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New Frontiers and Evolving Paradigms in Cancer and Thrombosis Optimizing Prevention, Risk Assessment, and Management of Thrombotic Complications in Malignancy:

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Presentation on theme: "New Frontiers and Evolving Paradigms in Cancer and Thrombosis Optimizing Prevention, Risk Assessment, and Management of Thrombotic Complications in Malignancy:"— Presentation transcript:

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2 New Frontiers and Evolving Paradigms in Cancer and Thrombosis Optimizing Prevention, Risk Assessment, and Management of Thrombotic Complications in Malignancy: What Do the Trials Teach Us? How Should the Science Guide Us? Program Chairman Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School A Year 2010 Milestone Summit

3 Program Faculty Program Chairman Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School Craig Kessler, MD Professor of Medicine Department of Hematology Anticoagulation Services Georgetown University Medical Center Washington, DC Alok A. Khorana, MD, FACP Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P. Wilmot Cancer Center University of Rochester Rochester, NY Frederick R. Rickles, MD Clinical Professor of Medicine, Pediatrics, Pharmacology and Physiology Pharmacology and Physiology Division of Hematology-Oncology Department of Medicine The George Washington University School of Medicine and Health Sciences Medicine and Health Sciences Washington, DC

4 Program Agenda 8:15 PM 8:30 PM Program Chairmans Concluding Vision Statement: Current and Near Future Perspectives of VTE Management in the Setting of Malignancy Translating Scientific Advances into Clinical Practice Program Chairman Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School 8:30 PM 8:45 PM Interactive Q&A and Discussion Session

5 Disclosures Research Support BMS; Boehringer-Ingelheim; Eisai; Johnson & Johnson, Sanofi-Aventis Consultant Boehringer-Ingelheim; BMS; Eisai; EKOS: Medscape; Merck; Pfizer; Sanofi-Aventis

6 New Frontiers and Evolving Paradigms in Cancer And Thrombosis Epidemiology, Trials, Guidelines A Year 2010 Milestone Summit Program Chairman Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

7 Epidemiology New Frontiers and Evolving Paradigms in Cancer and Thrombosis

8 As Number of Cancer Survivors Increase, VTE Rates Increase Stein PD, et al. Am J Med 2006; 119: 60-68

9 VTE Risk and Cancer Type: Solid and Liquid Stein PD, et al. Am J Med 2006; 119: Relative Risk of VTE in Cancer Patients PancreasBrainMyeloprolStomachLymphomaUterusLungEsophagusProstateRectalKidneyColonOvaryLiverLeukemiaBreastCervixBladder Relative Risk of VTE Ranged From 1.02 to 4.34

10 Rate of PE Diagnosis is Increasing in the USA CHEST 2009; 136: , , , ,000 50, Total cohort Surgical patients Non-surgical patients 229, ,096 66,541 36,078 90, ,546

11 Hospital Costs are Skyrocketing CHEST 2009; 136:

12 DVT: Ominous Sequellae 30% recur over 10 years (after anticoagulation is discontinued) 30% recur over 10 years (after anticoagulation is discontinued) More than ½ of DVTs result in chronic venous insufficiency More than ½ of DVTs result in chronic venous insufficiency Leads to PE, potentially fatal Leads to PE, potentially fatal 1% to 4% of PEs evolve chronic thromboembolic pulmonary hypertension (CTEPH) 1% to 4% of PEs evolve chronic thromboembolic pulmonary hypertension (CTEPH)

13 Recurrent VTE is Common After A First Episode of Symptomatic DVT Cumulative Cumulative Incidence (%) Years Prandoni et al, Ann Intern Med 1996;125: patients followed for 8 years

14 Stages of Chronic Venous Insufficiency 1.Varicose veins 2.Ankle/ leg edema 3.Stasis dermatitis 4.Lipodermatosclerosis 5.Venous stasis ulcer

15 Progression of Chronic Venous Insufficiency From UpToDate 2006

16 U.S.A. SURGEON GENERAL: CALL TO ACTION TO PREVENT DVT AND PE September 15, , ,000 Deaths/year in USA

17 Lang, I. M. NEJM 2004;350: CTEPHRECURRENT ACUTE PE

18 DVT FREE Registry 5,451 patients enrolled prospectively Consecutive acute DVT diagnosed by venous ultrasonography Consecutive acute DVT diagnosed by venous ultrasonography No exclusions No exclusions 183 participating sites in the U.S. 183 participating sites in the U.S. Goldhaber SZ, Tapson VF. Am J Cardiol 2004;93:

19 DVT FREE Registry (N=5,541): TOP 5 Medical Comorbidities 1.Hypertension 2.Immobility 3.Cancer 4.Obesity (BMI > 30) 5.Cigarette Smoking Am J Cardiol 2004; 93:

20 Pivotal VTE Primary Prevention Trials New Frontiers and Evolving Paradigms in Cancer and Thrombosis

21 Trials of VTE Prophylaxis in Hospitalized Medical Patients MEDENOX (enoxaparin 40 mg) MEDENOX (enoxaparin 40 mg) Samama MM, et al. N Engl J Med. 1999;341: Samama MM, et al. N Engl J Med. 1999;341: PREVENT (dalteparin 5000 IU) PREVENT (dalteparin 5000 IU) Leizorovicz A, et al. Circulation. 2004;110: Leizorovicz A, et al. Circulation. 2004;110: ARTEMIS (fondaparinux 2.5 mg) ARTEMIS (fondaparinux 2.5 mg) Cohen AT, et al. Cohen AT, et al. BMJ 2006; 332: 325. BMJ 2006; 332: 325.

22 PREVENT-Dalteparin Trial (N=3,681) A multicenter, randomized, controlled study in acutely ill medical patients A multicenter, randomized, controlled study in acutely ill medical patients Compared the incidence in the dalteparin and placebo groups of : Compared the incidence in the dalteparin and placebo groups of : Any symptomatic VTE Any symptomatic VTE Asymptomatic proximal DVT Asymptomatic proximal DVT Sudden death Sudden death Circulation 2004; 110:

23 Randomization Dalteparin 5000 Units SC once daily (12-14 d) Dalteparin 5000 Units SC once daily (12-14 d) Placebo SC once daily (12-14 d) Placebo SC once daily (12-14 d) PREVENT Study Design (N=3,681) Follow-up period Treatment period Day 14Day 90 Day 21 Primary endpoint / Bilateral leg U/S Dalteparin Placebo No study drug

24 Primary Efficacy Endpoint: VTE (Day 21) % % P = to to % CI Risk Ratio Difference in Incidence (%) Dalteparin N=1518 Placebo N=1473 Circulation 2004; 110:

25 Dalteparin Benefit Similar Across Subgroups Age Age Gender Gender Cancer Cancer Obesity Obesity Previous DVT Previous DVT

26 Quality Improvement Initiative to Improve VTE Prophylaxis Randomized controlled trial to issue or withhold electronic alerts to MDs whose high-risk patients were not receiving VTE prophylaxis Randomized controlled trial to issue or withhold electronic alerts to MDs whose high-risk patients were not receiving VTE prophylaxis Kucher N et al. NEJM 2005; 352: 969

27 Computer Program We developed a computer program linked to the patient database that screened the system daily to identify high-risk patients. We developed a computer program linked to the patient database that screened the system daily to identify high-risk patients. We included consecutive high-risk patients on medical and surgical services who were not receiving DVT prophylaxis. We included consecutive high-risk patients on medical and surgical services who were not receiving DVT prophylaxis. Kucher N et al. NEJM 2005; 352: 969

28 Definition: High Risk VTE risk score 4 points: Cancer3(ICD codes) Cancer3(ICD codes) Prior VTE3(ICD codes) Prior VTE3(ICD codes) Hypercoagulability 3(Leiden, ACLA) Hypercoagulability 3(Leiden, ACLA) Major surgery2(> 60 minutes) Major surgery2(> 60 minutes) Bed rest1(bed rest order) Bed rest1(bed rest order) Advanced age1(> 70 years) Advanced age1(> 70 years) Obesity1(BMI > 29 kg/m 2 ) Obesity1(BMI > 29 kg/m 2 ) HRT/OC1(order entry) HRT/OC1(order entry)

