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An Oncologists Perspective on Cancer and Thrombosis Gary H. Lyman, MD, MPH, FRCP(Edin) Professor of Medicine and Director Health Services, Effectiveness.

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Presentation on theme: "An Oncologists Perspective on Cancer and Thrombosis Gary H. Lyman, MD, MPH, FRCP(Edin) Professor of Medicine and Director Health Services, Effectiveness."— Presentation transcript:

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

2 Cancer and Venous Thromboembolism (VTE) Association recognized since Trousseaus observation more than 130 years ago 1 Of all cases of VTE, approximately 20% occur in cancer patients. 2 VTE affects 4-20% of cancer patients antemortem but has been reported in up to 50% on postmortem examination. 3-4 Cancer-associated VTE has important clinical and economic consequences 5-7 Armand Trousseau 1. Trousseau, Armand. In Clinique Medicale de l'Hôtel-Dieu de Paris, 2nd ed. Paris: J.B. Bailliere et Fils; 1865 2. Lee AY. Br J. Haematol. 2005;128:291-302. 3. Gao S et al: Expert Rev Anticncer Ther 2004; 4: 303-320. 4. Lyman GH et al: J Clin Oncol 2007; 25: 5490-5505. 5. Sorensen HT, et al. N Engl J Med. 2000;343:1846-1850. 6. Prandoni P, et al. Blood. 2002;100:3484-3488. 7. Khorana AA, et al. J Clin Oncol. 2006;24:484-490. Patients with cancer: 20% All deep venous thrombosis and pulmonary embolism

3 Pathogenesis: Virchows Triad Stasis Bed rest and immobility, extrinsic compression of vessel by mass Blood Components [Hypercoagulability] Tumors and macrophages produce procoagulants, inflammatory cytokines Vessel Damage Direct tumor invasion, indwelling catheters, chemotherapy, erythropoietin, antiangiogenic agents

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

5 876543210876543210 Chemotherapy Risk of VTE in the cancer population Remission Risk of VTE in the general population Time Diagnosis Metastasis End of life Hospitalization Risk (Odds Ratio) Risk of VTE Varies Over Natural History of Cancer Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

6 Chew, H. K. et al. Arch Intern Med 2006;166:458-464. The California Cancer Registry linked to the California Discharge Data, 1993 - 1995. Among 235,149 cancer cases, 3775 (1.6%) were diagnosed with VTE within 2 years including 463 (12%) at the time cancer and 3312 (88%) subsequently. Metastatic Disease Local-Regional Disease VTE within Two years of Cancer Diagnosis

7 Incidence of VTE in US Patients With and Without Cancer, 1979-1999 19791981198319851987198919911993199519971999 1 0 2 3 4 National Hospital Discharge Survey VTE Incidence (%) Cancer No cancer Years Stein PD, et al. Am J Med. 2006;119:60-68.

8 Risk Factors for VTE in Patients with Cancer Patient-related factors Older ageOlder age GenderGender Race (higher in African Americans, lower in Asians)Race (higher in African Americans, lower in Asians) Patient comorbiditiesPatient comorbidities History of VTEHistory of VTE Treatment-related factors Major surgeryMajor surgery HospitalizationHospitalization ChemotherapyChemotherapy Hormonal therapyHormonal therapy Antiangiogenic agentsAntiangiogenic agents ESAs, ?TransfusionsESAs, ?Transfusions Biomarkers Platelet and leukocyte countsPlatelet and leukocyte counts Tissue factorTissue factor P-selectinP-selectin D-dimerD-dimer Cancer-related factors Site of cancerSite of cancer Advanced stageAdvanced stage Initial period after diagnosisInitial period after diagnosis Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

9 Risk Factors for VTE in Patients with Cancer Patient-related factors Older age Gender Race (higher in African Americans, lower in Asians) Patient comorbidities History of VTE Treatment-related factors Major surgery Hospitalization Chemotherapy Hormonal therapy Antiangiogenic agents ESAs, ?Transfusions Biomarkers Platelet and leukocyte counts Tissue factor P-selectin D-dimer Cancer-related factors Site of cancer Advanced stage Initial period after diagnosis

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

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

12 CA Cancer Registry linked to Discharge Data Overall Mortality –HR=3.7 [1.3-14.4] Multivariate analysis –Stratified by stage –Adjusted for age, race –VTE is a significant predictor for 1 year mortality for each cancer type Effect of VTE on Risk of Death Stratified by Stage, Adjusted for Age and Race Chew, H. K. et al. Arch Intern Med 2006;166:458-464.

13 VTE in Diffuse Large B-cell Lymphoma Retrospective review of patients with DLBCL treated 1990-2001 Symptomatic VTE at diagnosis or during initial treatment. –27/211 patients (12.8%). Median survival (years) –Controls: 5.20 [1.80 – 8.60] –VTE: 1.04 [0.75 – 1.33] –P = 0.038 Multivariate Analysis for Mortality* Komorokji RS et al. Leuk Lymph 2006; 47: 1029-1033 VariableHRP-value Age1.02.014 IPI1.45.015 VTE1.92.025 * Adjusted for sex, race, and stage

14 Retrospective review of 70 patients with unsuspected PE found on staging CT –2003 – 2006 –VTE, anticoagulation or multiple cancers excluded 2:1 matching based on –Cancer type –Age –Stage Unsuspected PE: –Subsegmental: 24.3% –Proximal: 75.7% Unsuspected PE On Routine Cancer Staging Impact on Survival HR=1.79 [95% CI: 1.10-2.90; P=0.018] OConnell CL et al: ASH 2008

