al. Am J Med. 2006;119:60-68.
1. Stein PD, Beemath A, Meyers FA, et al. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 2006;119:60-68.

8. 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
Treatment-related factors
Major surgery
Hospitalization
Chemotherapy
Hormonal therapy
Antiangiogenic agents
ESAs, ?Transfusions
Cancer-related factors
Site of cancer
Advanced stage
Initial period after diagnosis
Biomarkers
Platelet and leukocyte counts
Tissue factor
P-selectin
D-dimer
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

9. 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
Treatment-related factors
Major surgery
Hospitalization
Chemotherapy
Hormonal therapy
Antiangiogenic agents
ESAs, ?Transfusions
Cancer-related factors
Site of cancer
Advanced stage
Initial period after diagnosis
Biomarkers
Platelet and leukocyte counts
Tissue factor
P-selectin
D-dimer

10. Increased risk of recurrent VTE Bleeding complications
Important Consequences of VTE in Cancer Patients
Increased morbidity
Hospitalization
Anticoagulation
Postphlebitic syndrome
Increased mortality
Increased risk of recurrent VTE
Bleeding complications
Cancer treatment delays
Increased healthcare costs

11. Increased risk of recurrent VTE Bleeding complications
Important Consequences of VTE in Cancer Patients
Increased morbidity
Hospitalization
Anticoagulation
Postphlebitic syndrome
Increased mortality
Increased risk of recurrent VTE
Bleeding complications
Cancer treatment delays
Increased healthcare costs

12. Effect of VTE on Risk of Death Stratified by Stage, Adjusted for Age and Race
CA Cancer Registry linked to Discharge Data
Overall Mortality
HR=3.7 [ ]
Multivariate analysis
Stratified by stage
Adjusted for age, race
VTE is a significant predictor for 1 year mortality for each cancer type
Chew, H. K. et al. Arch Intern Med 2006;166:

13. VTE in Diffuse Large B-cell Lymphoma
Retrospective review of patients with DLBCL treated
Symptomatic VTE at diagnosis or during initial treatment.
27/211 patients (12.8%).
Median survival (years)
Controls: 5.20 [1.80 – 8.60]
VTE: 1.04 [0.75 – 1.33]
P = 0.038
Multivariate Analysis for Mortality*
Variable HR
P-value
Age
1.02
.014
IPI
1.45
.015
VTE
1.92
.025
* Adjusted for sex, race, and stage
Komorokji RS et al. Leuk Lymph 2006; 47:

14. Unsuspected PE On Routine Cancer Staging Impact on Survival
Retrospective review of 70 patients with unsuspected PE found on staging CT
2003–2006
VTE, anticoagulation or multiple cancers excluded
2:1 matching based on
Cancer type
Age
Stage
Unsuspected PE:
Subsegmental: 24.3%
Proximal: 75.7%
HR=1.79 [95% CI: ; P=0.018]
O’Connell CL et al: ASH 2008

15. Unsuspected VTE in Cancer Patients Results from Autopsy Series
Roswell Park Cancer Institute
University of Missouri
Consecutive autopsies in 506 cancer patients
Causes of Death, n (%)
Major
Infection 184 (36%)
Hemorrhage 55 (11%)
VTE 35 (7%)
MI 35 (7%)
Contributing
Infection 68 (13%)
Hemorrhage (25%)
VTE 91 (18%)
MI 13 (3%)
578 consecutive autopsies
145 cancer patients, n (%)
PE 24 (17%)
Fatal PE 20 (14%)
433 noncancer patients
PE 55 (13%)
Fatal PE 343 (8%)
Author’s conclusions:
1 in 7 hospitalized cancer pts died of PE
60% of fatal PEs occur in early or limited metastatic disease
P<.05
Ambrus J et al J Med 1975; 6: 61-64
Shen VS et al. South Med J 1980; 73:

16. Causes of Early Death in Ambulatory Cancer Patients Results from Prospective Study of Series
Patient Population
Prospective study of 4466 patients starting new chemotherapy
Consecutive patients accrued at 117 US practices
Median followup of 75 days, 141 (3.2%) died.
Causes of Death, n (%)
All 141 (100)
Progression of cancer 100 (70.9)
Thromboembolism 13 (9.2)
Arterial 8 (5.6)
Venous 5 (3.5)
Infection 15 (10.6)
Respiratory failure 5 (3.5)
Bleeding 2 (1.4)
Other 9 (6.4)
Unknown 5 (3.5)
Distribution of Cancer Type
Khorana AA et al. J Thromb Haemost 2007; 5:

17. ASCO Clinical Practice Guideline
Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer
ASCO Clinical Practice Guideline
Lyman GH et al: J Clin Oncol 2007; 25:

18. Clinical Questions
Should patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized? √
Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? √
Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis?
What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? √
Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? √
Lyman GH et al: J Clin Oncol 2007; 25: 18

19. 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: 19

20. Risk of Inpatient VTE By Site of Cancer – Solid Tumor
Discharge database of the University HealthSystem Consortium
115 U.S. academic medical centers
66,106 adult neutropenic cancer patients hospitalized 12 10 8
Rate (%) 6 4 2
All
Brain
Lung
Colon
Ovary
Stomach
Pancreas
Other GI
Uterine
Khorana et al, J Clin Oncol 2006; 24:

21. Risk of Inpatient VTE by Type of Cancer – Hematologic Malignancies
[Khorana.JClinOncol. Jan.2006/p488/Table 3, c2] 7 6 5
Percent (%) 4 3 2 1
All
Leukemia
NHL
Hodgkin
Myeloma
Account for one-third of all VTE
NHL=Non-Hodgkin’s lymphoma
Khorana AA, et al. J Clin Oncol. 2006;24: 21

22. VTE Inpatient Risk and Mortality
Discharge database of the University HealthSystem Consortium
133 U.S. academic medical centers
1,015,598 adult cancer patients hospitalized
7.0
VTE: 34, (3.4%)
PE: 11,515 (1.1%)
6.5 20
6.0 18
5.5 16
5.0
4.5 14
4.0
Rate of VTE (%) 12
3.5 10
3.0
Inpatient Mortality (%)
2.5 8
2.0 6
1.5 4
1.0
Consistent with prior reports, we found that the increased diagnosis of VTE continued to be strongly associated with adverse consequences for patients. Mortality was significantly and consistently greater among patients who developed VTE as compared to patients who did not over the duration of study (16.3% versus 6.3%, P<0.0001). Overall, however, the risk of in-hospital mortality declined from 1995 to 2003 both for patients who did and did not develop VTE (P< for trend for each).
P<0.0001
P<0.0001 2
0.5
0.0
1995
1996
1997
1998
1999
2000
2001
2002
2003
1995
1996
1997
1998
1999
2000
2001
2002
2003
VTE- patients on chemo
VTE-all patients
VTE
No VTE
DVT-all patients
PE-all patients
Khorana AA et al. Cancer 2007; 110: 22

23. MEDENOX (enoxaparin)1 ~ 15% PREVENT (dalteparin)2 ~5%
Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients
3 large, randomized, placebo-controlled, double-blind trials in medical patients at high risk including cancer
MEDENOX (enoxaparin)1 ~ 15%
PREVENT (dalteparin)2 ~5%
ARTEMIS (fondaparinux)3 ~15%
Screening for asymptomatic DVT with venography or ultrasound
Samama MM, et al. N Engl J Med. 1999;341:
Leizorovicz A, et al. Circulation. 2004;110:
Cohen AT, et al. BMJ. 2006;332:

24. Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: VTE
RRR
63%
45%
47%
Study RRR Thromboprophylaxis Patients with VTE (%)
MEDENOX1
Placebo
14.9
P < 0.001
Enoxaparin 40 mg
5.5
PREVENT2
Placebo
5.0
P =
Dalteparin 5,000 units
2.8
Data NOT specific to cancer patients
Placebo
10.5
ARTEMIS3
Fondaparinux 2.5 mg
5.6
1Samama MM, et al. N Engl J Med. 1999;341: Leizorovicz A, et al. Circulation. 2004;110:874-9.
3Cohen AT, et al. BMJ 2006; 332: 24