29 Randomization VTE risk score > 4 No prophylaxis N = 2,506 INTERVENTION: Single alert N = 1,255 CONTROL No computer alert N = 1,251 Kucher N, et al. NEJM 2005;352:

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31 Baseline Characteristics Median age: 62.5 years Median age: 62.5 years Medical services:83% Medical services:83% Surgical services:17% Surgical services:17% Comorbidities Comorbidities Cancer:80% Cancer:80% Hypertension:34% Hypertension:34% Infection:30% Infection:30% Prior VTE: 20% Prior VTE: 20% Kucher N, et al. NEJM 2005;352:

32 Primary End Point Intervention Control Number at risk Intervention Control Time (days) %Freedom from DVT/ PE Kucher N, et al. NEJM 2005;352:

33 Pivotal VTE Treatment Trial in Patients with Cancer New Frontiers and Evolving Paradigms in Cancer and Thrombosis

34 Cancer and VTE 3-fold higher recurrence and bleeding, when treating cancer patients (Prandoni. Blood 2002; 100: 3484) 3-fold higher recurrence and bleeding, when treating cancer patients (Prandoni. Blood 2002; 100: 3484) LMWH Monotherapy halves recurrence, compared with warfarin. LMWH Monotherapy halves recurrence, compared with warfarin. FDA approved May 2007 Lee AYY. NEJM 2003; 349:146

35 CLOT Trial Dalteparin monotherapy for 6 months was more effective (8.8% vs. 17% recurrence) than warfarin in 672 cancer patients with DVT. Dalteparin monotherapy for 6 months was more effective (8.8% vs. 17% recurrence) than warfarin in 672 cancer patients with DVT. Dalteparin dose: 200 u/kg daily 1 st month, then 150 u/kg daily. Dalteparin dose: 200 u/kg daily 1 st month, then 150 u/kg daily. Agnes Lee, et al. NEJM 2003; 349: )

36 Dalteparin Reduces VTE Recurrence in Cancer Patients (N = 676) NEJM 2003; 349: CLOT TRIAL

37 LMWH Monotherapy Cancer patients with DVT/PE Cancer patients with DVT/PE Any patient who fails warfarin (has recurrent DVT/PE) despite target INR Any patient who fails warfarin (has recurrent DVT/PE) despite target INR Difficulty maintaining target INR Difficulty maintaining target INR Poor GI absorption of meds Poor GI absorption of meds Alopecia or rash from Coumadin Alopecia or rash from Coumadin Bridging Bridging

38 ACCP VTE Rx in Cancer: Guidelines 8 th Edition 1.At least 3 months of LMWH. 2.Then administer LMWH or warfarin as long as the cancer is active. 3.Indefinite duration anticoagulation after 2 nd unprovoked VTE. CHEST 2008; 133: 454S

39 Conclusions 1.Cancer and VTE are closely linked. 2.Cancer increases VTE risk and may be occult when VTE is diagnosed. 3.Cancer patients are at high risk for VTE but receive less prophylaxis than any other at-risk group of hospitalized patients. 4.Dalteparin 5,000 U/d is effective for VTE prophylaxis in cancer patients.

40 Conclusions (Continued) 5.Dalteparin 200 U/kg/day is effective for treatment of acute VTE as monotherapy without warfarin. 6.NCCN, ASCO, and ACCP guidelines endorse VTE prevention with LMWH and VTE treatment of cancer patients with LMWH alone (monotherapy without warfarin).

41 The Role of the Coagulation Cascade in Malignant Transformation Can Anticoagulation Affect Cancer Survival? The Role of the Coagulation Cascade in Malignant Transformation Can Anticoagulation Affect Cancer Survival? Frederick R. Rickles, MD Professor of Medicine, Pediatrics, Pharmacology and Physiology The George Washington University Washington, DC Frederick R. Rickles, MD Professor of Medicine, Pediatrics, Pharmacology and Physiology The George Washington University Washington, DC New Frontiers and Evolving Paradigms in Cancer and Thrombosis

42 Disclosures Consultant Genmab, Bayer/Ortho McNeil/J & J, Pharmacyclics, Leo Speakers Bureau Eisai

43 Fibrinolytic activities : t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities FIBRIN Endothelial cells IL-1, TNF- VEGF Tumor cells Monocyte PMN leukocyte Activation of coagulation Platelets Angiogenesis, Basement matrix degradation. Falanga and Rickles, New Oncology:Thrombosis, 2005; Hematology, ASH Education Book, 2007 Interface of Coagulation and Cancer TF-rich MPs

44 Mechanisms of Cancer-Induced Thrombosis: Clot and Cancer Interface 1.Pathogenesis? 2.Biological significance? 3.Anticoagulation and cancer survival?

45 Activation of Blood Coagulation in Cancer Biological Significance? Epiphenomenon? Epiphenomenon? Is this a generic secondary event where thrombosis is an incidental finding Is this a generic secondary event where thrombosis is an incidental finding or, is clotting activation... or, is clotting activation... A Primary Event? A Primary Event? Linked to malignant transformation Linked to malignant transformation

46 TF VEGF Angiogenesis Endothelial cells IL-8 Blood Coagulation Activation FIBRIN PAR-2 Angiogenesis FVII/FVIIa THROMBIN Tumor Cell TF Falanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16; Ruf. J Thromb Haemost 2007;5:1584 Interface of Clotting Activation and Tumor Biology

47 Coagulation Cascade and Tumor Biology TFThrombin Clotting- dependent Clotting- independent Clotting- dependent Fibrin Clotting- independent PARs Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584 VIIa Xa Angiogenesis, Tumor Growth and Metastasis

48 In Situ Localization of Tissue Factor in Vascular Endothelium of Human Lung Adenocarcinoma – co-localization with vWF Shoji et al, Amer J Pathol 1998;152:

49 In Situ localization of Tissue Factor in Tumor Vascular Endothelium in Invasive Human Breast Cancer Contrino et al. Nature Med 1996;2:

50 In Situ Co-Localization of TF and VEGF mRNA in Lung Adenocarcinoma Shoji et al. Amer J Pathol 1998;152: H&E TF VEGF

51 Human melanoma cell lines grown as xenogeneic tumors in SCID mice Abe K et al. PNAS 1999;96: ©1999 by The National Academy of Sciences TF high producer TF low producer

52 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: ; Ruf et al Nature Med Abe et al Proc Nat Acad Sci 1999;96: ; Ruf et al Nature Med 2004;10:

53 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.This a and other data on signaling pathways activated by TF/VIIa engagement of PAR-2 b and/or thrombin engagement of PAR-1 c suggest that clotting pathways are directly involved in regulating tumor growth, angiogenesis and metastasis 5.Is this a paradigm shift? a Abe et al Proc Nat Acad Sci 1999;96: b Ruf et al Nature Med 2004;10:502-9 c Karpatkin et al Cancer Res 2009;69: Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor

54 Activation of Blood Coagulation in Cancer and Malignant Transformation Epiphenomenon vs. Malignant Transformation? Paradigm Shift (2005) 1.MET oncogene induction produces DIC in human liver carcinoma (Boccaccio lab) (Boccaccio et al 2005;434: ) (Boccaccio et al Nature 2005;434: ) 2.Pten loss and EGFR amplification produce TF activation and pseudopalisading necrosis through JunD/Activator Protein-1 in human glioblastoma (Bratt lab) (Rong et al 2005;65: ; 2009;69:2540-9) (Rong et al Cancer Res 2005;65: ; Cancer Res 2009;69:2540-9) 3.K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma; TF and angiogenesis regulation in epithelial tumors by EGFR (ErbB1) – relationship to EMTs (Rak lab) (Yu et al 2005;105: ; Milson et al 2008;68: ) (Yu et al Blood 2005;105: ; Milson et al Cancer Res 2008;68: )

55 MET encodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) 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) 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 Aberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastic transformation, invasion, and metastasis Boccaccio et al 2005;434: Boccaccio et al Nature 2005;434: MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis Activation of Blood Coagulation in Cancer: Malignant Transformation

