Welcome to this Science-to-Strategy Summit

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  • Let’s continue examining the association between DVT/PE and cancer.
    Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE.
    As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer.
    Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer.
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  • Several classes of agents have been used for prophylaxis and treatment of VTE
    Nonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filter
    Most commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs)
  • Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study.
    This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data.
    Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included.
    What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE.
    Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of 4.05. In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE.
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    METHODS: We analyzed data from a prospective observational study conducted by the Awareness of Neutropenia in Chemotherapy Study Group, funded by Amgen, Inc. Patients were enrolled on study at the start of a new chemotherapy regimen, and followed prospectively for a maximum of 4 cycles, at 115 participating US centers. Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis.
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    VTE events were recorded during mid-cycle or new-cycle visits. Since this was an observational study, VTE was diagnosed by the treating physician by usual tests based on clinical suspicion. Statistical analysis included generation of odds ratios to estimate relative risk, and a logistic regression analysis to adjust for other risk factors. The predictive model was constructed based on the multivariate analysis. The risk score estimates for each variable were derived using beta-coefficients from the multivariate model. First order interactions were incorporated into the final score.
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    RESULTS The characteristics of the study population are displayed on this and the next slide. A total of 3,196 patients were available for analysis. Over one-third of the study population was over the age of 65. A majority of patients were female. Patients with metastatic disease formed one-third of the study population. As would be expected in a population of patients initiating chemotherapy, over 90% had an ECOG performance status of 0 or 1. 22% of patients had a pre-chemotherapy platelet count of greater than 350,000 per cu mm.
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    Breast cancer was the most common solid tumor with 1,137 patients, followed by lung with 612 patients and colon with 353 patients. Non-Hodgkin’s lymphoma was the most common hematologic malignancy, with 287 patients carrying this diagnosis.
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    A total of 58 patients (1.93%) developed VTE during a median follow-up period of 2.4 months (0.8%/month). One patient developed VTE prior to starting chemotherapy. The rate of VTE did not differ significantly among chemotherapy cycles, occurring in 0.77% during cycle 1, 0.74% during cycle 2, and 0.7% during cycle 3. As shown in this figure, the cumulative rate of VTE was 2.2% (95% CI, 1.7-2.8) during cycles 1 through 3.
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    The primary site of cancer affected the risk of VTE (p=0.01), with the highest rates observed in patients with upper gastrointestinal cancers (particularly gastric and pancreatic) (2.3%/month), and lung cancer (1.2%/month). Among patients with hematologic malignancies, those with a diagnosis of Hodgkin’s or non-Hodgkin’s lymphoma had the highest rates of VTE (1.1%/month).
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    This figure depicts the incidence of venous thromboembolism by quartiles of pre-chemotherapy platelet count. As can be seen, elevated platelet counts were associated with an increased risk of venous thromboembolism. Patients in the highest quartile of pre-chemotherapy platelet count with a count of > 337,000/ cu mm, had a 3.6% risk of VTE, and this was significantly greater than the 1.1 % risk observed with patients in the lowest quartile, with a pre-chemotherapy platelet count of < 217,000/ cu mm. The p value for trend was highly significant at 0.005, and the difference between the highest and lowest quartile was also significant at 0.001.
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    We included clinically and statistically significant variables in a multivariate logistic regression analysis. This slide demonstrates variables found to be significant in this analysis. Risk factors independently associated with VTE included primary site of cancer (upper gastrointestinal or lung), an elevated pre-chemotherapy platelet count, hemoglobin < 10g/dL or use of erythropoietin (a combined variable), and use of white cell growth factors. We found a significant first-order interaction between site of cancer and use of white cell growth factors (p=0.02). Patients with sites of cancer associated with higher risk of VTE (upper gastrointestinal, lung or lymphoma) had a significantly increased risk of VTE associated with white cell growth factor use (VTE rate of 5.9% versus 1.52% without growth factor use, p =0.0001; odds ratio 4.0, [95% CI, 1.8-8.7]). In contrast, patients with other sites of cancer did not appear to have an increased risk of VTE with the use of white cell growth factors (VTE rate of 1.31% versus 1.42% without growth factor use, p =0.84).
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    The performance of the predictive risk assessment model is illustrated in this figure, which shows the rate of VTE by risk score. As you can see, the predicted incidence of VTE, shown as a yellow line, correlates closely with the actual incidence of VTE, shown as red triangles. The goodness of the model fit was confirmed by Hosmer and Lemeshow test.
    The proposed predictive model discriminates well between subgroups of patients at low and high risk of VTE during chemotherapy. Patients with a risk score of 0 had a VTE rate of 0.8% over the median 2.4 month follow-up. In contrast, patients with a risk score of 2 had a 3-fold higher rate at 2.7%, and those with a risk score of 3 had a 6.3% rate of VTE.
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    VTE prophylaxis is underused in patients with cancer
    The Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1
    Data from 3891 completed questionnaires were available for analysis1
    The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1
    These results can be compared with prophylaxis rates in other patient groups as determined by other recent studies
    A retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2
    A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3
    A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4
    In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5
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    In the 2004 guidelines on venous thromboembolism prophylaxis endorsed by the ACCP, Geerts and coworkers reviewed evidence from 11 studies on the use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in patients with general medical conditions1
    ACCP Grade 1A treatment options for deep vein thrombosis (DVT) prophylaxis in general medical patients with clinical risk factors for DVT/PE (including active cancer, bed rest, heart failure, severe lung disease, prior DVT/PE, sepsis, acute neurologic disease, or IBD)1
    LMWH
    Low-dose UFH
    The investigators assigned a Grade of 1A to 2 for treatment options, defined as follows:1
    Grade 1: Benefits of a given intervention are certain to outweigh the risks, burdens, and costs of the intervention
    Grade 2: Less certainty that the benefits outweigh the risks, burdens, and costs
    Methodological quality of evidence subcategorized by letters A-C
    A: Randomized clinical trials (RCTs) with consistent results
    B: RCTs with inconsistent results
    C: Observational studies, generalizations from single patient group in an RCT compared to a similar patient group not in the RCT. More compelling evidence in this category is graded C+
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    A study by Yu and colleagues showed that even when risk is recognized, the thromboprophylactic strategy chosen may be inadequate
    The study assessed compliance with the 2001 ACCP guidelines for prophylaxis for DVT and PE. The authors looked at records from more than 120,000 adult hospital admissions between January 2001 and March 20051
    Orthopedic surgery patients (n=2324) had the highest rate of compliance, 52.4%1
    The rate of compliance for patients with at-risk medical conditions (n=62,012) was 15.3%. For general surgery patients (n=35,124), the rate of compliance was 12.7%1
    For urologic (n=1338) and gynecologic (n=9175) surgery patients, the rates of compliance were 9.9% and 6.7%, respectively1
    Overall, only 23.4% of patients received some form of prophylaxis and only 13.3% of patients received guideline-recommended prophylaxis1
    Thus, only about a quarter of patients received prophylaxis at all, and of those only about half received the prophylaxis recommended by ACCP guidelines for patients with their condition1
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  • Welcome to this Science-to-Strategy Summit

    1. 1. Welcome to this Science-to-Strategy SummitWelcome to this Science-to-Strategy Summit
    2. 2. Critical Challenges and LandmarkCritical Challenges and Landmark Advances inAdvances in Thrombosis ManagementThrombosis Management The Evolving and Foundation Role of LMWHs in Cancer and VTEThe Evolving and Foundation Role of LMWHs in Cancer and VTE Prophylaxis: Applying Science, Expert Analysis, and LandmarkProphylaxis: Applying Science, Expert Analysis, and Landmark Trials to the Front Lines of Oncology PracticeTrials to the Front Lines of Oncology Practice Program ChairmanProgram Chairman Charles W. Francis, MDCharles W. Francis, MD Professor of Medicine and Pathology andProfessor of Medicine and Pathology and Laboratory MedicineLaboratory Medicine Department of MedicineDepartment of Medicine University of RochesterUniversity of Rochester School of Medicine and DentistrySchool of Medicine and Dentistry Rochester, New YorkRochester, New York Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies
    3. 3. CME-accredited symposiumCME-accredited symposium jointly sponsored by University ofjointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducationMassachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC Commercial Support:Commercial Support: Sponsored by an independent educational grantSponsored by an independent educational grant from Eisai, Inc.from Eisai, Inc. Mission statement:Mission statement: Improve patient care through evidence-basedImprove patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management Processes:Processes: Strives for fair balance, clinical relevance, on-labelStrives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence andindications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies COI:COI: Full faculty disclosures provided in syllabus and at the beginningFull faculty disclosures provided in syllabus and at the beginning of the programof the program Welcome and Program OverviewWelcome and Program Overview
    4. 4. Program Educational ObjectivesProgram Educational Objectives As a result of this session, physicians will:As a result of this session, physicians will: ► Review recent trials, research, and expert analysis of issues focused onReview recent trials, research, and expert analysis of issues focused on thrombosis and cancer.thrombosis and cancer. ► Learn how national guidelines for thrombosis prevention should impactLearn how national guidelines for thrombosis prevention should impact management of patients with cancer.management of patients with cancer. ► Be able to specify strategies for risk-directed prophylaxis against DVT in at riskBe able to specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer.patients with cancer. ► Be able to explain how to assess and manage special needs of cancer patientsBe able to explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT.at risk for DVT, with a focus on protecting against recurrent DVT. ► Be able to describe how to risk stratify patients undergoing cancer surgery, andBe able to describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measuresimplement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis.aimed at DVT prophylaxis.
    5. 5. Program FacultyProgram Faculty Program ChairmanProgram Chairman Charles W. Francis, MDCharles W. Francis, MD Professor of Medicine and Pathology and Laboratory MedicineProfessor of Medicine and Pathology and Laboratory Medicine Department of MedicineDepartment of Medicine University of RochesterUniversity of Rochester School of Medicine and DentistrySchool of Medicine and Dentistry Rochester, NYRochester, NY Frederick Rickles, MDFrederick Rickles, MD Professor of Medicine, Pediatrics, Pharmacology and PhysiologyProfessor of Medicine, Pediatrics, Pharmacology and Physiology Department of MedicineDepartment of Medicine Division of Hematology-OncologyDivision of Hematology-Oncology The George Washington UniversityThe George Washington University Washington, DCWashington, DC John Fanikos, RPh, MBAJohn Fanikos, RPh, MBA Assistant Director of PharmacyAssistant Director of Pharmacy Brigham and Women’s HospitalBrigham and Women’s Hospital Assistant Clinical Professor of PharmacyAssistant Clinical Professor of Pharmacy Northeastern UniversityNortheastern University Massachusetts College of PharmacyMassachusetts College of Pharmacy Boston, MABoston, MA
    6. 6. Faculty COI Financial DisclosuresFaculty COI Financial Disclosures Charles Francis, MDCharles Francis, MD Grants/research support:Grants/research support: Boehringer-Ingelheim, Eisai, Consultant: Eisai,Boehringer-Ingelheim, Eisai, Consultant: Eisai, Amgen, PfizerAmgen, Pfizer Frederick Rickles, MDFrederick Rickles, MD Consultant:Consultant: Pfizer, Eisai, sanofi-aventis, and Bristol-Myers SquibbPfizer, Eisai, sanofi-aventis, and Bristol-Myers Squibb Speakers Bureau:Speakers Bureau: EisaiEisai John Fanikos, RPh, MBAJohn Fanikos, RPh, MBA Speakers Bureau and ConsultingSpeakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The MedicinesPharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines CompanyCompany
    7. 7. Introduction and Chairman’s OverviewIntroduction and Chairman’s Overview Clotting, Cancer, And Controversies: WhatClotting, Cancer, And Controversies: What The Cascade Of Evidence And CurrentThe Cascade Of Evidence And Current Thinking Tell UsThinking Tell Us The Evolving Science, Epidemiology, and Foundation RoleThe Evolving Science, Epidemiology, and Foundation Role of Low Molecular Weight Heparin in the Setting of Cancerof Low Molecular Weight Heparin in the Setting of Cancer Program ChairmanProgram Chairman Charles W. Francis, MDCharles W. Francis, MD Professor of Medicine and Pathology andProfessor of Medicine and Pathology and Laboratory MedicineLaboratory Medicine Department of MedicineDepartment of Medicine University of RochesterUniversity of Rochester School of Medicine and DentistrySchool of Medicine and Dentistry Rochester, New YorkRochester, New York
    8. 8. COMORBIDITYCOMORBIDITY CONNECTIONCONNECTION CAPCAP UTIUTI CancerCancer Heart FailureHeart Failure ABE/COPDABE/COPD Respiratory FailureRespiratory Failure Myeloproliferative DisorderMyeloproliferative Disorder ThrombophiliaThrombophilia SurgerySurgery History of DVTHistory of DVT OtherOther SUBSPECIALISTSUBSPECIALIST STAKEHOLDERSSTAKEHOLDERS Infectious diseasesInfectious diseases OncologyOncology CardiologyCardiology Pulmonary medicinePulmonary medicine HematologyHematology Oncology/hematologyOncology/hematology Interventional RadiologyInterventional Radiology HospitalistHospitalist SurgeonsSurgeons EMEM PCPPCP Comorbidity ConnectionComorbidity Connection
    9. 9. Epidemiology of First-Time VTEEpidemiology of First-Time VTE White R.White R. CirculationCirculation. 2003;107:I-4 –I-8.). 2003;107:I-4 –I-8.) VariableVariable FindingFinding Seasonal VariationSeasonal Variation Possibly more common in winter and lessPossibly more common in winter and less common in summercommon in summer Risk FactorsRisk Factors 25% to 50% “idiopathic”25% to 50% “idiopathic” 15%-25% associated with cancer15%-25% associated with cancer 20% following surgery (3 months)20% following surgery (3 months) Recurrent VTERecurrent VTE 6-month incidence, 7%;6-month incidence, 7%; Higher rate in patients with cancerHigher rate in patients with cancer Recurrent PE more likely after PE thanRecurrent PE more likely after PE than after DVTafter DVT Death After Treated VTEDeath After Treated VTE 30-day incidence 6% after incident DVT30-day incidence 6% after incident DVT 30-day incidence 12% after PE30-day incidence 12% after PE Death strongly associated withDeath strongly associated with cancercancer,, age, and cardiovascular diseaseage, and cardiovascular disease
    10. 10. Epidemiology of VTEEpidemiology of VTE White R.White R. CirculationCirculation. 2003;107:I-4 –I-8.). 2003;107:I-4 –I-8.) ► One major risk factor for VTE is ethnicity, with aOne major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasianssignificantly higher incidence among Caucasians and African Americans than among Hispanicand African Americans than among Hispanic persons and Asian-Pacific Islanders.persons and Asian-Pacific Islanders. ► Overall, about 25% to 50% of patient with first-timeOverall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readilyVTE have an idiopathic condition, without a readily identifiable risk factor.identifiable risk factor. ► Early mortality after VTE is strongly associated withEarly mortality after VTE is strongly associated with presentation as PE, advanced age,presentation as PE, advanced age, cancer,cancer, andand underlying cardiovascular disease.underlying cardiovascular disease.