25. Incidence of Major Bleeding (%)
Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding
1.7%
1.1%
Incidence of Major Bleeding (%)
0.49%
0.16%
0.2%
Data NOT specific to cancer patients
Study
Samama MM, et al. N Engl J Med. 1999;341: Leizorovicz A, et al. Circulation. 2004;110:874-9.
Cohen AT, et al. BMJ 2006; 332: 25

26. Routine prophylaxis with an antithrombotic agent is not recommended.
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Ambulatory Cancer Patients
Routine prophylaxis with an antithrombotic agent is not recommended.
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.
Randomized clinical trials evaluating antithrombotic agents in pts with myeloma on thalidomide or lenalidomide are needed.
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: 26

27. Prospective Study of Adult Cancer Patients
Prospective Study of Adult Cancer Patients Receiving Systemic Chemotherapy
Prospective observational study conducted at 117 randomly selected US practice sites.
Data obtained on 4, consecutive adult patients initiating a new chemotherapy regimen between March and February 2006.
There were no exclusions for age, prior history or comorbid ities with nearly 40% of patients age 65 and older.
Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008).

28. Title Slide 28
Subtitle
Reported Cause of Early Mortality Cancer Patients Starting New Chemotherapy
Cause of Death
No VTE
N=4,365
VTE N=93
All N=4,458 PD
2.1
2.2
Infection
0.3 PE
5.4
0.1
Pulmonary
0.2
Bleeding
Other vascular
Unknown
All
3.2
7.6
3.3
[HR=5.48, 95%CI: ; P<.0001]
No VTE
Patients in the intermediate and high VT Risk Score Categories:
have significantly greater cumulative risk of developing VTE
during the first 4 months of chemotherapy
VTE
Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008)

29. RCTs of Thromboprophylaxis in Ambulatory Cancer Patients Warfarin
Double-blind, placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (INR ) 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 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:

30. RCTs of Thromboprophylaxis in Ambulatory Cancer Patients Low Molecular Weight Heparin
Trial N
Treatment
Chemo
Duration
VTE
Major
Bleeding
FAMOUS
Solid tumors
(Stage III/IV)
385
Dalteparin
Placebo
64%
12 months
2.4%
3.3%
0.5%
TOPIC-I
Breast
(Stage IV)
353
Certoparin
100%
6 months 4%
1.7%
TOPIC-2
NSCLC
547
4.5%†
8.3%
3.7%
2.2%
PRODIGE
Glioma
186 -
6-12 months
11%
17%
5.1%
1.2%
SIDERAS
Solid Tumors
141
Placebo/Control
54%
Indefinitely
5.9%
7.1%
2.9%
PROTECHT
1166
Nadroparin
2:1 Placebo
< 4 months
with chemo
1.4%
0.7%
1. Kakkar AK, et al. J Clin Oncol. 2004;22: Haas SK, et al. J Thromb Haemost. 2005(suppl 1): abstract OR Perry JR et al. Proc ASCO Sideras K et al. Mayo Clin Proc 2006; 81: Agnelli G et al. Am Soc Hemat Sunday December 7, 2008

31. The PROTECHT Study RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy DESIGN
Placebo-controlled, double blind, multicenter RCT
Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1
1150 patients receiving chemotherapy for locally advanced or metastatic cancer.
Start with new CTX; continue for maximum of 4 m
Mean treatment duration: 90 days
Primary outcome: clinically detected thrombotic events, i.e., composite of venous and arterial TE*
Main safety outcome: Major bleeding
* deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin
Agnelli G et al: ASH 2009

32. Primary Efficacy Outcome: Any TE Event*
The PROTECHT Study RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy RESULTS
Primary Efficacy Outcome: Any TE Event*
Nadroparin: 16 of 769 (2.1%)
Placebo: 15 of 381 (3.9%)
Relative risk reduction: 47.2%, (interim-adjusted p=0.033)
Absolute risk decrease: 1.8%; NNT = 53.8
Venous thromboembolism (VTE):
Nadroparin: 11 of 769 (1.4%)
Placebo: 11 of 381 (2.9%) NS
Major Bleeding:
Nadroparin: 5 (0.7%)
Placebo: 0 (p= 0.177)
Absolute risk increase: 0.7%; NNH = 153.8
Agnelli G et al: ASH 2009

33. Active, uncontrollable bleeding Active cerebrovascular hemorrhage
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Relative contraindications for anticoagulation
Active, uncontrollable bleeding
Active cerebrovascular hemorrhage
Dissecting or cerebral aneurysm
Bacterial endocarditis
Pericarditis, active peptic or other GI ulceration
Severe, uncontrolled or malignant hypertension
Severe head trauma
Pregnancy (warfarin)
Heparin-induced thrombocytopenia (heparin, LMWH)
Epidural catheter placement
Lyman GH et al: J Clin Oncol 2007; 25: 33

34. Risk of VTE in Cancer Patients Receiving Thalidomide Meta-analysis of RCTs [Estimates ± 95% CI]
Search identified 17 RCTs including 3,977 patients
Incidence of VTE
All Studies: 11.7% [8.1% %]
Multiple Myeloma: 17.7% [10.9% %]
Solid Tumors: 5.3% [2.1% %]
Relative Risk for VTE
All Studies: 2.4 [1.9 – 3.0], P<.001
Multiple Myeloma: 3.1 [2.1 – 4.4], P<.001
Solid Tumors: 3.5 [1.1 – 10.6], P=.028
Prophylaxis (all studies)
No prophylaxis: 3.5 [2.5 – 4.9], P<.001
Prophylaxis: 1.9 [1.4 – 2.5], P<.001
Gray KN et al: ASH 2008

35. Thromboembolism With Bevacizumab Arterial Thromboembolism
Pooled analysis of 5 clinical trials of bevacizumab in metastatic colorectal, breast, or non-small cell lung cancer (N=1,745)
Chemotherapy* plus bevacizumab (n=963)
Chemotherapy* alone (n=782)
HR=2.0 (95% CI, )
P=.031
ATE/VTE Rate (%)
*Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel
Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:

36. Thromboembolism With Bevacizumab Venous Thromboembolism: Meta-Analysis of RCTs
Relative Risk = 1.33 [95% CI: 1.13 – 1.56]
Absolute Risk Increase: 2.2% [95% CI: 1.1% - 3.3%]
Nalluri, S. R. et al. JAMA 2008;300:

37. Thromboembolic Complications in Cancer Patients Receiving ESAs
Hb Stopping Value
ESA
Cont RR
95% CI
< 12 g/dL 50
(0)
>12 - <13 g/dL
148
141
0.70
0.29, 1.67
>13 - <14 g/dL
1,596
1,290
1.71
1.23, 2.40
>14 - <15 g/dL
1,151
914
1.92
1.22, 3.02
>15 - <16 g/dL
368
303
1.66
1.08, 2.54
(Unclear) 42 39
5.59
0.71, 43.94
Comparative Effectiveness Review # 3
Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment
RR TE = 1.67 [1.35 – 2.06]
Bohlius, J. et al. JNCI :

38. Predictors of Venous Thromboembolism
Multivariate Logistic Regression Analysis
Retrospective cohort study of cancer pts at 60 US hospitals: 1995 – 2003.
Patients: N = 504,208
RBC trans: 70,542 (14%)
Platelet trans: 15,237 (3%)
RBC transfusions
VTE: 7.2%
ATE: 5.2%
Mortality
1.34 [95% CI: ]
Khorana, A. A. et al. Arch Intern Med 2008;168:

39. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Preventing Recurrence in Cancer Patients with Established VTE
LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE.
LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable for long-term therapy when LMWH is not available.
After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer.
The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long-term therapy with LMWH.
Lyman GH et al: J Clin Oncol 2007; 25: 39