56 2. Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma Pten = tumor suppressor with lipid and protein phosphatase activity 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 Loss or inactivation of Pten (70-80% of glioblastomas) leads to Akt activation and upregulation of Ras/MEK/ERK signaling cascade Rong et al Ca Res 2005;65:

57 Glioblastomas characterized histologically by pseudopalisading necrosis Glioblastomas characterized histologically by pseudopalisading necrosis Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosis 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 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) 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 GlioblastomaPten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma

58 Results: 1.Hypoxia and PTEN loss TF (mRNA, Ag and procoagulant activity); partially reversed with induction of PTEN 2.Both Akt and Ras pathways modulated TF in sequentially transformed astrocytes. 3.Ex vivo data: TF (by IH-chemical staining) in pseudopalisades of # 7 human glioblastoma specimens Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By GlioblastomaPten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma

59 Pseudopalisading necrosis Vascular Endothelium H&E TF IHC Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By GlioblastomaPten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma

60 Activation of Blood Coagulation in Cancer: Malignant Transforma tion Activation of Blood Coagulation in Cancer: Malignant Transforma tion 3. Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis 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 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 Transforming events dependent on MEK/MAPK and PI3K Cell-associated and MP-associated TF activity linked to genetic status of cancer cells 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 siRNA reduced cell surface TF expression, tumor growth and angiogenesis TF may be required for K-ras-driven phenotype TF may be required for K-ras-driven phenotype Yu et al 2005;105: Yu et al Blood 2005;105:

61 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 Activation of Blood Coagulation in Cancer: Malignant Transformation Activation of Blood Coagulation in Cancer: Malignant Transformation Yu et al 2005;105: Yu et al Blood 2005;105:

62 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 Activation of Blood Coagulation in Cancer: Malignant Transformation Activation of Blood Coagulation in Cancer: Malignant Transformation Similar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma and lung cancer cells; accompanied by epithelial-to-mesenchymal transition (EMT) Milsom et al 2008;68: Milsom et al CA Res 2008;68: Yu et al 2005;105: Yu et al Blood 2005;105:

63 Microparticles Originate directly from membrane surface of activated or apoptotic cell Originate directly from membrane surface of activated or apoptotic cell Express surface antigens derived from parent cell Express surface antigens derived from parent cell Anucleate Anucleate <1 µm in diameter <1 µm in diameter Procoagulant activity Procoagulant activity mediated by TF and/or PS Burnier L et al. Thromb Haemost 2009;101:

64 Cumulative incidence of VTE in cancer patients with (--) /without ( ) circulating TF-bearing microparticles Zwicker et al. Clin Cancer Res 2009;15:

65 Microparticle TF PCA in Cancer Patients ± VTE Manly DA, et al. Thromb Res 2010;125:

66 Activation of Blood Coagulation in Cancer: Malignant Transformation Q: What do these experiments tell us? Q: What do these experiments tell us? A: They suggest two things: A: They suggest two things: Tumor cell-derived, TF-rich microparticles (MPs) may be important as a predictive test for VTE Tumor cell-derived, TF-rich microparticles (MPs) may be important as a predictive test for VTE All patients with oncogene-driven cancer may need prophylactic anticoagulation All patients with oncogene-driven cancer may need prophylactic anticoagulation

67 Mechanisms of Cancer-Induced Thrombosis: Implications 1.Pathogenesis? 2.Biological significance? 3.Anticoagulation and cancer survival ?

68 Anticoagulants and Survival Inconclusive evidence to date Inconclusive evidence to date Experimental data supportive of antitumor effects but exact mechanisms not established Experimental data supportive of antitumor effects but exact mechanisms not established Clinical trials provide supportive data for LMWH but are heterogeneous in design and methodology: Clinical trials provide supportive data for LMWH but are heterogeneous in design and methodology: Tumour types Tumour types Stage or course of disease Stage or course of disease Treatment history or concurrent cancer therapies Treatment history or concurrent cancer therapies LMWH agents LMWH agents Doses and regimens of LMWHs Doses and regimens of LMWHs A Lee ICTHIC, 2010

69 Survival Effect of Anticoagulants Kuderer N et al. Cancer 2007;110:

70 Multicentre, double-blind, placebo-controlled RCT Multicentre, double-blind, placebo-controlled RCT Advanced lung, breast, GI, pancreas, ovary, H+N Advanced lung, breast, GI, pancreas, ovary, H+N Nadroparin vs placebo for duration of chemo (up to 4m) Nadroparin vs placebo for duration of chemo (up to 4m) NadroparinPlaceboP-valueNNT/H No. Patients ° endpoint: VTE + ATE 2.0%3.9%0.02*54 Major bleeding 0.7% Death4.3%4.2% 1-yr mortality 43%41% Agnelli et al. Lancet 2009;10: PROTECHT Study *1-sided

71 Prophylaxis in Pancreatic Cancer Riess et al. ASCO May 2009 and ISTH July Maraveyas et al. Presented at ESMO VTE bleeding P<0.0 1 P=0.6 VTE fatal PE Gr 3 bleed P<0.02 P=0.03 NS CONKO 004 FRAGEM No survival difference

72 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? Key Questions Key Questions Cancer and Thrombosis Year 2010 State-of-the-Science Update Cancer and Thrombosis Year 2010 State-of-the-Science Update

73 1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer 2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWHs in cancer patients indicate superiority to oral agents in preventing recurrent VTE; increasing survival (not due to prevention of VTE) not clear Cancer and Thrombosis Year 2010 State-of-the-Science Update Cancer and Thrombosis Year 2010 State-of-the-Science Update Tentative Answers

74 Survival Studies INPACT (NSCLC, prostate, pancreatic) INPACT (NSCLC, prostate, pancreatic) nadroparin + chemo vs. chemo nadroparin + chemo vs. chemo ABEL (limited SCLC) ABEL (limited SCLC) bemiparin + chemo vs. chemo bemiparin + chemo vs. chemo TILT (nonsmall cell lung cancer) TILT (nonsmall cell lung cancer) tinzaparin + chemo vs chemo tinzaparin + chemo vs chemo FRAGMATIC (newly diagnosed lung cancer) FRAGMATIC (newly diagnosed lung cancer) dalteparin + chemo vs chemo dalteparin + chemo vs chemo LMWH in Cancer A Lee ICTHIC, 2010 Stay tuned ! Stay tuned !

75 Optimizing Risk Assessment and Management of Cancer Patients at Risk for Venous Thromboembolism (VTE) Reducing DVT Recurrence and Related Complications New Frontiers and Evolving Paradigms in Cancer and Thrombosis Craig Kessler, MD Professor of Medicine Department of Hematology Anticoagulation Services Georgetown University Medical Center Washington, DC

76 COI Financial Disclosures Grant/Research Support: GlaxoSmithKline, sanofi-aventis, Eisai Consultant: sanofi-aventis, Eisai

77 Outline Guidelines for VTE prevention in cancer patients Guidelines for VTE prevention in cancer patients Opportunities for improvement Opportunities for improvement Guidelines for VTE Treatment Guidelines for VTE Treatment LMWHsWhat Do the Trials, NCCN and ASCO Guidelines Teach Us About Duration of Therapy and Patients at Risk? LMWHsWhat Do the Trials, NCCN and ASCO Guidelines Teach Us About Duration of Therapy and Patients at Risk?

78 Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer ASCO Clinical Practice Guideline NCCN Clinical Practice Guidelines in Oncology Guidelines for supportive care …the panel of experts includes a medical and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a pharmacist.