    11. 11. Comorbidity ConnectionComorbidity Connection ComorbidityComorbidity ConnectionConnection OverviewOverview
    12. 12. Acute Medical Illness and VTEAcute Medical Illness and VTE Among Patients Receiving Placebo orAmong Patients Receiving Placebo or Ineffective Antithrombotic TherapyIneffective Antithrombotic Therapy Alikhan R, Cohen A, et al.Alikhan R, Cohen A, et al. Arch Intern MedArch Intern Med. 2004;164:963-968. 2004;164:963-968 Acute MedicalAcute Medical IllnessIllness Relative RiskRelative Risk XX22 PP ValueValue Heart failureHeart failure NYHA class IIINYHA class III NYHA class IVNYHA class IV 1.08 (0.72-1.62)1.08 (0.72-1.62) 0.89 (0.55-1.43)0.89 (0.55-1.43) 1.48 (0.84-2.60)1.48 (0.84-2.60) 0.050.05 0.120.12 1.231.23 .82.82 .72.72 .27.27 Acute respiratoryAcute respiratory diseasedisease 1.26 (0.85-1.87)1.26 (0.85-1.87) 1.031.03 .31.31 Acute infectiousAcute infectious diseasedisease 1.50 (1.00-2.26)1.50 (1.00-2.26) 3.543.54 .06.06 Acute rheumaticAcute rheumatic diseasedisease 1.45 (0.84-2.50)1.45 (0.84-2.50) 1.201.20 .27.27
    13. 13. Acute Medical Illness and VTEAcute Medical Illness and VTE Multivariate Logistic Regression ModelMultivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE)for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968 Risk FactorRisk Factor Odds RatioOdds Ratio (95% CI)(95% CI) XX22 Age > 75 yearsAge > 75 years CancerCancer Previous VTEPrevious VTE 1.03 (1.00-1.06)1.03 (1.00-1.06) 1.62 (0.93-2.75)1.62 (0.93-2.75) 2.06 (1.10-3.69)2.06 (1.10-3.69) 0.00010.0001 0.080.08 0.020.02 Acute infectiousAcute infectious diseasedisease 1.74 (1.12-2.75)1.74 (1.12-2.75) 0.020.02 Chronic respiratoryChronic respiratory diseasedisease 0.60 (0.38-0.92)0.60 (0.38-0.92) 0.020.02
    14. 14. Comorbid Condition and DVT RiskComorbid Condition and DVT Risk ► Hospitalization for surgery (24%) and for medical illnessHospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while(22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%.nursing home residence accounted for 13%. ► The individual attributable risk estimates forThe individual attributable risk estimates for malignantmalignant neoplasmneoplasm, trauma, congestive heart failure, central venous, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease withcatheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis wereextremity paresis, and superficial vein thrombosis were 18%,18%, 12%, 10%, 9%, 7%, and 5%, respectively.12%, 10%, 9%, 7%, and 5%, respectively. ► Together, the 8 risk factors accounted for 74% of diseaseTogether, the 8 risk factors accounted for 74% of disease occurrenceoccurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd.Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern MedArch Intern Med. 2002 Jun. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study
    15. 15. VTE RecurrenceVTE Recurrence Predictors of First Overall VTE RecurrencePredictors of First Overall VTE Recurrence Heit J, Mohr D, et al.Heit J, Mohr D, et al. Arch Intern MedArch Intern Med. 2000;160:761-768. 2000;160:761-768 Baseline CharacteristicBaseline Characteristic Hazard RatioHazard Ratio (95% CI)(95% CI) AgeAge 1.17 (1.11-1.24)1.17 (1.11-1.24) Body Mass IndexBody Mass Index 1.24 (1.04-1.7)1.24 (1.04-1.7) Neurologic disease with extremityNeurologic disease with extremity paresisparesis 1.87 (1.28-2.73)1.87 (1.28-2.73) Malignant neoplasmMalignant neoplasm NoneNone With chemotherapyWith chemotherapy Without chemotherapyWithout chemotherapy 1.001.00 4.24 (2.58-6.95)4.24 (2.58-6.95) 2.21 (1.60-3.06)2.21 (1.60-3.06)
    16. 16. Cancer, Thrombosis, and theCancer, Thrombosis, and the Biology of MalignancyBiology of Malignancy Scientific Foundations for the Role ofScientific Foundations for the Role of Low-Molecular-Weight HeparinLow-Molecular-Weight Heparin Frederick R. Rickles, MDFrederick R. Rickles, MD Professor of Medicine, Pediatrics,Professor of Medicine, Pediatrics, Pharmacology and PhysiologyPharmacology and Physiology The George Washington UniversityThe George Washington University Washington, DCWashington, DC Clotting, Cancer, and Clinical StrategiesClotting, Cancer, and Clinical Strategies
    17. 17. Professor Armand TrousseauProfessor Armand Trousseau Lectures in Clinical MedicineLectures in Clinical Medicine ““ I have always been struck with theI have always been struck with the frequency with which cancerous patientsfrequency with which cancerous patients are affected with painful oedema of theare affected with painful oedema of the superior or inferior extremities….”superior or inferior extremities….” New Syndenham Society – 1865New Syndenham Society – 1865
    18. 18. Professor Armand TrousseauProfessor Armand Trousseau More Observations About Cancer and ThrombosisMore Observations About Cancer and Thrombosis ““In other cases, in which the absence ofIn other cases, in which the absence of appreciable tumor made me hesitate as toappreciable tumor made me hesitate as to the nature of the disease of the stomach, mythe nature of the disease of the stomach, my doubts were removed, and I knew thedoubts were removed, and I knew the disease to be cancerous whendisease to be cancerous when phlegmasiaphlegmasia alba dolensalba dolens appeared in one of the limbs.”appeared in one of the limbs.” Lectures in Clinical Medicine, 1865Lectures in Clinical Medicine, 1865
    19. 19. Trousseau’s SyndromeTrousseau’s Syndrome Ironically, Trousseau died of gastric carcinoma 6Ironically, Trousseau died of gastric carcinoma 6 months after writing to his student, Peter, on Januarymonths after writing to his student, Peter, on January 1st, 1867:1st, 1867: ““I am lost . . . the phlebitis that has justI am lost . . . the phlebitis that has just appeared tonight leaves me no doubt as toappeared tonight leaves me no doubt as to the nature of my illness”the nature of my illness”
    20. 20. Trousseau’s SyndromeTrousseau’s Syndrome ► Occult cancerOccult cancer in patients with idiopathicin patients with idiopathic venous thromboembolismvenous thromboembolism ► ThrombophlebitisThrombophlebitis in patientsin patients with cancerwith cancer
    21. 21. SilverSilver In:In: The Hematologist - modified from Blom et. al.The Hematologist - modified from Blom et. al. JAMAJAMA 2005;293:7152005;293:715 • Population-based case-control (MEGA) study • N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects • CA patients = OR 7x VTE risk vs. non-CA patients Effect of Malignancy on Risk ofEffect of Malignancy on Risk of Venous Thromboembolism (VTE)Venous Thromboembolism (VTE) 0 10 20 30 40 50 HematologicalHematological LungLung GastrointestinalGastrointestinal BreastBreast DistantDistant metastasesmetastases 0to3months0to3months 3to12months3to12months 1to3years1to3years 5to10years5to10years >15years>15years Adjustedoddsratio Type of cancer Time since cancer diagnosis 2828 22.222.2 20.320.3 4.94.9 19.819.8 53.553.5 14.314.3 2.62.6 1.11.13.63.6
    22. 22. Cancer, Mortality, and VTECancer, Mortality, and VTE Epidemiology and RiskEpidemiology and Risk ► Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patients ► Patients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patients ► Cancer patients undergoing surgery have a 2-fold increased risk for postoperative VTE ► Death rate from cancer is four-fold higher if patient has concurrent VTE ► VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection)) Heit et.al.Heit et.al. Arch Int MedArch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al.2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al. BloodBlood 2002;100:3484-3488;2002;100:3484-3488; White et.al.White et.al. Thromb HaemostThromb Haemost 2003;90:446-455; Sorensen et.al.2003;90:446-455; Sorensen et.al. New Engl J MedNew Engl J Med 2000;343:1846-1850); Levitan2000;343:1846-1850); Levitan et.al.et.al. MedicineMedicine 1999;78:285-291; Khorana et.al.1999;78:285-291; Khorana et.al. J Thromb HaemostJ Thromb Haemost 2007;5:632-42007;5:632-4
    23. 23. Mechanisms of Cancer-Induced Thrombosis:Mechanisms of Cancer-Induced Thrombosis: The InterfaceThe Interface 1.1. PathogenesisPathogenesis?? 2.2. Biological significance?Biological significance? 3.3. Potential importance for cancer therapy?Potential importance for cancer therapy?
    24. 24. ““There appears in the cachexiae…aThere appears in the cachexiae…a particular condition of the blood thatparticular condition of the blood that predisposes it to spontaneouspredisposes it to spontaneous coagulation.”coagulation.” Lectures in Clinical Medicine, 1865Lectures in Clinical Medicine, 1865 Trousseau’s Observations (continued)Trousseau’s Observations (continued)
    25. 25. Fibrinolytic activities: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities FIBRIN Endothelial cells IL-1, TNF- α, VEG F Tumor cells Monocyte PMN leukocyte Activation of coagulation Platelets Angiogenesis, Basement matrix degradation. Falanga and Rickles,Falanga and Rickles, New Oncology:ThrombosisNew Oncology:Thrombosis, 2005;, 2005; Hematology,Hematology, 20072007 Interface of Biology and CancerInterface of Biology and Cancer
    26. 26. Pathogenesis of Thrombosis in CancerPathogenesis of Thrombosis in Cancer A Modification of Virchow’s TriadA Modification of Virchow’s Triad 1.1. StasisStasis ● Prolonged bed restProlonged bed rest ● Extrinsic compression of blood vessels by tumorExtrinsic compression of blood vessels by tumor 2.2. Vascular InjuryVascular Injury ● Direct invasion by tumorDirect invasion by tumor ● Prolonged use of central venous cathetersProlonged use of central venous catheters ● Endothelial damage by chemotherapy drugsEndothelial damage by chemotherapy drugs ● Effect of tumor cytokines on vascular endotheliumEffect of tumor cytokines on vascular endothelium 3.3. HypercoagulabilityHypercoagulability ● Tumor-associated procoagulants and cytokines (tissue factor, CP,Tumor-associated procoagulants and cytokines (tissue factor, CP, TNFTNFαα, IL-1, IL-1ββ, VEGF, etc.), VEGF, etc.) ● Impaired endothelial cell defense mechanisms (APC resistance;Impaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT, Protein C and S)deficiencies of AT, Protein C and S) ● Enhanced selectin/integrin-mediated, adhesive interactionsEnhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and hostbetween tumor cells,vascular endothelial cells, platelets and host macrophagesmacrophages
    27. 27. Mechanisms of Cancer-Induced Thrombosis:Mechanisms of Cancer-Induced Thrombosis: Clot and Cancer InterfaceClot and Cancer Interface 1.1. Pathogenesis?Pathogenesis? 2.2. Biological significance?Biological significance? 3.3. Potential importance for cancer therapyPotential importance for cancer therapy??
