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					Welcome to this Science-to-Strategy Summit
       Clotting, Cancer, and Clinical Strategies


   Critical Challenges and Landmark
 Advances in Thrombosis Management
The Evolving and Foundation Role of LMWHs in Cancer and VTE
 Prophylaxis: Applying Science, Expert Analysis, and Landmark
         Trials to the Front Lines of Oncology Practice

                     Program Chairman
                        Craig M. Kessler, MD
                Professor of Medicine and Pathology
               Georgetown University Medical Center
               Director of the Division of Coagulation
                Department of Laboratory Medicine
              Lombardi Comprehensive Cancer Center
                           Washington, DC
         Welcome and Program Overview
CME-accredited symposium jointly sponsored by University of
Massachusetts Medical Center, office of CME and CMEducation
Resources, LLC

Commercial Support: Sponsored by an independent educational grant
from Eisai, Inc.

Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management

Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies

COI: Full faculty disclosures provided in syllabus and at the beginning
of the program
                 Program Educational Objectives

As a result of this session, physicians will be able to:

►   Specify strategies for risk-directed prophylaxis against DVT in at risk patients
    with cancer, using FDA-indicated and approved agents

►   Explain how to assess and manage special needs of cancer patients at risk for
    DVT, with a focus on protecting against recurrent DVT.

►   Describe how to risk stratify patients undergoing cancer surgery, and implement
    ACCP-mandated pharmacologic and non-pharmacologic measures aimed at
    DVT prophylaxis.

►   Review landmark clinical trials focusing on DVT prophylaxis in patients with
    cancer.

►   Explain how to appropriately use the range of pharmacologic options available
    for thrombosis management in patients with malignancy.
                             Program Faculty
Craig M. Kessler, MD
Professor of Medicine and Pathology
Georgetown University Medical Center
Director of the Division of Coagulation
Department of Laboratory Medicine
Washington, DC

John Fanikos, RPh, MBA
Assistant Director of Pharmacy
Brigham and Women’s Hospital
Assistant Clinical Professor of Pharmacy
Northeastern University
Massachusetts College of Pharmacy
Boston, MA

Samuel Z. Goldhaber, MD
Professor of Medicine
Cardiovascular Division
Harvard Medical School
Director, Venous Thromboembolism Research Unit
Brigham and Women’s Hospital
Boston, MA
             Faculty COI Financial Disclosures

Craig M. Kessler, MD
Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline,
Octapharma
Consultant: sanofi-aventis, Eisai, NovoNordisk

John Fanikos, RPh, MBA
Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca,
Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis,
The Medicines Company

Samuel Z. Goldhaber, MD
Grant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai;
GSK; Sanofi-Aventis;
Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; Sanofi-
Aventis
               Clots and Cancer—A Looming
                 National Healthcare Crisis


           MISSION AND CHALLENGES

Recognizing cancer patients at risk for DVT and identifying
    patients who are appropriate candidates for long-term
  prophylaxis and/or treatment with approved and indicated
     therapies are among the most important and difficult
      challenges encountered in contemporary oncology
                          practice.
       Introduction and Chairman’s Overview

Clotting, Cancer, And Controversies: What
 The Cascade Of Evidence And Current
             Thinking Tell Us
     The Evolving Science, Epidemiology, and
 Foundation Role of Low Molecular Weight Heparin
             in the Setting of Cancer
                   Program Chairman
                      Craig M. Kessler, MD
              Professor of Medicine and Pathology
             Georgetown University Medical Center
             Director of the Division of Coagulation
              Department of Laboratory Medicine
            Lombardi Comprehensive Cancer Center
                         Washington, DC
            Comorbidity Connection


COMORBIDITY                   SUBSPECIALIST
CONNECTION                    STAKEHOLDERS

CAP                           Infectious diseases
UTI                           Oncology
Cancer                        Cardiology
Heart Failure                 Pulmonary medicine
ABE/COPD                      Hematology
Respiratory Failure           Oncology/hematology
Myeloproliferative Disorder   Interventional Radiology
Thrombophilia                 Hospitalist
Surgery                       Surgeons
History of DVT                EM
Other                         PCP
                                    Epidemiology of First-Time VTE


                         Variable                           Finding
                                            Possibly more common in winter and less
          Seasonal Variation
                                            common in summer
                                            25% to 50% ―idiopathic‖
          Risk Factors                      15%–25% associated with cancer;
                                            20% following surgery (3 mo.)
                                            6-month incidence: 7%;
                                            higher rate in patients with cancer
          Recurrent VTE
                                            Recurrent PE more likely after PE than
                                            after DVT
                                            30 day incidence 6% after incident DVT
                                            30 day incidence 12% after PE
          Death After Treated VTE
                                            Death strongly associated with cancer,
                                            age, and cardiovascular disease


White R. Circulation. 2003;107:I-4 –I-8.)
                                       Epidemiology of VTE

                 ► One major risk factor for VTE is ethnicity, with a
                   significantly higher incidence among Caucasians
                   and African Americans than among Hispanic
                   persons and Asian-Pacific Islanders.

                 ► Overall, about 25% to 50% of patient with first-time
                   VTE have an idiopathic condition, without a readily
                   identifiable risk factor.

                 ► Early mortality after VTE is strongly associated with
                   presentation as PE, advanced age, cancer, and
                   underlying cardiovascular disease.

White R. Circulation. 2003;107:I-4 –I-8.)
 Comorbidity Connection



                    Overview




Comorbidity
Connection
                           Acute Medical Illness and VTE
                                  Among Patients Receiving Placebo or
                                   Ineffective Antithrombotic Therapy


          Acute Medical Illness                     Relative Risk      X2     P value

         Heart failure                              1.08 (0.72-1.62)   0.05     .82
         NYHA class III                             0.89 (0.55-1.43)   0.12     .72
         NYHA class IV                              1.48 (0.84-2.60)   1.23     .27

         Acute respiratory disease                  1.26 (0.85-1.87)   1.03     .31

         Acute infectious disease                   1.50 (1.00-2.26)   3.54     .06

         Acute rheumatic disease                    1.45 (0.84-2.50)   1.20     .27


Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
                          Acute Medical Illness and VTE
                                     Multivariate Logistic Regression Model
                                 for Definite Venous Thromboembolism (VTE)



                      Risk Factor                               Odds Ratio         X2
                                                                  (95% CI)
         Age > 75y                                             1.03 (1.00-1.06)   0.0001
         Cancer                                                1.26 (0.93-2.75)   0.08
         Previous VTE                                          2.06 (1.10-3.69)   0.02

         Acute infectious disease                              1.74 (1.12-2.75)    0.02


         Chronic respiratory disease                           0.60 (0.38-0.92)    0.02




Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
                           Comorbid Condition and DVT Risk

        ► Hospitalization for surgery (24%) and for medical illness (22%)
          accounted for a similar proportion of the cases, while nursing
          home residence accounted for 13%.

        ► The individual attributable risk estimates for malignant
          neoplasm, trauma, congestive heart failure, central venous
          catheter or pacemaker placement, neurological disease with
          extremity paresis, and superficial vein thrombosis were 18%,
          12%, 10%, 9%, 7%, and 5%, respectively.