79 Importance of Guidelines to Clinical Outcomes Clinicians armed with appropriate assessments and the best evidence-based practice guidelines can reduce some of the unpleasant and frequent side-effects that often accompany cancer and chemotherapy treatment, obtain the best possible clinical outcomes, and avoid unnecessary costs. Statement from Centers for Medicare and Medicaid Services, August 2005

80 Incidence of VTE in US Patients with Cancer Stein PD et al. Am J Med. 2006;119: National Hospital Discharge Survey data from 19 types of malignancies from 1979 through 1999 (non-age dependent) Overall, in patients with any of the 19 malignancies covered, 827,000 of 40,787,000 (2.0%) had VTE, which was twice the incidence in patients without these malignancies, 6,854,000 of 662,309,000 (1.0%) 1 The highest incidence of VTE was in patients with carcinoma of the pancreas (4.3%), and the lowest incidences were in patients with carcinoma of the bladder and carcinoma of the lip, oral cavity, or pharynx 1 The overall incidences of PE and DVT in patients with cancer were double the rates in patients without cancer and were not age dependent 1 Highest incidence of VTE: pancreatic CA (4.3%) Lowest incidence of VTE: oral cavity, or pharynx Rate Has Risen Although the Overall Incidence of Cancer Has Not Changed

81 Venous Thromboembolism in Cancer Patients Of all cases of VTE: Of all cases of VTE: 20% occur in cancer patients 20% occur in cancer patients Of all cancer patients: Of all cancer patients: 0.5% will have symptomatic VTE 0.5% will have symptomatic VTE As high as 50% have VTE at autopsy As high as 50% have VTE at autopsy Compared to patients without cancer: Compared to patients without cancer: Higher risk of first and recurrent VTE Higher risk of first and recurrent VTE Higher risk of bleeding on anticoagulants Higher risk of bleeding on anticoagulants Higher risk of dying Higher risk of dying VTE may be the presenting sign of occult malignancy 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: Lee & Levine. Circulation 2003;107:I17 – I21; Bura et. al., J Thromb Haemost 2004;2:445-51

82 Thrombosis and Survival: Likelihood of Death After Hospitalization DVT/PE and Malignant Disease Malignant Disease DVT/PE Only DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

83 Cancer and Venous Thromboembolism The Need for Risk Stratification Diagnosis Chemotherapy Hospitalization Remission End of Life Metastasis Average Risk Time Relative Risk

84 VTE in Hospitalized Cancer Patients VTE in Hospitalized Cancer Patients Cancer Rate of VTE (%) VTE all patients DVT all patients PE all patients 7.0 VTE patients on chemotherapy Years

85 VTE = venous thromboembolism; CA = cancer; OR = odds ratio. Silver In: The Hematologist - modified from Blom JW, et. al. JAMA. 2005;293: Effect of Malignancy on Risk of VTE Population-based case-control (MEGA) study N=3220 consecutive patients with 1 st VTE vs. n=2131 control subjects CA patients = OR 7x VTE risk vs. non-CA patients Hematological Lung Gastrointestinal Breast Distant metastases 0 to 3 months 3 to 12 months 1 to 3 years 5 to 10 years > 15 years Type of cancer Time since cancer diagnosis Adjusted odds ratio MEGA = Multiple Environmental and Genetic Assessment case- control study

86 The Importance of DVT Prophylaxis in Patients With Cancer: ASCO Guidelines VTE is a leading causes of death in CA, occurring in 4% to 20% patients VTE is a leading causes of death in CA, occurring in 4% to 20% patients Hospitalized CA pt and those on chemo tx have greatest VTE risk Hospitalized CA pt and those on chemo tx have greatest VTE risk Cancer increased the risk of VTE 4.1-fold Cancer increased the risk of VTE 4.1-fold Chemotherapy increased the risk 6.5-fold Chemotherapy increased the risk 6.5-fold Major risk factors: older age, comorbid conditions, recent surgery or hospitalization, active chemotherapy or hormonal therapy Major risk factors: older age, comorbid conditions, recent surgery or hospitalization, active chemotherapy or hormonal therapy All hospitalized CA patients should be considered for prophylaxis All hospitalized CA patients should be considered for prophylaxis Patients with cancer undergoing surgery should be considered for prophylaxis Patients with cancer undergoing surgery should be considered for prophylaxis LMWH is the preferred drug LMWH is the preferred drug Lyman GH, et al. J Clin Oncol. 2007;25:

87 Updated ASCO Guidelines Hospitalized Patients with Cancer Role of VTE Prophylaxis Evidence Patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants (UFH, LMWH, or fondaparinux) in the absence of bleeding or other contraindications to anticoagulation Multiple RCTs of hospitalized medical patients with subgroups of patients with cancer. The 8th ACCP guidelines strongly recommend (1A) prophylaxis with either low- dose heparin or LMWH for bedridden patients with active cancer. VOLUME 25 NUMBER 34 DECEMBER

88 Prophylaxis in Cancer Patients Cancer patients undergoing surgical procedures: routine thromboprophylaxis that is appropriate for the type of surgery (Grade 1A) Cancer patients undergoing surgical procedures: routine thromboprophylaxis that is appropriate for the type of surgery (Grade 1A) Cancer patients who are bedridden with an acute medical illness: routine thromboprophylaxis as for other high-risk medical patients (Grade 1A) Cancer patients who are bedridden with an acute medical illness: routine thromboprophylaxis as for other high-risk medical patients (Grade 1A) Cancer patients receiving chemotherapy or hormonal therapy: recommend against the routine use of thromboprophylaxis for the primary prevention of VTE (Grade 1C) Cancer patients receiving chemotherapy or hormonal therapy: recommend against the routine use of thromboprophylaxis for the primary prevention of VTE (Grade 1C) Cancer patients overall: recommend against the routine use of primary thromboprophylaxis to try to improve survival (Grade 1B) Cancer patients overall: recommend against the routine use of primary thromboprophylaxis to try to improve survival (Grade 1B) Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S ACCP Prevention of Venous Thromboembolism Practice Guidelines

89 Therapeutic Anticoagulation Treatment for VenousThromboembolism The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy Panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post- operation. Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post- operation.

90 Caveats No randomized controlled trials (RCTs) designed ad hoc for hospitalized medical cancer patients are available No randomized controlled trials (RCTs) designed ad hoc for hospitalized medical cancer patients are available Recommendations are based on RCTs of acutely ill medical patients, involving a small proportion of patients with cancer Recommendations are based on RCTs of acutely ill medical patients, involving a small proportion of patients with cancer No bleeding data are reported specifically in the subgroup of patients with cancer No bleeding data are reported specifically in the subgroup of patients with cancer

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

92 MEDENOX 1 StudyRRR Thromboprophylaxis Patients with VTE (%) StudyRRR Thromboprophylaxis Patients with VTE (%) Samama MM, et al. N Engl J Med. 1999;341: Leizorovicz A, et al. Circulation. 2004;110: Cohen AT, et al. BMJ 2006; 332: P < P = RRR 63% 45% 47% Placebo Enoxaparin 40 mg Dalteparin 5,000 units Fondaparinux 2.5 mg ARTEMIS 3 PREVENT 2 Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients

93 0.49% 0.16% 0.2% 1.7% 1.1% Samama MM, et al. N Engl J Med. 1999;341: Leizorovicz A, et al. Circulation. 2004;110: Cohen AT, et al. BMJ 2006; 332: Incidence of Major Bleeding (%) Study Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding

94 (Hull RD et al. Ann Intern Med 2010; 153:8) EXCLAIM: Extended-duration Enoxaparin Prophylaxis in High-risk Medical Patients End points Outcome, extended prophylaxis, n=2052 (%) Outcome, placebo, n=2062(%) RR reduction (%) p Major bleeding 0.8%0.3% VTE events % 38%0.001 Symptomatic % 73%0.004 No Sxs % 34%0.032 (Most benefit seen in Level 1 Disability Patients with bedrest or sedentary without BRP-some with CA)

95 PRODIGE: Dalteparin for Primary VTE Prophylaxis in Newly Diagnosed Malignant Glioma Reduced VTE for dalteparin 5,000 anti-Xa units qd for 6 mos: 11% vs 17% for placebo Reduced VTE for dalteparin 5,000 anti-Xa units qd for 6 mos: 11% vs 17% for placebo Increased ICH: 5.1% vs 1.2% for placebo Increased ICH: 5.1% vs 1.2% for placebo Both NS significant Both NS significant Perry JR et al. JTH 2010;8;1959

96 2009 NCCN Guidelines: DVT Prophylaxis Adult Cancer Inpatient Contraindication to Anticoagulation Treatment No Yes Pharmacologic Prophylaxis UFHLMWHPentasaccharide Mechanical Prophylaxis Sequential Compression Devices Compression Stockings NCCN, National Comprehensive Cancer Network. NCCN. Venous Thromboembolic Disease: Version Available at: physician_gls/PDF/vte.pdf.