    28. 28. Activation of Blood Coagulation in CancerActivation of Blood Coagulation in Cancer Biological Significance?Biological Significance? ► EpiphenomenonEpiphenomenon?? Is this a generic secondary event whereIs this a generic secondary event where thrombosis is an incidental findingthrombosis is an incidental finding oor, is clotting activation . . .r, is clotting activation . . . ► A Primary Event?A Primary Event? Linked to malignant transformationLinked to malignant transformation
    29. 29. TF VEGF AngiogenesisAngiogenesis Endothelial cells IL-8IL-8 Blood CoagulationBlood Coagulation ActivationActivation FIBRINFIBRIN PAR-2PAR-2 AngiogenesisAngiogenesis FVII/FVIIaFVII/FVIIa THROMBINTHROMBIN TumorTumor CCellell TF Falanga and Rickles, New Oncology:Thrombosis, 2005 Interface of Clotting ActivationInterface of Clotting Activation and Tumor Biologyand Tumor Biology
    30. 30. Coagulation Cascade and Tumor BiologyCoagulation Cascade and Tumor Biology TFTF ThrombinThrombin Clotting-Clotting- dependentdependent Clotting-Clotting- dependentdependent Clotting-Clotting- independentindependent Clotting-Clotting- dependentdependent FibrinFibrin Clotting-Clotting- independentindependent PARsPARs Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584 VIIaVIIa XaXa Angiogenesis, TumorAngiogenesis, Tumor Growth and MetastasisGrowth and Metastasis Angiogenesis, TumorAngiogenesis, Tumor Growth and MetastasisGrowth and Metastasis
    31. 31. VEGF and AngiogenesisVEGF and Angiogenesis 1.1. TF regulates VEGF expression in human cancerTF regulates VEGF expression in human cancer cell linescell lines 2.2. Human cancer cells with increased TF are moreHuman cancer cells with increased TF are more angiogenic (and, therefore, more “metastatic’)angiogenic (and, therefore, more “metastatic’) inin vivovivo due to high VEGF productiondue to high VEGF production Abe et.al.Abe et.al. Proc Nat Acad SciProc Nat Acad Sci 1999;96:8663-8668; Ruf et.al.1999;96:8663-8668; Ruf et.al. Nature MedNature Med 2004;10:502-5092004;10:502-509 Regulation of Vascular Endothelial Growth Factor ProductionRegulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factorand Angiogenesis by the Cytoplasmic Tail of Tissue Factor
    32. 32. 3.3. The cytoplasmic tail of TF, which contains threeThe cytoplasmic tail of TF, which contains three serine residues, appears to play a role in regulatingserine residues, appears to play a role in regulating VEGF expression in human cancer cells, perhapsVEGF expression in human cancer cells, perhaps by mediating signal transductionby mediating signal transduction 4.4. Data consistent with new mechanism(s) by whichData consistent with new mechanism(s) by which TF signals VEGF synthesis in human cancer cellsTF signals VEGF synthesis in human cancer cells may provide insight into the relationship betweenmay provide insight into the relationship between clotting and cancerclotting and cancer Abe et.al.Abe et.al. Proc Nat Acad SciProc Nat Acad Sci 1999;96:8663-8668; Ruf et.al.1999;96:8663-8668; Ruf et.al. Nature MedNature Med. 2004;10:502-509. 2004;10:502-509 VEGF and AngiogenesisVEGF and Angiogenesis Regulation of Vascular Endothelial Growth Factor ProductionRegulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factorand Angiogenesis by the Cytoplasmic Tail of Tissue Factor
    33. 33. Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan,Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan, Charles W. Francis, Ralph H. Hruban, Ying Chuan Hu, Galen Hostetter,Charles W. Francis, Ralph H. Hruban, Ying Chuan Hu, Galen Hostetter, Jennifer Harvey and Mark B.TaubmanJennifer Harvey and Mark B.Taubman (U Rochester, U Pitt, Johns Hopkins,(U Rochester, U Pitt, Johns Hopkins, Translational Genomics)Translational Genomics) Clin Cancer ResClin Cancer Res 2007;13:28702007;13:2870 ► Retrospective IH and microarray study of TF, VEGF and MVD inRetrospective IH and microarray study of TF, VEGF and MVD in:: ● Normal pancreas (10)Normal pancreas (10) ● Intraductal papillary mucinous neoplasms (IPMN; 70)Intraductal papillary mucinous neoplasms (IPMN; 70) ● Pancreatic intrepithelial neoplasia (PanIN; 40)Pancreatic intrepithelial neoplasia (PanIN; 40) ● Resected or metastatic pancreatic adenoca(130)Resected or metastatic pancreatic adenoca(130) ► SurvivalSurvival ► VTE RateVTE Rate Tissue Factor Expression, Angiogenesis, andTissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic CancerThrombosis in Pancreatic Cancer
    34. 34. Correlation of Tissue Factor Expression with theCorrelation of Tissue Factor Expression with the Expression of Other Angiogenesis Cariables in ResectedExpression of Other Angiogenesis Cariables in Resected Pancreatic CancerPancreatic Cancer Khorana et.al. Clin CA Res 2007:13:2870 High TFHigh TF expressionexpression Low TFLow TF expressionexpression PP VEGF expressionVEGF expression NegativeNegative PositivePositive 1313 5353 4141 1515 <0.0001<0.0001 Microvessel densityMicrovessel density V6 per tissue coreV6 per tissue core >6 per tissue core>6 per tissue core MedianMedian 2727 3939 88 3333 2323 66 0.0470.047 0.010.01
    35. 35. 0 5 10 15 20 25 30 Low TF High TF Symptomatic VTE in Pancreatic CancerSymptomatic VTE in Pancreatic Cancer 1/22; 4.5%1/22; 4.5% 5/19; 26.3%5/19; 26.3% Khorana et.al.Khorana et.al. Clin CA ResClin CA Res 2007:13:28702007:13:2870 RateofVTE(%)RateofVTE(%)
    36. 36. Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation ► Epiphenomenon?Epiphenomenon? ► Linked to malignant transformation?Linked to malignant transformation? 1.1. METMET oncogene induction produces DIC inoncogene induction produces DIC in human liver carcinomahuman liver carcinoma (Boccaccio et. al.(Boccaccio et. al. NatureNature 2005;434:396-400)2005;434:396-400) 2.2. PtenPten loss produces TF activation andloss produces TF activation and pseudopalisading necrosis in humanpseudopalisading necrosis in human glioblastomaglioblastoma (Rong et.al.(Rong et.al. Ca ResCa Res 2005;65:1406-1413)2005;65:1406-1413) 3.3. K-K-rasras oncogene, p53 inactivation and TFoncogene, p53 inactivation and TF induction in human colorectal carcinomainduction in human colorectal carcinoma (Yu et.al.(Yu et.al. BloodBlood 2005;105:1734-1741)2005;105:1734-1741)
    37. 37. ► METMET encodes a tyrosine kinase receptor for hepatocyteencodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF)growth factor/scatter factor (HGF/SF) →→ ● Drives physiologicalDrives physiological cellular program of “invasivecellular program of “invasive growth” (tissue morphogenesis, angiogenesisgrowth” (tissue morphogenesis, angiogenesis and repair)and repair) ● Aberrant execution (e.g. hypoxia-inducedAberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastictranscription) is associated with neoplastic transformation, invasion, and metastasistransformation, invasion, and metastasis Boccaccio et alBoccaccio et al NatureNature 2005;434:396-4002005;434:396-400 ““1.1. METMET Oncogene Drives a Genetic ProgrammeOncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Linking Cancer to Haemostasis” Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation
    38. 38. ► Mouse model of Trousseau’s SyndromeMouse model of Trousseau’s Syndrome ● Targeted activated human MET to the mouse liver withTargeted activated human MET to the mouse liver with lentiviral vector and liver-specific promoterlentiviral vector and liver-specific promoter →→ slowly,slowly, progressive hepatocarcinogenesisprogressive hepatocarcinogenesis ● Preceded and accompanied by a thrombohemorrhagicPreceded and accompanied by a thrombohemorrhagic syndromesyndrome ● Venous thrombosis in tail vein occurred early and wasVenous thrombosis in tail vein occurred early and was followed by fatal internal hemorrhagefollowed by fatal internal hemorrhage ● Syndrome characterized bySyndrome characterized by ↑↑ d-dimer and PT andd-dimer and PT and ↓↓ platelet count (DIC)platelet count (DIC) ““METMET Oncogene Drives a Genetic ProgrammeOncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Linking Cancer to Haemostasis”
    39. 39. Blood Coagulation Parameters in MiceBlood Coagulation Parameters in Mice Transduced with theTransduced with the METMET OncogeneOncogene TransgeneTransgene ParameterParameter Time after Transduction (days)Time after Transduction (days) 0 30 900 30 90 GFPGFP __________________ METMET Platelets (x10Platelets (x1033 )) D-dimer (D-dimer (µg/ml)µg/ml) PT (s)PT (s) ________________________________ Platelets (x10Platelets (x1033 )) D-dimer (µg/ml)D-dimer (µg/ml) PT (s)PT (s) 968 656 800968 656 800 <0.05 <0.05 <0.05<0.05 <0.05 <0.05 12.4 11.6 11.412.4 11.6 11.4 ______________________________________________________________ 974 350 150974 350 150 <0.05 0.11 0.22<0.05 0.11 0.22 12.9 11.8 25.112.9 11.8 25.1 Boccaccio et alBoccaccio et al NatureNature 2005;434:396-4002005;434:396-400
    40. 40. ► Mouse model of Trousseau’s SyndromeMouse model of Trousseau’s Syndrome ● Genome-wide expression profiling of hepatocytesGenome-wide expression profiling of hepatocytes expressingexpressing METMET upregulation ofupregulation of PAI-1PAI-1 andand COX-2COX-2 genes with 2-3xgenes with 2-3x ↑↑ circulating protein levelscirculating protein levels ● Using either XR5118 (Using either XR5118 (PAI-1 inhibitorPAI-1 inhibitor) or Rofecoxib) or Rofecoxib (Vioxx;(Vioxx; COX-2 inhibitorCOX-2 inhibitor) resulted in inhibition of) resulted in inhibition of clinical and laboratory evidence for DIC in miceclinical and laboratory evidence for DIC in mice ““METMET Oncogene Drives a Genetic ProgrammeOncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Linking Cancer to Haemostasis”
    41. 41. Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation 2. “2. “PtenPten and Hypoxia Regulate Tissue Factorand Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation ByExpression and Plasma Coagulation By Glioblastoma”Glioblastoma” ► PtenPten = Tumor suppressor with lipid and protein= Tumor suppressor with lipid and protein phosphatase activityphosphatase activity ► Loss or inactivation ofLoss or inactivation of PtenPten (70-80% of(70-80% of glioblastomas) leads to Akt activation andglioblastomas) leads to Akt activation and upregulation ofupregulation of Ras/MEK/ERKRas/MEK/ERK signaling cascadesignaling cascade Rong, Brat et.al.Rong, Brat et.al. Ca ResCa Res 2005;65:1406-14132005;65:1406-1413
    42. 42. ► Glioblastomas characterized histologically byGlioblastomas characterized histologically by “pseudopalisading necrosis”“pseudopalisading necrosis” ► Thought to be wave of tumor cells migrating awayThought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created byfrom a central hypoxic zone, perhaps created by thrombosisthrombosis ► Pseudopalisading cells produce VEGF and IL-8Pseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growthand drive angiogenesis and rapid tumor growth ► TF expressed by >90% of grade 3 and 4 malignantTF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2)astrocytomas (but only 10% of grades 1 and 2) ““PtenPten and Hypoxia Regulate Tissue Factor Expressionand Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”and Plasma Coagulation By Glioblastoma”
    43. 43. Results:Results: 1.1. Hypoxia andHypoxia and PTENPTEN lossloss →↑→↑ TF (mRNA, Ag andTF (mRNA, Ag and procoagulant activity); partially reversed withprocoagulant activity); partially reversed with induction ofinduction of PTENPTEN 2.2. BothBoth AktAkt andand RasRas pathways modulated TF inpathways modulated TF in sequentially transformed astrocytes.sequentially transformed astrocytes. 3.3. Ex vivoEx vivo data:data: ↑↑ TF (by immunohistochemicalTF (by immunohistochemical staining) in pseudopalisades of # 7 humanstaining) in pseudopalisades of # 7 human glioblastoma specimensglioblastoma specimens ““PtenPten and Hypoxia Regulate Tissue Factor Expressionand Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”and Plasma Coagulation By Glioblastoma”
    44. 44. Both Akt and Ras Pathways Modulate TFBoth Akt and Ras Pathways Modulate TF Expression By Transformed AstrocytesExpression By Transformed Astrocytes Rong, Brat et.al.Rong, Brat et.al. Ca ResCa Res 2005;65:1406-14132005;65:1406-1413 N=NormoxiaN=Normoxia H=hypoxiaH=hypoxia
    45. 45. pseudopalisading necrosis Vascular Endothelium H&E TF Immuno- histochemistry ““PtenPten and Hypoxia Regulate Tissue Factor Expressionand Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”and Plasma Coagulation By Glioblastoma” Rong, Brat et.al. Ca Res 2005;65:1406-1413
    46. 46. Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation 3. “Oncogenic Events Regulate Tissue Factor3. “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications forExpression In Colorectal Cancer Cells: Implications for Tumor Progression And Angiogenesis”Tumor Progression And Angiogenesis” ► Activation of K-Activation of K-rasras oncogene and inactivation ofoncogene and inactivation of p53p53 tumortumor suppressorsuppressor ↑↑ TF expression inTF expression in humanhuman colorectal cancer cellscolorectal cancer cells ► Transforming events dependent on MEK/MAPK and PI3KTransforming events dependent on MEK/MAPK and PI3K ► Cell-associated and MP-associated TF activity linked toCell-associated and MP-associated TF activity linked to genetic status of cancer cellsgenetic status of cancer cells ► TF siRNA reduced cell surface TF expression, tumor growthTF siRNA reduced cell surface TF expression, tumor growth and angiogenesisand angiogenesis ► TF may be required for K-TF may be required for K-ras-ras-driven phenotypedriven phenotype Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41
    47. 47. ““Oncogenic Events Regulate Tissue Factor Expression InOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor ProgressionColorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”And Angiogenesis” TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p53 status Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41 0 50 100 150 200 250 300 350 400 450 HKh-2 HCT116 379.2 0 20 40 60 80 100 120 140 160 HKh-2 HCT116 379.2 MeanChannelTFFlourescenceMeanChannelTFFlourescence TFActivity(U/10TFActivity(U/1066 cells)cells) del/+del/+ mut/+mut/+ mut/+mut/+ +/++/+ +/++/+ del/deldel/del
    48. 48. ““Oncogenic Events Regulate Tissue FactorOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells:Expression In Colorectal Cancer Cells: Implications For Tumor Progression AndImplications For Tumor Progression And Angiogenesis”Angiogenesis” Effect of TF si mRNA on tumor growth in vitro and in vivo Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41 Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation
    49. 49. 0 2 4 6 8 10 12 14 HCT116 SI-2 SI-3 MG only Effect of TF si mRNA on new vessel formation in colon cancer ““Oncogenic Events Regulate Tissue FactorOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells”Expression In Colorectal Cancer Cells” Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41 %VWF-PositiveArea%VWF-PositiveArea
    50. 50. ““Oncogenic Events Regulate Tissue Factor Expression InOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For TumorColorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”Progression And Angiogenesis” Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41
    51. 51. Mechanisms of Cancer-Induced Thrombosis:Mechanisms of Cancer-Induced Thrombosis: ImplicationsImplications 1.1. Pathogenesis?Pathogenesis? 2.2. Biological significance?Biological significance? 3.3. Potential importance for cancerPotential importance for cancer therapy?therapy?