15 Unsuspected VTE in Cancer Patients Results from Autopsy Series Consecutive autopsies in 506 cancer patients Causes of Death, n (%) –Major – Infection 184 (36%) – Hemorrhage 55 (11%) – VTE 35 (7%) – MI 35 (7%) –Contributing – Infection 68 (13%) – Hemorrhage (25%) – VTE 91 (18%) – MI 13 (3%) 578 consecutive autopsies 145 cancer patients, n (%) –PE 24 (17%) –Fatal PE 20 (14%) 433 noncancer patients –PE 55 (13%) –Fatal PE 343 (8%) Author s conclusions: –1 in 7 hospitalized cancer pts died of PE –60% of fatal PEs occur in early or limited metastatic disease Ambrus J et al J Med 1975; 6: 61-64 P<.05 Shen VS et al. South Med J 1980; 73: 841-843 Roswell Park Cancer Institute University of Missouri

16 Causes of Early Death in Ambulatory Cancer Patients Results from Prospective Study of Series Patient Population –Prospective study of 4466 patients starting new chemotherapy –Consecutive patients accrued at 117 US practices –Median followup of 75 days, 141 (3.2%) died. Causes of Death, n (%) –All 141 (100) –Progression of cancer 100 (70.9) –Thromboembolism 13 (9.2) – Arterial 8 (5.6) – Venous 5 (3.5) –Infection 15 (10.6) –Respiratory failure 5 (3.5) –Bleeding 2 (1.4) –Other 9 (6.4) –Unknown 5 (3.5) Khorana AA et al. J Thromb Haemost 2007; 5: 632-634 Distribution of Cancer Type

17 Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer ASCO Clinical Practice Guideline Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

18 Clinical Questions 1.Should patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized? 2.Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? 3.Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis? 4.What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? 5.Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

19 Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Hospitalized Cancer Patients Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

20 Risk of Inpatient VTE By Site of Cancer – Solid Tumor 0 2 4 6 8 10 12 All Brain Lung Stomach Colon Pancreas Other GI Ovary Uterine Rate (%) Khorana et al, J Clin Oncol 2006; 24: 484-490 Discharge database of the University HealthSystem Consortium 115 U.S. academic medical centers 66,106 adult neutropenic cancer patients hospitalized 1995 - 2002

21 Risk of Inpatient VTE by Type of Cancer – Hematologic Malignancies Percent (%) Account for one-third of all VTE 0 1 2 3 4 5 6 7 All LeukemiaNHL Hodgkin Myeloma NHL=Non-Hodgkin s lymphoma Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

22 VTE Inpatient Risk and Mortality 0 2 4 6 8 10 12 14 16 18 20 199519961997199819992000200120022003 Inpatient Mortality (%) VTENo VTE P<0.0001 Khorana AA et al. Cancer 2007; 110: 2339-2346 VTE- patients on chemo VTE-all patients DVT-all patients PE-all patients 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 199519961997199819992000200120022003 Rate of VTE (%) P<0.0001 Discharge database of the University HealthSystem Consortium 133 U.S. academic medical centers 1,015,598 adult cancer patients hospitalized 1995 - 2003 VTE: 34,357 (3.4%) PE: 11,515 (1.1%)

23 Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients 3 large, randomized, placebo-controlled, double-blind trials in medical patients at high risk including cancer –MEDENOX (enoxaparin) 1 ~ 15% –PREVENT (dalteparin) 2 ~5% –ARTEMIS (fondaparinux) 3 ~15% Screening for asymptomatic DVT with venography or ultrasound 1.Samama MM, et al. N Engl J Med. 1999;341:793-800. 2.Leizorovicz A, et al. Circulation. 2004;110:874-879. 3.Cohen AT, et al. BMJ. 2006;332:325-329.

24 MEDENOX 1 StudyRRR Thromboprophylaxis Patients with VTE (%) 14.9 5.5 5.0 2.8 10.5 5.6 1 Samama MM, et al. N Engl J Med. 1999;341:793-800. 2 Leizorovicz A, et al. Circulation. 2004;110:874-9. 3 Cohen AT, et al. BMJ 2006; 332: 325-329. P < 0.001 P = 0.0015 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: VTE

25 0.49% 0.16% 0.2% 1.7% 1.1% Samama MM, et al. N Engl J Med. 1999;341:793-800. Leizorovicz A, et al. Circulation. 2004;110:874-9. Cohen AT, et al. BMJ 2006; 332: 325-329.. Incidence of Major Bleeding (%) Study Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding

26 1.Routine prophylaxis with an antithrombotic agent is not recommended. 2.Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. LMWH or adjusted dose warfarin (INR~1.5) is recommended. This recommendation is based on extrapolation from studies of post-operative prophylaxis in orthopedic surgery and a trial of adjusted dose warfarin in patients with breast cancer. 3.Randomized clinical trials evaluating antithrombotic agents in pts with myeloma on thalidomide or lenalidomide are needed. 4.Research is also urgently needed to identify better markers in ambulatory patients with cancer likely to develop VTE. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Ambulatory Cancer Patients Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

27 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. Data obtained on 4,458 consecutive adult patients initiating a new chemotherapy regimen between March 2003 and February 2006. There were no exclusions for age, prior history or comorbid- ities with nearly 40% of patients age 65 and older.