97 Mechanical thromboprophylaxis in critically ill patients: a systematic review and meta-analysis RESULTS: 21 relevant studies (5 randomized controlled trials, 13 observational studies, and 3 surveys) were found. A total of 811 patients were randomized in the 5 randomized controlled trials; 3421 patients participated in the observational studies. Trauma patients only were enrolled in 4 randomized controlled trials and 4 observational studies. Meta-analysis of 2 randomized controlled trials with similar populations and outcomes revealed that use of compression and pneumatic devices did not reduce the incidence of venous thromboembolism. The pooled risk ratio was 2.37 (CI,95% ). A range of methodological issues, including bias and confounding variables, make meaningful interpretation of the observational studies difficult. The role of mechanical approaches to thromboprophylaxis for intensive care patients remains uncertain. CONCLUSIONS: The role of mechanical approaches to thromboprophylaxis for intensive care patients remains uncertain. Limbus A et al. Am J Crit Care, 2006;15: The beneficial role for mechanical thromboprophylaxis in cancer pts is empiric and derived from benefits seen in surgical studies; No controlled studies in cancer patients

98 VTE Prophylaxis Is Underused in Patients With Cancer 1.Kakkar AK et al. Oncologist. 2003;8: Stratton MA et al. Arch Intern Med. 2000;160: Bratzler DW et al. Arch Intern Med. 1998;158: Cancer: FRONTLINE Survey Clinician Respondents Rate of Appropriate Prophylaxis, % Major Surgery 2 Major Abdominothoracic Surgery (Elderly) 3 Medical Inpatients 4 Confirmed DVT (Inpatients) 5 Cancer: Surgical Surgical Cancer: Medical 4.Rahim SA et al. Thromb Res. 2003;111: Goldhaber SZ et al. Am J Cardiol. 2004;93:

99 Despite Evidence, Medical Patients at Risk Remain Unprotected MedicalSurgical No. of patients 37,35630,827 At risk for VTE 42%64% Receiving ACCP Tx 40%59% ENDORSE 1 1.Cohen AT, et al. Presented at: 2007 Congress of the International Society on Thrombosis and Haemostasis; July 6-12, 2007; Geneva, Switzerland. 2.Tapson VF, et al. Chest. 2007;132(3): IMPROVE 2 United States Other Countries No. of patients 3,41011,746 VTE prophylaxis 1852 (54%)5788 (49%) LMWH476 (14%)4657 (40%) UFH717 (21%)1014 (9%)

100 Electronic Alerts to Prevent VTE in Hospitalized Patients P<.001 by the log-rank test for the comparison of the outcome between groups at 90 days. Reprinted with permission from Kucher N, et al. N Engl J Med. 2005;352: Freedom From DVT or PE (%) Days 90 Intervention group Control group P<.001 No. at Risk Intervention group Control group

101 Ambulatory Patients with Cancer Without VTE Receiving Systemic Chemotherapy Role of VTE Prophylaxis Evidence Routine prophylaxis with an antithrombotic agents is not recommended except as noted below Routine prophylaxis in ambulatory patients receiving chemotherapy is not recommended due to conflicting trials, potential bleeding, the need for laboratory monitoring and dose adjustment, and the relatively low incidence of VTE. LMWH or adjusted dose warfarin (INR ~ 1.5) is recommended in myeloma patients on thalidomide or lenalidomide plus chemotherapy or dexamethasone This recommendation is based on nonrandomized trial data and extrapolation from studies of postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose warfarin in breast cancer Updated ASCO Guidelines

102 Prospective Study of Adult Cancer Patients Receiving Systemic Chemotherapy Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008). Prospective observational study conducted at 117 randomly selected US practice sites. Prospective observational study conducted at 117 randomly selected US practice sites. Data obtained on 4,458 consecutive adult patients initiating a new chemotherapy regimen between March 2003 and February Data obtained on 4,458 consecutive adult patients initiating a new chemotherapy regimen between March 2003 and February There were no exclusions for age, prior history or comorbid- ities with nearly 40% of patients age 65 and older. There were no exclusions for age, prior history or comorbid- ities with nearly 40% of patients age 65 and older.

103 Reported Cause of Early Mortality Cancer Patients Starting New Chemotherapy Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008) Cause of Death No VTE N=4,365 VTE N=93 All N=4,458 PD Infection0.30 PE Pulmonary0.20 Bleeding0.10 Other vascular 0.20 Unknown0.30 All [HR=5.48, 95%CI: ; P<.0001] VTE No VTE

104 RCTs of Thromboprophylaxis in Ambulatory Cancer Patients: Warfarin Double-blind, placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (INR ) in patients receiving chemotherapy for metastatic breast cancer 311 women with metastatic breast cancer on 1st- or 2nd-line chemotherapy Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR or placebo 1 VTE in warfarin group vs 7 in placebo arm 85% risk reduction, P =.03, with no increased bleeding Levine M, et al. Lancet. 1994;343: INR=international normalized ratio

105 TrialNTreatmentChemoDurationVTEMajor Bleeding FAMOUS Solid tumors (Stage III/IV) 385Dalteparin Placebo 64%12 months2.4% 3.3% 0.5% 0 TOPIC-I Breast (Stage IV) 353Certoparin Placebo 100%6 months4% 1.7% 0 TOPIC-2 NSCLC (Stage IV) 547Certoparin Placebo 100%6 months 4.5% 8.3% 3.7% 2.2% PRODIGE Glioma 186Dalteparin Placebo months11% 17% 5.1% 1.2% SIDERAS Solid Tumors (Stage IV) 141Dalteparin Placebo/Control 54%Indefinitely5.9% 7.1% 2.9% 7.1% PROTECHT Solid Tumors (Stage III/IV) 1166Nadroparin 2:1 Placebo 100%< 4 months with chemo 1.4% 2.9% 0.7% 0 1. Kakkar AK, et al. J Clin Oncol. 2004;22: Haas SK, et al. J Thromb Haemost. 2005(suppl 1): abstract OR Perry JR et al. Proc ASCO Sideras K et al. Mayo Clin Proc 2006; 81: Agnelli G et al. Am Soc Hemat Sunday December 7, 2008 Low Molecular Weight Heparin in RCTs of Thromboprophylaxis in Ambulatory Cancer Patients

106 The PROTECHT Study RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy DESIGN Placebo-controlled, double blind, multicenter RCT Placebo-controlled, double blind, multicenter RCT Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1 Nadroparin 3,800 anti Xa IU daily vs placebo: 2: patients receiving chemotherapy for locally advanced or metastatic cancer patients receiving chemotherapy for locally advanced or metastatic cancer. Start with new CTX; continue for maximum of 4 mos Start with new CTX; continue for maximum of 4 mos Mean treatment duration: 90 days Mean treatment duration: 90 days Primary outcome: clinically detected thrombotic events, i.e., composite of venous and arterial TE* Primary outcome: clinically detected thrombotic events, i.e., composite of venous and arterial TE* Main safety outcome: Major bleeding Main safety outcome: Major bleeding * deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin Agnelli G et al: Lancet 2009;10, 930

107 The PROTECHT Study RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy Primary Efficacy Outcome: Any TE Event* Primary Efficacy Outcome: Any TE Event* Nadroparin: 16 of 769 (2.1%) Nadroparin: 16 of 769 (2.1%) Placebo: 15 of 381 (3.9%) Placebo: 15 of 381 (3.9%) Relative risk reduction: 47.2%, (interim-adjusted p=0.033) Relative risk reduction: 47.2%, (interim-adjusted p=0.033) Absolute risk decrease: 1.8%; NNT = 53.8 Absolute risk decrease: 1.8%; NNT = 53.8 Venous thromboembolism (VTE): Venous thromboembolism (VTE): Nadroparin: 11 of 769 (1.4%) Nadroparin: 11 of 769 (1.4%) Placebo: 11 of 381 (2.9%) NS Placebo: 11 of 381 (2.9%) NS Major Bleeding: Major Bleeding: Nadroparin: 5 (0.7%) Nadroparin: 5 (0.7%) Placebo: 0 (p= 0.177) Placebo: 0 (p= 0.177) Absolute risk increase: 0.7%; NNH = Absolute risk increase: 0.7%; NNH = Agnelli G et al: Lancet 2009;10:930 RESULTS 33 patients in the nadroparin group and 16 in the placebo group had died; 48 of these deaths were due to disease progression.