    52. 52. 1. Does activation of blood coagulation affect1. Does activation of blood coagulation affect the biology of cancer positively or negatively?the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using2. Can we treat tumors more effectively using coagulation protein targets?coagulation protein targets? 3. Can anticoagulation alter the biology of cancer?3. Can anticoagulation alter the biology of cancer? Cancer and ThrombosisCancer and Thrombosis Year 2008 State-of-the-Science UpdateYear 2008 State-of-the-Science Update Key QuestionsKey Questions
    53. 53. 1.1. Epidemiologic evidence isEpidemiologic evidence is suggestivesuggestive that VTE is athat VTE is a bad prognostic sign in cancerbad prognostic sign in cancer 2. Experimental evidence is2. Experimental evidence is supportivesupportive of the use ofof the use of antithrombotic strategies for both prevention ofantithrombotic strategies for both prevention of thrombosis and inhibition of tumor growththrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWH3. Results of recent, randomized clinical trials of LMWH in cancer patients indicate superiority in preventingin cancer patients indicate superiority in preventing recurrent VTE and suggest increased survival (notrecurrent VTE and suggest increased survival (not due to just preventing VTE)—due to just preventing VTE)— “Titillating”“Titillating” Tentative AnswersTentative Answers Cancer and ThrombosisCancer and Thrombosis Year 2008 State-of-the-Science UpdateYear 2008 State-of-the-Science Update
    54. 54. Coagulation Cascade and Tumor BiologyCoagulation Cascade and Tumor Biology TFTF ThrombinThrombin Clotting-Clotting- dependentdependent Clotting-Clotting- dependentdependent Clotting-Clotting- independentindependent Clotting- dependent FibrinFibrin Clotting-Clotting- independentindependent PARsPARs Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584 VIIaVIIa XaXa Angiogenesis, TumorAngiogenesis, Tumor Growth and MetastasisGrowth and Metastasis ?? LMWHLMWH (e.g. dalteparin)(e.g. dalteparin)
    55. 55. A Systematic Overview of VTE ProphylaxisA Systematic Overview of VTE Prophylaxis in the Setting of Cancerin the Setting of Cancer Linking Science to Clinical PracticeLinking Science to Clinical Practice Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies Program ChairmanProgram Chairman Charles W. Francis, MDCharles W. Francis, MD Professor of Medicine and Pathology andProfessor of Medicine and Pathology and Laboratory MedicineLaboratory Medicine Department of MedicineDepartment of Medicine University of RochesterUniversity of Rochester School of Medicine and DentistrySchool of Medicine and Dentistry Rochester, New YorkRochester, New York
    56. 56. VTE and Cancer: EpidemiologyVTE and Cancer: Epidemiology ► Of all cases of VTE:Of all cases of VTE: ● About 20% occur in cancer patientsAbout 20% occur in cancer patients ● Annual incidence of VTE in cancerAnnual incidence of VTE in cancer patients ≈ 1/250patients ≈ 1/250 ► Of all cancer patients:Of all cancer patients: ● 15% will have symptomatic VTE15% will have symptomatic VTE ● As many as 50% have VTE at autopsyAs many as 50% have VTE at autopsy ► Compared to patients without cancer:Compared to patients without cancer: ● Higher risk of first and recurrent VTEHigher risk of first and recurrent VTE ● Higher risk of bleeding on anticoagulantsHigher risk of bleeding on anticoagulants ● Higher risk of dyingHigher risk of dying Lee AY, Levine MN.Lee AY, Levine MN. CirculationCirculation. 2003;107:23 Suppl 1:I17-I21. 2003;107:23 Suppl 1:I17-I21
    57. 57. 1.1. Ambrus JL et al.Ambrus JL et al. J MedJ Med. 1975;6:61-64. 1975;6:61-64 2.2. Donati MB.Donati MB. HaemostasisHaemostasis. 1994;24:128-131. 1994;24:128-131 3.3. Johnson MJ et al.Johnson MJ et al. Clin Lab HaemClin Lab Haem. 1999;21:51-54. 1999;21:51-54 4.4. Prandoni P et al.Prandoni P et al. Ann Intern MedAnn Intern Med. 1996;125:1-7. 1996;125:1-7 DVT and PE in CancerDVT and PE in Cancer Facts, Findings, and Natural HistoryFacts, Findings, and Natural History ► VTE is the second leading cause of deathVTE is the second leading cause of death inin hospitalized cancer patientshospitalized cancer patients1,21,2 ► The risk of VTE in cancer patients undergoingThe risk of VTE in cancer patients undergoing surgery issurgery is 3- to 5-fold higher3- to 5-fold higher than those withoutthan those without cancercancer22 ► Up toUp to 50% of cancer patients50% of cancer patients may have evidence ofmay have evidence of asymptomatic DVT/PEasymptomatic DVT/PE33 ► Cancer patients with symptomatic DVT exhibit aCancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists forhigh risk for recurrent DVT/PE that persists for many yearsmany years44
    58. 58. Clinical Features of VTE in CancerClinical Features of VTE in Cancer ► VTE has significant negative impact onVTE has significant negative impact on quality of lifequality of life ► VTE may be the presenting sign of occultVTE may be the presenting sign of occult malignancymalignancy • 10% with idiopathic VTE develop cancer10% with idiopathic VTE develop cancer within 2 yearswithin 2 years • 20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE • 25% have bilateral DVT25% have bilateral DVT BuraBura et. al.,et. al., J Thromb HaemostJ Thromb Haemost 2004;2:445-512004;2:445-51
    59. 59. Thrombosis and SurvivalThrombosis and Survival Likelihood of Death After HospitalizationLikelihood of Death After Hospitalization 00 2020 4040 6060 8080 100100 120120140 160 180140 160 180 0.000.00 0.200.20 0.400.40 1.001.00 0.800.80 0.600.60 DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease Malignant DiseaseMalignant Disease DVT/PE OnlyDVT/PE Only Nonmalignant DiseaseNonmalignant Disease Number of DaysNumber of Days ProbabilityofProbabilityof DeathDeath Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285
    60. 60. Hospital Mortality With or Without VTEHospital Mortality With or Without VTE Khorana, JCO, 2006Khorana, JCO, 2006 7.98 10.59 8.67 14.85 16.13 16.41 0 2 4 6 8 10 12 14 16 18 All Non-metastatic Metastatic No VTE VTE Mortality(%)Mortality(%) N=66,016 N=20,591 N=17,360
    61. 61. Trends in VTE in Hospitalized Cancer PatientsTrends in VTE in Hospitalized Cancer Patients VTE- patients on chemotherapyVTE- patients on chemotherapy VTE-all patientsVTE-all patients DVT-all patientsDVT-all patients PE-all patientsPE-all patients 0.00.0 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.0 4.54.5 5.05.0 5.55.5 6.06.0 6.56.5 7.07.0 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003 RateofVTE(%)RateofVTE(%) P<0.0001P<0.0001 Khorana AA et al.Khorana AA et al. Cancer.Cancer. 2007.2007.
    62. 62. Thrombosis Risk In CancerThrombosis Risk In Cancer Primary ProphylaxisPrimary Prophylaxis ► Medical InpatientsMedical Inpatients ► SurgerySurgery ► RadiotherapyRadiotherapy ► Central Venous CathetersCentral Venous Catheters
    63. 63. Risk Factors for Cancer-Associated VTERisk Factors for Cancer-Associated VTE ► CancerCancer ● TypeType • Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung • Women: breast, ovary, lungWomen: breast, ovary, lung ● StageStage ► TreatmentsTreatments ● SurgerySurgery • 10-20% proximal DVT10-20% proximal DVT • 4-10% clinically evident PE4-10% clinically evident PE • 0.2-5% fatal PE0.2-5% fatal PE ● Systemic therapySystemic therapy ● Central venous cathetersCentral venous catheters (~4% generate clinically(~4% generate clinically relevant VTE)relevant VTE) ► PatientPatient ● Prior VTEPrior VTE ● Co-morbitiesCo-morbities ● Genetic backgroudGenetic backgroud
    64. 64. VTE Risk And Cancer TypeVTE Risk And Cancer Type “Solid And Liquid Malignancies”“Solid And Liquid Malignancies” Stein PD, et al. Am J Med 2006; 119: 60-68Stein PD, et al. Am J Med 2006; 119: 60-68 RelativeRiskofVTEinRelativeRiskofVTEin CancerPatientsCancerPatients PancreasPancreas BrainBrain MyeloprolMyeloprol StomachStomach LymphomaLymphoma UterusUterus LungLung EsophagusEsophagus ProstateProstate RectalRectal KidneyKidney ColonColon OvaryOvary LiverLiver LeukemiaLeukemia BreastBreast CervixCervix BladderBladder 4.54.5 44 3.53.5 33 2.52.5 22 1.51.5 11 0.50.5 Relative Risk of VTE Ranged From 1.02 to 4.34Relative Risk of VTE Ranged From 1.02 to 4.34
    65. 65. Medical InpatientsMedical Inpatients Cancer and ThrombosisCancer and Thrombosis
    66. 66. Thromboembolism in HospitalizedThromboembolism in Hospitalized Neutropenic Cancer PatientsNeutropenic Cancer Patients ► Retrospective cohort study of discharges usingRetrospective cohort study of discharges using the University Health System Consortiumthe University Health System Consortium ► 66,106 adult neutropenic cancer patients66,106 adult neutropenic cancer patients between 1995 and 2002 at 115 centersbetween 1995 and 2002 at 115 centers Khorana, JCO, 2006Khorana, JCO, 2006
    67. 67. Neutropenic Patients: ResultsNeutropenic Patients: Results ► 8% had thrombosis8% had thrombosis ► 5.4% venous and 1.5% arterial in 15.4% venous and 1.5% arterial in 1stst hospitalizationhospitalization ► Predictors of thrombosisPredictors of thrombosis ● Age over 55Age over 55 ● Site (lung, GI, gynecologic, brain)Site (lung, GI, gynecologic, brain) ● Comorbidities (infection, pulmonary and renalComorbidities (infection, pulmonary and renal disease, obesity)disease, obesity) Khorana, JCO, 2006Khorana, JCO, 2006
    68. 68. Predictors of VTE inPredictors of VTE in Hospitalized Cancer PatientsHospitalized Cancer Patients CharacteristicCharacteristic OROR PP ValueValue Site of CancerSite of Cancer LungLung StomachStomach PancreasPancreas Endometrium/cervixEndometrium/cervix BrainBrain 1.31.3 1.61.6 2.82.8 22 2.22.2 <0.001<0.001 0.00350.0035 <0.001<0.001 <0.001<0.001 <0.001<0.001 AgeAge ≥≥65 y65 y 1.11.1 0.0050.005 Arterial thromboembolismArterial thromboembolism 1.41.4 0.0080.008 Comorbidities (lung/renal disease,Comorbidities (lung/renal disease, infection, obesity)infection, obesity) 1.3-1.61.3-1.6 <0.001<0.001 Khorana AA et al.Khorana AA et al. J Clin Oncol.J Clin Oncol. 2006;24:484-490.2006;24:484-490.
    69. 69. PharmacologicPharmacologic (Prophylaxis & Treatment)(Prophylaxis & Treatment) Low MolecularLow Molecular Weight HeparinWeight Heparin (LMWH)(LMWH) NonpharmacologicNonpharmacologic (Prophylaxis)(Prophylaxis) UnfractionatedUnfractionated Heparin (UH)Heparin (UH) OralOral AnticoagulantsAnticoagulants ElasticElastic StockingsStockings InferiorInferior Vena CavaVena Cava FilterFilter IntermittentIntermittent PneumaticPneumatic CompressionCompression Antithrombotic Therapy: ChoicesAntithrombotic Therapy: Choices New Agents: e.g.New Agents: e.g. Fondaparinux,Fondaparinux, Direct anti-Xa inhibitors,Direct anti-Xa inhibitors, Direct anti-IIa, etc.?Direct anti-IIa, etc.?