40. Recurrent VTE and bleeding during anticoagulant treatment Patients with cancer and venous thrombosis30 30
Hazard ratio 3.2 [ ]
Hazard ratio 2.2 [ ]
Cancer 21% 20 20
Cancer 12%
Recurrent VTE, %
Major Bleeding, % 10 10
No Cancer 7%
No Cancer 5% 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
Time (months)
Prandoni P et al. Blood 2002; 100:

41. RCTs of Long-term Treatment in Cancer Patients with VTE: RCTs of LMWH vs. Vitamin K Antagonists in Cancer
Study
No.
Long-Term Treatment
Recurrent VTE, %
Major Bleed, %
Death, %
Meyer1
2002 71
Warfarin
21.1*
22.7 67
Enoxaparin 1.5 mg/kg
10.5*
11.3
Lee2
2003
336
17* 4 41
Dalteparin 200/150 IU/kg 9* 6 39
Deitcher3
2006 30 10
2.9
8.8 29
Enoxaparin 1.0 mg/kg
6.9
6.5 32
6.3
11.1
19.4
Hull4
100
10* 7 19
Tinzaparin 175 IU/kg 6* 20
* P < .05
1. Meyer G, et al. Arch Intern Med. 2002;162: Lee AY, et al. N Engl J Med. 2003;349: Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12: Hull RD, et al. Am J Med. 2006;119:

42. The CLOT Trial Study Schema
Control Group
Dalteparin 200 IU/kg OD
Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo
Randomization
Experimental Group
Source: Protocol
Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo
5 to 7 days
1 month
6 months
Lee AY, et al. N Engl J Med. 2003;349:
Slide #6

43. CLOT Trial: Results: Symptomatic Recurrent VTE risk reduction = 52%5 10 15 20 25
Days Post Randomization 30 60 90
120
150
180
210
Probability of Recurrent VTE, %
dalteparin, 9%
VKA, 17%
risk reduction = 52%
HR 0.48 (95% CI 0.30, 0.77)
log-rank p = 0.002
Lee AY, et al. N Engl J Med. 2003;349:

44. CLOT Trial: Results: Bleeding Dalteparin N=338 VKA N=335 p- value
Major bleed
19 (5.6%)
12 (3.6%)
0.27
associated with death 1
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%)
0.09
*intracranial, intraspinal, pericardial, retroperitoneal, intra-ocular, intra- articular
Lee AY, et al. N Engl J Med. 2003;349:

45. CLOT Trial Results: 12-month Mortality dalteparin OAC10 20 30 40 50 60 70 80 90
100
dalteparin
Probability of Survival, %
OAC
HR = (P=0.40)* 30 60 90
120
180
240
300
360
Days Post Randomization
* Solid tumor patients without metastatic disease: HR = (P = .03)
Lee AY, et al. N Engl J Med. 2003;349:
Lee, A. Y.Y. et al. J Clin Oncol; 23:

46. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Improving survival in absence of established VTE
Anticoagulants are not recommended to improve survival in patients with cancer without VTE.
People with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies.
Lyman GH et al: J Clin Oncol 2007; 25: 46

47. 1-Year Overall Mortality by Type of Anticoagulation
Systematic Review of Anticoagulants as Cancer Treatment:
Impact on Survival
1-Year Overall Mortality by Type of Anticoagulation
Treatment
Cancer
Citation
Rate 1
Rate 2
0.5 1 2 RR
[95% CI]
P Value
SCLC
Altinbas
.487
.700
.696
.476
1.018
.054
Mixed
Kakkar
.542
.592
.915
.766
1.093
.327
Mixed
Klerk
.608
.727
.836
.711
.983
.028
Mixed
Sideras
.603
.600
1.005
.766
1.319
.972
LMWH
.88
.79
.98
.015
SCLC
Lebeau
.601
.698
.862
.724
1.026
.093
UFH
.86
.72
1.03
.095
SCLC
Chahinian
.728
.802
.908
.775
1.063
.233
Breast
Levine
.382
.403
.948
.719
1.251
.705
SCLC
Maurer
.242
.278
.869
.608
1.240
.438
NSCLC
Zacharski (1)
.802
.796
1.008
.875
1.161
.915
SCLC
Zacharski (2)
.600
.840
.714
.497
1.027
.059
CRC
Zacharski (3)
.588
.529
1.111
.727
1.697
.625
Prostate
Zacharski (4)
.357
.300
1.190
.366
3.871
.770 HN
Zacharski (5)
.850
.667
1.275
.895
1.817
.172
NSCLC (early)
Zacharski (6)
.143
.300
.476
.137
1.651
.224
Warfarin
.94
.85
1.04
.239
Combined
.91
.85
.97
.003
Anticoagulation
Control
SCLC=small cell lung cancer; NSCLC=non-small cell lung cancer;
HN=head and neck; CRC=colorectal cancer
Kuderer NM, et al. Cancer. 2007;110:

48. Major Bleeding Complications by Type of Anticoagulation
Systematic Review of Anticoagulants as Cancer Treatment:
Impact on Survival
Major Bleeding Complications by Type of Anticoagulation
Treatment
Cancer
Study
Rate 1
Rate 2
0.1
0.2
0.5 1 2 5 10
RR [95% CI]
P Value
SCLC
Altinbas
.000
.000
1.025
.021
50.418
.990
NSCLC
Haas (2)
.037
.023
1.642
.605
4.453
.325
Mixed
Sideras
.029
.071
.412
.083
2.051
.261
Mixed
Klerk
.034
.006
5.203
.615
44.006
.089
Mixed
Kakkar
.005
.000
2.906
.119
70.874
.492
Breast
Haas (1)
.017
.000
7.120
.370
.127
LMWH
1.68
.86
3.27
.128
SCLC
Lebeau
.007
.007
1.007
.064
15.943
.996
UFH
1.01
.06
15.94
.996
SCLC
Zacharski (2)
.400
.080
5.000
1.217
20.549
.008
SCLC
Maurer
.067
.018
3.798
1.091
13.223
.023
SCLC
Chahinian
.068
.000
12.548
.727
.023
Prostate
Zacharski (4)
.571
.200
2.857
.763
10.695
.069
NSCLC (early)
Zacharski (6)
.524
.250
2.095
.885
4.960
.072
NSCLC
Zacharski (1)
.323
.071
4.521
2.092
9.768
.000 HN
Zacharski (5)
.500
.381
1.312
.652
2.642
.443
CRC
Zacharski (3)
.618
.206
3.000
1.473
6.109
.001
Breast
Levine
.007
.013
.523
.048
5.709
.588
Warfarin
2.98
2.13
4.16
<.001
Combined
2.59
1.94
3.49
<.001
Control
Anticoagulation
Kuderer NM, et al. Cancer. 2007;110:

49. Systematic Review of Anticoagulants as Cancer Treatment:
Impact on Survival
Findings
Anticoagulation significantly decreased 1-year overall mortality with a relative risk of [95% CI, ]; P=.003
Conclusions
Anticoagulants, particularly LMWH, significantly improved overall survival in cancer patients without VTE while increasing the risk for bleeding complications
Improved survival with anticoagulation may be dependent on tumor type
However: given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results
Kuderer NM, et al. Cancer. 2007;110: 49

50. Principal Investigator
Ongoing Randomized Clinical Trials Testing the Effect of LMWH on Survival in Cancer Patients
Study
LMWH
Tumor Type(s)
Principal Investigator
INPACT
Nadroparin
Advanced prostate, non-small cell lung, pancreatic
H. Buller
FOCUS
Dalteparin
Ovarian
A. Lee
FRAGMATIC
Lung
S. Noble
ABEL
Bemiparin
Small cell lung
R. Lecumberri
TILT
Tinzaparin
Non-small cell lung (I, II, III-A)
G. Meyer & P. Girard
GASTRANOX
Enoxaparin
Gastric (III/IV)
A. K. Kakkar
INPACT=Improving with Nadroparin the Prognosis in Advanced Cancer Treatment; FOCUS=Fragmin® in Ovarian Cancer: Utility on Survival; FRAGMATIC=Fragmin® Added to Standard Therapy in Patients with Lung Cancer; ABEL=Adjuvant Bemiparin in Small Cell Lung Carcinoma; TILT=Tinzaparin in Lung Tumors.
Courtesy Dr Anna Falanga 50