108 LMWH halves VTE in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy PROTECHT All cause thrombo- embolic events: 2% LMWH vs 3.9% in placebo All cause thrombo- embolic events: 2% LMWH vs 3.9% in placebo Major bleeding: 0.7% LMWH vs none in placebo (P=0.18) Major bleeding: 0.7% LMWH vs none in placebo (P=0.18) By the end of study treatment, 33 LMWH deaths vs 16 in placebo group; 48 of these deaths due to CA progression By the end of study treatment, 33 LMWH deaths vs 16 in placebo group; 48 of these deaths due to CA progression Benefits most apparent in those with lung or GI CA (not pancreatic) Benefits most apparent in those with lung or GI CA (not pancreatic) 1% DVT and 0.4% PE with LMWH (N=769 pts) 2.1% DVT and 0.8% PE with placebo (N=381 pts) Agnelli G et al. Oct 2009www.thelancet.com/Oncology p=0.02 NNT=53.8

109 VTE Incidence In Various Tumors Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Oncology Setting VTE Incidence Breast cancer (Stage I & II) w/o further treatment0.2% Breast cancer (Stage I & II) w/ chemo2% Breast cancer (Stage IV) w/ chemo8% Non-Hodgkins lymphomas w/ chemo3% Hodgkins disease w/ chemo6% Advanced cancer (1-year survival=12%)9% High-grade glioma26% Multiple myeloma (thalidomide + chemo)28% Renal cell carcinoma43% Solid tumors (anti-VEGF + chemo)47% Wilms tumor (cavoatrial extension) 4%

110 Arterial Thrombotic Complications of Myeloma VAD (n 6, 5.9%) TAD (n 2, 4.5%) PAD (n 3, 6.4%) N=195 ATE=11 5.6% Libourel et al. Blood 2010;116:2 4 developed thrombosis while on VKAs; 2 on LMWH

111 Palumbo A et al. Leukemia 2008;22:414 LMWH Warfarin ASA (LDW) 3-14

112 These VTE prophylaxis regimens have not been assessed in any prospective, randomized trial and are recommended based on anecdotal experience Palumbo A et al. Leukemia 2008;22:414

113 Naluri SR et al. JAMA. 2008;300:2277 VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in Myeloma

114 Pritchard, J Clin Onc, TamoxifenTamoxifen + CT Rate of thrombosis (%) p= (n=352) (n=353) 1.4% 9.6% Tamoxifen and Chemotherapy 705 postmenopeusal women with breast cancer 705 postmenopeusal women with breast cancer CMF regimen CMF regimen Total thromboembolic events Total thromboembolic events 39 of 54 events occurred during chemotherapy 39 of 54 events occurred during chemotherapy

115 Treatment of Patients with Established VTE to Prevent Recurrence (continued) Role of VTE Prophylaxis Evidence Anticoagulation for an indefinite period should be considered for patients with active cancer (metastatic disease, continuing chemotherapy) In the absence of clinical trials, benefits and risks of continuing LMWH beyond 6 months is a clinical judgment in the individual patient. Caution is urged in elderly patients and those with intracranial malignancy. Inferior vena cava filters are reserved for those with contraindications to anticoagulation or PE despite adequate long-term LMWH. Consensus recommendations due to lack of date in cancer-specific populations

116 Treatment of Patients with Established VTE to Prevent Recurrence Role of VTE Prophylaxis Evidence LMWH is the preferred approach for the initial 5-10 days in cancer patient with established VTE. LMWH for 3-6 months is more effective than vitamin K antagonists given for a similar duration for preventing recurrent VTE. LMWH for at least 6 months is preferred for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable when LMWH is not available. The CLOT study demonstrated a relative risk reduction of 49% with LMWH vs. a vitamin K antagonist. Dalteparin sodium approved by the FDA for extended treatment of symptomatic VTE to reduce the risk of recurrence of VTE in patients with cancer (FDA 2007)

117 5 to 7 days Dalteparin 200 IU/kg OD Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo Control Group Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo Experimental Group Randomization 1 month 6 months The CLOT Trial Study Schema Lee AY, et al. N Engl J Med. 2003;349:

118 Days Post Randomization Probability of Recurrent VTE, % dalteparin, 9% VKA, 17% risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) log-rank p = CLOT Trial: Results: Symptomatic Recurrent VTE Lee AY, et al. N Engl J Med. 2003;349:

119 Results DalteparinN=338VKAN=335 p- value Major bleed19 (5.6%)12 (3.6%)0.27 Associated with death10 Critical site*43 Transfusion of > 2 units of RBC or drop in Hb > 20 g/L 149 Any bleed46 (13.6%)62 (18.5%)0.09 *intracranial, intraspinal, pericardial, retroperitoneal, intra-ocular, intra- articular CLOT Trial: Results: Bleeding Lee AY, et al. N Engl J Med. 2003;349:

120 Overall, these meta-analyses and clinical trials do not conclusively establish the need for prophylaxis of CVC- related thrombosis in cancer patients Chaukiyal P et al. Thromb Haemost 2008;99:38

121 Influence of Thrombophilia on Thrombotic Complications of CVADs in Cancer In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls: CA + FVL OR=5.18 (95% confidence interval: ) CA + G20210A OR=3.95 (95% confidence interval: ) The attributable risk of catheter associated thrombosis conferred by: FVL 13.5% G20210A 3.6% G20210A 3.6% CAVD = central venous access devices Dentali F, et al. JTH. 2007;5(Suppl 2):P-S-564.

122 Patient Group Recommended Not Recommended Hospitalized patients with cancer VTE prophylaxis with anticoagulants If bleeding or contraindication to anticoagulation Ambulatory patients with cancer receiving chemotherapy Myeloma patients receiving thalidomide or lenalidomide + chemotherapy/ dexamethasone. LMWH or adjusted dose warfarin. Otherwise, no routine prophylaxis Patients with cancer undergoing surgery Prophylaxis with low-dose UFH or LMWH Prophylaxis with mechanical methods for patients with contraindications to pharmacologic methods Consider mechanical methods when contraindications to anticoagulation. Patients with cancer with established VTE Pharmacologic treatment for at least 6 months. Consider continued anticoagulation beyond 6 months in those with active cancer. - To improve survival-Not recommended ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Lyman GH et al: J Clin Oncol 2007; 25: Summary

123 What the ASCO/NCCN Guidelines Do Not Tell Us What is the role for emerging novel anticoagulant medications? No comparisons with LMWH What is the role for emerging novel anticoagulant medications? No comparisons with LMWH Is there equivalent safety and efficacy between m- enoxaparin and Lovenox? Is there equivalent safety and efficacy between m- enoxaparin and Lovenox? Is there a survival advantage to the use of LMWH in cancer patients? Is there a survival advantage to the use of LMWH in cancer patients? Is there a role for adjunctive statins with anticoagulation in cancer patients? Is there a role for adjunctive statins with anticoagulation in cancer patients? Is there a role for monitoring hypercoagulability markers in cancer patients? Is there a role for monitoring hypercoagulability markers in cancer patients? How does palliative care influence the survival and VTE incidence data in cancer patients? How does palliative care influence the survival and VTE incidence data in cancer patients? How should incidental VTE be anticoagulated? How should incidental VTE be anticoagulated? What is the role for retrievable IVC filters in CA patients What is the role for retrievable IVC filters in CA patients

124 Risk Stratification Tools to Identify Patients for Primary and Secondary Prevention of VTE in the Setting of Malignancy Screening and VTE Risk Assessment Across the Complex Spectrum of Malignant DisordersWhat Works? What Doesnt? Alok A. Khorana, MD, FACP Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P. Wilmot Cancer Center University of Rochester Rochester, New York New Frontiers and Evolving Paradigms in Cancer and Thrombosis

125 Disclosures Consultant sanofi aventis, Eisai, Leo Pharma Speakers Bureau sanofi aventis, Leo Pharma Grant/Research Support sanofi aventis