        ► Together, the 8 risk factors accounted for 74% of disease
          occurrence


Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun
10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study
                                                 VTE Recurrence

                                 Predictors of First Overall VTE Recurrence


                  Baseline Characteristic                      Hazard Ratio
                                                                  (95% CI)

            Age                                                1.17 (1.11-1.24)

            Body Mass Index                                    1.24 (1.04-1.47)

            Neurologic disease with extremity
                                                               1.87 (1.28-2.73)
            paresis
            Malignant neoplasm
             None                                              1.00
             With chemotherapy                                 4.24 (2.58-6.95)
             Withot chemotherapy                               2.21 (1.60-3.06)




Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
 Clotting, Cancer, and Clinical Strategies


Cancer, Thrombosis, and the
   Biology of Malignancy
 Scientific Foundations for the Role of
    Low-Molecular-Weight Heparin


          John Fanikos, RPh, MBA
         Assistant Director of Pharmacy
         Brigham and Women’s Hospital
     Assistant Clinical Professor of Pharmacy
             Northeastern University
      Massachusetts College of Pharmacy
                    Boston, MA
           Professor Armand Trousseau
              Lectures in Clinical Medicine




― I have always been struck with the
frequency with which cancerous patients
are affected with painful oedema of the
superior or inferior extremities….‖

New Syndenham Society – 1865
           Professor Armand Trousseau
      More Observations About Cancer and Thrombosis




―In other cases, in which the absence of
appreciable tumor made me hesitate as to
the nature of the disease of the stomach, my
doubts were removed, and I knew the
disease to be cancerous when phlegmasia
alba dolens appeared in one of the limbs.‖

Lectures in Clinical Medicine, 1865
             Trousseau’s Syndrome


Ironically, Trousseau died of gastric carcinoma 6
months after writing to his student, Peter, on January
1st, 1867:


―I am lost . . . the phlebitis that has just
appeared tonight leaves me no doubt as to
the nature of my illness‖
          Trousseau’s Syndrome



►   Occult cancer in patients with idiopathic
    venous thromboembolism


►   Thrombophlebitis in patients
    with cancer
                                                       Effect of Malignancy on Risk of
                                                      Venous Thromboembolism (VTE)
                                                                                                            53.5
                                 50        • Population-based case-control
                                             (MEGA) study
                                           • N=3220 consecutive patients with 1st
                                 40          VTE vs. n=2131 control subjects
           Adjusted odds ratio




                                           • CA patients = OR 7x VTE risk vs. non-
                                             CA patients
                                 30      28
                                              22.2
                                                     20.3                 19.8
                                 20
                                                                                                                             14.3

                                 10                                                4.9
                                                                                                                                               3.6             2.6
                                                                                                                                                                                1.1
                                  0




                                                                                                                                                                                 > 15 years
                                                         Lung




                                                                                     Breast




                                                                                                  Distant




                                                                                                                                                1 to 3 years

                                                                                                                                                                5 to 10 years
                                                                Gastrointestinal




                                                                                              metastases




                                                                                                             0 to 3 months

                                                                                                                              3 to 12 months
                                      Hematological




                                                      Type of cancer                                        Time since cancer diagnosis
Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
                                        Cancer, Mortality, and VTE
                                                  Epidemiology and Risk

         ►    Patients with cancer have a 4- to 6-fold increased risk
              for VTE vs. non-cancer patients
         ►    Patients with cancer have a 3-fold increased risk for
              recurrence of VTE vs. non-cancer patients
         ►    Cancer patients undergoing surgery have a 2-fold
              increased risk for postoperative VTE
         ►    Death rate from cancer is four-fold higher if patient has
              concurrent VTE
         ►    VTE 2nd most common cause of death in ambulatory
              cancer patients (tied with infection)


Heit et.al. Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al. Blood 2002;100:3484-3488;
White et.al. Thromb Haemost 2003;90:446-455; Sorensen et.al. New Engl J Med 2000;343:1846-1850); Levitan et.al.
Medicine 1999;78:285-291; Khorana et.al. J Thromb Haemost 2007;5:632-4
     Mechanisms of Cancer-Induced Thrombosis
                      The Interface




1. Pathogenesis?

2. Biological significance?


3. Potential importance for cancer therapy?
    Trousseau’s Observations (continued)


―There appears in the cachexiae…a
particular condition of the blood that
predisposes it to spontaneous
coagulation.‖

Lectures in Clinical Medicine, 1865
                         Interface of Biology and Cancer
                                                         Tumor cells

     Angiogenesis,                  Fibrinolytic                            Procoagulant Activities
     Basement matrix                activities:
     degradation.                   t-PA, u-PA, u-PAR,
                                    PAI-1, PAI-2


                                                          IL-1,                      Activation of
                                                          TNF-a,                     coagulation
                                                          VEGF



          PMN leukocyte                                                         FIBRIN




                                                                                                     Platelets

                                Monocyte                    Endothelial cells




Falanga and Rickles, New Oncology:Thrombosis, 2005; Hematology, 2007
          Pathogenesis of Thrombosis in Cancer – A
                      Modification of Virchow’s Triad

1. Stasis
  ●   Prolonged bed rest
  ●   Extrinsic compression of blood vessels by tumor

2. Vascular Injury
  ●   Direct invasion by tumor
  ●   Prolonged use of central venous catheters
  ●   Endothelial damage by chemotherapy drugs
  ●   Effect of tumor cytokines on vascular endothelium

3. Hypercoagulability
  ●   Tumor-associated procoagulants and cytokines (tissue factor, CP,
      TNFa, IL-1, VEGF, etc.)
  ●   Impaired endothelial cell defense mechanisms (APC resistance;
      deficiencies of AT, Protein C and S)
  ●   Enhanced selectin/integrin-mediated, adhesive interactions between
      tumor cells,vascular endothelial cells, platelets and host
      macrophages
     Mechanisms of Cancer-Induced Thrombosis:
             Clot and Cancer Interface


1. Pathogenesis?


2. Biological significance?


3. Potential importance for cancer therapy?
         Activation of Blood Coagulation in Cancer
                         Biological Significance?



►   Epiphenomenon?
    Is this a generic secondary event where
    thrombosis is an incidental finding


    or, is clotting activation . . .


►   A Primary Event?
    Linked to malignant transformation
                                    Interface of Clotting Activation
                                          and Tumor Biology

                                        FVII/FVIIa
                Tumor                                         Blood Coagulation
                                  TF                             Activation
                 Cell

                        VEGF
                                                                   THROMBIN



                                                                    FIBRIN
                                                                             Angiogenesis
                                                                              IL-8
                 PAR-2                  TF


                                               Endothelial cells
            Angiogenesis

Falanga and Rickles, New Oncology:Thrombosis, 2005
                    Coagulation Cascade and Tumor Biology

                           Clotting-                                        Clotting-
                          dependent                                        dependent
           TF                                     Thrombin                                       Fibrin

                      VIIa              Xa
                                                      Clotting-
                                                    independent
       Clotting-                                                                                  Clotting-
     independent                                                                                 dependent


                                                     PARs


                                         Angiogenesis, Tumor
                                         Growth and Metastasis




Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
                  Regulation of Vascular Endothelial Growth Factor Production
                   and Angiogenesis by the Cytoplasmic Tail of Tissue Factor




           1.       TF regulates VEGF expression in human cancer
                    cell lines

           2.       Human cancer cells with increased TF are more
                    angiogenic (and, therefore, more ―metastatic’) in
                    vivo due to high VEGF production




Abe et.al. Proc Nat Acad Sci 1999;96:8663-8668; Ruf et.al. Nature Med 2004;10:502-509
                  Regulation of Vascular Endothelial Growth Factor Production
                   and Angiogenesis by the Cytoplasmic Tail of Tissue Factor



         3.       The cytoplasmic tail of TF, which contains three
                  serine residues, appears to play a role in regulating
                  VEGF expression in human cancer cells, perhaps
                  by mediating signal transduction

         4.       Data consistent with new mechanism(s) by which
                  TF signals VEGF synthesis in human cancer cells
                  may provide insight into the relationship between
                  clotting and cancer




Abe et.al. Proc Nat Acad Sci 1999;96:8663-8668; Ruf et.al. Nature Med. 2004;10:502-509
             Tissue Factor Expression, Angiogenesis, and
                  Thrombosis in Pancreatic Cancer

Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan, Charles W. Francis, Ralph H.
  Hruban, Ying Chuan Hu, Galen Hostetter, Jennifer Harvey and Mark B.Taubman
           (U Rochester, U Pitt, Johns Hopkins, Translational Genomics)
                          Clin Cancer Res 2007;13:2870


 ►   Retrospective IH and microarray study of TF, VEGF and MVD in:
     ●   Normal pancreas (10)
     ●   Intraductal papillary mucinous neoplasms (IPMN; 70)
     ●   Pancreatic intrepithelial neoplasia (PanIN; 40)
     ●   Resected or metastatic pancreatic adenoca(130)