28 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 PD2.12.22.1 Infection0.30 PE05.40.1 Pulmonary0.20 Bleeding0.10 Other vascular 0.20 Unknown0.30 All3.27.63.3 [HR=5.48, 95%CI: 2.21-13.61; P<.0001] VTE No VTE

29 RCTs of Thromboprophylaxis in Ambulatory Cancer Patients Warfarin Double-blind, placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancer 311 women with metastatic breast cancer on 1st- or 2nd-line chemotherapy Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebo 1 VTE in warfarin group vs 7 in placebo arm –85% risk reduction, P =.03, with no increased bleeding Levine M, et al. Lancet. 1994;343:886-889. INR=international normalized ratio

30 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 -6-12 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;22:1944-1948. 2. Haas SK, et al. J Thromb Haemost. 2005(suppl 1): abstract OR059. 3. Perry JR et al. Proc ASCO 2007. 2011 4. Sideras K et al. Mayo Clin Proc 2006; 81:758-767. 5. Agnelli G et al. Am Soc Hemat Sunday December 7, 2008 RCTs of Thromboprophylaxis in Ambulatory Cancer Patients Low Molecular Weight Heparin

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

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

33 Active, uncontrollable bleeding Active cerebrovascular hemorrhage Dissecting or cerebral aneurysm Bacterial endocarditis Pericarditis, active peptic or other GI ulceration Severe, uncontrolled or malignant hypertension Severe head trauma Pregnancy (warfarin) Heparin-induced thrombocytopenia (heparin, LMWH) Epidural catheter placement ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Relative contraindications for anticoagulation Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

34 Risk of VTE in Cancer Patients Receiving Thalidomide Meta-analysis of RCTs [Estimates ± 95% CI] Search identified 17 RCTs including 3,977 patients Incidence of VTE –All Studies: 11.7% [8.1% - 16.5%] Multiple Myeloma: 17.7% [10.9% - 22.1%] Solid Tumors: 5.3% [2.1% - 12.8%] Relative Risk for VTE –All Studies: 2.4 [1.9 – 3.0], P<.001 Multiple Myeloma: 3.1 [2.1 – 4.4], P<.001 Solid Tumors: 3.5 [1.1 – 10.6], P=.028 –Prophylaxis (all studies) No prophylaxis: 3.5 [2.5 – 4.9], P<.001 Prophylaxis: 1.9 [1.4 – 2.5], P<.001 Gray KN et al: ASH 2008

35 Thromboembolism With Bevacizumab Arterial Thromboembolism Chemotherapy* plus bevacizumab (n=963) Chemotherapy* alone (n=782) Pooled analysis of 5 clinical trials of bevacizumab in metastatic colorectal, breast, or non-small cell lung cancer (N=1,745) *Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:1232-1239. HR=2.0 (95% CI, 1.05-3.75) P=.031 ATE/VTE Rate (%)

36 Nalluri, S. R. et al. JAMA 2008;300:2277-2285. Relative Risk = 1.33 [95% CI: 1.13 – 1.56] Absolute Risk Increase: 2.2% [95% CI: 1.1% - 3.3%] Thromboembolism With Bevacizumab Venous Thromboembolism: Meta-Analysis of RCTs

37 Bohlius, J. et al. JNCI 2006 98:708-714 Thromboembolic Complications in Cancer Patients Receiving ESAs RR TE = 1.67 [1.35 – 2.06] Hb Stopping Value ESAContRR95% CI < 12 g/dL50 (0) >12 - <13 g/dL1481410.700.29, 1.67 >13 - <14 g/dL1,5961,2901.711.23, 2.40 >14 - <15 g/dL1,1519141.921.22, 3.02 >15 - <16 g/dL3683031.661.08, 2.54 (Unclear)42395.590.71, 43.94 Comparative Effectiveness Review # 3 Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment

38 Khorana, A. A. et al. Arch Intern Med 2008;168:2377-2381. Retrospective cohort study of cancer pts at 60 US hospitals: 1995 – 2003. Patients: N = 504,208 RBC trans: 70,542 (14%) Platelet trans: 15,237 (3%) RBC transfusions VTE: 7.2% ATE: 5.2% Mortality 1.34 [95% CI:1.29-1.38] Predictors of Venous Thromboembolism Multivariate Logistic Regression Analysis

39 1.LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE. 2.LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable for long-term therapy when LMWH is not available. 3.After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer. 4.The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long- term therapy with LMWH. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Preventing Recurrence in Cancer Patients with Established VTE Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

40 0123456789101112 Time (months) 0 10 20 30 Recurrent VTE, % Hazard ratio 3.2 [1.9-5.4] Cancer 21% No Cancer 7% Prandoni P et al. Blood 2002; 100: 3484-3488. 01234567891011 12 Time (months) 0 10 20 30 Major Bleeding, % Cancer 12% No Cancer 5% Hazard ratio 2.2 [1.2-4.1] Recurrent VTE and bleeding during anticoagulant treatment Patients with cancer and venous thrombosis

41 RCTs of Long-term Treatment in Cancer Patients with VTE: RCTs of LMWH vs. Vitamin K Antagonists in Cancer 1. Meyer G, et al. Arch Intern Med. 2002;162:1729-1735. 2. Lee AY, et al. N Engl J Med. 2003;349:146-153. 3. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12:389-396. 4. Hull RD, et al. Am J Med. 2006;119:1062-1072. StudyNo.Long-Term Treatment Recurrent VTE, % Major Bleed, % Death, % Meyer 1 2002 71Warfarin21.1*22.7 67Enoxaparin 1.5 mg/kg10.5*11.3 Lee 2 2003 336Warfarin17*441 336Dalteparin 200/150 IU/kg9*639 Deitcher 3 2006 30Warfarin102.98.8 29Enoxaparin 1.0 mg/kg6.96.5 32Enoxaparin 1.5 mg/kg6.311.119.4 Hull 4 2006 100Warfarin10*719 100Tinzaparin 175 IU/kg6*720 * P <.05

42 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;349:146-153.