51. Development Cohort N (%) Validation Cohort N (%)
Clinical Risk Model for Chemotherapy-associated VTE Patient Characteristics
Characteristic
Development Cohort N (%)
Validation Cohort N (%)
P value
All
2,701 (100)
1,365 (100) ─
All VTE
60 (2.2)
28 (2.1)
.72
Age >65 yr
PS 0-1
BMI >35
1,083 (40.1)
2,473 (91.6)
332 (12.3)
515 (37.7)
1,242 (91)
166 (12.2)
.14
.54 .9
Stage IV
Platelet count ≥350,000/mm3
997 (36.9)
604 (22.4)
477 (34.9)
295 (21.6)
.06
.59
ESA
Recent surgery
764 (28.3)
829 (30.7)
358 (26.2)
473 (34.7)
.17
.01
RESULTS: The study population comprised 4,066 patients, split into 2,701 patients in the development cohort and 1,365 patients in the validation cohort. General characteristics of the development and validation cohorts are presented here. Rates of VTE were similar at 2.2 and 2.1% in the two cohorts. Older patients comprised over one-third of the population in each cohort, over 90% of patients had a good PS, and one-third had stage IV disease.
As you can see, patient characteristics in the two cohorts were well-balanced, with the exception of recent history of surgery.
PS=performance status; BMI=body mass index; ESA=erythropoiesis-stimulating agents.
Khorana AA et al. Blood. 2008; 111: 51

52. Clinical Risk Model for Chemotherapy-associated VTE Predictors of VTE: Multivariate Analysis
Characteristic β
OR*
P-value
Site of cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, genitourinary excluding prostate)
1.46
.43
4.3
1.5
Platelet count >350,000/mm3 .6
1.8
.03
Hemoglobin <10 g/dL or use of ESA
.89
2.4
.001
Leukocyte count >11,000/mm3
.77
2.1
.008
BMI >35 .9
2.5
.01
.05
Variables associated with an increased risk of VTE in univariate analysis or clinically important variables (e.g gender) were included in the stepwise regression model. The site of cancer and stage of disease were incorporated in every step a priori. For further analysis, sites of cancer were categorized into very high risk if the risk was 3-fold or greater and high risk if it was higher than average. The variables anemia and use of ESA showed significant association and were combined into one variable. Results of the multivariate analysis including odds ratios, P values and regression coefficients are shown on this slide. In the final multivariate analysis, the following variables were independently associated with risk of VTE adjusted for stage: primary site of cancer (very high risk or high risk), pre-chemotherapy platelet count ≥ 350,000/ mm3, hemoglobin < 10g/dL and/or use of ESAs, leukocyte count > 11,000/mm3 and body mass index ≥ 35.
*Odds ratio adjusted for stage
Khorana AA et al. Blood. 2008; 111: 52

53. Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors
Title Slide 53
Subtitle
Risk Factors
Risk score
 1. Site of cancer 
     a) Very high risk cancer (stomach, pancreas) 
 2 
     b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 
 1 
 2. Platelet count >350,000/mm3
 3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors 
4. Leukocyte count >11,000 /mm3
 5. BMI > 35 kg/m2
We have recently developed and validated a clinical risk model for chemotherapy-associated venous thrombosis.
This model includes the following risk factors:
The site of cancer:
with a very high risk cancer category (including stomach and pancreatic CA),
and a high risk cancer group (lung, lymphoma, gynecologic, bladder, testicular cancer).
 2. Prechemotherapy platelet count >350 x 109/L
 3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors 
4. Prechemotherapy leukocyte count >11,000/mm3
 5. BMI > 35 kg/m2
Khorana AA et al. Blood. 2008; 111:

54. Title Slide 54
Subtitle
Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors
Risk Factors
Risk score
 1. Site of cancer 
     a) Very high risk cancer (stomach, pancreas) 
 2 
     b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 
 1 
 2. Platelet count >350,000/mm3
 3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors 
4. Leukocyte count >11,000 /mm3
 5. BMI > 35 kg/m2
We have recently developed and validated a clinical risk model for chemotherapy-associated venous thrombosis.
This model includes the following risk factors:
The site of cancer:
with a very high risk cancer category (including stomach and pancreatic CA),
and a high risk cancer group (lung, lymphoma, gynecologic, bladder, testicular cancer).
 2. Prechemotherapy platelet count >350 x 109/L
 3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors 
4. Prechemotherapy leukocyte count >11,000/mm3
 5. BMI > 35 kg/m2
Khorana AA et al. Blood. 2008; 111:

55. Risk Factors Risk score
Title Slide 55
Subtitle
Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors
Risk Factors
Risk score
 1. Site of cancer 
     a) Very high risk cancer (stomach, pancreas) 
 2 
     b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 
 1 
 2. Platelet count >350,000/mm3
 3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors 
4. Leukocyte count >11,000 /mm3
 5. BMI > 35 kg/m2
We have recently developed and validated a clinical risk model for chemotherapy-associated venous thrombosis.
This model includes the following risk factors:
The site of cancer:
with a very high risk cancer category (including stomach and pancreatic CA),
and a high risk cancer group (lung, lymphoma, gynecologic, bladder, testicular cancer).
 2. Prechemotherapy platelet count >350 x 109/L
 3. Hemoglobin level < 10 g/dL or use of
Red cell growth factors 
4. Prechemotherapy leukocyte count >11,000/mm3
 5. BMI > 35 kg/m2
Khorana AA et al. Blood. 2008; 111:

56. VTE Prediction Risk Score Chemotherapy – Associated Thrombosis
Title Slide 56
Subtitle
RISK SCORE: Low (0) Intermediate (1-2) High (>3)
n=374
n=842
n=149
Rate of VTE (%) 0% 1% 2% 3% 4% 5% 6% 7% 8%
n=734
n=1,627
n=340
Development cohort
0.3%
2.0%
6.7%
Validation cohort
0.8%
1.8%
7.1%
We have recently confirmed, that based on our VT risk score
we can categorize patients into three major VT risk groups
Utilizing only readily available clinical parameters
However, improved identification of at-risk patients remains a clinically need.
Khorana AA et al. Blood. 2008; 111:

57. Venous Thromboembolism and Overall Survival by VTE Risk Score Categories
Mortality
Grp
Low
Intermed
High %
1.2
5.9
12.7 HR
1.0
3.56
[ ]
6.89
[ ]
Kuderer NM et al; Blood 2008 (ASH 2008)

58. Title Slide 58
Subtitle
LMWH prophylaxis NIH trial in cancer outpatients Phase III Multicenter Trial of Thromboprophylaxis in High Risk Ambulatory Cancer Patients Receiving Chemotherapy
Trial Design
Phase III, multicenter, randomized controlled trial of primary LMWH thromboprophylaxis in ambulatory cancer chemotherapy patients
Patient Population
400 consenting adult solid tumor or lymphoma patients starting a new chemotherapy regimen
Considered high risk based on the VTE model, ie, risk score for VTE ≥3
Study Outcomes
Primary Outcomes: Symptomatic and asymptomatic VTE
Secondary Outcomes: Overall mortality, bleeding complications
Correlative Studies
Blood for biomarkers and microarray studies
Fig. 1. Study Schema. (R=randomization, H&P=history and physical examination, US=ultrasound, CT=computed tomography scan of the chest). All time points are ± 1 week. Baseline CT up to 4 weeks prior to enrollment will be accepted.
The second specific aims will be accomplished
with a recently NIH-funded, LMWH-prophylaxis trial in cancer outpatients
[Status of trial]
The trial is a collaboration between University of Rochester and Duke
Currently, I am helping Rochester with finalizing protocol and CRF-forms for IRB submission.
[Trial Design]
This is designed as a phase III, single-blinded, multi-center trial,
Randomizing patients to LMWH or an untreated control group
[Patient Population]
The patient population will consist of: 400 solid tumor or lymphoma outpatients
at high risk for VTE, all starting new chemotherapy regimen
VTE risk assessment is performed by the recently published clinical prediction model*
[Study Outcomes]
Primary Outcomes consist of: Symptomatic and asymptomatic VTE
Secondary Outcomes are: Overall mortality and bleeding complications
[Correlative Studies]
Next to serving as Fellow-PI at Duke, I will be working together with Dr. Chi and Dr. Ortel
On the prediction model validation and clinical integration.
Rochester will evaluate blood biomarkers