 ►   Survival


 ►   VTE Rate
                      Correlation of Tissue Factor Expression with the
                  Expression of Other Angiogenesis Cariables in Resected
                                     Pancreatic Cancer


                                           High TF      Low TF
                                                                      P
                                          Expression   Expression

    VEGF expression
       Negative                               13           41
                                                                    <0.0001
       Positive                               53           15

    Microvessel density
       V6 per tissue core                     27           33        0.47
       >6 per tissue core                     39           23
       Median                                 8            6         0.01




Khorana et.al. Clin CA Res 2007:13:2870
                         Symptomatic VTE in Pancreatic Cancer

                       30%                          5/19
                                                   26.3%
                       25%
         Rate of VTE




                       20%

                       15%

                       10%                 1/22
                                          4.5%
                       5%

                       0%
                                          Low TF   High TF


Khorana et.al. Clin CA Res 2007;13:2872
              Activation of Blood Coagulation
           in Cancer: Malignant Transformation
►    Epiphenomenon?
►    Linked to malignant transformation?
    1.   MET oncogene induction produces DIC in
         human liver carcinoma
         (Boccaccio et. al. Nature 2005;434:396-400)

    2.   Pten loss produces TF activation and
         pseudopalisading necrosis in human
         glioblastoma
         (Rong et.al. Ca Res 2005;65:1406-1413)

    3.   K-ras oncogene, p53 inactivation and TF
         induction in human colorectal carcinoma
         (Yu et.al. Blood 2005;105:1734-1741)
                      Activation of Blood Coagulation
                   in Cancer: Malignant Transformation

           ―1. MET Oncogene Drives a Genetic Programme
                    Linking Cancer to Haemostasis‖

        ►    MET encodes a tyrosine kinase receptor for hepatocyte
             growth factor/scatter factor (HGF/SF) 
               ●    Drives physiological cellular program of ―invasive
                    growth‖ (tissue morphogenesis, angiogenesis
                    and repair)
               ●    Aberrant execution (e.g. hypoxia-induced
                    transcription) is associated with neoplastic
                    transformation, invasion, and metastasis

Boccaccio et al Nature 2005;434:396-400
    ―MET Oncogene Drives a Genetic Programme
          Linking Cancer to Haemostasis‖

►   Mouse model of Trousseau’s Syndrome

    ●   Targeted activated human MET to the mouse liver
        with lentiviral vector and liver-specific promoter 
        slowly, progressive hepatocarcinogenesis
    ●   Preceded and accompanied by a
        thrombohemorrhagic syndrome
    ●   Venous thrombosis in tail vein occurred early and
        was followed by fatal internal hemorrhage
    ●   Syndrome characterized by  d-dimer and PT and 
        platelet count (DIC)
            Blood Coagulation Parameters in Mice
             Transduced with the MET Oncogene


                                Time after Transduction (days)
Transgene       Parameter        0          30           90
   GFP      Platelets (x103)   968          656         800
            D-dimer (µg/ml)    <0.05       <0.05      <0.05
            PT (s)             12.4         11.6       11.4
_________   ________________   _______________________________
   MET      Platelets (x103)   974          350        150
            D-dimer (µg/ml)    <0.05        0.11       0.22
            PT (s)             12.9         11.8       25.1
    ―MET Oncogene Drives a Genetic Programme
          Linking Cancer to Haemostasis‖

►   Mouse model of Trousseau’s Syndrome

    ●   Genome-wide expression profiling of hepatocytes
        expressing MET upregulation of PAI-1 and COX-2
        genes with 2-3x  circulating protein levels

    ●   Using either XR5118 (PAI-1 inhibitor) or Rofecoxib
        (Vioxx; COX-2 inhibitor) resulted in inhibition of
        clinical and laboratory evidence for DIC in mice
                                Activation of Blood Coagulation
                             in Cancer: Malignant Transformation

               2. ―Pten and Hypoxia Regulate Tissue Factor
                   Expression and Plasma Coagulation By
                               Glioblastoma‖
        ►    Pten = tumor suppressor with lipid and protein
             phosphatase activity
        ►    Loss or inactivation of Pten (70-80% of
             glioblastomas) leads to Akt activation and
             upregulation of Ras/MEK/ERK signaling cascade




Rong, Brat 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 immunohistochemical
   staining) in pseudopalisades of # 7 human
   glioblastoma specimens
                        Both Akt and Ras Pathways Modulate TF
                         Expression By Transformed Astrocytes



N=Normoxia

H=hypoxia




Rong, Brat et.al. Ca Res 2005;65:1406-1413
                    ―Pten and Hypoxia Regulate Tissue Factor Expression
                          and Plasma Coagulation By Glioblastoma‖
                                                       pseudopalisading
                                                       necrosis




                                                                           H&E




                                             Vascular
                                             Endothelium


                                                                          TF Immuno-
                                                                          histochemistry
Rong, Brat et.al. Ca Res 2005;65:1406-1413
                               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, Mackman, Rak 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‖
                                   TF expression in cancer cells parallels genetic tumor progression
                                                        with an impact of K-ras and p53 status
    Mean Channel TF Flourescence




                                   450                                                                   160




                                                                             TF Activity (U/106 cells)
                                   400                                                                   140
                                   350                                                                   120
                                   300
                                                                                                         100
                                   250
                                                                                                         80
                                   200
                                                                                                         60
                                   150
                                   100                                                                   40
                                    50                                                                   20
                                     0                                                                    0
                                          HKh-2      HCT116      379.2                                         HKh-2   HCT116   379.2

                                          del/+      mut/+      mut/+
                                          +/+         +/+       del/del


Yu, Mackman, Rak 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, Mackman, Rak et.al. Blood 2005;105:1734-41
                                      ―Oncogenic Events Regulate Tissue Factor
                                        Expression In Colorectal Cancer Cells‖

                          Effect of TF si mRNA on new vessel formation in colon cancer


                                 14
            %VWF-Positive Area




                                 12
                                 10
                                 8
                                 6
                                 4
                                 2
                                 0
                                      HCT116     SI-2       SI-3      MG only



Yu, Mackman, Rak 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




Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
Mechanisms of Cancer-Induced Thrombosis:
              Implications


1. Pathogenesis?


2. Biological significance?


3. Potential importance for cancer
   therapy?
               Cancer and Thrombosis
        Year 2008 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 2008 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 LMWH in
     cancer patients indicate superiority in preventing recurrent
     VTE and suggest increased survival (not due to just
     preventing VTE)— “Titillating”
           Coagulation Cascade and Tumor Biology
                     Clotting-                                        Clotting-
                    dependent                                        dependent
    TF                                     Thrombin                                         Fibrin

               VIIa              Xa
                                               Clotting-
                                             independent
  Clotting-                                                                                   Clotting-
independent                                                                                  dependent
                     ?
                                              PARs


                                  Angiogenesis, Tumor
                                  Growth and Metastasis


LMWH (e.g. FRAGMIN)
  Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
 Clotting, Cancer, and Clinical Strategies


A Systematic Overview of VTE
     Prophylaxis In The
      Setting of Cancer
 Linking Science to Clinical Practice


            Craig M. Kessler, MD
        Professor of Medicine and Pathology
       Georgetown University Medical Center
       Director of the Division of Coagulation
        Department of Laboratory Medicine
      Lombardi Comprehensive Cancer Center
                   Washington, DC
                              VTE and Cancer: Epidemiology

           ►    Of all cases of VTE:
                  ●    About 20% occur in cancer patients
                  ●    Annual incidence of VTE in cancer
                       patients ≈ 1/250

           ►    Of all cancer patients:
                  ●    15% will have symptomatic VTE
                  ●    As many 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
Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
                                               DVT and PE in Cancer
                                      Facts, Findings, and Natural History