43 0 5 10 15 20 25 Days Post Randomization 0306090120150180210 Probability of Recurrent VTE, % dalteparin, 9% VKA, 17% risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) log-rank p = 0.002 CLOT Trial: Results: Symptomatic Recurrent VTE Lee AY, et al. N Engl J Med. 2003;349:146-153.

44 Dalteparin N=338 VKA N=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;349:146-153.

45 0 10 20 30 40 50 60 70 80 90 100 0306090120180240300360 dalteparin OAC HR = 0.94 (P=0.40)* Days Post Randomization Probability of Survival, % CLOT Trial Results: 12-month Mortality Lee AY, et al. N Engl J Med. 2003;349:146-153 Lee, A. Y.Y. et al. J Clin Oncol; 23:2123-2129 2005 * Solid tumor patients without metastatic disease: HR = 0.50 (P =.03)

46 1.Anticoagulants are not recommended to improve survival in patients with cancer without VTE. 2.People with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Improving survival in absence of established VTE Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

47 Treatment CancerCitationRate 1 Rate 2 RR P Value SCLCAltinbas.487. 700.696.4761.018. 054 MixedKakkar.542.592. 915.7661.093.327 MixedKlerk.608.727.836.711.983.028 MixedSideras.603. 6001.005.7661.319.972 LMWH.88.79.98.015 SCLCLebeau.601.698.862.7241.026.093 UFH.86.72 1.03. 095 SCLCChahinian.728.802.908.7751.063.233 BreastLevine.382.403.948.7191.251.705 SCLCMaurer.242.278.869.6081.240.438 NSCLCZacharski (1).802.7961.008.8751.161.915 SCLCZacharski (2).600.840.714.4971.027.059 CRCZacharski (3).588.5291.111.7271.697.625 ProstateZacharski (4).357.3001.190.3663.871.770 HNZacharski (5).850.6671.275.8951.817.172 NSCLC (early)Zacharski (6).143.300.476.1371.651.224 Warfarin.94.851.04.239 Combined.91.85.97.003 0.51 2 Anticoagulation Control 1-Year Overall Mortality by Type of Anticoagulation Kuderer NM, et al. Cancer. 2007;110:1149-1161 [95% CI] Systematic Review of Anticoagulants as Cancer Treatment: Impact on Survival SCLC=small cell lung cancer; NSCLC=non-small cell lung cancer; HN=head and neck; CRC=colorectal cancer

48 Major Bleeding Complications by Type of Anticoagulation TreatmentCancerStudyRate 1 Rate 2 RR [95% CI] P Value SCLCAltinbas.000 1.025.02150.418.990 NSCLCHaas (2).037.0231.642.6054.453.325 MixedSideras.029.071.412.0832.051.261 MixedKlerk.034.0065.203.61544.006.089 MixedKakkar.005.0002.906.11970.874.492 BreastHaas (1).017.0007.120.370136.830.127 LMWH 1.68.863.27.128 SCLCLebeau.007 1.007.06415.943.996 UFH 1.01.0615.94.996 SCLCZacharski (2).400.0805.0001.21720.549.008 SCLCMaurer.067.0183.7981.09113.223.023 SCLCChahinian.068.00012.548.727216.606.023 ProstateZacharski (4).571.2002.857.76310.695.069 NSCLC (early)Zacharski (6).524.2502.095.8854.960.072 NSCLCZacharski (1).323.0714.5212.0929.768.000 HNZacharski (5).500.3811.312.6522.642.443 CRCZacharski (3).618.2063.0001.4736.109.001 BreastLevine.007.013.523.0485.709.588 Warfarin 2.982.134.16<.001 Combined 2.591.943.49<.001 0.10.20.512510 Control Anticoagulation Systematic Review of Anticoagulants as Cancer Treatment: Impact on Survival Kuderer NM, et al. Cancer. 2007;110:1149-1161

49 Findings Anticoagulation significantly decreased 1-year overall mortality with a relative risk of 0.905 [95% CI, 0.847-0.967]; P=.003 Conclusions Anticoagulants, particularly LMWH, significantly improved overall survival in cancer patients without VTE while increasing the risk for bleeding complications Improved survival with anticoagulation may be dependent on tumor type However: given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results Kuderer NM, et al. Cancer. 2007;110:1149-1161. Systematic Review of Anticoagulants as Cancer Treatment: Impact on Survival

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

51 CharacteristicDevelopment Cohort N (%) Validation Cohort N (%) P value All2,701 (100)1,365 (100) All VTE60 (2.2)28 (2.1).72 Age >65 yr PS 0-1 BMI >35 1,083 (40.1) 2,473 (91.6) 332 (12.3) 515 (37.7) 1,242 (91) 166 (12.2).14.54.9 Stage IV Platelet count 350,000/mm 3 997 (36.9) 604 (22.4) 477 (34.9) 295 (21.6).06.59 ESA Recent surgery 764 (28.3) 829 (30.7) 358 (26.2) 473 (34.7).17.01 PS=performance status; BMI=body mass index; ESA=erythropoiesis-stimulating agents. Khorana AA et al. Blood. 2008; 111:4902-4907 Clinical Risk Model for Chemotherapy-associated VTE Patient Characteristics

52 CharacteristicβOR*P-value Site of cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, genitourinary excluding prostate) 1.46.43 4.3 1.5 Platelet count >350,000/mm 3.61.8.03 Hemoglobin <10 g/dL or use of ESA.892.4.001 Leukocyte count >11,000/mm 3.772.1.008 BMI >35.92.5.01 *Odds ratio adjusted for stage.05 Khorana AA et al. Blood. 2008; 111:4902-4907 Clinical Risk Model for Chemotherapy-associated VTE Predictors of VTE: Multivariate Analysis