59. Cancer and Venous Thromboembolism Conclusions
Title Slide 59
Subtitle
Cancer and Venous Thromboembolism Conclusions
VTE is a common complication of cancer and cancer treatment and is associated with considerable morbidity, mortality and costs.
The US Surgeon General has recently issued a Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism including new research initiatives to lower the burden of this serious illness.
Hospitalized medical and surgical cancer patients are at increased risk for VTE and should be considered for pharmacologic prophylaxis if no contraindication to anticoagulation is present.
Cancer patients treated for documented VTE should be considered for continued anticoagulation, preferably with LMWH, for up to six months or longer in patients with active malignancy.
While cancer patients experienced a significant reduction in VTE with LMWH
None of the trials by themselves showed statistical significant results for VTE outcome
Questions remain, especially regarding: bleeding risk, patient monitoring requirements, safety with different cancer therapies, timing or length of prophylaxis
Further studies are required, before routine VTE prophylaxis in ambulatory cancer patients can be recommended.
Clinical VTE prediction models are promising:
Further, improved risk stratification is required for optimal risk-benefit ration for VTE prophylaxis
Novel strategies may aid in the targeting of prophylactic strategies
Both, VTE itself and the venous thrombosis risk score are:
Independent predictors for early mortality
Further potential evidence between the link of VTE and more aggressive or less treatment responsive tumors
Understanding the ‘biologic VTE phenotype’ may shed further light on our understanding of tumor biology

60. Cancer and Venous Thromboembolism Conclusions
Title Slide 60
Subtitle
Cancer and Venous Thromboembolism Conclusions
Routine thromboprophylaxis of ambulatory cancer patients is not currently recommended.
While results from prospective controlled trials are needed, thromboprophylaxis may be considered in selective high risk settings such as multiple myeloma patients receiving thalidomide or lenalidomide along with chemotherapy and/or dexamethasone.
Consideration of prophylactic anticoagulation in cancer patients must always balance the risk of VTE with the increased risk of bleeding.
Improved methods for the identification of ambulatory cancer patients at increased risk for VTE and targeted thromboprophylaxis are needed and under active investigation.
While cancer patients experienced a significant reduction in VTE with LMWH
None of the trials by themselves showed statistical significant results for VTE outcome
Questions remain, especially regarding: bleeding risk, patient monitoring requirements, safety with different cancer therapies, timing or length of prophylaxis
Further studies are required, before routine VTE prophylaxis in ambulatory cancer patients can be recommended.
Clinical VTE prediction models are promising:
Further, improved risk stratification is required for optimal risk-benefit ration for VTE prophylaxis
Novel strategies may aid in the targeting of prophylactic strategies
Both, VTE itself and the venous thrombosis risk score are:
Independent predictors for early mortality
Further potential evidence between the link of VTE and more aggressive or less treatment responsive tumors
Understanding the ‘biologic VTE phenotype’ may shed further light on our understanding of tumor biology

61. Acknowledgments Duke University University of Rochester
Nicole Kuderer MD
Thomas Ortel MD
Jeffrey Crawford MD
Eva Culakova PhD
Marek Poniewierski MD
Debra Wolff, MS PCNP
University of Rochester
Alok Khorana MD
Charles Francis MD
Mark Taubman MD
Rami Komrokji, MD
ASCO VTE Guideline Panel Members
Anna Falanga, Co-Chair

62. Just Wait Until Next Year………..
Official Duke University Slide for Presentations at the University of North Carolina

63. Cancer and Thrombosis What to Look For……..
Cancer Investigation, 2009
Special Issue on Cancer and Thrombosis
Journal of Clinical Oncology, 2009
ASCO 2009
Education Session on Cancer and Thrombosis
3 Chapters in the Education Book
NHLBI Trials on going at Duke/Rochester and UNC
ISTH 2009: Boston July 11-16
5th International Conference on Thrombosis and Hemostasis: Issues in Cancer, Stresa, Italy, April 23-25, 2010
Any much more………….

64. ASCO VTE Guideline Panel Members
Gary H. Lyman, MD, MPH, FRCP (Edin), Co-Chair
Duke University
Anna Falanga, MD, Co-Chair
Ospedali Riuiniti, Bergamo, Italy
Daniel Clarke-Pearson, MD
University of North Carolina
Christopher Flowers, MD, MS
Emory University
Charles W. Francis, MD
University of Rochester
Leigh Gates, Patient Representative
University of Colorado
Mohammad Jahanzeb, MD
University of Tennessee
Ajay Kakkar, MD, PhD
Barts and The London School of Medicine 64

65. ASCO VTE Guideline Panel Members
Alok A. Khorana, MD
University of Rochester
Nicole M. Kuderer, MD
Duke University
Mark Levine, MD, PhD
McMaster University
Howard A. Liebman, MD
University of Southern California
David S. Mendelson, M.D.
Premiere Oncology
Gary Edward Raskob, PhD
University of Oklahoma
Paul A. Thodiyil, MD
New York Methodist Hospital
David Trent, MD, PhD
Virginia Cancer Center 65

66. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Summary
Patient Group
Recommended
Not Recommended
Hospitalized patients with cancer
VTE prophylaxis with anticoagulants
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
Not recommended
Lyman GH et al: J Clin Oncol 2007; 25: 66

67. Symptomatic VTE in Hematopoietic Stem Cell Transplantation (HSCT)
Implications for VTE Prevention
Retrospective review of HSCT patients
Median F/U: 642 days
Symptomatic VTE: 75 (4.6%)
Catheter-related: 55 (73%)
Clinical bleeding: 230 (15.2%)
Fatal bleeding: 55 (3.6%)
OR with anticoagulation: 3.1
OR with VOD: 2.2
Gerber, D. E. et al. Blood 2008;112:

68. Pulmonary Embolism n=8)
Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic VTE Hospitalized Medical Patients
9 studies with 19,958 patients
Anticoagulant prophylaxis:
Pulmonary embolism (PE):
RR = 0.43; CI
ARD = 0.29%; NNT = 345
Fatal PE:
RR = 0.38; CI
ARD = 0.25%; NNT = 400
Symptomatic DVT:
RR = 0.47; CI
ARD = 0.43%; NNT = 233
Major bleeding
RR = 1.32; CI
ARD = 0.14%; NNH = 714
Pulmonary Embolism n=8)
Major Bleeding (n=7)
Treatment of symptomatic disease is important but insufficient
Asymptomatic disease is common
Death from pulmonary embolism is often rapid
Prophylaxis
Current guidelines agree that all hospitalized patients with cancer should be considered for VTE prophylaxis
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
Dentali F, et al. Ann Intern Med. 2007;146:

69. Risk Factors for Early Mortality in Patients Receiving Cancer Chemotherapy
Variables
Hazard Ratio
95% CI
P value
VTE*
3.059
1.309
7.153
.010
Patient Demographics
Age
1.021
1.004
1.038
.017
ECOG >1
1.287
.830
1.996
.260
Charlson comorbidity index >1
1.338
.911
1.966
.137
Body mass index [kg/m2]
.959
.927
.992
.016
Stage IV
2.304
1.509
3.516
<.0001
Cancer Type
.009
Colorectal
1.666
.765
3.626
.199
Small cell lung cancer
1.530
.609
3.842
.365
Non-small cell lung cancer
3.072
1.590
5.937
.001
Ovary
1.543
.565
4.211
.397
Breast
1.059
.442
2.536
.898
Lymphoma
1.580
.756
3.304
.224
Relative Dose Intensity
.026
<85%
.617
1.595
.973
Unknown
2.071
1.132
3.789
.018
Year
.039
2003
1.166
.685
1.983
.571
2004
.821
.461
1.464
.505
2005
.300
.100
.031
Baseline Laboratory Values
WBC >11,000/mm3
1.976
1.331
2.932
Creatinine >1.5 mg/dL
2.214
1.223
4.008
Alkaline phosphatase >120 U/L
1.678
1.146
2.455
.008
Protein <5.5 g/dL
3.194
1.698
6.009
Albumin <3.5 g/dL
2.373
1.594
3.532
*Time-dependent covariate
Kuderer NM, et al. ASCO 2008

70. Coagulation Proteases in Tumor Biology
Tissue Factor/FVIIa
Factor Xa
Thrombin
Growth
Invasion
Metastasis
Angiogenesis
Fibrin generation plays additional roles in these processes 70

71. Fibrinogen Kinetics in Cancer Patients
Patients: 25 patients with known advanced or active cancer
Methods: Plasma and urine fractional fibrinogen catabolic rates were estimated
Findings: Significantly shortened fibrinogen survival found in patients with active cancer
Categories N T½
TO* P
Controls 6
3.89
.828
<.05
All Cancers 25
3.01
1.433
Leukemia
3.19
.671 NS
Lymphoma 4
2.88
1.881
Solid Tumor 15
2.98
1.617 GI 3
2.52
2.234
No Chemo
3.28
Chemo 10
2.61
*TO= mean turnover in mg/ml/day
Lyman GH et al. Cancer 1978; 41:

72. Adjusted Odds Ratio (95% CI)
Risk of VTE in Cancer Patients by Type of Malignancy
Population-based, case-control study [MEGA] of risk factors for VTE
6 clinics in Holland
3220 consecutive patients, 18 to 70 years, with a first DVT or PE
2131 control participants (partners of the patients)
Type of Cancer
Adjusted Odds Ratio (95% CI)
Hematologic
28 ( )
Lung
22.2 ( )
Gastrointestinal
20.3 (4.9-83)
Breast
4.9 ( )
Prostate
2.2 ( )
Risk was greatest in first few months following diagnosis of cancer
Patients with distant metastases and carriers of
factor V Leiden mutation were are further increased risk.
Blom JW, et al. JAMA. 2005;293:

73. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism
September 15, 2008

74. Risk Factors for Inpatient VTE: Multivariate Analysis*
Characteristic OR
P value
Site of Cancer
Lung
Stomach
Pancreas
Uterine
Brain
1.3
1.6
2.8 2
2.2
<0.001
0.0035
Age > 65
1.1
0.005
Arterial Thromboembolism
1.4
0.008
Major Comorbidities**
We included clinically and statistically significant variables in a multivariate logistic regression analysis. This slide demonstrates variables found to be significant in this analysis. Risk factors independently associated with VTE included primary site of cancer (upper gastrointestinal or lung), an elevated pre-chemotherapy platelet count, hemoglobin < 10g/dL or use of erythropoietin (a combined variable), and use of white cell growth factors. We found a significant first-order interaction between site of cancer and use of white cell growth factors (p=0.02). Patients with sites of cancer associated with higher risk of VTE (upper gastrointestinal, lung or lymphoma) had a significantly increased risk of VTE associated with white cell growth factor use (VTE rate of 5.9% versus 1.52% without growth factor use, p =0.0001; odds ratio 4.0, [95% CI, ]). In contrast, patients with other sites of cancer did not appear to have an increased risk of VTE with the use of white cell growth factors (VTE rate of 1.31% versus 1.42% without growth factor use, p =0.84).
* Adjusted for sex, race, HBP, DM, CHF, hepatic disease (NS)
** lung/renal disease, infection, obesity
Khorana et al, J Clin Oncol 2006; 24:

75. VTE Risk and Prevention in Multiple Myeloma Chemotherapy ± Thalidomide
They are within trial comparisons of cohorts of patients on and off anticoagulants and thus are subject to bias.
Zangari et al: Brit J Haematol 2004; 126: 75

76. Ambulatory Cancer Patients: Prophylaxis in Multiple Myeloma Patients
Prophylaxis with low-molecular-weight heparin (LMWH) or adjusted dose warfarin (INR~1.5) is recommended in multiple myeloma patients receiving thalidomide or lenalidomide plus chemotherapy or dexamethasone (high VTE risk)
However:
No RCTs available
Recommendation is based on extrapolation from nonrandomized trials or randomized studies in other similar high-risk categories
Well-designed RCTs are urgently needed
They are within trial comparisons of cohorts of patients on and off anticoagulants and thus are subject to bias.
Lyman GH et al: J Clin Oncol 2007; 25: 76

77. No anticoagulation (first two years): 11/65 (17%)
VTE Risk and Prevention in Multiple Myeloma Melphalan + Prednisone ± Thalidomide
VTE
No anticoagulation (first two years):
11/65 (17%)
Enoxaparin 40 mg QD for four months:
2/65 (3%)
(P=.005)
Palumbo A et al: The Lancet 2006; 367:

78. Older Age and History of Arterial Thromboembolism
Chemotherapy* plus bevacizumab
Chemotherapy* alone (control group)
ATE Rate (%)
Total cohort n=963 bev
n=872 ctrl
No risk factors
n=602 bev
n=490 ctrl
Age ≥65 yr n=339 bev
n=279 ctrl
ATE history n=89 bev
n=59 ctrl
ATE history + age ≥65 yr
n=67 bev
n=46 ctrl
*Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel
Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:

79. Reduction in thrombosis
Increase in bleeding

80. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Preventing Recurrence in Cancer Patients with Established VTE
In patients with central nervous system malignancies and in the elderly, anticoagulation is recommended for established VTE as described for other patients with cancer .
Careful monitoring of anticoagulation is necessary to limit the risk of hemorrhagic complications.
Anticoagulation should be avoided in the presence of active intracranial bleeding or preexisting bleeding diathesis such as thrombocytopenia (platelet count <50,000/mm3) or coagulopathy.
Lyman GH et al: J Clin Oncol 2007; 25: 80

81. The CLOT Trial multinational, open-label, randomized study
treatment period 6 months (or until death)
primary endpoint: symptomatic VTE recurrence
follow-up for survival up to 12 months
Control Group:
dalteparin + VKA
Cancer patients with proximal DVT, PE or both R
Experimental Group:
dalteparin alone
Lee AY, et al. N Engl J Med. 2003;349:

82. CLOT Trial Results:
Survival in Solid Tumor Patients ± metastatic disease
P = 0.62
HR=0.50[.27 to .95]; P=.03
HR=1.1[.87 to 1.4]; P=.46
For patients without metastatic disease, the hazard ratio was 0.50 (95% CI, 0.27 to 0.95; P = .03) for the overall comparison between the treatment groups.
For patients with metastatic disease, the hazard ratio was 1.1 (95% CI, 0.87 to 1.4; P = .46) for the overall comparison between the treatment groups.
Lee, A. Y.Y. et al. J Clin Oncol; 23:

83. Mortality and PFS in Univariate Analysis by VTE Risk Score Categories
Title Slide 83
Subtitle
Mortality and PFS in Univariate Analysis by VTE Risk Score Categories
Outcomes
(at 4 months)
Risk Group
Low
N=1,206
Intermed.
N=2,709
High N=543
All
N=4,458
Overall Mortality
Risk (%)
1.2%
5.9%
12.7%
5.6%
HR [+/- CI]
1.0
3.56 [ ]
6.89 [ ] -
PFS
93%
82%
72%
84%
2.77 [ ]
4.27 [ ]
In univariate analysis, Overall Mortality at 4 months:
Significantly increases from 1.2% in the low risk group:
to 5.9% in the intermed. Group,
and to 12.7% in the high risk group
With HRs of 3.56 and 6.89, respectively, compared to the low risk group
PFS at 4 months:
Decreases to 82% and 72% in the intermed. and high risk groups,
compared to 93% in the low risk group
With HRs of 2.77 and 4.27, respectively.
Kuderer NM et al; Blood 2008 (ASH 2008)

84. VTE Risk Score Independent Predictor for: PFS Multivariate Analysis*
Title Slide 84
Subtitle
VTE Risk Score Independent Predictor for: PFS Multivariate Analysis*
Variables
P-value HR
95% CI for HR
Lower
Upper
VTE Risk Score(1)
0.001
Intermed. Risk Group (II)
<0.001
2.077
1.397
3.086
High Risk Group (III)
2.344
1.465
3.751
VTE(2)
0.028
2.043
1.079
3.870
Patient Characteristics
Age
0.107
1.008
0.998
1.017
ECOG >1
1.498
1.175
1.909
Charlson >1
0.047
1.256
1.003
1.574
BMI [kg/m2]
0.962
0.944
0.981
Stage IV(3)
1.982
1.567
2.506
Year
0.792
0.700
0.896
This holds true for PFS as well.
The VT risk score remains an independent predictor for reduced progression-free survival –
after accounting for the same major risk factors: including VT
With HRs of 2.07 and 2.34 in the intermediate and risk categories
*Adjusted for: Cancer Type, and Relative Dose Intensity
(1) Comparison to low risk group (I) (2) Time-dependent covariate
(3) Comparison to stages I-III
Kuderer NM et al; Blood 2008 (ASH 2008)

85. LMWH prophylaxis NIH trial in cancer outpatients
Title Slide 85
Subtitle
LMWH prophylaxis NIH trial in cancer outpatients
Inclusion Criteria:
Age 18 years or older
A histologic diagnosis of malignancy (not basal cell or squamous cell);
At planned initiation of a new systemic chemotherapy regimen (including patients starting on first chemotherapy or patients previously treated but starting on a new regimen);
A risk score for VTE ≥3. Any counts meeting criteria drawn within 2 weeks prior to enrollment are considered acceptable.
Exclusion Criteria:
Patients will be excluded from the trial if they have any of the following:
Active bleeding or at high risk of serious bleeding complication in the opinion of the investigator
Diagnosis of primary brain tumor, multiple myeloma, acute leukemia, chronic myelogenous leukemia or myelodysplastic syndrome
Planned stem cell transplant
Life expectancy < 6 months
Known allergy to heparin or LMWH
Incapable of daily self-injection
Acute or chronic renal insufficiency with creatinine clearance < 30 mL/min
History of heparin-induced thrombocytopenia
Allergy to contrast agents
Need for anticoagulant therapy
Platelet count < 50,000/mm3
Pregnancy
The second specific aims will be accomplished
with a recently NIH-funded, LMWH-prophylaxis trial in cancer outpatients
[Status of trial]
The trial is a collaboration between University of Rochester and Duke
Currently, I am helping Rochester with finalizing protocol and CRF-forms for IRB submission.
[Trial Design]
This is designed as a phase III, single-blinded, multi-center trial,
Randomizing patients to LMWH or an untreated control group
[Patient Population]
The patient population will consist of: 400 solid tumor or lymphoma outpatients
at high risk for VTE, all starting new chemotherapy regimen
VTE risk assessment is performed by the recently published clinical prediction model*
[Study Outcomes]
Primary Outcomes consist of: Symptomatic and asymptomatic VTE
Secondary Outcomes are: Overall mortality and bleeding complications
[Correlative Studies]
Next to serving as Fellow-PI at Duke, I will be working together with Dr. Chi and Dr. Ortel
On the prediction model validation and clinical integration.
Rochester will evaluate blood biomarkers

86. Tumor cells Procoagulant activities Fibrinolytic activities
Cytokines and growth factors
Activation of coagulation
Extracellular matrix remodeling
Activation of vascular blood cells
Angiogenesis
Falanga A: Cancer Invest 2009; 27:

87. Survival of Cancer Patients Developing VTE Compared to Matched Controls
Data from the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files
Control patients, who did not have VTE, were matched by
cancer type
Sex
Age
year of diagnosis
One-Year Mortality
Cancer with VTE
12%
Cancer w/o VTE
36%
HR = 2.20 [ ]
P<.0001
Sorensen, H. T. et al. N Engl J Med 2000;343:

88. Venous Thromboembolism
RCTs of Thromboprophylaxis in Ambulatory Cancer Patients Low Molecular Weight Heparin: Meta-Analysis
Summary Estimates [N=6 RCTs]
Venous Thromboembolism
Relative Risk: 0.64 [95% CI: 0.44 – 0.94]
Absolute Risk Reduction: 1.8% [95% CI: 0.2% - 3.4%]
Major Bleeding
Relative Risk: 1.85 [95% CI: 0.93 – 3.68]
Absolute Risk Increase: 0.9% [95% CI: 0% - 1.8%]
Kuderer NM et al: ASCO 2009

89. Title Slide 89
Subtitle
VTE Risk Score Independent Predictor for: Mortality Multivariate Analysis
Variables
P-value
HR*
95% CI for HR
VTE Risk Score(1)
0.028
Intermed. Risk Group (II)
0.025
2.222
1.106
4.464
High Risk Group (III)
0.008
2.926
1.332
6.428
VTE(2)
<0.001
4.472
1.928
10.370
Patient Characteristics
Age
0.026
1.018
1.002
1.035
ECOG >1
0.027
1.613
1.055
2.464
Charlson >1
0.014
1.582
1.096
2.284
BMI [kg/m2]
0.941
0.910
0.973
Stage IV(3)
2.659
1.755
4.028
Year
0.016
0.771
0.624
0.953
This increased risk of mortality persisted in multivariate analysis,
after adjusting for major risk factors:
Including: age, ECOG-PS, Charlson Comorbidity Ind, BMI, Stage, Year, Tumor Type, RDI
As well as the occurrence of VT itself.
With HRs of 2.22 and 2.92 in the intermediate and high risk groups.
*Adjusted for: Cancer Type, and Relative Dose Intensity
(1) Comparison to low risk group (I) (2) Time-dependent covariate
(3) Comparison to stages I-III
Kuderer et al. Oral Presentation ASH 2008

90. Cancer and Venous Thromboembolism The Need for Risk Stratification
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5 6
Diagnosis
Chemotherapy
Hospitalization
Remission
End of Life
Metastasis
Relative Risk
Average Risk
Time

91. 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
CMS, the Centers for Medicare and Medicaid Services

92. Candidate Biomarkers Platelet count Leukocyte count Tissue factor
P-selectin
Others (D-dimer, C-reactive protein) 92 92

93. Soluble P-Selectin and VTE in Cancer
Ay C, et al. Blood. 2008;112:

94. 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

95. Venous Thromboembolism and
Highlights from ASCO Advances in Supportive Care Managing Disease and Treatment-Related Complications
Venous Thromboembolism and
Thromboprophylaxis

96. Low-molecular-weight heparin for venous thromboprophylaxis in ambulatory cancer patients: A meta-analysis Nicole M. Kuderer, Alok A. Khorana, Charles W. Francis et al Duke University, Durham, NC; University of Rochester, Rochester, NY
Literature Search:
Medline, EMBASE, Cochrane Library, Conference Proceedings, Hand Searching of References
Major Inclusion Criteria:
RCT of LMWH VTE prophylaxis in adult ambulatory cancer patients
Treatment Group: LMWH
Control Group: placebo or no Rx
Major Exclusion Criteria:
Non-cancer patients
Non-randomized trials
Surgery, Catheter trials, or intraportal heparin infusion
Combination of anticoagulants