    70. 70. Prophylaxis Studies in Medical PatientsProphylaxis Studies in Medical Patients Francis, NEJM, 2007Francis, NEJM, 2007 14.9 5 10.5 5.5 2.8 5.6 0 5 10 15 20 Placebo EnoxaparinPlacebo Enoxaparin MEDENOX TrialMEDENOX Trial Placebo DalteparinPlacebo Dalteparin PREVENTPREVENT Placebo FondaparinuxPlacebo Fondaparinux ARTEMISARTEMIS RateofVTE(%)RateofVTE(%) RelativeRelative riskrisk reductionreduction 63%63% RelativeRelative riskrisk reductionreduction 44%44% RelativeRelative riskrisk reductionreduction 47%47%
    71. 71. ASCO GuidelinesASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXISVTE PROPHYLAXIS?? Recommendation.Recommendation. Hospitalized patients with cancerHospitalized patients with cancer should be considered candidates for VTE prophylaxisshould be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or otherwith anticoagulants in the absence of bleeding or other contraindications to anticoagulation.contraindications to anticoagulation. Lyman, JCO, 2007Lyman, JCO, 2007
    72. 72. Surgical PatientsSurgical Patients Cancer and ThrombosisCancer and Thrombosis
    73. 73. ► Cancer patients haveCancer patients have 2-fold risk of post-operative DVT/PE2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxisand >3-fold risk of fatal PE despite prophylaxis:: Kakkar AK, et al.Kakkar AK, et al. Thromb HaemostThromb Haemost 2001; 86 (suppl 1): OC17322001; 86 (suppl 1): OC1732 Incidence of VTE in Surgical PatientsIncidence of VTE in Surgical Patients No CancerNo Cancer N=16,954N=16,954 CancerCancer N=6124N=6124 P-valueP-value Post-op VTEPost-op VTE 0.61%0.61% 1.26%1.26% <0.0001<0.0001 Non-fatal PENon-fatal PE 0.27%0.27% 0.54%0.54% <0.0003<0.0003 Autopsy PEAutopsy PE 0.11%0.11% 0.41%0.41% <0.0001<0.0001 DeathDeath 0.71%0.71% 3.14%3.14% <0.0001<0.0001
    74. 74. Natural History of VTE in Cancer Surgery:Natural History of VTE in Cancer Surgery: The @RISTOS RegistryThe @RISTOS Registry ► Web-Based Registry of Cancer SurgeryWeb-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patientsTracked 30-day incidence of VTE in 2373 patients Type of surgeryType of surgery •• 52% General52% General •• 29% Urological29% Urological •• 19% Gynecologic19% Gynecologic 82% received in-hospital thromboprophylaxis82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis31% received post-discharge thromboprophylaxis FindingsFindings ► 2.1% incidence of clinically overt VTE (0.8% fatal)2.1% incidence of clinically overt VTE (0.8% fatal) ► Most events occur after hospital dischargeMost events occur after hospital discharge ► Most common cause of 30-day post-op deathMost common cause of 30-day post-op death Agnelli, abstract OC191, ISTH 2003Agnelli, abstract OC191, ISTH 2003
    75. 75. LMWH vs. UFHLMWH vs. UFH ► Abdominal or pelvic surgery for cancer (mostly colorectal)Abdominal or pelvic surgery for cancer (mostly colorectal) ► LMWH once daily vs. UFH tid for 7–10 days post-opLMWH once daily vs. UFH tid for 7–10 days post-op ► DVT on venography at day 7–10 and symptomatic VTEDVT on venography at day 7–10 and symptomatic VTE 1. ENOXACAN Study Group.1. ENOXACAN Study Group. Br J SurgBr J Surg 1997;84:1099–1031997;84:1099–103 2. McLeod R, et al.2. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-4442001;233:438-444 Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients StudyStudy NN DesignDesign RegimensRegimens ENOXACANENOXACAN 11 631631 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH Canadian ColorectalCanadian Colorectal DVT ProphylaxisDVT Prophylaxis 22 475475 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH
    76. 76. Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients 0% 5% 10% 15% 20% UFH 5000 U tid enoxaparin 40 mg VTE Major Bleeding IncidenceofOutcomeEvent ENOXACANENOXACAN14.7%14.7% 2.9% 4.1%2.9% 4.1% 18.2% N=319N=319 N=312N=312 ENOXACAN Study Group. Br J Surg 1997;84:1099–103 P>0.05P>0.05
    77. 77. 0% 5% 10% 15% 20% UFH 5000 U tid enoxaparin 40 mg CanadianCanadian Colorectal DVTColorectal DVT Prophylaxis TrialProphylaxis Trial 13.9%13.9% 1.5% 2.7%1.5% 2.7% 16.9%16.9% N=234N=234 N=241N=241 McLeod R, et al.McLeod R, et al. Ann SurgAnn Surg 2001;233:438-4442001;233:438-444 P=0.052P=0.052 IncidenceofOutcomeEvent VTEVTE Major BleedingMajor Bleeding (Cancer) (All)(Cancer) (All) Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients
    78. 78. Extended prophylaxisExtended prophylaxis ► Abdominal or pelvic surgery for cancerAbdominal or pelvic surgery for cancer ► LMWH for ~ 7 days vs. 28 days post-opLMWH for ~ 7 days vs. 28 days post-op ► Routine bilateral venography at ~day 28Routine bilateral venography at ~day 28 1. Bergqvist D, et al. (for the ENOXACAN II investigators)1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J MedN Engl J Med 2002;346:975-9802002;346:975-980 2. Rasmussen M, et al (FAME)2. Rasmussen M, et al (FAME) BloodBlood 2003;102:56a2003;102:56a Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients StudyStudy NN DesignDesign RegimensRegimens ENOXACAN IIENOXACAN II 332332 Double-blindDouble-blind Enoxaparin vs. placeboEnoxaparin vs. placebo FAMEFAME (subgroup)(subgroup) 198198 Open-labelOpen-label Dalteparin vs. no prophylaxisDalteparin vs. no prophylaxis
    79. 79. 0% 5% 10% 15% placebo enoxaparin 40 mg VTE Prox Any Major DVT Bleeding Bleeding P=0.02 5.1% 1.8% Bergqvist D, et al. (for the ENOXACAN II investigators)Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J MedN Engl J Med 2002;346:975-9802002;346:975-980 ENOXACAN IIENOXACAN II IncidenceofOutcomeEvent N=167 N=165 0% 0.4% 12.0% 4.8% NNT = 140.6% 3.6% Extended Prophylaxis inExtended Prophylaxis in Surgical PatientsSurgical Patients
    80. 80. ► A multicenter, prospective, assessor-blinded, open-label,A multicenter, prospective, assessor-blinded, open-label, randomized trial:randomized trial: Dalteparin administered for 28 daysDalteparin administered for 28 days after major abdominal surgeryafter major abdominal surgery compared to 7 days ofcompared to 7 days of treatmenttreatment ► RESULTS:RESULTS: CumulativeCumulative incidence of VTE was reducedincidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3%patients) to 7.3% after prolonged thromboprophylaxisafter prolonged thromboprophylaxis (12/165) ((12/165) (relative risk reduction 55%;relative risk reduction 55%; 95% confidence95% confidence interval 15-76; P=0.012).interval 15-76; P=0.012). ► CONCLUSIONS:CONCLUSIONS: 4-week administration of dalteparin,4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTEsignificantly reduces the rate of VTE, without increasing, without increasing the risk of bleeding, compared with 1 week ofthe risk of bleeding, compared with 1 week of thromboprophylaxis.thromboprophylaxis. Major Abdominal Surgery: FAME Investigators—Major Abdominal Surgery: FAME Investigators— Dalteparin ExtendedDalteparin Extended Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
    81. 81. ASCO Guidelines: VTE ProphylaxisASCO Guidelines: VTE Prophylaxis ► All patients undergoing major surgical interventionAll patients undergoing major surgical intervention for malignant disease should be considered forfor malignant disease should be considered for prophylaxis.prophylaxis. ► Patients undergoing laparotomy, laparoscopy, orPatients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receivethoracotomy lasting > 30 min should receive pharmacologic prophylaxis.pharmacologic prophylaxis. ► Prophylaxis should be continued at least 7 – 10Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoingweeks may be considered in patients undergoing major surgery for cancer with high-risk features.major surgery for cancer with high-risk features. Lyman, JCO, 2007Lyman, JCO, 2007
    82. 82. Thrombosis is a potential complication of centralThrombosis is a potential complication of central venous catheters, including these events:venous catheters, including these events: –Fibrin sheath formationFibrin sheath formation –Superficial phlebitisSuperficial phlebitis –Ball-valve clotBall-valve clot –Deep vein thrombosis (DVT)Deep vein thrombosis (DVT) •• Incidence up to 60% from historical dataIncidence up to 60% from historical data •• ACCP guidelines recommended routine prophylaxisACCP guidelines recommended routine prophylaxis with low dose warfarin or LMWHwith low dose warfarin or LMWH Central Venous CathetersCentral Venous Catheters Geerts W, et al.Geerts W, et al. ChestChest 2001;119:132S-175S2001;119:132S-175S
    83. 83. Placebo-Controlled TrialsPlacebo-Controlled Trials StudyStudy RegimenRegimen NN CRT (%)CRT (%) Reichardt*Reichardt* 20022002 Dalteparin 5000 U odDalteparin 5000 U od placeboplacebo 285285 140140 11 (3.7)11 (3.7) 5 (3.4)5 (3.4) Couban*Couban* 20022002 Warfarin 1mg odWarfarin 1mg od placeboplacebo 130130 125125 6 (4.6)6 (4.6) 5 (4.0)5 (4.0) ETHICSETHICS†† 20042004 Enoxaparin 40 mg odEnoxaparin 40 mg od placeboplacebo 155155 155155 22 (14.2)22 (14.2) 28 (18.1)28 (18.1) ** symptomatic outcomessymptomatic outcomes;; †† routine venography at 6 weeksroutine venography at 6 weeks Prophylaxis for Venous CathetersProphylaxis for Venous Catheters Reichardt P, et al.Reichardt P, et al. Proc ASCOProc ASCO 2002;21:369a; Couban S, et al,2002;21:369a; Couban S, et al, BloodBlood 2002;100:703a; Agnelli G, et al.2002;100:703a; Agnelli G, et al. Proc ASCOProc ASCO 2004;23:7302004;23:730
    84. 84. Tolerability of Low-Dose WarfarinTolerability of Low-Dose Warfarin ► 95 cancer patients receiving FU-based infusion95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailychemotherapy and 1 mg warfarin daily ► INR measured at baseline and four time pointsINR measured at baseline and four time points ► 10% of all recorded INRs >1.510% of all recorded INRs >1.5 ► Patients with elevated INRPatients with elevated INR 2.0–2.92.0–2.9 6%6% 3.0–4.93.0–4.9 19%19% >5.0>5.0 7%7% Central Venous Catheters: WarfarinCentral Venous Catheters: Warfarin Masci et al. J Clin Oncol. 2003;21:736-739
    85. 85. SummarySummary ► Recent studies demonstrate a lowRecent studies demonstrate a low incidence of symptomatic catheter-relatedincidence of symptomatic catheter-related thrombosis (~4%)thrombosis (~4%) ► Routine prophylaxis isRoutine prophylaxis is not warrantednot warranted toto prevent catheter-related thrombosis, butprevent catheter-related thrombosis, but catheter patency rates/infections have notcatheter patency rates/infections have not been studiedbeen studied ► Low-dose LMWH and fixed-dose warfarinLow-dose LMWH and fixed-dose warfarin have not been shown to be effective forhave not been shown to be effective for preventing symptomatic and asymptomaticpreventing symptomatic and asymptomatic thrombosisthrombosis Prophylaxis for Central VenousProphylaxis for Central Venous Access DevicesAccess Devices
    86. 86. 77thth ACCP Consensus GuidelinesACCP Consensus Guidelines Geerts W, et al.Geerts W, et al. ChestChest 2004; 126: 338S-400S2004; 126: 338S-400S No routine prophylaxis to preventNo routine prophylaxis to prevent thrombosis secondary to central venousthrombosis secondary to central venous catheters, including LMWH (2B) andcatheters, including LMWH (2B) and fixed-dose warfarin (1B)fixed-dose warfarin (1B)
    87. 87. Primary Prophylaxis in Cancer RadiotherapyPrimary Prophylaxis in Cancer Radiotherapy The Ambulatory PatientThe Ambulatory Patient ► No recommendations from ACCPNo recommendations from ACCP ► No data from randomized trials (RCTs)No data from randomized trials (RCTs) ► Weak data from observational studies inWeak data from observational studies in high risk tumors (e.g. brain tumors; mucin-high risk tumors (e.g. brain tumors; mucin- secreting adenocarcinomas: Colorectal,secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian)pancreatic, lung, renal cell, ovarian) ► Recommendations extrapolated fromRecommendations extrapolated from other groups of patients if additional riskother groups of patients if additional risk factors present (e.g. hemiparesis in brainfactors present (e.g. hemiparesis in brain tumors, etc.)tumors, etc.)