53 Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors Risk Factors Risk score 1. Site of cancer a) Very high risk cancer (stomach, pancreas) 2 b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 1 2. Platelet count >350,000/mm 3 1 3. Hemoglobin level < 10 g/dL or use of Red cell growth factors 1 4. Leukocyte count >11,000 /mm 3 1 5. BMI > 35 kg/m 2 1 Khorana AA et al. Blood. 2008; 111:4902-4907

54 Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors Risk Factors Risk score 1. Site of cancer a) Very high risk cancer (stomach, pancreas) 2 b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 1 2. Platelet count >350,000/mm 3 1 3. Hemoglobin level < 10 g/dL or use of Red cell growth factors 1 4. Leukocyte count >11,000 /mm 3 1 5. BMI > 35 kg/m 2 1 Khorana AA et al. Blood. 2008; 111:4902-4907

55 Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors Risk Factors Risk score 1. Site of cancer a) Very high risk cancer (stomach, pancreas) 2 b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 1 2. Platelet count >350,000/mm 3 1 3. Hemoglobin level < 10 g/dL or use of Red cell growth factors 1 4. Leukocyte count >11,000 /mm 3 1 5. BMI > 35 kg/m 2 1 Khorana AA et al. Blood. 2008; 111:4902-4907

56 RISK SCORE: Low (0) Intermediate (1-2) High (>3) n=374 n=842n=149 Rate of VTE (%) 0% 1% 2% 3% 4% 5% 6% 7% 8% n=734 n=1,627n=340 Development cohort 0.3% 2.0% 6.7% Validation cohort 0% 1% 2% 3% 4% 5% 6% 7% 8% n=734 n=1,627n=340 0.8% 1.8% 7.1% Development cohort 0.3% 2.0% 6.7% Validation cohort n=374 n=842n=149 VTE Prediction Risk Score Chemotherapy – Associated Thrombosis Khorana AA et al. Blood. 2008; 111:4902-4907

57 Venous Thromboembolism and Overall Survival by VTE Risk Score Categories Kuderer NM et al; Blood 2008 (ASH 2008) GrpLowIntermedHigh %1.25.912.7 HR1.03.56 [1.91-6.66] 6.89 [3.50-13.57] Mortality

58 Trial Design Phase III, multicenter, randomized controlled trial of primary LMWH thromboprophylaxis in ambulatory cancer chemotherapy patients Patient Population 400 consenting adult solid tumor or lymphoma patients starting a new chemotherapy regimen Considered high risk based on the VTE model, ie, risk score for VTE 3 Study Outcomes Primary Outcomes: Symptomatic and asymptomatic VTE Secondary Outcomes: Overall mortality, bleeding complications Correlative Studies Blood for biomarkers and microarray studies LMWH prophylaxis NIH trial in cancer outpatients Phase III Multicenter Trial of Thromboprophylaxis in High Risk Ambulatory Cancer Patients Receiving Chemotherapy Fig. 1. Study Schema. (R=randomization, H&P=history and physical examination, US=ultrasound, CT=computed tomography scan of the chest). All time points are ± 1 week. Baseline CT up to 4 weeks prior to enrollment will be accepted.

59 Conclusions Cancer and Venous Thromboembolism Conclusions VTE is a common complication of cancer and cancer treatment and is associated with considerable morbidity, mortality and costs. The US Surgeon General has recently issued a Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism including new research initiatives to lower the burden of this serious illness. Hospitalized medical and surgical cancer patients are at increased risk for VTE and should be considered for pharmacologic prophylaxis if no contraindication to anticoagulation is present. Cancer patients treated for documented VTE should be considered for continued anticoagulation, preferably with LMWH, for up to six months or longer in patients with active malignancy.

60 Routine thromboprophylaxis of ambulatory cancer patients is not currently recommended. While results from prospective controlled trials are needed, thromboprophylaxis may be considered in selective high risk settings such as multiple myeloma patients receiving thalidomide or lenalidomide along with chemotherapy and/or dexamethasone. Consideration of prophylactic anticoagulation in cancer patients must always balance the risk of VTE with the increased risk of bleeding. Improved methods for the identification of ambulatory cancer patients at increased risk for VTE and targeted thromboprophylaxis are needed and under active investigation. Conclusions Cancer and Venous Thromboembolism Conclusions

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

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

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

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

65 Alok A. Khorana, MDUniversity of Rochester Nicole M. Kuderer, MDDuke University Mark Levine, MD, PhDMcMaster University Howard A. Liebman, MDUniversity of Southern California David S. Mendelson, M.D.Premiere Oncology Gary Edward Raskob, PhDUniversity of Oklahoma Paul A. Thodiyil, MDNew York Methodist Hospital David Trent, MD, PhDVirginia Cancer Center ASCO VTE Guideline Panel Members

66 Patient GroupRecommendedNot Recommended Hospitalized patients with cancer VTE prophylaxis with anticoagulantsIf 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 Summary Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

67 Retrospective review of 1514 HSCT patients Median F/U: 642 days Symptomatic VTE: 75 (4.6%) – Catheter-related: 55 (73%) Clinical bleeding: 230 (15.2%) – Fatal bleeding: 55 (3.6%) – OR with anticoagulation: 3.1 – OR with VOD: 2.2 Gerber, D. E. et al. Blood 2008;112:504-510 Symptomatic VTE in Hematopoietic Stem Cell Transplantation (HSCT) Implications for VTE Prevention