97. Risk - Benefit Comparison VTE – Prophylaxis with LMWH
Harm
Venous Thrombosis ARD*
Major Bleeding Events ARD*
All Bleeding Events ARD*1
1.8% ↓
0.9% ↑
2.4% ↑↑
1Kuderer et al. Cancer 2007
*ARD = Absolute Risk Difference

98. Conclusions VTE – Prophylaxis with LMWH
While ambulatory cancer patients experienced a 36% relative risk reduction in VTE with LMWH, the average absolute risk reduction for VTE was only 1.8%.
Concern remains about the potential increase in major bleeding with an absolute risk increase in major bleeding of 0.9%.
Major bleeding was not a primary outcome in any of the studies and were not powered to adequately assess major bleeding.
Weighing risks and benefits, routine VTE prophylaxis in the general outpatient cancer population cannot be recommended at this time.
Studies are ongoing to better identify cancer outpatients at increased risk for VTE, in whom prophylaxis may have a more favorable risk-benefit ratio.

99. 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

100. 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

101. Patient Characteristic
Risk Model
Patient Characteristic
Score
Site of Cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2 1
Platelet count > 350,000/mm3
Hb < 10g/dL or use of ESA
Leukocyte count > 11,000/mm3
BMI > 35 kg/m2
Based on the multivariate analysis, we developed a predictive risk model for identifying patients at high risk for development of VTE at time of initiation of chemotherapy. Risk scores were developed based on the beta-coefficient for each variable in the multivariate model shown on the prior slide, rounded to the nearest integer to make the model clinically usable. A patient with a very high risk site of cancer (such as stomach or pancreas) would be assigned a score of 2; patients with high risk sites of cancer (such as lung, lymphoma, gynecologic or GU cancers) as well as elevated pre-chemotherapy platelet count, anemia with a Hgb < 10 g/dL or use of erythropoiesis-stimulating agent, elevated leukocyte count or a BMI >=35 would all be assigned scores of 1.
Khorana AA et al. Blood 2008
101

102. VTE Prediction Risk Score Chemotherapy – Associated Thrombosis
Title Slide 102
Subtitle
VTE Prediction Risk Score Chemotherapy – Associated Thrombosis
Development cohort
Validation cohort 8% 8%
7.1% 7% 7%
6.7%
6.7% 6% 6% 5% 5%
Rate of VTE (%) 4% 4% 3% 3%
We have recently confirmed, that based on our VT risk score
we can categorize patients into three major VT risk groups
Utilizing only readily available clinical parameters
However, improved identification of at-risk patients remains a clinically need.
2.0%
2.0%
1.8% 2% 2%
0.8% 1% 1%
0.3%
0.3% 0% 0%
n=374
n=374
n=734
n=734
n=1,627
n=1,627
n=842
n=842
n=340
n=340
n=149
n=149
RISK SCORE: Low (0) Intermediate (1-2) High (>3)
Khorana AA et al. Blood. 2008; 111:

103. Mortality and PFS By VTE Risk Score
Outcomes
Low Risk
N=1,206
Intermediate Risk
N=2,709
High Risk
N=543
All
N=4,458
Mortality
Risk (%)
1.2%
5.9%
12.7%
5.6%
HR [+/- CI]
1.0
3.6 [ ]
6.9 [ ] -
Progression-free survival
93%
82%
72%
84%
2.8 [2-3.9]
4.3 [ ]
Kuderer NM et al. ASH 2008

104. PHACS Study R LMWH prophylaxis x 12 weeks
with 4-weekly screening US and
start/end CT chest
Patients starting
chemotherapy
Risk score ≥3 R
Observe x 12 weeks
with 4-weekly screening US and
start/end CT chest
Sites: Duke, Duke Oncology Network, Univ of Rochester
R01 HL

105. A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin enoxaparin in patients with advanced pancreatic cancer: Results of the CONKO 004 trial H. Riess, U. Pelzer, G. Deutschinoff, B. Opitz, M. Stauch, P. Reitzig, S. Hahnfeld, A. Hilbig, J. Stieler, H. Oettle

106. A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin enoxaparin in patients with advanced pancreatic cancer: Results of the CONKO 004 trial H. Riess, U. Pelzer, G. Deutschinoff, B. Opitz, M. Stauch, P. Reitzig, S. Hahnfeld, A. Hilbig, J. Stieler, H. Oettle
Randomization
Response evaluation at least every 12 weeks:
VTE, Bleeding, RR, PFS, OS
Primary endpoint
Chemotherapy
Chemotherapy + Enoxaparin
Treatment for 3 months:
VTE
, Bleeding, RR, PFS, OS
E 1 mg/kg/d
E 40 mg/kg/d
until PD

107. KPS 60-70% or creatinine > ULN
CONKO-004: Chemotherapy
Favorable results in randomized phase II/III in patients with good PS: with Gem/CDDP or Gem/FA/5-FU and Gem/Cap
Gem/CDDP/5-FU and Gem/FA/5-FU/CDDP with remarkable RR and 1-year OS
Patient allocation according to Karnofsky-PS (KPS) and plasma creatinine level
KPS ≥ 80% + creatinine ≤ ULN
KPS 60-70% or creatinine > ULN
Gemcitabine (1000 mg/m2)
Folinic acid (100 mg/m2)
d1, 8, 15; 29
5-FU (750 mg/m2 24 h CI)
CDDP (30 mg/m2)
d1, 8; 22

108. Results: VTE and Major Bleeding
Observation
Enoxaparin
Patients (N)
152
160
VTE (at 3 months)*
Major Bleeding (at 3 months)
9.9%
2.6%
1.2%
3.8%
VTE (at 30.4 months)**
15.5% 5%
Major Bleeding (at 30.4 months)
6.3%
Median survival
29 weeks
31 weeks
*p<0.01; **p<0.05

109. Results: VTE and Major Bleeding
Observation
Enoxaparin
Patients (N)
152
160
VTE (at 3 months)*
Major Bleeding (at 3 months)
9.9%
2.6%
1.2%
3.8%
VTE (at 30.4 months)**
15.5% 5%
Major Bleeding (at 30.4 months)
6.3%
Median survival
29 weeks
31 weeks
*p<0.01; **p<0.05

110. Venous thromboembolic events
Results: VTE at 3 Months
Venous thromboembolic events
Event
Observation
N= 162
Enoxaparin
N= 150
All
Pulmonary embolism 2
Proximal leg DVT 9 11
Distal leg DVT only
Upper extremity DVT 3
All (VTE) 16 18
All (Patients)* 15 17

111. Results: Relative VTE rates Results: Relative VTE rates
Percent (%)
n=5
n=10
■ Gem
■ GFFC
n=1
Δ=6.6%;RRR=90%;P=.025
Δ=12.4%;RRR=79%;P=.300
■ Gem
■ GFFC
■ Gem
■ GFFC
n=5
n=5
Δ=12.4%;RRR=79%;P=.300
Δ=12.4%;RRR=79%;P=.300
Percent (%)
Percent (%)
n=10
n=10
n=1
n=1
n=1
n=1
Δ=6.6%;RRR=90%;P=.025
Δ=6.6%;RRR=90%;P=.025

112. CONKO-004: Summary Major Limitations Unusual study design
Non-standard chemotherapy
Chemo allocated by PS/creat.
Small study: trial stopped early
Paradoxical major bleeding results
No information on catheters
Conclusions
Enoxaparin (1mg/kg/day) significantly reduces VTE
No OS improvement
High overall major bleeding
Unusual study design
Clinical relevance of data?
Reducing non-PE VTE
Setting of high major bleeding
? Long-term complications:
Osteoporosis
HIT