             ►   VTE is the second leading cause of death in
                 hospitalized cancer patients1,2
             ►   The risk of VTE in cancer patients undergoing
                 surgery is 3- to 5-fold higher than those without
                 cancer2
             ►   Up to 50% of cancer patients may have evidence of
                 asymptomatic DVT/PE3
             ►   Cancer patients with symptomatic DVT exhibit a
                 high risk for recurrent DVT/PE that persists for
                 many years4

1.   Ambrus JL et al. J Med. 1975;6:61-64
2.   Donati MB. Haemostasis. 1994;24:128-131
3.   Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
4.   Prandoni P et al. Ann Intern Med. 1996;125:1-7
                          Clinical Features of VTE in Cancer


   ► VTE     has significant negative impact on
        quality of life
   ► 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


Bura et. al., J Thromb Haemost 2004;2:445-51
Risk Factors for Cancer-Associated VTE

► Cancer
    ●   Type
        • Men: prostate, colon, brain, lung
        • Women: breast, ovary, lung
    ●   Stage
►   Treatments
    ●   Surgery
        • 10-20% proximal DVT
        • 4-10% clinically evident PE
        • 0.2-5% fatal PE
    ●   Systemic
    ●   Central venous catheters (~4% generate clinically
        relevant VTE)
                                              Thrombosis and Survival:
                                      Likelihood of Death After Hospitalization


                               1.00
                                                 DVT/PE and Malignant Disease
                               0.80
        Probability of Death




                               0.60
                                                                 Malignant Disease
                               0.40
                                                                           DVT/PE Only
                               0.20
                                                              Nonmalignant Disease
                               0.00
                                       0   20   40   60     80   100 120     140 160 180
                                                          Number of Days
Levitan N, et al. Medicine 1999;78:285
                                         As Number Of Cancer Survivors Increases, VTE
                                                       Rates Increase

                                            4
                                           3.5
                                                                                 Cancer Patients
            And Noncancer Patients (%)
            VTE in Hospitalized Cancer




                                            3
                                           2.5
                                            2
                                           1.5
                                            1
                                                                                  Noncancer Patients
                                           0.5
                                            0
                                            79

                                                 81

                                                      83

                                                           85

                                                                87

                                                                     89

                                                                            91

                                                                                 93

                                                                                      95

                                                                                            97

                                                                                                   99
                                                                     Year

Stein PD, et al. Am J Med 2006; 119: 60-68
                                                                Relative Risk of VTE in
                                                                   Cancer Patients




                                                                          2
                                                                                    3
                                                                                              4




                                                                1
                                                          0.5
                                                                    1.5
                                                                              2.5
                                                                                        3.5
                                                                                                  4.5




                                             Pancreas




Stein PD, et al. Am J Med 2006; 119: 60-68
                                                  Brain
                                              Myeloprol
                                              Stomach
                                             Lymphoma
                                                Uterus
                                                  Lung
                                             Esophagus
                                               Prostate
                                                 Rectal
                                                Kidney
                                                                                                                                                            ―Solid And Liquid‖




                                                 Colon
                                                 Ovary
                                                                                                                                                        VTE Risk And Cancer Type:




                                                  Liver
                                              Leukemia
                                                                                                        Relative Risk of VTE Ranged From 1.02 to 4.34




                                                Breast
                                                 Cervix
                                               Bladder
      Thrombosis Risk In Cancer

              Primary Prophylaxis
►   Surgery

►   Chemotherapy

►   Radiotherapy

►   Central Venous Catheters

►   Acute Illness (immobilization)
           Prevention and Management
                of VTE in Cancer

►   Sparse data specifically related to cancer patients
    was available until recently


►   Cancer patients are a small subset (< 20%) in
    most of the largest trials of antithrombotic therapy


►   Therefore, until the last two or three years, we
    needed to extrapolate from non-cancer patients,
    bearing in mind that cancer patients are in the
    highest risk groups
                Antithrombotic Therapy: Choices

     Nonpharmacologic                 Pharmacologic
       (Prophylaxis)             (Prophylaxis & Treatment)



 Intermittent       Elastic    Unfractionated            Low Molecular
 Pneumatic         Stockings   Heparin (UH)              Weight Heparin
Compression                                                (LMWH)


            Inferior
           Vena Cava                         Oral
             Filter                     Anticoagulants
                                       New Agents: e.g.
                                       Fondaparinux,
                                       Direct anti-Xa inhibitors,
                                       Direct anti-IIa, etc.?
                      Incidence of VTE in Surgical Patients

                  ►    Cancer patients have 2-fold risk of post-
                       operative DVT/PE and >3-fold risk of fatal
                       PE despite prophylaxis:

                                                  No Cancer    Cancer
                  Outcome                                               P-value
                                                    N=16,954   N=6124

                  Post-op VTE                        0.61%     1.26%    <0.0001

                  Non-fatal PE                       0.27%     0.54%    <0.0003

                  Autopsy PE                          0.11%    0.41%    <0.0001

                  Death                              0.71%     3.14%    <0.0001


Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
                                 Natural History of VTE in Cancer
                                 Surgery: The @RISTOS Registry

      ►    Web-Based Registry of Cancer Surgery
                     Tracked 30-day incidence of VTE in 2373 patients
                     Type of surgery
                          • 52% General
                          • 29% Urological
                          • 19% Gynecologic
                     82% received in-hospital thromboprophylaxis
                     31% received post-discharge thromboprophylaxis
                                        Findings
      ►    2.1% incidence of clinically overt VTE (0.8% fatal)
      ►    Most events occur after hospital discharge
      ►    Most common cause of 30-day post-op death

Agnelli, abstract OC191, ISTH 2003
                                 Colorectal Cancer Resection
                          Overall, 1% incidence of VTE with 3.8 fold mortality
  Transfused women 1.8-fold more likely to develop VTE
              than non-transfused women
   Association Between Transfusion and Venous Thromboembolism Stratified by Sex
   in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000

   Variable                      Incidence of VTE, %   P Value      Stratified OR     Adjusted
                                                                     (95% CI)*        P Value

   Male Sex
    No Transfusion (n = 5683)            0.7                          Referent
   Transfusion (n = 1156)                0.8             .84        0.9 (0.5-1.9)       .85

   Female Sex
    No Transfusion (n = 5565)            0.9                          Referent
    Transfusion (n = 1610)               2.1            <.001       1.8 (1.2-2.6)       .004




Nilsson: Arch Surg, 142;2007:126–132
          VTE Risk Factors in Surgical
              Oncology Patients

►   Age >40 years
►   Cancer procoagulants
►   Thrombophilias
►   Adjuvant chemotherapy or hormonal
    treatment
►   Complicated, lengthy surgery (tissue
    trauma, immobilization)
►   Debilitation and slower recovery
►   Indwelling venous access
                                             Surgical Prophylaxis


                                LMWH better                            UFH better

                             Asymptomatic DVT
                                             Clinical PE
                    Clinical thromboembolism                                           Cancer
                                                 Death                                 Non-cancer
                               Major hemorrhage
                                Total hemorrhage
                                Wound hematoma
                                    Transfusion
                                                           0   1.0   2.0   3.0   4.0


Mismetti P et al. Br J Surg 2001;88:913–30
                           Prophylaxis in Surgical Patients

   LMWH vs. UFH
   ►   Abdominal or pelvic surgery for cancer (mostly colorectal)
   ►   LMWH once daily vs. UFH tid for 7–10 days post-op
   ►   DVT on venography at day 7–10 and symptomatic VTE


        Study                              N            Design          Regimens

        ENOXACAN 1                        631         double-blind   enoxaparin vs. UFH

        Canadian Colorectal
                                          475         double-blind   enoxaparin vs. UFH
        DVT Prophylaxis 2



1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103
2. McLeod R, et al. Ann Surg 2001;233:438-444
                                                Prophylaxis in Surgical Patients


                                          20%
                                                  18.2%
                                                              P>0.05
                                                                                  ENOXACAN
             Incidence of Outcome Event




                                                      14.7%
                                          15%

                                                                                  UFH 5000 U tid
                                          10%                                      N=319

