Ash Syllabus Cast 137

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CMEducation Resources, LLC New Frontiers and Evolving Paradigms in Cancer and Thrombosis
Agenda
Friday, December 3, 2010 Orange County Convention Centre Orlando, FL
TIME 6:00 6:30 p.m. LOCATION Conference Room: 109B SESSION Program Registration, Distribution of Program Materials to ASH Satellite Symposium Attendees New Frontiers and Evolving Paradigms in Cancer and Thrombosis: The Journey From Science to Strategy, From Bench to Bed Side Samuel Z. Goldhaber, MD Program Chairman The Complex Interface of Malignancy, Thrombosis, and Clinical End Points Frederick R. Rickles, MD Optimizing Risk Assessment and Management of Cancer Patients at Risk for Venous Thromboembolism (VTE): Reducing DVT Recurrence and Related Complications Craig Kessler, MD Risk Stratification Tools to Identify Patients For Primary and Secondary Prevention of VTE in Patients with Malignancy Alok A. Khorana, MD, FACP Program Chairmans Concluding Vision Statement: Current and Near Future Perspectives of VTE Management in the Setting of Malignancy Samuel Z. Goldhaber, MD Program Chairman Interactive Q & A Discussion Session
6:30 6:50 p.m.
Conference Room: 109B
6:50 7:15 p.m.
7:15 7:45 p.m.
7:45 8:15 p.m.
8:15 8:30 p.m.
8:30 8:45 p.m.
Faculty Roster
Samuel Z. Goldhaber, MD Program Chairman Senior Staff Physician, Director, VTE Research Group Brigham and Womens Hospital Professor of Medicine Harvard Medical School Boston, MA ______________________________________________________________________________ Frederick R. Rickles, MD Professor of Medicine The George Washington University Washington, DC
Craig Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Washington, DC ______________________________________________________________________________ Alok A. Khorana, MD, FACP Associate Professor Vice Chief James P. Wilmot Cancer Center University of Rochester Rochester, NY
LEARNING AND PROGRAM OBJECTIVES After participating in this program, physicians should be able to:
Apply current guidelines for pharmacologic prophylaxis of DVT issued by national professional organizations (ASH, ASCO, NCCN, ACCP, ASHP) in at risk patients with cancer, medical and surgical conditions. Risk stratify medical, oncology, and surgical patients, evaluate their likelihood for incurring DVT, and learn how to assess and implement prophylaxis measures that can reduce the incidence of DVT in these patient populations.
Faculty Roster
Assess and manage special needs of both inpatients and discharged outpatients at risk for DVT, with a focus on long-term prophylaxis against recurrent DVT in patients with cancer, medical disorders, and in cancer patients. Apply landmark clinical trials focusing on DVT prevention in medical and surgical patientsin particular, those with cancerto their clinical practice. Evaluate, select among, and appropriately use the range of pharmacologic options available for DVT prophylaxis, including warfarin, unfractionated heparin, and LMWHs. Apply current guidelines issued by national professional organizations such as NCCN and ACCP in at risk patients with medical and surgical conditions. Risk stratify medical and surgical oncology patients, assess their likelihood for incurring DVT, and be aware of prophylaxis measures that can reduce the incidence of DVT in patients with a variety of tumor types, and with chemotherapy. Assess and manage special needs of cancer and critical care patients at risk for DVT, with a focus on protecting against recurrent DVT in patients undergoing surgery
ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The University of Massachusetts Medical School, Office of CME and CMEducation Resources, LLC. The University of Massachusetts Medical School is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT The University of Massachusetts Medical School designates this educational activity for a maximum of 3.5 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. POLICY ON FACULTY AND PROVIDER DISCLOSURE It is the policy of the University of Massachusetts Medical School to ensure fair balance, independence, objectivity and scientific rigor in all activities. All faculty participating in CME activities sponsored by the University of Massachusetts Medical School are required to present evidence-based data, identify and reference off-label product use and disclose all relevant financial relationships with those supporting the activity or others whose products or services are discussed. Faculty disclosure will be provided in the activity materials.
Supported by an independent educational grant from Eisai, Inc.
UniversityofMassachusettsMedicalSchool OfficeofContinuingMedicalEducation
SummaryofFacultyDisclosureInformation
FacultyDisclosures: AsasponsoraccreditedbytheACCME,TheUniversityofMassachusettsMedicalSchoolOfficeofContinuing
Medical Education (UMMSOCME) must ensure balance, independence, objectivity, and scientific rigor in all its individually sponsoredandjointlysponsorededucationalactivities.Allfacultyparticipatinginasponsoredactivityareexpectedtodiscloseto theactivityaudienceanydiscussionofofflabeluseorinvestigationsuseofaproduct,andanyrelevantfinancialinterestorother relationshipwhichthey,ortheirspouse/partner,have(a)withthemanufacture(s)ofanycommercialproduct(s)and/orprovider(s) ofcommercialservicesdiscussedinaneducationalpresentationand(b)withanycommercialsupportersoftheactivity.(Relevant financial interest or other relationship can include such things as grants or research support, employee, consultant, major stockholder,memberofspeakersbureau,etc.) The following faculty members have indicated their financial interests and/or relationships with commercial manufacture(s) (and/orthoseoftheirspouse/partner)below.FacultywithnorelevantfinancialrelationshipsarelistedwithN/A.
FINANCIALINTERESTSORRELATIONSHIPS
FacultyMember
SamuelZ.Goldhaber,MD FrederickR.Rickles,MD
Relationship
Consultant: SpeakersBureau: Grant/Research: Consultant: SpeakersBureau: Grant/Research: Consultant: SpeakersBureau: Grant/Research: Consultant: SpeakersBureau: Grant/Research:
Corporation/Manufacturer
SanofiAventis,BMS,BI,EKOS, Medscape,Eisai N/A SanofiAventis,BMS,BI,Eisai,J&J Genmab,Bayer/OrthoMcNeil/J&J, Pharmacyclics,Leo Eisai SanofiAventis,Eisai SanofiAventis,Eisai SanofiAventis,Eisai,LeoPharma SanofiAventis,LeoPharma SanofiAventis
CraigKessler,MD AlokA.Khorana,MD,FACP
Thespeakermustdiscloseanydiscussionofofflabeluseand/orinvestigationalproductstotheaudienceduringthepresentation.
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ThefollowingCMEprogramplannershaveindicatedtheirfinancialinterestsand/orrelationshipswithcommercial manufacturer(s)(and/orthoseoftheirspouse/partnerbelow.Plannerswithnorelevantfinancialrelationshipsarelistedwith N/A. COMMITTEE/STAFF GideonBosker MiloFalcon RELATIONSHIP N/A N/A
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CMEducation Resources, LLC
New Frontiers and Evolving Paradigms
in Cancer and Thrombosis