126 Risk assessment for VTE in cancer patients Risk assessment for VTE in cancer patients Clinical risk factors Clinical risk factors Biomarkers Biomarkers Risk assessment tools Risk assessment tools Implications for thromboprophylaxis studies Implications for thromboprophylaxis studies Secondary prophylaxis Secondary prophylaxis VTE in Cancer Patients

127 Risk Factors for VTE Patient-related factors Older age Older age Race, gender Race, gender Comorbidities Comorbidities Treatment-related factors Hospitalization Chemotherapy Anti-angiogenics Major surgery Erythropoiesis-stimulating agents Transfusions Cancer-related factors Site of cancer Site of cancer Advanced stage Advanced stage Initial period after diagnosis Initial period after diagnosis Rao et al., in Cancer-Associated Thrombosis. (Khorana and Francis, Eds) 2007

128 Type of cancer Adjusted OR (95% CI) Hematologic 28 ( ) Lung 22.2 ( ) GI 20.3 (4.9-83) Breast 4.9 ( ) Prostate 2.2 ( ) Blom JW et al. JAMA 2005 VTE and Site of Cancer

129 VTE With Bevacizumab Bevacizum ab (n=1,196) Control (n=1,08 3) Nalluri SR, et al. JAMA. 2008;300: Chu D. and Wu S. JAMA 2009; In reply RR=1.29 (95% CI, ) Rate of VTE (%) Rate of VTE (%) 13% 9.9 % Bevacizumab (n=3,795) Control (n=3,167) 6.2% 4.2% RR=1.38 (95% CI, ) All-Grade VTE (6 studies) High-Grade VTE (13 studies) However, when corrected for exposure time, RR =1.1 (95% CI, )

130 Biomarkers for Cancer-Associated VTE Blood counts Blood counts Platelet count Platelet count Leukocyte count Leukocyte count Hemoglobin Hemoglobin D-dimer D-dimer Soluble P-selectin Soluble P-selectin Tissue factor Tissue factor C-reactive protein C-reactive protein Factor VIII Factor VIII

131 Incidence of VTE By Quartiles Of Pre-Chemotherapy Platelet Count Khorana AA et al. Cancer % 1% 2% 3% 4% 5% 6% < >350 Pre-chemotherapy Platelet Counts (x1000) Incidence Of VTE Over 2.5 Months(%) P =0.005

132 Incidence of VTE by Pre-Chemotherapy Leukocyte Count Khorana AA et al. Blood % 1% 2% 3% 4% 5% 6% <4.5 (n=342) (n=3202) >11 (n=513) Pre-chemotherapy WBC Counts (x1000/mm 3 ) Incidence Of VTE Over 2.4 Months (%) P =0.0008

133 Incidence of VTE by Type of Leukocyte Absolute Neutrophil Count Absolute Monocyte Count P= P< Connolly et al ISTH 2009 Abs 1573 Proportion with VTE

134 Effect of Leukocyte and Platelet Counts on VTE Risk In the Vienna CATS registry, platelet count >443,000 was associated with VTE (HR3.5) In the Vienna CATS registry, platelet count >443,000 was associated with VTE (HR3.5) Simanek et al, J Thromb Hemost 2009 Simanek et al, J Thromb Hemost 2009 In the REAL-2 study of advanced GEJ/gastric cancers, leukocytosis was associated with VTE during chemotherapy (HR 2.0) In the REAL-2 study of advanced GEJ/gastric cancers, leukocytosis was associated with VTE during chemotherapy (HR 2.0) Starling et al, J Clin Oncol 2009 Starling et al, J Clin Oncol 2009

135 Mortality by Pre-chemotherapy Leukocyte Count 14.0% (8.9%-21.6%) 4.4% (3.2%-6.1%) P < MVA for early mortality: HR 2.0, p = Kuderer et al ASH 2008 Connolly et al ISTH 2009, Throm Res 2010 WBC>11x10 9 /L WBC<11x10 9 /L Time (Days) Proportion Died

136 Tissue Factor in Cancer: Lack of Standardized Assays Immunohistochemistry of tumor specimens Immunohistochemistry of tumor specimens TF ELISA TF ELISA TF MP procoagulant activity assay TF MP procoagulant activity assay Impedance-based flow cytometry Impedance-based flow cytometry

137 Tissue Factor Expression and VTE Khorana AA, et al. Clin Cancer Res. 2007;13: Rate of VTE (%) P = 0.04

138 Cumulative Incidence of VTE for Cancer Patients According to TF–bearing Microparticles Zwicker J I et al. Clin Cancer Res 2009;15: Log Rank P=0.002 Months Cumulative Incidence of VTE

139 FRAGEM and TF Biomarker Data Maraveyas, et al. Blood Coagul Fibrinolysis ControlDalteparin Boxplot of the percentage change of tissue factor antigen in the sera of pancreatic cancer patients in both the control and dalteparin groups

140 TF and Survival In Pancreatic Cancer Bharthuar et al ASCO GI 2010 Median Survival in pts with TF MP-PCA >2.5 and 2.5 and 2.5 pg/mL vs. 231 days for TF

141 Ay, C. et al. J Clin Oncol; 27: D-dimer, F1/2 and VTE in Cancer Elevated D-d + F1/2 Elevated F1/2 Elevated D-dimer Noneleva Nonelevated D-dimer and F1/2 Observation Time (Days) Cumulative Risk (probability)

142 Risk assessment for VTE in cancer patients Risk assessment for VTE in cancer patients Clinical risk factors Clinical risk factors Biomarkers Biomarkers Risk assessment tools Risk assessment tools Implications for thromboprophylaxis studies Implications for thromboprophylaxis studies Secondary prophylaxis Secondary prophylaxis VTE in Cancer Patients

143 VTE in Cancer Outpatients The overwhelming majority of cancer patients are treated in the outpatient/ambulatory setting The overwhelming majority of cancer patients are treated in the outpatient/ambulatory setting Which patients are most at risk? Which patients are most at risk? Which patients will benefit most from prophylaxis? Which patients will benefit most from prophylaxis? How do you define high risk? Level of risk for which prophylaxis is considered acceptable by both patients and oncologists

144 Risk Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate)21 Platelet count > 350,000/mm 31 Hb < 10g/dL or use of ESA1 Leukocyte count > 11,000/mm 31 BMI > 35 kg/m 21 Khorana AA et al. Blood 2008

145 Risk Model Validation Risk Low (0) Intermediate(1-2) High(>3) 0% 1% 2% 3% 4% 5% 6% 7% 8% Rate of VTE over 2.5 mos (%) n=734 n=1627n= % 1.8%7.1% Development cohort 0.3% 2.0%6.7% Validation cohort n=374 n=842n=149 Khorana AA et al. Blood 2008

146 Full data available in 839 patients Full data available in 839 patients Median observation time/follow-up: 643 days Median observation time/follow-up: 643 days Score 0 Score 1 Score 2 Score 3 6 months 1.5% 3.8% 9.4% 17.7% Number of PatientsEvents nn (%) Score (17%) Score (11%) Score (6%) Score (3%) Vienna CATS Validation Ay et al ISTH 2009 Abs

147 Expanded Risk Score with D-Dimer and sP-selectin Expanded Risk Score with D-Dimer and sP-selectin Score 5 Score 4 Score 3 Score 2 Score 1 Score % 1.0% 6 months Number of PatientsEvents n n (%) Score (29%) Score (19%) Score (11%) Score (5%) Score (7%) Score (2%) Ay et al ISTH 2009 Abs

148 Risk Score and Short-Term Mortality by VTE Risk Score Categories Low Intermediate High P < Kuderer NM et al. ASH 2008

149 International Myeloma Working Group Thromboprophylaxis Recommendations Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide associated thrombosis in myeloma. Leukemia Feb;22(2): Individual risk factors: obesity (BMI 30), prior VTE, central venous catheter Comorbid risk factors: cardiac disease, chronic renal disease, diabetes, acute infection, immobilization Surgery risk factors: trauma, general surgery or any anesthesia Medications: erythropoietin Myeloma-related risk factors: diagnosis, hyperviscosity Myeloma therapy risk factors: multiagent chemotherapy, doxorubicin, high-dose steroids Patients with 1 VTE risk factor: Aspirin ( mg daily) Patients with 1 VTE risk factor: Aspirin ( mg daily) Patients with 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose warfarin, although less existing supporting data for the latter Patients with 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose warfarin, although less existing supporting data for the latter Patients receiving thalidomide/lenalidomide concurrently with high-dose dexamethasone or doxorubicin should receive LMWH thromboprophylaxis Patients receiving thalidomide/lenalidomide concurrently with high-dose dexamethasone or doxorubicin should receive LMWH thromboprophylaxis Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk factors are present Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk factors are present