                                                                                  enoxaparin 40 mg
                                                                2.9%   4.1%        N=312
                                          5%


                                          0%
                                                    VTE          Major Bleeding


ENOXACAN Study Group. Br J Surg 1997;84:1099–103
                                                 Prophylaxis in Surgical Patients


                                           20%                                     Canadian Colorectal
                                                   16.9%                           DVT Prophylaxis
              Incidence of Outcome Event




                                                        13.9%   P=0.052            Trial
                                           15%
                                                                                   UFH 5000 U tid
                                                                                   N=234
                                           10%
                                                                                   enoxaparin 40 mg
                                                                                   N=241
                                           5%
                                                                    1.5% 2.7%


                                           0%
                                                     VTE          Major Bleeding
                                                    (Cancer)            (All)

McLeod R, et al. Ann Surg 2001;233:438-444
                               Prophylaxis in Surgical Patients

                   Extended prophylaxis
                   ►    Abdominal or pelvic surgery for cancer
                   ►    LMWH for ~ 7 days vs. 28 days post-op
                   ►    Routine bilateral venography at ~day 28

      Study                                    N             Design                          Regimens

      ENOXACAN 1                             332          double-blind              Enoxaparin vs. placebo

                                                                                           Dalteparin vs. no
      FAME                                   198           Open-label
                                                                                             prophylaxis




1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
2. Rasmussen M, et al (FAME) Blood 2003;102:56a
                                                      Extended Prophylaxis in
                                                         Surgical Patients

                                            15%
               Incidence of Outcome Event




                                                  12.0%
                                                                                              ENOXACAN II
                                            10%             P=0.02                            placebo
                                                                                              N=167

                                                     4.8%                 5.1%                enoxaparin 40 mg
                                            5%                     3.6%                       N=165

                                                          1.8%
                                                             0.6%                0% 0.4%         NNT = 14

                                            0%     VTE      Prox       Any          Major
                                                            DVT       Bleeding     Bleeding


Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
                 Major Abdominal Surgery: FAME Investigators—
                             Dalteparin Extended
      ►    A multicenter, prospective, assessor-blinded, open-label,
           randomized trial: Dalteparin administered for 28 days
           after major abdominal surgery compared to 7 days of
           treatment
      ►    RESULTS: Cumulative incidence of VTE was reduced
           from 16.3% with short-term thromboprophylaxis (29/178
           patients) to 7.3% after prolonged thromboprophylaxis
           (12/165) (relative risk reduction 55%; 95% confidence
           interval 15-76; P=0.012).
      ►    CONCLUSIONS: 4-week administration of dalteparin,
           5000 IU once daily, after major abdominal surgery
           significantly reduces the rate of VTE, without increasing
           the risk of bleeding, compared with 1 week of
           thromboprophylaxis.
Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
              Gynecological Cancer Surgery

►   Paucity of level I/II studies in this population
►   Based on small historical studies:
    ●   Postoperative risk of DVT/PE varies 12%–35%
    ●   LDUH (5000 u bid) ineffective
    ●   LDUH 5000 u tid reduces risk by 50%–60%
    ●   Once-daily LMWH comparable to LDUH for efficacy and
        safety
                                   Gynecological Surgery


   Cochrane Systematic Review
   ►    Meta-analysis of 8 randomized controlled trials
   ►    Heparin reduces risk of DVT by 70% (95% CI
        0.10–0.89)
   ►    No evidence that anticoagulation reduces risk of
        PE
   ►    No statistical difference between LDUH and LMWH
        in efficacy and bleeding

Oates-Whitehead et al. Cochrane Database Syst Rev 2003;4:CD003679
                                     Urological Cancer Surgery

                 Poorly studied population
                Risk of VTE varies with type of surgery and diagnosis

                                                    DVT          PE     Fatal PE
              Radical retropubic prostatectomy      1–3%       1–3%       0.6%

                             Cystectomy              8%        2–4%        2%

                       Radiological studies         51%         22%



            ►    Small studies have suggested prophylaxis with either LDUH or LMWH
                 is effective and safe
            ►    Possible increased risk of pelvic hematoma and lymphocele formation


Kibel, Loughlin. J Urol. 1995;153:1763-1774
               Neurosurgery and VTE

                  OBSERVATIONS
►   Majority of patients undergoing neurosurgery
    for malignancy
►   Risk of venographic VTE ~30%-40%
►   High risk of intracranial or intraspinal
    hemorrhage
►   Mechanical prophylaxis preferred method
►   Use of anticoagulant prophylaxis remains
    controversial in this setting
                          Neurosurgery and VTE Prophylaxis

        Meta-analysis of three (3) RCTs evaluating
                   LMWH prophylaxis
                                           ES             LMWH    RR    NNT/NNH    P

         VTE                             28.3%            17.5%   0.6      9      0.001

         Proximal DVT                    12.5%            6.2%    0.5     16      <0.01

         Total bleeding                   3.0%            6.1%    2.0     33      0.02

         Major bleeding                   1.3%            2.2%    1.7     115     0.30


►   One major bleeding event observed for every 7 proximal DVTs
    prevented with LMWH
Iorio A, Agnelli G. Arch Intern Med. 2000;160:2327-2332
                             7th ACCP Consensus Guidelines

      Grade                   Recommendations for Cancer Patients

                     Patients undergoing surgery should receive LDUH 5000 U tid
         1A
                     or LMWH > 3400 U daily

                     Patients undergoing surgery may receive post-hospital
         2A
                     discharge prophylaxis with LMWH

                     No routine prophylaxis to prevent thrombosis secondary to
         2A          central venous catheters, including LMWH (2B) and fixed-
                     dose warfarin (1B)

                     Patients hospitalized with an acute medical illness should
         1A
                     receive LDUH or LMWH



Geerts W, et al. Chest 2004; 126: 338S-400S
                                    Central Venous Catheters

        Thrombosis is a potential complication of central
            venous catheters, including these events:
                        –Fibrin sheath formation
                        –Superficial phlebitis
                        –Ball-valve clot
                        –Deep vein thrombosis (DVT)
        • Incidence up to 60% from historical data

        • ACCP guidelines recommended routine prophylaxis
          with low dose warfarin or LMWH

Geerts W, et al. Chest 2001;119:132S-175S
                            Prophylaxis for Venous Catheters

                                              Placebo-Controlled Trials

            Study                              Regimen                            N                CRT (%)

             Reichardt*                Dalteparin 5000 U od                      285               11 (3.7)
               2002                              placebo                         140                 5 (3.4)

              Couban*                      Warfarin 1mg od                       130                 6 (4.6)
                 2002                            placebo                         125                 5 (4.0)

              ETHICS†                  Enoxaparin 40 mg od                       155              22 (14.2)
                 2004                            placebo                         155              28 (18.1)
            *symptomatic outcomes; †routine venography at 6 weeks




Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730
                      Central Venous Catheters: Warfarin

                       Tolerability of Low-Dose Warfarin
►   95 cancer patients receiving FU-based infusion
    chemotherapy and 1 mg warfarin daily
►   INR measured at baseline and four time points
►   10% of all recorded INRs >1.5
►   Patients with elevated INR
                         2.0–2.9             6%
                         3.0–4.9             19%
                         >5.0                7%



Masci et al. J Clin Oncol. 2003;21:736-739
              Prophylaxis for Central
              Venous Access Devices
Summary
►   Recent studies demonstrate a low
    incidence of symptomatic catheter-related
    thrombosis (~4%)
►   Routine prophylaxis is not warranted to
    prevent catheter-related thrombosis, but
    catheter patency rates/infections have not
    been studied
►   Low-dose LMWH and fixed-dose warfarin
    have not been shown to be effective for
    preventing symptomatic and asymptomatic
    thrombosis
                             7th ACCP Consensus Guidelines

         Grade                    Recommendations for Cancer Patients
                         Patients undergoing surgery should receive LDUH 5000 U tid or
             1A
                         LMWH > 3400 U daily

                         Patients undergoing surgery may receive post-hospital discharge
             2A
                         prophylaxis with LMWH