68 Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic VTE Hospitalized Medical Patients 9 studies with 19,958 patients Anticoagulant prophylaxis: –Pulmonary embolism (PE): RR = 0.43; CI 0.26-0.71 ARD = 0.29%; NNT = 345 –Fatal PE: RR = 0.38; CI 0.21-0.69 ARD = 0.25%; NNT = 400 –Symptomatic DVT: RR = 0.47; CI 0.22-1.00 ARD = 0.43%; NNT = 233 –Major bleeding RR = 1.32; CI 0.73-2.37 ARD = 0.14%; NNH = 714 Dentali F, et al. Ann Intern Med. 2007;146:278-288. Pulmonary Embolism n=8) Major Bleeding (n=7)

69 Risk Factors for Early Mortality in Patients Receiving Cancer Chemotherapy Kuderer NM, et al. ASCO 2008 VariablesHazard Ratio95% CIP value VTE*3.0591.3097.153.010 Patient Demographics Age1.0211.0041.038.017 ECOG >11.287.8301.996.260 Charlson comorbidity index >11.338.9111.966.137 Body mass index [kg/m 2 ].959.927.992.016 Stage IV2.3041.5093.516<.0001 Cancer Type.009 Colorectal1.666.7653.626.199 Small cell lung cancer1.530.6093.842.365 Non-small cell lung cancer3.0721.5905.937.001 Ovary1.543.5654.211.397 Breast1.059.4422.536.898 Lymphoma1.580.7563.304.224 Relative Dose Intensity.026 <85%.992.6171.595.973 Unknown2.0711.1323.789.018 Year.039 20031.166.6851.983.571 2004.821.4611.464.505 2005.300.100.898.031 Baseline Laboratory Values WBC >11,000/mm 3 1.9761.3312.932.001 Creatinine >1.5 mg/dL2.2141.2234.008.009 Alkaline phosphatase >120 U/L1.6781.1462.455.008 Protein <5.5 g/dL3.1941.6986.009<.0001 Albumin <3.5 g/dL2.3731.5943.532<.0001 *Time-dependent covariate

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

71 Fibrinogen Kinetics in Cancer Patients Patients: 25 patients with known advanced or active cancer Methods: Plasma and urine fractional fibrinogen catabolic rates were estimated Findings: Significantly shortened fibrinogen survival found in patients with active cancer CategoriesNT½T½ TO*P Controls63.89.828 <.05 All Cancers253.011.433 Leukemia63.19.671NS Lymphoma42.881.881<.05 Solid Tumor152.981.617<.05 GI32.522.234<.05 No Chemo153.28 NS Chemo102.61 *TO= mean turnover in mg/ml/day Lyman GH et al. Cancer 1978; 41: 1113-1122

72 6 clinics in Holland 3220 consecutive patients, 18 to 70 years, with a first DVT or PE 2131 control participants (partners of the patients) Risk of VTE in Cancer Patients by Type of Malignancy Population-based, case-control study [MEGA] of risk factors for VTE Type of Cancer Adjusted Odds Ratio (95% CI) Hematologic28 (4-199.7) Lung 22.2 (3.6-136.1) Gastrointestinal20.3 (4.9-83) Breast 4.9 (2.3-10.5) Prostate 2.2 (0.9-5.4) Blom JW, et al. JAMA. 2005;293:715-722. Risk was greatest in first few months following diagnosis of cancer Patients with distant metastases and carriers of factor V Leiden mutation were are further increased risk.

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

74 Risk Factors for Inpatient VTE: Multivariate Analysis* CharacteristicORP value Site of Cancer Lung Stomach Pancreas Uterine Brain 1.3 1.6 2.8 2 2.2 <0.001 0.0035 <0.001 Age > 651.10.005 Arterial Thromboembolism1.40.008 Major Comorbidities** 1.3-1.6 <0.001 Khorana et al, J Clin Oncol 2006; 24: 484-490 * Adjusted for sex, race, HBP, DM, CHF, hepatic disease (NS) ** lung/renal disease, infection, obesity

75 VTE Risk and Prevention in Multiple Myeloma Chemotherapy ± Thalidomide Zangari et al: Brit J Haematol 2004; 126: 715-721

76 Ambulatory Cancer Patients: Prophylaxis in Multiple Myeloma Patients Prophylaxis with low-molecular-weight heparin (LMWH) or adjusted dose warfarin (INR~1.5) is recommended in multiple myeloma patients receiving thalidomide or lenalidomide plus chemotherapy or dexamethasone (high VTE risk) However: –No RCTs available –Recommendation is based on extrapolation from nonrandomized trials or randomized studies in other similar high-risk categories –Well-designed RCTs are urgently needed Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

77 VTE Risk and Prevention in Multiple Myeloma Melphalan + Prednisone ± Thalidomide VTE No anticoagulation (first two years): 11/65 (17%) Enoxaparin 40 mg QD for four months: 2/65 (3%) (P=.005) Palumbo A et al: The Lancet 2006; 367: 825-831

78 Older Age and History of Arterial Thromboembolism Chemotherapy* plus bevacizumab Chemotherapy* alone (control group) ATE Rate (%) Total cohort n=963 bev n=872 ctrl ATE history + age 65 yr n=67 bev n=46 ctrl ATE history n=89 bev n=59 ctrl Age 65 yr n=339 bev n=279 ctrl No risk factors n=602 bev n=490 ctrl Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:1232-1239. * Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel

79 Reduction in thrombosis Increase in bleeding

80 5.In patients with central nervous system malignancies and in the elderly, anticoagulation is recommended for established VTE as described for other patients with cancer. 6.Careful monitoring of anticoagulation is necessary to limit the risk of hemorrhagic complications. 7.Anticoagulation should be avoided in the presence of active intracranial bleeding or preexisting bleeding diathesis such as thrombocytopenia (platelet count <50,000/mm 3 ) or coagulopathy. ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Preventing Recurrence in Cancer Patients with Established VTE Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

81 multinational, open-label, randomized study treatment period 6 months (or until death) primary endpoint: symptomatic VTE recurrence follow-up for survival up to 12 months The CLOT Trial R Cancer patients with proximal DVT, PE or both Control Group: dalteparin + VKA Experimental Group: dalteparin alone Lee AY, et al. N Engl J Med. 2003;349:146-153.