    88. 88. Ambulatory Chemotherapy PatientsAmbulatory Chemotherapy Patients Cancer and ThrombosisCancer and Thrombosis
    89. 89. Risk Factors for VTE inRisk Factors for VTE in Medical Oncology PatientsMedical Oncology Patients ► Tumor typeTumor type ● Ovary, brain, pancreas, lung, colonOvary, brain, pancreas, lung, colon ► Stage, grade, and extent of cancerStage, grade, and extent of cancer ● Metastatic disease, venous stasis due toMetastatic disease, venous stasis due to bulky diseasebulky disease ► Type of antineoplastic treatmentType of antineoplastic treatment ● Multiagent regimens, hormones,Multiagent regimens, hormones, anti-VEGF, radiationanti-VEGF, radiation ► Miscellaneous VTE risk factorsMiscellaneous VTE risk factors ● Previous VTE,Previous VTE, hospitalization, immobility,hospitalization, immobility, infection, thrombophiliainfection, thrombophilia
    90. 90. Independent Risk Factors for DVT/PEIndependent Risk Factors for DVT/PE Risk Factor/CharacteristicRisk Factor/Characteristic O.R.O.R. Recent surgery with institutionalizationRecent surgery with institutionalization 21.7221.72 TraumaTrauma 12.6912.69 Institutionalization without recent surgeryInstitutionalization without recent surgery 7.987.98 Malignancy with chemotherapyMalignancy with chemotherapy 6.536.53 Prior CVAD or pacemakerPrior CVAD or pacemaker 5.555.55 Prior superficial vein thrombosisPrior superficial vein thrombosis 4.324.32 Malignancy without chemotherapyMalignancy without chemotherapy 4.054.05 Neurologic disease w/ extremity paresisNeurologic disease w/ extremity paresis 3.043.04 Serious liver diseaseSerious liver disease 0.100.10 Heit JA et al.Heit JA et al. Thromb HaemostThromb Haemost. 2001;86:452-463. 2001;86:452-463
    91. 91. VTE Incidence In Various TumorsVTE Incidence In Various Tumors Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Oncology SettingOncology Setting VTEVTE IncidenceIncidence Breast cancer (Stage I & II) w/o further treatmentBreast cancer (Stage I & II) w/o further treatment 0.2%0.2% Breast cancer (Stage I & II) w/ chemoBreast cancer (Stage I & II) w/ chemo 2%2% Breast cancer (Stage IV) w/ chemoBreast cancer (Stage IV) w/ chemo 8%8% Non-Hodgkin’s lymphomas w/ chemoNon-Hodgkin’s lymphomas w/ chemo 3%3% Hodgkin’s disease w/ chemoHodgkin’s disease w/ chemo 6%6% Advanced cancer (1-year survival=12%)Advanced cancer (1-year survival=12%) 9%9% High-grade gliomaHigh-grade glioma 26%26% Multiple myeloma (thalidomide + chemo)Multiple myeloma (thalidomide + chemo) 28%28% Renal cell carcinomaRenal cell carcinoma 43%43% Solid tumors (anti-VEGF + chemo)Solid tumors (anti-VEGF + chemo) 47%47% Wilms tumor (cavoatrial extension)Wilms tumor (cavoatrial extension) 4%4%
    92. 92. PrimaryPrimary VTE ProphylaxisVTE Prophylaxis ► Recommended for hospitalizedRecommended for hospitalized cancer patientscancer patients ► Not recommended or generally usedNot recommended or generally used for outpatientsfor outpatients ● Very little dataVery little data ● HeterogeneousHeterogeneous Need for risk stratificationNeed for risk stratification
    93. 93. Ambulatory Cancer plus ChemotherapyAmbulatory Cancer plus Chemotherapy Study MethodsStudy Methods ► Prospective observational study ofProspective observational study of ambulatory cancer patients initiating a newambulatory cancer patients initiating a new chemotherapy regimen, and followed for achemotherapy regimen, and followed for a maximum of 4 cyclesmaximum of 4 cycles ► 115 U.S. centers participated115 U.S. centers participated ► Patients enrolled between March, 2002 andPatients enrolled between March, 2002 and August, 2004 who had completed at leastAugust, 2004 who had completed at least one cycle of chemotherapy were included inone cycle of chemotherapy were included in this analysisthis analysis Khorana, Cancer, 2005Khorana, Cancer, 2005
    94. 94. Ambulatory Cancer plus ChemotherapyAmbulatory Cancer plus Chemotherapy ► VTE events were recorded during mid-cycle or new-cycleVTE events were recorded during mid-cycle or new-cycle visitsvisits ► Symptomatic VTE was a clinical diagnosis made by theSymptomatic VTE was a clinical diagnosis made by the treating cliniciantreating clinician ► Statistical analysisStatistical analysis ● Odds ratios to estimate relative riskOdds ratios to estimate relative risk ● Multivariate logistic regression to adjust for other risk factorsMultivariate logistic regression to adjust for other risk factors Khorana, Cancer, 2005Khorana, Cancer, 2005 Study MethodsStudy Methods
    95. 95. Patient CharacteristicsPatient Characteristics CharacteristicCharacteristic No. (%)No. (%) All patientsAll patients 3,1963,196 AgeAge >> 6565 1,243 (39)1,243 (39) FemaleFemale 2,136 (67)2,136 (67) Stage IVStage IV 1,150 (37)1,150 (37) Performance status 0-1Performance status 0-1 2,912 (91)2,912 (91) Pre-chemotherapy platelet countPre-chemotherapy platelet count >> 350,000/mm350,000/mm33 691 (22)691 (22) Khorana, Cancer, 2005Khorana, Cancer, 2005
    96. 96. Site of CancerSite of Cancer No. (%)No. (%) All patientsAll patients 3,1963,196 BreastBreast 1,137 (36)1,137 (36) LungLung 612 (19)612 (19) ColonColon 353 (11)353 (11) OvaryOvary 225 (7)225 (7) Upper GIUpper GI 91 (3)91 (3) Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma 287 (9)287 (9) Hodgkin’s diseaseHodgkin’s disease 53 (2)53 (2) OthersOthers 438 (14)438 (14) Patient Characteristics (2)Patient Characteristics (2) Khorana, Cancer, 2005Khorana, Cancer, 2005
    97. 97. Incidence of VTEIncidence of VTE VTE / 2.4 monthsVTE / 2.4 months VTE/monthVTE/month VTE /cycleVTE /cycle Cumulative rateCumulative rate (95% CI)(95% CI) 1.93%1.93% 0.8%0.8% 0.7%0.7% 2.2% (1.7-2.8)2.2% (1.7-2.8) 0.0%0.0% 0.5%0.5% 1.0%1.0% 1.5%1.5% 2.0%2.0% 2.5%2.5% 3.0%3.0% BaselineBaseline Cycle 1Cycle 1 Cycle 2Cycle 2 Cycle 3Cycle 3 RateofVTE(%)RateofVTE(%) Khorana, Cancer, 2005Khorana, Cancer, 2005
    98. 98. Risk Factors: Site of CancerRisk Factors: Site of Cancer 00 22 44 66 88 1010 1212 Allpatients Allpatients Breast Breast C olon C olon Lung Lung U pperG I U pperG IH odgkin’s H odgkin’s N H L N H L O thers O thers Site of CancerSite of Cancer VTE(%)/2.4monthsVTE(%)/2.4months Khorana, Cancer, 2005Khorana, Cancer, 2005
    99. 99. Incidence of Venous Thromboembolism ByIncidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet CountQuartiles of Pre-chemotherapy Platelet Count p for trend=0.005p for trend=0.005 0.0%0.0% 0.5%0.5% 1.0%1.0% 1.5%1.5% 2.0%2.0% 2.5%2.5% 3.0%3.0% 3.5%3.5% 4.0%4.0% 4.5%4.5% 5.0%5.0% <217<217 217-270217-270 270-337270-337 >337>337 Pre-chemotherapy Platelet Count/mmPre-chemotherapy Platelet Count/mm 33 (x1000)(x1000) IncidenceOfVTEOver2.4IncidenceOfVTEOver2.4 Months(%)Months(%) Khorana, Cancer, 2005Khorana, Cancer, 2005
    100. 100. Risk Factors: Multivariate AnalysisRisk Factors: Multivariate Analysis CharacteristicCharacteristic OROR P valueP value Site of CancerSite of Cancer Upper GIUpper GI LungLung LymphomaLymphoma 3.883.88 1.861.86 1.51.5 0.030.03 0.00760.0076 0.050.05 0.320.32 Pre-chemotherapy platelet countPre-chemotherapy platelet count >> 350,000/mm350,000/mm33 2.812.81 0.00020.0002 Hgb < 10g/dL or use of red cellHgb < 10g/dL or use of red cell growth factorgrowth factor 1.831.83 0.030.03 Use of white cell growth factor in high-Use of white cell growth factor in high- risk sitesrisk sites 2.092.09 0.0080.008 Khorana, Cancer, 2005Khorana, Cancer, 2005
    101. 101. Predictive ModelPredictive Model Patient CharacteristicPatient Characteristic ScoreScore Site of CancerSite of Cancer Very high risk (stomach, pancreas)Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GUHigh risk (lung, lymphoma, gynecologic, GU excluding prostate)excluding prostate) 22 11 Platelet countPlatelet count >> 350,000/mm350,000/mm33 11 Hgb < 10g/dL or use of ESAHgb < 10g/dL or use of ESA 11 Leukocyte count > 11,000/mmLeukocyte count > 11,000/mm33 11 BMIBMI >> 3535 11 Khorana AA et al.Khorana AA et al. JTHJTH Suppl Abs O-T-002Suppl Abs O-T-002
    102. 102. Risk ScoreRisk Score 00 11 22 33 44 NN 1,3521,352 974974 476476 160160 3333 VTE(%) /2.4 mo.sVTE(%) /2.4 mo.s 0.80.8 1.81.8 2.72.7 6.36.3 13.213.2 IncidenceofVTEOver2.4MonthsIncidenceofVTEOver2.4Months 0%0% 2%2% 4%4% 6%6% 8%8% 10%10% 12%12% 14%14% 16%16% 18%18% 00 11 22 33 44 Actual IncidenceActual Incidence Estimated IncidenceEstimated Incidence 95 % Confidence Limits95 % Confidence Limits Predictive ModelPredictive Model
    103. 103. Predictive Model ValidationPredictive Model Validation RiskRisk Low (0) Intermediate(1-2) High(Low (0) Intermediate(1-2) High(>>3)3) 0%0% 1%1% 2%2% 3%3% 4%4% 5%5% 6%6% 7%7% 8%8% RateofVTEover2.5mos(%)RateofVTEover2.5mos(%) n=734n=734 n=1627n=1627 n=340n=340 0.8%0.8% 1.8%1.8% 7.1%7.1% Development cohortDevelopment cohort 0.3%0.3% 2.0%2.0% 6.7%6.7% Validation cohortValidation cohort n=374n=374 n=842n=842 n=149n=149 Khorana AA et al.Khorana AA et al. JTHJTH Suppl Abs O-T-002Suppl Abs O-T-002
    104. 104. VTE TreatmentVTE Treatment Cancer and ThrombosisCancer and Thrombosis
    105. 105. Vitamin K antagonist (INR 2.0 - 3.0)Vitamin K antagonist (INR 2.0 - 3.0) >> 3 months3 months LMWH or UFHLMWH or UFH 5 to 7 days5 to 7 daysInitial treatment Long-term therapy Standard Treatment of VTEStandard Treatment of VTE Can We Do Better Than This?Can We Do Better Than This?
    106. 106. Recurrent VTE in CancerRecurrent VTE in Cancer Recurrent VTERecurrent VTE Events per 100 patient yearsEvents per 100 patient years P valueP value MalignantMalignant Non- MalignantNon- Malignant 27.127.1 9.09.0 0.0030.003 Hutten et.al.Hutten et.al. J Clin OncolJ Clin Oncol 2000;18:30782000;18:3078 Subset Analysis of the Home Treatment StudiesSubset Analysis of the Home Treatment Studies (UH/VKA vs. LMWH/VKA)(UH/VKA vs. LMWH/VKA)
    107. 107. Recurrent VTE in CancerRecurrent VTE in Cancer Major BleedingMajor Bleeding Events per 100 patient yearsEvents per 100 patient years P-valueP-value MalignantMalignant Non-Non- malignantmalignant 13.313.3 2.12.1 0.0020.002 Hutten et.al.Hutten et.al. J Clin OncolJ Clin Oncol 2000;18:30782000;18:3078 Subset Analysis of the Home Treatment StudiesSubset Analysis of the Home Treatment Studies
    108. 108. Oral Anticoagulant TherapyOral Anticoagulant Therapy in Cancer Patients: Problematicin Cancer Patients: Problematic ► Warfarin therapy is complicated by:Warfarin therapy is complicated by: ● Difficulty maintaining tight therapeutic control, dueDifficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc.to anorexia, vomiting, drug interactions, etc. ● Frequent interruptions for thrombocytopenia andFrequent interruptions for thrombocytopenia and proceduresprocedures ● Difficulty in venous access for monitoringDifficulty in venous access for monitoring ● Increased risk of both recurrence and bleedingIncreased risk of both recurrence and bleeding ► Is it reasonable to substitute long-term LMWHIs it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?for warfarin ? When? How? Why?