                         No routine prophylaxis to prevent thrombosis secondary to
             2A          central venous catheters, including LMWH (2B) and fixed-dose
                         warfarin (1B)

                         Patients hospitalized with an acute medical illness should receive
             1A
                         LDUH or LMWH



Geerts W, et al. Chest 2004; 126: 338S-400S
      Primary Prophylaxis in Cancer Radiotherapy in the
                      Ambulatory Patient

►   No recommendations from ACCP
►   No data from randomized trials (RCTs)
►   Weak data from observational studies in
    high risk tumors (e.g. brain tumors; mucin-
    secreting adenocarcinomas-colorectal,
    pancreatic, lung, renal cell, ovarian)
►   Recommendations extrapolated from
    other groups of patients if additional risk
    factors present (e.g. hemiparesis in brain
    tumors, etc.)
                   Risk Factors for VTE in
                  Medical Oncology Patients

► Tumor       type
    ●   Ovary, brain, pancreas, lung, colon

► Stage,      grade, and extent of cancer
    ●   Metastatic disease, venous stasis due to bulky
        disease
►   Type of antineoplastic treatment
    ●   Multiagent regimens, hormones,
        anti-VEGF, radiation
►   Miscellaneous VTE risk factors
    ●   Previous VTE, hospitalization, immobility, infection,
        thrombophilia
                            Independent Risk Factors for DVT/PE


     Risk Factor/Characteristic                              O.R.
     Recent surgery w/ institutionalization                  21.72
     Trauma                                                  12.69
     Institutionalization without recent surgery             7.98
     Malignancy with chemotherapy                            6.53
     Prior CVAD or pacemaker                                 5.55
     Prior superficial vein thrombosis                       4.32
     Malignancy without chemotherapy                         4.05

     Neurologic disease w/ extremity paresis                 3.04

     Serious liver disease                                   0.10

Heit JA et al. Thromb Haemost. 2001;86:452-463
                            VTE Incidence In Various Tumors

                         Oncology Setting                                      VTE Incidence
       Breast cancer (Stage I & II) w/o further
                                                                                   0.2%
       treatment
       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
                Strategies for Thromboprophylaxis in
                 Thalidomide Treated MM Patients

                                                                                       Aspirin
                                         Warfarin       Warfarin
  Therapy           No prophylaxis                                       LMWH           (81
                                         1mg/daily      (INR 2 – 3)
                                                                                       mg/d)

                                      25% Weber, 2002
                26% Cavo, 2002
T+ D in newly                         (24 pts)          7% Weber,
                  (19 pts)
diagnosed                                               2002
                18% Rajkumar, 2004
patients                              13% Cavo, 2004    (46 pts)
                  (102 pts)
                                      (52 pts)


                                                                      14.7%
T+ dox in
                                                                      Zangari, 2004
newly           34.5% Zangari, 2004   31.4% Zangari,
                                                                      (68pts)
diagnosed         (87 pts)            2004 (35 pts)                                    17.8%
                                                                      7% Minnema,
patients                                                                               Baz,
                                                                      2004 (412 pts)
                                                                                       2004
                                                                                       (103 pts)
T+dox at        16% Zangari, 2002
relapse           (192 pts)
                    MM-009/010: Thromboembolic Events



        16
        14
        12
        10
                                                                  DVT
           8
           6                                                      PE

           4
           2
          0
                Len + D(%)          D (%)   Len + D(%)    D (%)

                        MM-009                   MM-010


Weber D. ASCO 2005 Annual Meeting
                          Incidence of VTE: USA and Canada
                             >Israel, Australia, and Europe
                                                                     ►   rEPO used
   Multivariate Analysis of the Risk of Thrombosis Associated with
   Lenalidomide plus High-Dose Dexamethasone and Concomitant             more in USA
   Erythropoietin for the Treatment of Multiple Myeloma                  and Canada
                                                                     ►   L+Dex: 23%
   Treatment                           Odds Ratio       P Value          VTE with EPO
                                        (95% CI)                         vs 5% w/o
                                                                         EPO
   Lenalidomide plus                 3.51 (1.77-6.97)   <0.001
                                                                     ►   Placebo + Dex:
   High-dose dexamethasone
                                                                         7% VTE with
                                                                         EPO vs 1%
   Concomitant erythropoietin        3.21 (1.72-6.01)   <0.001           without EPO




Knight: N Engl J Med.2006,354:2079
         Thrombotic Outcomes from rEPO or
         Darbopoietin Use in Cancer Patients

                                                 Among 6,769 pts
                                                 with cancer, RR
                                                 for DVT with
                                                 rEPO/Darbepo
                                                 was increased by
                                                 67% (RR=1.67;
                                                 95% CI 1.35 to
                                                 2.06)




Bohlius: The Cochrane Library, Volume (4).2006
           Standard Treatment of VTE
              Can We Do Better Than This?



Initial treatment      5 to 7 days

 LMWH or UFH



Long-term therapy                       > 3 months

 Vitamin K antagonist (INR 2.0 - 3.0)
                    Recurrent VTE in Cancer – Subset Analysis of
                   the Home Rx Studies (UH/VKA vs. LMWH/VKA)



                            Recurrent VTE
                  Events per 100 patient years
                                                           P value

             Malignant                    Non- Malignant

                   27.1                        9.0         0.003




Hutten et.al. J Clin Oncol 2000;18:3078
                     Recurrent VTE in Cancer – Subset Analysis of
                                the Home Rx Studies



                                 Major Bleeding
                        Events per 100 patient years
                                                       P-value
                                           Non-
                       Malignant
                                          malignant

                             13.3            2.1       0.002




Hutten et.al. J Clin Oncol 2000;18:3078
                Oral Anticoagulant Therapy
              in Cancer Patients: Problematic

► Warfarin  (Coumadin®) therapy is
    complicated by:

    ●   Difficulty maintaining tight therapeutic control, due
        to anorexia, vomiting, drug interactions, etc.
    ●   Frequent interruptions for thrombocytopenia and
        procedures
    ●   Difficulty in venous access for monitoring
    ●    Increased risk of both recurrence and bleeding

►   Is it reasonable to substitute long-term LMWH
    for warfarin ? When? How? Why?
                          CLOT: Landmark Cancer/VTE Trial

                                                                 Dalteparin    Dalteparin


 CANCER PATIENTS WITH
                      Randomization
    ACUTE DVT or PE
                                                                                   Oral
                                                                 Dalteparin   Anticoagulant
                [N = 677]

       ►     Primary Endpoints: Recurrent VTE and Bleeding

       ►     Secondary Endpoint: Survival


Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
                                                             Landmark CLOT Cancer Trial
                                                                  Reduction in Recurrent VTE

                      Probability of Recurrent VTE, %   25                          Risk reduction = 52%
                                                                  Recurrent VTE
                                                                                    p-value = 0.0017
                                                        20


                                                        15                                  OAC


                                                        10
                                                                                            Dalteparin
                                                         5


                                                        0

                                                              0     30   60   90    120   150      180   210

Lee, Levine, Kakkar, Rickles et.al. N Engl                               Days Post Randomization
J Med, 2003;349:146
                                   Bleeding Events in CLOT


                                              Dalteparin          OAC
                                                                  N=335
                                                                              P-value*
                                                    N=338

             Major bleed                         19 ( 5.6%)      12 ( 3.6%)     0.27


               Any bleed                         46 (13.6%)      62 (18.5%)    0.093



              * Fisher’s exact test



Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
                 Treatment of Cancer-Associated VTE

                                   Length
                                                              Major
                                     of            Recurrent                 Death
       Study         Design                  N               Bleeding
                                  Therapy          VTE (%)                    (%)
                                                                (%)
                                  (Months)
CLOT Trial          Dalteparin               336   9     0.002   6    NS     39   NS

(Lee 2003)          OAC              6       336   17            4           41


CANTHENOX           Enoxaparin               67    11    0.09    7    0.09   11 0.03
(Meyer 2002)        OAC              3       71    21            16          23