82 Lee, A. Y.Y. et al. J Clin Oncol; 23:2123-2129 2005 CLOT Trial Results: Survival in Solid Tumor Patients ± metastatic disease For patients without metastatic disease, the hazard ratio was 0.50 (95% CI, 0.27 to 0.95; P =.03) for the overall comparison between the treatment groups. For patients with metastatic disease, the hazard ratio was 1.1 (95% CI, 0.87 to 1.4; P =.46) for the overall comparison between the treatment groups. P = 0.62 HR=1.1[.87 to 1.4]; P=.46 HR=0.50[.27 to.95]; P=.03

83 Mortality and PFS in Univariate Analysis by VTE Risk Score Categories Outcomes (at 4 months) Risk Group Low N=1,206 Intermed. N=2,709 High N=543 All N=4,458 Overall Mortality Risk (%)1.2%5.9%12.7%5.6% HR [+/- CI]1.03.56 [1.91-6.66]6.89 [3.50-13.57]- PFS Risk (%)93%82%72%84% HR [+/- CI]1.02.77 [1.97-3.87]4.27 [2.90-6.27]- Kuderer NM et al; Blood 2008 (ASH 2008)

84 VTE Risk Score Independent Predictor for: PFS Multivariate Analysis* VariablesP-valueHR95% CI for HR LowerUpper VTE Risk Score (1) 0.001 Intermed. Risk Group (II)<0.0012.0771.3973.086 High Risk Group (III)<0.0012.3441.4653.751 VTE (2) 0.0282.0431.0793.870 Patient Characteristics Age0.1071.0080.9981.017 ECOG >10.0011.4981.1751.909 Charlson >10.0471.2561.0031.574 BMI [kg/m2]<0.0010.9620.9440.981 Stage IV (3) <0.0011.9821.5672.506 Year<0.0010.7920.7000.896 *Adjusted for: Cancer Type, and Relative Dose Intensity (1) Comparison to low risk group (I)(2) Time-dependent covariate (3) Comparison to stages I-III Kuderer NM et al; Blood 2008 (ASH 2008)

85 Inclusion Criteria: Age 18 years or older A histologic diagnosis of malignancy (not basal cell or squamous cell); At planned initiation of a new systemic chemotherapy regimen (including patients starting on first chemotherapy or patients previously treated but starting on a new regimen); A risk score for VTE 3. Any counts meeting criteria drawn within 2 weeks prior to enrollment are considered acceptable. Exclusion Criteria: Patients will be excluded from the trial if they have any of the following: – Active bleeding or at high risk of serious bleeding complication in the opinion of the investigator – Diagnosis of primary brain tumor, multiple myeloma, acute leukemia, chronic myelogenous leukemia or myelodysplastic syndrome – Planned stem cell transplant – Life expectancy < 6 months – Known allergy to heparin or LMWH – Incapable of daily self-injection – Acute or chronic renal insufficiency with creatinine clearance < 30 mL/min – History of heparin-induced thrombocytopenia – Allergy to contrast agents – Need for anticoagulant therapy – Platelet count < 50,000/mm3 – Pregnancy LMWH prophylaxis NIH trial in cancer outpatients

86 Falanga A: Cancer Invest 2009; 27: 105-115 Procoagulant activities Fibrinolytic activities Cytokines and growth factors Activation of coagulation Angiogenesis Extracellular matrix remodeling Tumor cells Activation of vascular blood cells

87 Data from the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files Control patients, who did not have VTE, were matched by –cancer type –Sex –Age –year of diagnosis Survival of Cancer Patients Developing VTE Compared to Matched Controls Cancer with VTE12% Cancer w/o VTE36% One-Year Mortality HR = 2.20 [2.05-2.40] P<.0001 Sorensen, H. T. et al. N Engl J Med 2000;343:1846-1850

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

89 VTE Risk Score Independent Predictor for: Mortality Multivariate Analysis VariablesP-valueHR*95% CI for HR VTE Risk Score (1) 0.028 Intermed. Risk Group (II)0.0252.2221.1064.464 High Risk Group (III)0.0082.9261.3326.428 VTE (2) <0.0014.4721.92810.370 Patient Characteristics Age0.0261.0181.0021.035 ECOG >10.0271.6131.0552.464 Charlson >10.0141.5821.0962.284 BMI [kg/m2]<0.0010.9410.9100.973 Stage IV (3) <0.0012.6591.7554.028 Year0.0160.7710.6240.953 *Adjusted for: Cancer Type, and Relative Dose Intensity (1) Comparison to low risk group (I)(2) Time-dependent covariate (3) Comparison to stages I-III Kuderer et al. Oral Presentation ASH 2008

90 Cancer and Venous Thromboembolism The Need for Risk Stratification 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 123456 Diagnosis Chemotherapy Hospitalization Remission End of Life Metastasis Average Risk Time Relative Risk