    109. 109. CLOT: Landmark Cancer/VTE TrialCLOT: Landmark Cancer/VTE Trial CANCER PATIENTS WITHCANCER PATIENTS WITH ACUTE DVT or PEACUTE DVT or PE RandomizationRandomization DalteparinDalteparin DalteparinDalteparin Oral AnticoagulantOral Anticoagulant DalteparinDalteparin [N = 677][N = 677] ► Primary Endpoints:Primary Endpoints: Recurrent VTE and BleedingRecurrent VTE and Bleeding ► Secondary EndpointSecondary Endpoint:: SurvivalSurvival Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146
    110. 110. Landmark CLOT Cancer TrialLandmark CLOT Cancer Trial Reduction in Recurrent VTEReduction in Recurrent VTE 00 55 1010 1515 2020 2525 Days Post RandomizationDays Post Randomization 00 3030 6060 9090 120120 150150 180180 210210 ProbabilityofRecurrentVTE,%ProbabilityofRecurrentVTE,% Risk reduction = 52%Risk reduction = 52% pp-value = 0.0017-value = 0.0017 DalteparinDalteparin OACOAC Recurrent VTERecurrent VTE Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. N EnglN Engl J Med,J Med, 2003;349:1462003;349:146
    111. 111. DalteparinDalteparin N=338N=338 OACOAC N=335N=335 P-value*P-value* Major bleedMajor bleed 19 ( 5.6%)19 ( 5.6%) 12 ( 3.6%)12 ( 3.6%) 0.270.27 Any bleedAny bleed 46 (13.6%)46 (13.6%) 62 (18.5%)62 (18.5%) 0.0930.093 * Fisher’s exact test* Fisher’s exact test Bleeding Events in CLOTBleeding Events in CLOT Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146
    112. 112. Treatment of Cancer-Associated VTETreatment of Cancer-Associated VTE StudyStudy DesignDesign Length ofLength of TherapyTherapy (Months)(Months) NN RecurrentRecurrent VTEVTE (%)(%) MajorMajor BleedingBleeding (%)(%) DeathDeath (%)(%) CLOT TrialCLOT Trial (Lee 2003)(Lee 2003) DalteparinDalteparin OACOAC 66 336336 336336 99 1717 66 44 3939 4141 CANTHENOXCANTHENOX (Meyer 2002)(Meyer 2002) EnoxaparinEnoxaparin OACOAC 33 6767 7171 1111 2121 77 1616 1111 2323 LITELITE (Hull ISTH 2003)(Hull ISTH 2003) TinzaparinTinzaparin OACOAC 33 8080 8787 66 1111 66 88 2323 2222 ONCENOXONCENOX (Deitcher ISTH(Deitcher ISTH 2003)2003) Enox (Low)Enox (Low) Enox (High)Enox (High) OACOAC 66 3232 3636 3434 3.43.4 3.13.1 6.76.7 NS NS0.03 NS NS0.002 NS NS NR 0.09 0.030.09
    113. 113. Treatment and 2Treatment and 2° Prevention of VTE° Prevention of VTE in Cancer – Bottom Linein Cancer – Bottom Line ► New standard of care is LMWH at therapeutic dosesNew standard of care is LMWH at therapeutic doses for afor a minimum of 3-6 monthsminimum of 3-6 months (Grade 1A(Grade 1A recommendation—ACCP)recommendation—ACCP) ► NOTENOTE:: Dalteparin is only LMWH approved (May,Dalteparin is only LMWH approved (May, 2007) for both the2007) for both the treatment and secondarytreatment and secondary preventionprevention of VTE in cancerof VTE in cancer ► Oral anticoagulant therapy to follow for as long asOral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP)cancer is active (Grade 1C recommendation—ACCP) Buller et.al. Chest Suppl 2004;126:401S-428SBuller et.al. Chest Suppl 2004;126:401S-428S New DevelopmentNew Development
    114. 114. CLOT 12-month MortalityCLOT 12-month Mortality All PatientsAll Patients 00 1010 2020 3030 4040 5050 6060 7070 8080 9090 100100 00 3030 6060 9090 120120 180180 240240 300300 360360 DalteparinDalteparin OACOAC HR 0.94 P-value = 0.40HR 0.94 P-value = 0.40 Days Post RandomizationDays Post Randomization ProbabilityofSurvival,%ProbabilityofSurvival,% Lee A, et al. ASCO. 2003Lee A, et al. ASCO. 2003
    115. 115. 00 1010 2020 3030 4040 5050 6060 7070 8080 9090 100100 Days Post RandomizationDays Post Randomization 00 3030 6060 9090 120120 150150 180180 240240 300300 360360 ProbabilityofSurvival,%ProbabilityofSurvival,% OACOAC DalteparinDalteparin HR = 0.50 P-value = 0.03HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWHAnti-Tumor Effects of LMWH CLOT 12-month MortalityCLOT 12-month Mortality Lee A, et al. ASCO. 2003Lee A, et al. ASCO. 2003 Patients Without Metastases (N=150)Patients Without Metastases (N=150)
    116. 116. ► 84 patients randomized: CEV +/- LMWH (18 weeks)84 patients randomized: CEV +/- LMWH (18 weeks) ► Patients balanced for age, gender, stage, smoking history,Patients balanced for age, gender, stage, smoking history, ECOG performance statusECOG performance status LMWH for Small Cell Lung CancerLMWH for Small Cell Lung Cancer Turkish StudyTurkish Study Altinbas et al. J Thromb Haemost 2004;2:1266.Altinbas et al. J Thromb Haemost 2004;2:1266. ChemotherapyChemotherapy plus Dalteparinplus Dalteparin Chemo aloneChemo alone P-valueP-value 1-y overall survival, %1-y overall survival, % 51.351.3 29.529.5 0.010.01 2-y overall survival, %2-y overall survival, % 17.217.2 0.00.0 0.010.01 Median survival, mMedian survival, m 13.013.0 8.08.0 0.010.01 CEV = cyclophosphamide, epirubicin, vincristine;CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units dailyLMWH = Dalteparin, 5000 units daily
    117. 117. VTE Prophylaxis Is UnderusedVTE Prophylaxis Is Underused in Patients With Cancerin Patients With Cancer 5 89 38 33 42 52 0 10 20 30 40 50 60 70 80 90 100 FRONTLINE Surgical FRONTLINE: Medical Stratton Bratzler Rahim DVT FREE 1. Kakkar AK et al. Oncologist. 2003;8:381-388 2. Stratton MA et al. Arch Intern Med. 2000;160:334-340 3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 Cancer:Cancer: FRONTLINE SurveyFRONTLINE Survey11 —— 3891 Clinician3891 Clinician RespondentsRespondents RateofAppropriateProphylaxis,% Major Surgery2 Major Abdominothoracic Surgery (Elderly)3 Medical Inpatients4 Confirmed DVT (Inpatients)5 Cancer: Surgical Cancer: Medical 4. Rahim SA et al. Thromb Res. 2003;111:215-219 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
    118. 118. Venous Thromboembolism (VTE)Venous Thromboembolism (VTE) Prophylaxis in theProphylaxis in the Cancer Patient and BeyondCancer Patient and Beyond Guidelines and Implications for Clinical PracticeGuidelines and Implications for Clinical Practice John Fanikos, RPh, MBAJohn Fanikos, RPh, MBA Assistant Director of PharmacyAssistant Director of Pharmacy Brigham and Women’s HospitalBrigham and Women’s Hospital Assistant Clinical Professor of PharmacyAssistant Clinical Professor of Pharmacy Northeastern UniversityNortheastern University Massachusetts College of PharmacyMassachusetts College of Pharmacy Boston, MABoston, MA Clotting, Cancer, and Clinical StrategiesClotting, Cancer, and Clinical Strategies
    119. 119. Outline of PresentationOutline of Presentation ► Guidelines for VTE preventionGuidelines for VTE prevention ► Performance to datePerformance to date ► Opportunities for improvementOpportunities for improvement ► Guidelines for VTE TreatmentGuidelines for VTE Treatment ► Performance to datePerformance to date
    120. 120. • www.nccn.orgwww.nccn.org • NCCN Clinical Practice Guidelines inNCCN Clinical Practice Guidelines in Oncology™Oncology™ • “…“…The panel of experts includes medicalThe panel of experts includes medical and surgical oncologists, hematologists,and surgical oncologists, hematologists, cardiologists, internists, radiologists. And acardiologists, internists, radiologists. And a pharmacist.”pharmacist.” • www.asco.orgwww.asco.org •Recommendations for VTE Prophylaxis &Recommendations for VTE Prophylaxis & Treatment in Patients with CancerTreatment in Patients with Cancer
    121. 121. 2004 ACCP Recommendations2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that isCancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A)appropriate for their current risk state (Grade 1A) ● General, Gynecologic, Urologic SurgeryGeneral, Gynecologic, Urologic Surgery • Low Dose Unfractionated Heparin 5,000 units TIDLow Dose Unfractionated Heparin 5,000 units TID • LMWH > 3,400 units DailyLMWH > 3,400 units Daily – Dalteparin 5,000 unitsDalteparin 5,000 units – Enoxaparin 40 mgEnoxaparin 40 mg – Tinzaparin 4,500 unitsTinzaparin 4,500 units • GCS and/or IPCGCS and/or IPC Cancer patients with an acute medical illness receive prophylaxisCancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1A)that is appropriate for their current risk state (Grade 1A) • Low Dose Unfractionated HeparinLow Dose Unfractionated Heparin • LMWHLMWH Contraindication to anticoagulant prophylaxis (Grade 1C+)Contraindication to anticoagulant prophylaxis (Grade 1C+) • GCS or IPCGCS or IPC Geerts WH et al. Chest. 2004;126(suppl):338S-400S 1A is the highest possible grade Indicates that benefits outweigh risks, burdens, and costs, with consistent RCT level of evidence
    122. 122. NCCN Practice Guidelines in VTE DiseaseNCCN Practice Guidelines in VTE Disease At Risk Population Initial ProphylaxisAt Risk Population Initial Prophylaxis http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf ► Adult patientAdult patient ► Diagnosis orDiagnosis or clinicalclinical suspicion ofsuspicion of cancercancer ► InpatientInpatient Relative contra-Relative contra- indication toindication to anticoagulationanticoagulation treatmenttreatment Prophylactic anticoagulationProphylactic anticoagulation therapy (category 1)therapy (category 1) ++ sequentialsequential compression device (SCD)compression device (SCD) Mechanical prophylaxis (options)Mechanical prophylaxis (options) - SCD- SCD - Graduated compression stockings- Graduated compression stockings NONO YES YES RISK FACTOR ASSESSMENTRISK FACTOR ASSESSMENT ► AgeAge ► Prior VTE ► Familial thrombophilia ► Active cancer ► Trauma ► Major surgical procedures ► Acute or chronic medical illness requiring hospitalization or prolonged bed rest ► Central venous catheter/IV catheter ► Congestive heart failure ► Pregnancy ► Regional bulky lymphadenopathy with extrinsic vascular compression AGENTS ASSOCIATEDAGENTS ASSOCIATED WITH INCREASED RISKWITH INCREASED RISK ► ChemotherapyChemotherapy ► Exogenous estrogenExogenous estrogen compoundscompounds - HRT- HRT - Oral contraceptives- Oral contraceptives - Tamoxifen/Raloxifene- Tamoxifen/Raloxifene - Diethystilbestrol- Diethystilbestrol ► Thalidomide/lenalidomideThalidomide/lenalidomide Modifiable risk factors: Lifestyle,Modifiable risk factors: Lifestyle, smoking, tobacco, obesity,smoking, tobacco, obesity, activity level/exerciseactivity level/exercise ContinueContinue ProphylaxisProphylaxis AfterAfter Discharge ?Discharge ? ContinueContinue ProphylaxisProphylaxis AfterAfter Discharge ?Discharge ?