LITE                Tinzaparin               80    6      0.03   6    NS     23   NS
(Hull ISTH 2003)    OAC              3       87    11            8           22


ONCENOX             Enox (Low)               32    3.4    NS          NS          NR
(Deitcher ISTH      Enox (High)      6       36    3.1
2003)               OAC                      34    6.7
                              Treatment and 2° Prevention of VTE
                                   in Cancer – Bottom Line

                                        New Development

        ►    New standard of care is LMWH at therapeutic
             doses for a minimum of 3-6 months (Grade 1A
             recommendation—ACCP)


        ►    Oral anticoagulant therapy to follow for as long
             as cancer is active (Grade 1C
             recommendation—ACCP)



Buller et.al. Chest Suppl 2004;126:401S-428S
                                                      CLOT 12-month Mortality
                                                           All Patients

                                            100
                                            90
               Probability of Survival, %




                                            80
                                            70
                                                                           Dalteparin
                                            60
                                            50                OAC
                                            40
                                            30
                                            20
                                            10                             HR 0.94 P-value = 0.40
                                             0

                                                  0   30 60 90 120   180      240    300     360
                                                             Days Post Randomization
Lee A, et al. ASCO. 2003
                                                      Anti-Tumor Effects of LMWH
                                                         CLOT 12-month Mortality
                                                        Patients Without Metastases (N=150)

                                            100
                                            90                                 Dalteparin
               Probability of Survival, %




                                            80
                                            70
                                            60                                     OAC
                                            50
                                            40
                                            30
                                            20
                                            10
                                                                        HR = 0.50 P-value = 0.03
                                             0

                                                  0   30 60 90 120 150 180   240    300     360

                                                             Days Post Randomization
Lee A, et al. ASCO. 2003
                                LMWH for Small Cell Lung Cancer
                                        Turkish Study
        ►   84 patients randomized: CEV +/- LMWH (18 weeks)

        ►   Patients balanced for age, gender, stage, smoking history,
            ECOG performance status

                                                Chemo +
                                                                 Chemo alone   P-value
                                                Dalteparin

     1-y overall survival, %                       51.3             29.5        0.01

     2-y overall survival, %                       17.2              0.0        0.01

     Median survival, m                            13.0              8.0        0.01

              CEV = cyclophosphamide, epirubicin, vincristine;
              LMWH = Dalteparin, 5000 units daily
Altinbas et al. J Thromb Haemost 2004;2:1266.
                                                              VTE Prophylaxis Is Underused
                                                                in Patients With Cancer
                                                    Cancer:                 Major
                                             100    FRONTLINE Survey1—     Surgery2
        Rate of Appropriate Prophylaxis, %




                                                    3891 Clinician           89
                                              90    Respondents
                                              80
                                                   Cancer:
                                              70   Surgical                                Major                             Confirmed DVT
                                              60       52
                                                                                      Abdominothoracic                        (Inpatients)5
                                                                                      Surgery (Elderly)3       Medical
                                              50                                                             Inpatients4
                                                                                                                                     42
                                                                                               38
                                              40                                                                 33
                                                                 Cancer:
                                              30                 Medical
                                              20
                                              10                    5
                                               0
                                                   FRONTLINE FRONTLINE:    Stratton         Bratzler           Rahim           DVT FREE
                                                    Surgical   Medical

1. Kakkar AK et al. Oncologist. 2003;8:381-388
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340                       4. Rahim SA et al. Thromb Res. 2003;111:215-219
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912                     5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
         Cancer and Venous Thrombosis


 VTE Prophylaxis in the Cancer Patient
            and Beyond
Guidelines and Implications for Day-to-day Practice



            Samuel Z. Goldhaber, MD
                 Cardiovascular Division
             Brigham and Women’s Hospital
                  Professor of Medicine
                 Harvard Medical School
                 Learning Objectives


►   Scope of the problem


►   Tools in the toolkit: drugs, devices


►   Guidelines: ASCO, NCCN, ACCP


►   Implementation: voluntary or mandatory
                   Scope of the Problem


►   Epidemiology


►   Long-term sequelae


►   Failure to prophylax Medical Service patients,
    especially Medical Oncology patients
                             Annual Patients At-Risk For VTE
                                                        U.S. Hospitals



►     7.7 million Medical Service inpatients

►     4.3 million Surgical Service inpatients

►     Based upon ACCP guidelines for VTE prophylaxis




Anderson FA Jr, et al. Am J Hematol 2007; 82: 777-782
             Patients At-Risk For VTE


An 86-year-old man underwent successful
gastrectomy for newly diagnosed stomach cancer.
He was recovering uneventfully.


On POD #4, he had a witnessed cardiac arrest
while transferring from commode to bed. ACLS
yielded repeated PEA.


After 35 minutes, the code was ―called.‖ An
autopsy was obtained.
                             ICOPER Cumulative Mortality

                    25


                    20                        17.5%
    Mortality (%)




                    15


                    10


                    5



                    0

                         7   14    30                   60   90
                                  Days From Diagnosis


Lancet 1999; 353: 1386-1389
       Progression Of
Chronic Venous Insufficiency
         VTE Prophylaxis: Underused


Implementation of VTE prophylaxis continues
to be problematic, despite detailed North
American and European Consensus
guidelines.
                                         The Amin Report
                                      VTE Prophylaxis Rates in USA


    ►   Studied 196,104 Medical Service discharges from
        227 hospitals.


    ►   VTE prophylaxis rate was 62%.


    ►   ACCP-deemed appropriate prophylaxis rate was
        34%.



J Thromb Haemostas 2007; 5: 1610-6)
                                      The Amin Report
                                     Medical Oncology Patients


    ►   Of 196,104 Medical Service discharges, 30,708
        were medical oncology patients.


    ►   Only 56% received any VTE prophylaxis.


    ►   Only 28% received ACCP-deemed appropriate
        prophylaxis



J Thromb Haemostas 2007; 5: 1610-6
                                          Medical Patient
                                         Prophylaxis In Canada


►   Studied 1,894 Medical Service discharges from 29
    hospitals.

►   VTE prophylaxis was indicated in 90% of patients.

►   ACCP-deemed appropriate prophylaxis rate was
    16%.




Thrombosis Research 2007; 119: 145-155
                                     Cancer: Medical Patient
                                         Prophylaxis In Canada



   ►       19% of the 1,894 Medical Service patients had
           cancer, either as the admission diagnosis (9%) or
           an active comorbid condition (19%).

   ►       The most common cancers were: lung, breast,
           prostate, and colon.




Thrombosis Research 2007; 119: 145-155
                         Cancer: Decreased Likelihood Of VTE
                                Prophylaxis In Canada


   ►   Multivariable analysis: 60% less likely to prescribe
       VTE prophylaxis (95% CI: 32% to 76% less likely;
       p=0.0007).

   ►   Perhaps MDs fear an increased risk of bleeding in
       cancer patients?




Thrombosis Research 2007; 119: 145-155
                                   VTE in Cancer Patients

    ►   Prospective registry of 5,451 consecutive
        ultrasound-confirmed DVT patients at 183 U.S.
        institutions. (Am J Cardiol 2004; 93:259-262 )

    ►   Cancer occurred in 1,768 (39%), of whom 1,096
        (62%) had active cancer, of whom 599 (55%) were
        receiving chemotherapy.




Thromb Haemost 2007; 98: 656-661
                                   VTE in Cancer Patients

    ►   Lung, colorectal, and breast cancer were the most
        common cancers.

    ►   Cancer patients less often received VTE prophylaxis
        (28%) compared with the other DVT Registry
        patients (35%) (p<0.0001).

    ►   Cancer patients were more likely to receive IVC
        filters (22% vs. 14%; p<0.0001) than non-cancer
        patients.