150 Risk assessment for VTE in cancer patients Risk assessment for VTE in cancer patients Clinical risk factors Clinical risk factors Biomarkers Biomarkers Risk assessment tools Risk assessment tools Implications for thromboprophylaxis studies Implications for thromboprophylaxis studies Secondary prophylaxis Secondary prophylaxis VTE in Cancer Patients

151 Rates of VTE in Recent Prophylaxis Studies N=930N=312N=123N=1165 Agnelli et al Lancet Onc 2009 Palumbo et al ASH 2009 Riess et al ISTH 2009 Maraveyas et al ESMO 2009

152 VTE in Lung Cancer: PROTECHT and TOPIC studies sVTE LMWH sVTE Placebo All VTE LMWH All VTE Placebo PROTECHT3.5%5%4%6.2% TOPIC-23%5.7%4.5%8.3% All3.2%5.5%4.3%7.8% Verso et al. JTH 2010 online Major Bleeding LMWH Major Bleeding Placebo PROTECHT1%0% TOPIC-23.7%2.2% All2.5%1.7% NNT=50 (sVTE) NNT=28 (allVTE) RRR=46% NNH=125

153 Ongoing Clinical Trials Study (Agent) Criteria for inclusion* NEndpoints PHACS (dalteparin x 12 wks) -Risk score >=3 404 Asymptomatic and symptomatic VTE SAVE-ONCO (semuloparin up to 4 mos) -Lung, bladder, GI, ovary -Metastatic or locally advanced 3200 DVT, PE, VTE- related death MicroTEC (enoxaparin x 6 mos) -Lung, colon, pancreas -Metastatic or unresectable -Elevated TF MPs 227VTE * All studies enroll patients initiating a new chemotherapy regimen

154 Risk assessment for VTE in cancer patients Risk assessment for VTE in cancer patients Clinical risk factors Clinical risk factors Biomarkers Biomarkers Risk assessment tools Risk assessment tools Implications for thromboprophylaxis studies Implications for thromboprophylaxis studies Secondary prophylaxis Secondary prophylaxis VTE in Cancer Patients

155 Predictors of Recurrent VTE: Findings from the RIETE Registry Recurrent PE Recurrent PE Age < 65 (OR 3.0) Age < 65 (OR 3.0) PE at entry (OR 1.9) PE at entry (OR 1.9) < 3 months from diagnosis of cancer (OR 2.0) < 3 months from diagnosis of cancer (OR 2.0) Recurrent DVT Recurrent DVT Age < 65 (OR 1.6) Age < 65 (OR 1.6) < 3 months from diagnosis of cancer (OR 2.4) < 3 months from diagnosis of cancer (OR 2.4) Patients with leukocytosis had increased risk of recurrent VTE and death (OR 2.7) Patients with leukocytosis had increased risk of recurrent VTE and death (OR 2.7) Trujillo-Santos et al Thromb Haem 2008

156 CLOT Study: Reduction in Recurrent VTE Lee et.al. N Engl J Med, 2003;349: Days Post Randomization Probability of Recurrent VTE, % Risk reduction = 52% p-value = Dalteparin OAC Recurrent VTE

157 Treatment of Cancer-Associated VTE StudyDesign Length of Therapy (Months)N Recurrent VTE (%) Major Bleeding (%)Death(%) CLOT Trial (Lee 2003) Dalteparin OAC CANTHENOX (Meyer 2002) Enoxaparin OAC LITE (Hull ISTH 2003) Tinzaparin OAC ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC NS NSNS 0.03 NSNS NS0.002 NSNS NSNS NR

158 Conclusions Cancer patients are clearly at increased risk for VTE but risk varies widely Cancer patients are clearly at increased risk for VTE but risk varies widely Yet, 53% of cancer patients are unaware that they are at high risk for VTE Yet, 53% of cancer patients are unaware that they are at high risk for VTE Sousou et al, Ca Inv 2010 High-risk subgroups can be identified based on clinical risk factors and biomarkers High-risk subgroups can be identified based on clinical risk factors and biomarkers A recently validated risk model can predict risk of VTE (and mortality) using 5 simple clinical and laboratory variables A recently validated risk model can predict risk of VTE (and mortality) using 5 simple clinical and laboratory variables

159 Conclusions LMWH-based prophylaxis is safe and effective in certain high-risk settings LMWH-based prophylaxis is safe and effective in certain high-risk settings Hospitalized and surgical patients Hospitalized and surgical patients Highly selected cancer outpatients (myeloma, ?pancreas, ?? lung) Highly selected cancer outpatients (myeloma, ?pancreas, ?? lung) Ongoing studies are adopting novel approaches to selecting patients for prophylaxis Ongoing studies are adopting novel approaches to selecting patients for prophylaxis Clinicians need to conduct baseline and ongoing risk assessment for VTE in cancer patients receiving chemotherapy Clinicians need to conduct baseline and ongoing risk assessment for VTE in cancer patients receiving chemotherapy

160 VISION STATEMENT VTE in the Setting of Malignancy Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School New Frontiers and Evolving Paradigms in Cancer and Thrombosis

161 Disclosures Research Support: BMS; Boehringer-Ingelheim; Eisai; Johnson & Johnson, Sanofi-Aventis Consultant: Boehringer-Ingelheim; BMS; Eisai; EKOS: Medscape; Merck; Pfizer; Sanofi-Aventis

162 Toward Eradication of In- Hospital VTE: The Promise of Prophylaxis VITAE Studies New Frontiers and Evolving Paradigms in Cancer and Thrombosis

163 VTE Prophylaxis in 19,958 Medical Patients/9 Studies (Meta-analysis) 62% reduction in fatal PE 62% reduction in fatal PE 57% reduction in fatal or nonfatal PE 57% reduction in fatal or nonfatal PE 53% reduction in DVT 53% reduction in DVT Dentali F, et al. Ann Intern Med 2007; 146:

164 VITAE I VITAE I uses a Federal database to model Hospitalized Medical Patients with VTE. VITAE I uses a Federal database to model Hospitalized Medical Patients with VTE. 2 of every 100 hospitalized Medical Service patients suffer VTE. 2 of every 100 hospitalized Medical Service patients suffer VTE. With universal in-hospital prophylaxis, the VTE rate would be cut by 58%. Thromb Haemost 2009; 102:

165 58% Reduction in VTE with Universal Prophylaxis in Hospitalized Medical Patients Thromb Haemostas 2009; 102:

166 VITAE II VITAE II models the 5-year aftermath of initial VTE among these same Hospitalized Medical Patients who were initially stricken. VITAE II models the 5-year aftermath of initial VTE among these same Hospitalized Medical Patients who were initially stricken. If universal prophylaxis had been utilized initially, the 5-year VTE complication rates of death, recurrence, PTS, and CTEPH would have been reduced by 60%. If universal prophylaxis had been utilized initially, the 5-year VTE complication rates of death, recurrence, PTS, and CTEPH would have been reduced by 60%. Thromb Haemost 2009; 102:

167 VITAE II Thromb Haemost 2009; 102: Status Quo 100% VTE Prophylaxis

168 Conclusions 1.Electronic alerts can identify hospitalized cancer patients at risk for VTE. 2.Optimal prophylaxis for hospitalized cancer patients is LMWH. 3.When VTE is diagnosed in cancer patients, the only FDA-approved LMWH for Rx as monotherapy without warfarin is dalteparin.

169 Conclusions (Continued) 4.ACCP guidelines state that every hospital should develop a formal strategy to prevent VTE. 5.As cancer therapies improve, quality life- years will be extended. 6.DVT and PE will be mostly prevented in cancer patients, and when necessary to treat, will be managed will LMWH monotherapy.


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