    123. 123. http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesNCCN Practice Guidelines in VTE Diseasein VTE Disease Inpatient Prophylactic Anticoagulation TherapyInpatient Prophylactic Anticoagulation Therapy ► LMWHLMWH - Dalteparin 5,000 units subcutaneous daily- Dalteparin 5,000 units subcutaneous daily - Enoxaparin 40 mg subcutaneous daily- Enoxaparin 40 mg subcutaneous daily - Tinzaparin 4,500 units (fixed dose) subcutaneous daily or- Tinzaparin 4,500 units (fixed dose) subcutaneous daily or 75 units/kg subcutaneous daily75 units/kg subcutaneous daily ► PentasaccharidePentasaccharide - Fondaparinux 2.5 mg subcutaneous daily- Fondaparinux 2.5 mg subcutaneous daily ► Unfractionated heparin 5,000 units subcutaneous 3 times dailyUnfractionated heparin 5,000 units subcutaneous 3 times daily
    124. 124. http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesNCCN Practice Guidelines in VTE Diseasein VTE Disease Relative Contraindications to Prophylactic orRelative Contraindications to Prophylactic or Therapeutic AnticoagulationTherapeutic Anticoagulation ► Recent CNS bleed, intracranial or spinal lesion at high risk for bleedingRecent CNS bleed, intracranial or spinal lesion at high risk for bleeding ► Active bleeding (major): more than 2 units transfused in 24 hoursActive bleeding (major): more than 2 units transfused in 24 hours ► Chronic, clinically significant measurable bleeding > 48 hoursChronic, clinically significant measurable bleeding > 48 hours ► Thrombocytopenia (platelets < 50,000/mcL)Thrombocytopenia (platelets < 50,000/mcL) ► Severe platelet dysfunction (uremia, medications, dysplasticSevere platelet dysfunction (uremia, medications, dysplastic hematopoiesis)hematopoiesis) ► Recent major operation at high risk for bleedingRecent major operation at high risk for bleeding ► Underlying coagulopathyUnderlying coagulopathy ► Clotting factor abnormalitiesClotting factor abnormalities - Elevated PT or aPTT (excluding lupus inhibitors)- Elevated PT or aPTT (excluding lupus inhibitors) - Spinal anesthesia/lumbar puncture- Spinal anesthesia/lumbar puncture ► High risk for fallsHigh risk for falls
    125. 125. ► Should hospitalized patients with cancerShould hospitalized patients with cancer receive anticoagulation for VTEreceive anticoagulation for VTE prophylaxis ?prophylaxis ? ● ““Hospitalized patients with cancer should beHospitalized patients with cancer should be considered candidates for VTE prophylaxis inconsidered candidates for VTE prophylaxis in the absence of bleeding or otherthe absence of bleeding or other contraindications to anticoagulation”contraindications to anticoagulation” Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
    126. 126. ► Should ambulatory patients with cancerShould ambulatory patients with cancer receive anticoagulation for VTEreceive anticoagulation for VTE prophylaxis during systemicprophylaxis during systemic chemotherapy?chemotherapy? ● ““Routine prophylaxis is not recommended.”Routine prophylaxis is not recommended.” ● ““Patients receiving thalidomide or lenalidomidePatients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at highwith chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.”risk for thrombosis and warrant prophylaxis.” Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
    127. 127. ► Should hospitalized patients with cancerShould hospitalized patients with cancer undergoing surgery receive perioperative VTEundergoing surgery receive perioperative VTE prophylaxis ?prophylaxis ? ● All patients should be considered forAll patients should be considered for thromboprophylaxis.thromboprophylaxis. ● Procedures greater than 30 minutes should receiveProcedures greater than 30 minutes should receive pharmacologic prophylaxis.pharmacologic prophylaxis. ● Mechanical methods should not be used asMechanical methods should not be used as monotherapy.monotherapy. ● Prophylaxis should continue for at least 7-10 daysProphylaxis should continue for at least 7-10 days post-op. Prolonged prophylaxis may be consideredpost-op. Prolonged prophylaxis may be considered for cancer with high risk features.for cancer with high risk features. Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
    128. 128. Compliance With ACCP VTECompliance With ACCP VTE Prophylaxis Guidelines Is PoorProphylaxis Guidelines Is Poor 9.9% 6.7% 35,124 62,012 0 5,000 10,000 70,000 Numberofpatients At risk for DVT/PE Received compliant care 15.3% 12.7% 52.4% 2324 9175 1388 Orthopedic Surgery At-risk Medical Conditions General Surgery Urologic Surgery Gynecologic Surgery Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient GroupCompliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group
    129. 129. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 Started LateStarted Late Started late &Started late & Ended EarlyEnded Early Ended EarlyEnded Early At-Risk MedicalAt-Risk Medical (n=5,994)(n=5,994) 1,347 (22.5)1,347 (22.5) 2,961 (49.4)2,961 (49.4) 1,686 (28.1)1,686 (28.1) Abdominal SurgeryAbdominal Surgery (n=3,240)(n=3,240) 824 (25.4)824 (25.4) 1,764 (54.4)1,764 (54.4) 652 (20.1)652 (20.1) Urologic surgeryUrologic surgery (n=158)(n=158) 18 (11.4)18 (11.4) 73 (46.2)73 (46.2) 67 (42.4)67 (42.4) Gynecologic surgeryGynecologic surgery (n=163)(n=163) 13 (8.0)13 (8.0) 43 (26.4)43 (26.4) 107 (65.6)107 (65.6) NeurosurgeryNeurosurgery (n=250)(n=250) 66 (26.4)66 (26.4) 125 (50.0)125 (50.0) 59 (23.6)59 (23.6) Reasons for Inadequate DurationReasons for Inadequate Duration of VTE Prophylaxisof VTE Prophylaxis
    130. 130. Odds Ratio Malignancy 0.40 Others 0.58 Infection 0.83 Bleeding Risk 0.91 Gender 0.92 Hospital Size 0.93 Age 1.00 LOS 1.05 Cardiovascular Disease 1.06 Internal Medicine 1.33 Respiratory 1.35 AMC 1.46 Duration of Immobility 1.60 VTE Risk Factors 1.78 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Effect Odds Ratio (95% CI) Predictors of the Use ofPredictors of the Use of ThromboprophylaxisThromboprophylaxis Kahn SR et Al. Thromb Res 2007; 119:145-155Kahn SR et Al. Thromb Res 2007; 119:145-155
    131. 131. Computer Reminder SystemComputer Reminder System ► Computer program linked to patient database to identifyComputer program linked to patient database to identify consecutive hospitalized patients at risk for VTEconsecutive hospitalized patients at risk for VTE ► Patients randomized to intervention group or control groupPatients randomized to intervention group or control group ► In the intervention group the physicians were alerted to the VTEIn the intervention group the physicians were alerted to the VTE risk and offered the option to order VTE prophylaxisrisk and offered the option to order VTE prophylaxis ► Point scale for VTE riskPoint scale for VTE risk ● Major riskMajor risk:: CancerCancer, prior VTE, hypercoagulability, prior VTE, hypercoagulability (3 points)(3 points) ● Intermediate riskIntermediate risk: Major surgery (2 points): Major surgery (2 points) ● Minor riskMinor risk: Advanced age, obesity, bedrest, HRT,: Advanced age, obesity, bedrest, HRT, use of oral contraceptives (1 point)use of oral contraceptives (1 point) ► VTE prophylaxis (VTE prophylaxis (graduated elastic stockingsgraduated elastic stockings, IPC, UFH,, IPC, UFH, LMWH, warfarin)LMWH, warfarin) Kucher N, et al. N Engl J Med. 2005;352:969-77Kucher N, et al. N Engl J Med. 2005;352:969-77
    132. 132. MD Computer AlertMD Computer Alert
    133. 133. Electronic Alerts to Prevent VTEElectronic Alerts to Prevent VTE 88 90 92 94 96 98 100 0 30 60 90 Freedomfrom DVTorPE(%) Number at risk Intervention group 1,255 977 900 853 Control group 1,251 876 893 839 Control groupControl group Intervention groupIntervention group P<0.001 Time (days) Kucher N, et al. N Engl J Med. 2005;352:969-77Kucher N, et al. N Engl J Med. 2005;352:969-77
    134. 134. Mechanical Thromboprophylaxis In Critically Ill Patients:Mechanical Thromboprophylaxis In Critically Ill Patients: Review And Meta-analysisReview And Meta-analysis RESULTSRESULTS: 21 relevant studies (5 randomized controlled trials, 13: 21 relevant studies (5 randomized controlled trials, 13 observational studies, and 3 surveys) were found. A total of 811 patientsobservational studies, and 3 surveys) were found. A total of 811 patients were randomized in the 5 randomized controlled trials; 3421 patientswere randomized in the 5 randomized controlled trials; 3421 patients participated in the observational studies.participated in the observational studies. Trauma patients only were enrolled in 4 randomized controlled trials and 4Trauma patients only were enrolled in 4 randomized controlled trials and 4 observational studies. Meta-analysis of 2 randomized controlled trials withobservational studies. Meta-analysis of 2 randomized controlled trials with similar populations and outcomes revealed that use of compression andsimilar populations and outcomes revealed that use of compression and pneumatic devices did not reduce the incidence of venouspneumatic devices did not reduce the incidence of venous thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90). A range of methodological issues, including bias and confounding variables,A range of methodological issues, including bias and confounding variables, make meaningful interpretation of the observational studies difficult.make meaningful interpretation of the observational studies difficult. CONCLUSIONSCONCLUSIONS: The role of mechanical approaches to: The role of mechanical approaches to thromboprophylaxis for intensive care patients remainsthromboprophylaxis for intensive care patients remains uncertainuncertain Limbus A et al. Am J Crit Care, 2006;15:402-10Limbus A et al. Am J Crit Care, 2006;15:402-10
    135. 135. Dahan et al, 1986 (41) 1/132 3/131 0.33 (0.03 to 3.14) Garlund at al, 1996 (35) 3/5776 12/5917 0.26 (0.07 to 0.91) Leizorovic et al, 2004 (23) 0/1829 2/1807 0.20 (0.01 to 4.11) Mahe et al, 2005 (22) 10/1230 17/1244 0.59 (0.27 to 1.29) Cohen at, 2006 (42) 0/321 5/323 0.09 (0.01 to 1.65) Total (95% CI) 0.38 (0.21 to 0.69) Total events 14 39 Dentali, F. et. al. Ann Intern Med 2007;146:278-288Dentali, F. et. al. Ann Intern Med 2007;146:278-288 Fatal Pulmonary Embolism DuringFatal Pulmonary Embolism During Anticoagulant ProphylaxisAnticoagulant Prophylaxis 0.001 0.01 0.1 1.0 10 100 1000 Favors Treatment Favors Placebo Study, Year (Reference) Prophylaxis n/n Placebo n/n RR Fixed (95% CI) RR Fixed (95% CI)
    136. 136. Unfractionated Heparin Prophylaxis:Unfractionated Heparin Prophylaxis: BID vs TID—What Works, What Doesn’t?BID vs TID—What Works, What Doesn’t? Meta-analysis: 12Meta-analysis: 12 RCTsRCTs ► DVT, PE, all VTE events, BleedingDVT, PE, all VTE events, Bleeding ► Proximal DVT plus PEProximal DVT plus PE ● BID VTE event rate:BID VTE event rate: 2.34 events per 1,0002.34 events per 1,000 patient dayspatient days ● TID event rate:TID event rate: 0.86 events per 1,0000.86 events per 1,000 patient dayspatient days P=0.05P=0.05 ► NNTNNT ● 676 hospital prophylaxis days676 hospital prophylaxis days with UFH TID to preventwith UFH TID to prevent ● 1 major bleed with 1,649 hospital1 major bleed with 1,649 hospital prophylaxis days of TID dosingprophylaxis days of TID dosing King CS et al. CHEST 2007;131:507-516King CS et al. CHEST 2007;131:507-516
    137. 137. Heparin, Low MolecularHeparin, Low Molecular Weight Heparin ProphylaxisWeight Heparin Prophylaxis Wein L et al.Wein L et al. Arch Intern Med.Arch Intern Med. 2007;167:1476-86.2007;167:1476-86. LMWH vs UFH DVT Risk Study Reduction (95% CI) W % Harenberg et al, 1990 0.70 (0.16-3.03) Turpie et al, 1992 0.29 (0.10-0.81) 1 Dumas et al, 1994 0.74 (0.38-1.43) 14.4 Bergmann & Neuhart 0.94 (0.39-2.26) et al, 1996 Harenberg et al, 1996 2.89 (0.30-27.71) Lechler et al, 1996 0.25 (0.03-2.23) 3.3 Hillbom et al, 2002 0.55 (0.31-0.98) 20.5 Kleber, et al 2003 0.77 (0.43-1.38) 19.4 Diener et al, 2006 0.76 (0.42-1.38) 18.9 Overall (95% CI) 0.68 (0.52-0.88)LMWH Better LMWH WorseLMWH Better LMWH Worse 0.1 1.0 100.1 1.0 10 Risk RatioRisk Ratio ►Meta-analysisMeta-analysis ►36 randomized36 randomized controlled trialscontrolled trials ►23,000 hospitalized23,000 hospitalized medical patientsmedical patients ►UFH 5,000 units TIDUFH 5,000 units TID is more effective inis more effective in preventing DVT thanpreventing DVT than UFH BIDUFH BID ►Low molecular weightLow molecular weight heparin is 33% moreheparin is 33% more effective thaneffective than unfractionated heparinunfractionated heparin in preventing DVTin preventing DVT ● RR for DVT 0.68RR for DVT 0.68 (p=0.004)(p=0.004)
    138. 138. BWH/DFCI PartnersBWH/DFCI Partners Cancer Care ExperienceCancer Care Experience Reasons for Non-Compliance 4 28 68 0 10 20 30 40 50 60 70 80 Off Floor Refused Unknown Percent Compliance with UFH TID 95 82 29 0 10 20 30 40 50 60 70 80 90 100 < 3 doses Day 1 < 3 Doses Day 2+ 4 doses Percent • Consecutive patients, < 60 daysConsecutive patients, < 60 days • 2 Nursing units2 Nursing units • LOS ranged from 3 days to 31 daysLOS ranged from 3 days to 31 days • Number of days where doses were omitted ranged fromNumber of days where doses were omitted ranged from 1 to 6 days1 to 6 days
    139. 139. VTE Incidence: More CommonVTE Incidence: More Common in the Outpatient Settingin the Outpatient Setting ► Medical records of residents (n=477,800)Medical records of residents (n=477,800) ► 587 VTE events (104 per 100,000 population)587 VTE events (104 per 100,000 population) ► 30 Day recurrence 4.8 %30 Day recurrence 4.8 % 25% 75% Inpatient Outpatient VTE Event Location 48% 49% 49% 50% 50% 51% 51% 52% Prophylaxis None Patients receiving prophylaxisPatients receiving prophylaxis during high risk periodsduring high risk periods Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777
    140. 140. DVT, PE Diagnosis and TreatmentDVT, PE Diagnosis and Treatment http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf

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