Thromb Haemost 2007; 98: 656-661
                   Tools in the Toolkit


►   LMWH, Unfractionated Heparin,
    Fondaparinux, Warfarin

►   IVC Filters

►   Graduated Compression Stockings and
    Intermittent Pneumatic Compression Devices
                      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
              Dalteparin Prophylaxis in 3,706 Medical Patients
                                      Cancer Subgroup


 ►      Dalteparin 5,000 U/d vs. placebo

 ►      6 of 72 placebo patients (8.3%) developed VTE,
        compared with 2 of 65 dalteparin patients
        (3.1%)

 ►      Dalteparin was effective in all subgroups.




Vascular Medicine 2007; 12: 123-128
                               Filters

     Filter insertion has increased, especially retrievable
     filters. Filters prevent PE but increase DVT rate
     (and do not halt the thrombotic process).

Main indications:
1)   Severe bleeding that precludes anticoagulation
2)   Recurrent PE despite therapeutic anticoagulation
3)   Prophylaxis
                                              Retrievable Filters
                                             Prospective Series (N=228)


    ►      Retrieval attempted in only 25%
    ►      Filter tilting: 5.7%
    ►      Puncture site hematoma: 4.2%
    ►      Filter migration: 1.4%
    ►      Infection: 0.9%
    ►      DVT: 15%
    ►      Fatal PE: 2.3%



Mismetti P et al. Chest 2007; 131: 223-229
                    Intermittent Pneumatic Compression
                                  Meta-analysis In Postop Patients


              ►      2,270 patients in 15 randomized
                     trials


              ►      IPC devices reduced DVT risk by
                     60% (Relative Risk 0.40, 95% CI
                     0.29-0.56, p< 0.001)




Urbankova J. Thromb Haemost 2005; 94: 1181-5
           Guidelines



►   ASCO

►   NCCN

►   ACCP
                     National Comprehensive Cancer Network
                                    (NCCN)

 ►     The NCCN ―recommends prophylactic
       anticoagulation for all inpatients with a diagnosis
       of active cancer who do not have a
       contraindication.‖

 ►     ―Anticoagulation should be administered
       throughout hospitalization.‖

 ►     ―VTE prophylaxis after hospital discharge should
       be strongly considered.‖


J NCCN 2006; 4: 838-869
                   American Society Of Clinical Oncology
                                 (ASCO)

►   ―Consider all hospitalized cancer patients for VTE
    prophylaxis with anticoagulants, in absence of
    bleeding…‖

►   ―Give routine prophylaxis to outpatients receiving
    thalidomide or lenalidomide.‖

►   ―LMWH represents the preferred agent.‖

►   ―Impact of anticoagulants on cancer patient survival
    requires additional study.‖

JCO 2007; 25: 5490-5505
               American College Of Chest Physicians
                             (ACCP)

 ►     VTE prophylaxis while hospitalized

 ►     Treat acute DVT or PE with LMWH as monotherapy
       without warfarin for at least 3-6 months

 ►     Continue anticoagulant therapy indefinitely or until
       the cancer resolves.




CHEST 2004; 126: 338S-400S
CHEST 2004; 126: 401S-428S
                      Implementation


►   Electronic (computerized) alerts to physicians

►   Human Alerts

►   JCAHO

►   Medicare payments

►   ―Opt out‖ strategies
                   Implementation

The high death rate from PE (exceeding acute
MI!) and the high frequency of undiagnosed PE
causing ―sudden cardiac death‖ emphasize the
need for improved preventive efforts.

Failure to institute prophylaxis is a much bigger
problem with Medical Service patients,
especially medical oncology patients, than
Surgical Service patients.
                 Implementation


We have initiated trials to change MD
behavior and improve implementation of VTE
prophylaxis—not trials of specific types of
prophylaxis—eAlert RCT, eAlert cohort,
human Alert, 3-screen eAlert.
                Quality Improvement Initiative to Improve
                            Clinical Practice


  Randomized (―eAlert‖) controlled trial to
  issue or withhold electronic alerts to MDs
  whose high-risk patients were not receiving
  DVT prophylaxis.




Kucher N, et al. NEJM 2005;352:969-977
             Definition of ―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)
                                 DVT Prophylaxis at BWH

     ►    There were 13,922 patients with a VTE risk score
          ≥ 4 from September 2000 to January 2004

     ►    11,416 (82%) patients received DVT prophylaxis

     ►    2506 (18%) patients did not receive DVT
          prophylaxis




Kucher N, et al. NEJM 2005;352:969-977
                                            Randomization


                                         VTE risk score > 4
                                          No prophylaxis
                                              N = 2506




           INTERVENTION                                   CONTROL
             Single alert                                  No alert
              n = 1255                                    n = 1251

Kucher N, et al. NEJM 2005;352:969-977
                                         Baseline Characteristics

     ►     Median age = 62.5 years
     ►     Medical services: 83%
     ►     Surgical services: 17%
     ►     Comorbidities
              ●    Cancer:                          80%
              ●    Hypertension:                    34%
              ●    Infection:                       30%
              ●    Prior VTE:                       20%




Kucher N, et al. NEJM 2005;352:969-977
                                  90-Day Primary Endpoint

                           Intervent. Control Hazard Ratio p
                             N=1255 N=1251       (95% CI)
Total VTE                   61 (4.9)     103 (8.2)   0.59 (0.43-0.81) 0.001

Acute PE                    14 (1.1)     35 (2.8)    0.40 (0.21-0.74) 0.004

Proximal DVT                 10 (0.8)    23 (1.8)    0.47 (0.20-1.09) 0.08

Distal DVT                  5 (0.4)      12 (1.0)     0.42 (0.15-1.18) 0.10

UE DVT                       32 (2.5)     33 (2.6)    0.97 (0.60-1.58) 0.90




Kucher N, et al. NEJM 2005;352:969-977
                                                      Primary End Point

                    %Freedom from DVT/ PE   100

                                            98
                                                                          Intervention
                                            96

                                            94

                                            92                                Control

                                            90
                                                  0     30           60                  90
         Number at risk                                   Time (days)
         Intervention   1255                             977       900             853
         Control        1251                             976       893             839

Kucher N, et al. NEJM 2005;352:969-977
                                         Conclusions

    Electronic alerts
    1. Facilitated the detection of patients at high risk of
       DVT/PE


    2. Increased the rate of DVT prophylaxis from 14.5%
       to 33.5%


    3. Reduced the incidence of DVT/PE by 41%, without
       increasing bleeding


Kucher N, et al. NEJM 2005;352:969-977
              JCAHO Performance Measures

Prophylaxis (Approved in May 2006)
►   Surgery patients with recommended VTE prophylaxis
    ordered
►   Surgery patients who received appropriate VTE
    prophylaxis within 24 hours preop to 24 hours after
    surgery


Risk Assessment/Prophylaxis (Pending)
►   VTE risk assessment/ prophylaxis within 24 hours of
    hospital admission
►   VTE risk assessment/ prophylaxis within 24 hours of
    transfer to ICU
                   Quality Measures

►2   measures are in current use
 ●   SCIP VTE 1: Was DVT/PE prophylaxis
     ordered?
 ●   SCIP VTE 2: Was DVT/PE prophylaxis
     received?

►Implementation     by Medicare
 ●   Hospitals must report on the 2 measures
     beginning January 2007 to receive full
     payment in 2008
 ●   Medicare adjusted rate increase will be
     reduced by 2.0% for noncompliance
                                  Default (―Opt Out‖) Options


    ►      Flu, pneumonia vaccines.
    ►      Remove urinary catheters within 72h.
    ►      Head of bed at 30-45 angle in ICU.
    ►      Interrupt sedatives daily: vented pts.
    ►      Prophylax against VTE.



Halpern SD et al. NEJM 2007; 357: 1340
                         Summary

1.   Cancer and VTE is a disabling and at times deadly
     combination.
2.   VTE prophylaxis is safe and effective.
3.   ASCO, NCCN, and ACCP endorse VTE
     prophylaxis in cancer patients.
4.   For unclear reasons, VTE prophylaxis is
     underutilized.
5.   VTE prophylaxis of cancer patients will increase,
     through a combination of voluntary initiatives and
     regulatory mandates.

				
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