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

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

93 Ay C, et al. Blood. 2008;112:2703-2708 Soluble P-Selectin and VTE in Cancer

94 Rheological effects of increased or increasing red cell mass Young red cells in circulation augment platelet reactivity (red cell–platelet interaction) ESAs synergize with TPO to activate platelets (ESA–TPO interactions) Direct, receptor-mediated effects on endothelium that enhance interaction with platelets (ESA–endothelial interactions) Lancet 2003;362:1265 TPO, thrombopoietin Mechanisms for ESAs to Increase Thrombosis

95 Venous Thromboembolism and Thromboprophylaxis Highlights from ASCO 2009 Advances in Supportive Care Managing Disease and Treatment-Related Complications

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

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

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

99 ASCO Guidelines for Thromboprophylaxis Hospitalized cancer patients Should be considered candidates for VTE prophylaxis in the absence of contraindications Surgical cancer patients All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis Prophylaxis should be continued for at least 7-10 days postoperatively and may be extended into the post discharge period for selected high-risk patients Ambulatory cancer patients Routine prophylaxis not recommended Exception: Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone Lyman et al. JCO 2007

100 ASCO Guidelines for Thromboprophylaxis Hospitalized cancer patients Should be considered candidates for VTE prophylaxis in the absence of contraindications Surgical cancer patients All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis Prophylaxis should be continued for at least 7-10 days postoperatively and may be extended into the post discharge period for selected high-risk patients Ambulatory cancer patients Routine prophylaxis not recommended Exception: Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone

101 Risk Model Patient CharacteristicScore Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2121 Platelet count > 350,000/mm 3 1 Hb < 10g/dL or use of ESA1 Leukocyte count > 11,000/mm 3 1 BMI > 35 kg/m 2 1 Khorana AA et al. Blood 2008

102 RISK SCORE: Low (0) Intermediate (1-2) High (>3) n=374 n=842n=149 Rate of VTE (%) 0% 1% 2% 3% 4% 5% 6% 7% 8% n=734 n=1,627n=340 Development cohort 0.3% 2.0% 6.7% Validation cohort 0% 1% 2% 3% 4% 5% 6% 7% 8% n=734 n=1,627n=340 0.8% 1.8% 7.1% 0.3% 2.0% 6.7% n=374 n=842n=149 VTE Prediction Risk Score Chemotherapy – Associated Thrombosis Khorana AA et al. Blood. 2008; 111:4902-4907

103 Mortality and PFS By VTE Risk Score Outcomes Low Risk N=1,206 Intermediate Risk N=2,709 High Risk N=543 All N=4,458 Mortality Risk (%)1.2%5.9%12.7%5.6% HR [+/- CI]1.03.6 [1.9-6.7]6.9 [3.5-13.6]- Progression-free survival Risk (%)93%82%72%84% HR [+/- CI]1.02.8 [2-3.9]4.3 [2.9-6.3]- Kuderer NM et al. ASH 2008

104 PHACS Study Patients starting chemotherapy Risk score 3 R LMWH prophylaxis x 12 weeks with 4-weekly screening US and start/end CT chest Observe x 12 weeks with 4-weekly screening US and start/end CT chest R01 HL095109-01 Sites: Duke, Duke Oncology Network, Univ of Rochester

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

106 Randomization Response evaluation at least every 12 weeks: VTE, Bleeding, RR, PFS, OS Primary endpoint Chemotherapy Chemotherapy + Enoxaparin Treatment for 3 months:VTE, Bleeding, RR, PFS, OS E 1 mg/kg/d E 40 mg/kg/d until PD Randomization Response evaluation at least every 12 weeks: VTE, Bleeding, RR, PFS, OS Primary endpoint Chemotherapy Chemotherapy + Enoxaparin Treatment for 3 months:VTE, Bleeding, RR, PFS, OS E 1 mg/kg/d E 40 mg/kg/d until PD

107 Favorable results in randomized phase II/III in patients with good PS: with Gem/CDDP or Gem/FA/5-FU and Gem/Cap Gem/CDDP/5-FU and Gem/FA/5-FU/CDDP with remarkable RR and 1- year OS Patient allocation according to Karnofsky-PS (KPS) and plasma creatinine level KPS 80% + creatinine ULNKPS 60-70% or creatinine > ULN Gemcitabine (1000 mg/m 2 ) Folinic acid (100 mg/m 2 )d1, 8, 15; 29 5-FU (750 mg/m 2 24 h CI) CDDP (30 mg/m 2 ) d1, 8; 22 CONKO-004: Chemotherapy

108 Results: VTE and Major Bleeding ObservationEnoxaparin Patients (N)152160 VTE (at 3 months)* Major Bleeding (at 3 months) 9.9% 2.6% 1.2% 3.8% VTE (at 30.4 months)**15.5%5% Major Bleeding (at 30.4 months)9.9%6.3% Median survival29 weeks31 weeks *p<0.01; **p<0.05

109 Results: VTE and Major Bleeding ObservationEnoxaparin Patients (N)152160 VTE (at 3 months)* Major Bleeding (at 3 months) 9.9% 2.6% 1.2% 3.8% VTE (at 30.4 months)**15.5%5% Major Bleeding (at 30.4 months)9.9%6.3% Median survival29 weeks31 weeks *p<0.01; **p<0.05

110 Venous thromboembolic events Event Observation N= 162 Enoxaparin N= 150 All Pulmonary embolism202 Proximal leg DVT9211 Distal leg DVT only202 Upper extremity DVT303 All (VTE)16218 All (Patients)*15217 Results: VTE at 3 Months

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

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


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