New Frontiers and Evolving Paradigms in Cancer and Thrombosis: The Journey From Science to Strategy, From Bench to Bed Side
Faculty: Samuel Z. Goldhaber, MD Program Chairman Notes: Time: 6:30 6:50 p.m.
A Year 2010 Milestone Summit
New Frontiers and Evolving Paradigms in Cancer and Thrombosis

Optimizing Prevention, Risk Assessment, and Management of Thrombotic Complications in Malignancy: What Do the Trials Teach Us? How Should the Science Guide Us?
Program Chairman Samuel Z. Goldhaber, MD
Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School
Welcome and Program Overview
CME-certified symposium jointly sponsored by the University of d b th U i it f Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an unrestricted educational grant from Eisai, Inc. Faculty disclosures: Listed in program syllabus
We Request That You PLEASE FILL OUT

QUESTION AND ANSWER (Q&A) CARDS as program proceeds
so we can collect them and discuss during the Q&A session
forms to obtain CME credit Please credit. hand all survey forms to the staff at the desk outside following the program
COURSE SURVEY AND EVALUATION
Program Faculty
Cardiovascular Division Brigham and Women s Hospital Womens Professor of Medicine Harvard Medical School
Alok A. Khorana, MD, FACP
Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P Wilmot Cancer Center P. University of Rochester Rochester, NY
Craig Kessler, MD
Professor of Medicine Department of Hematology Anticoagulation Services Georgetown University Medical Center Washington, DC
Frederick R. Rickles, MD
Clinical Professor of Medicine, Pediatrics, Pharmacology and Physiology Division of Hematology-Oncology Department of Medicine The George Washington University School of Medicine and Health Sciences Washington, DC
Program Agenda
6:30 PM 6:50 PM
New Frontiers and Evolving Paradigms in Cancer and Thrombosis: The Journey From Science to Strategy, From Bench to Bed Side
Program Chairman
Samuel Z. Goldhaber, MD
6:50 PM 7:15 PM
The Complex Interface of Malignancy, Thrombosis, and Clinical End Points

Clinical Professor of Medicine, Pediatrics, Pharmacology and Physiology Division of Hematology-Oncology Department of Medicine The George Washington University School of Medicine and Health Sciences Washington, DC
Program Agenda
7:15 PM 7:45 PM
Optimizing Risk Assessment and Management of Cancer Patients at Risk for Venous Thromboembolism (VTE): Reducing DVT Recurrence and Related Complications
Craig Kessler, MD
7:45 PM 8:15 PM
Risk Stratification Tools to Identify Patients For Primary and Secondary Prevention of VTE in Patients with y Malignancy
Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P. Wilmot Cancer Center University of Rochester Rochester, NY
Program Agenda
8:15 PM 8:30 PM
Program Chairmans Concluding Vision Statement: Current and Near Future Perspectives of VTE Management in the Setting of Malignancy
Translating Scientific Advances into Clinical Practice
Program Chairman
8:30 PM 8:45 PM
Interactive Q&A and Discussion Session
A Virtual World Forum on Cancer and Thrombosis on Your Laptop and iPad
Please Visit www.iQandA-cme.com for the iQ&A interactive Medical Intelligence Zone for Cancer and Thrombosis
More than 100 questions answered by experts and investigators
A Year 2010 Milestone Summit
New Frontiers and Evolving Paradigms in C i Cancer And Thrombosis A d Th b i

Epidemiology, Trials, Guidelines
Disclosures Research Support BMS; Boehringer-Ingelheim; Ei i Johnson BMS B h i I lh i Eisai; J h & Johnson, Sanofi-Aventis Consultant Boehringer-Ingelheim; BMS Eisai; EKOS: B hi I lh i BMS; Ei i EKOS Medscape; Merck; Pfizer; Sanofi-Aventis
Epidemiology
As Number of Cancer Survivors Increase, VTE Rates Increase
Stein PD, et al. Am J Med 2006; 119: 60-68
VTE Risk and Cancer Type: Solid and Liquid

Relative Risk of VTE Ranged From 1.02 to 4.34
Relative Risk of VTE in n Cancer Patients 4.5 4 3.5 3 2.5 2 1.5 1 0.5
Kidney
Ovary
Leukemia
Cervix
Liver
Stomach
Prostate
Lymphoma
Myeloprol
Stein PD, et al. Am J Med 2006; 119: 60-68
Rate of PE Diagnosis is Increasing in the USA

250,000
Esophagus
Pancreas
200,000 200 000
Total cohort Surgical patients Non surgical Non-surgical patients 126,546 90,468
229,637
163,096
150,000
100,000
66,541
50,000
36,078
0 1998
CHEST 2009; 136: 983-990
1999 2000 2001 2002 2003 2004 2005
Bladder
Brain
Uterus
Breast
Lung
Rectal
Colon
Hospital Costs are Skyrocketing
CHEST 2009; 136: 983-990 983-
DVT: Ominous Sequellae
30% recur over 10 years ( y (after anticoagulation is g discontinued) More than of DVTs result in chronic venous insufficiency Leads to PE, potentially fatal 1% to 4% of PEs evolve chronic thromboembolic pulmonary hypertension (CTEPH)
Recurrent VTE is Common After A First Episode of Symptomatic DVT 355 patients followed for 8 years
30 25 20
Cumulative Incidence (%)
15 10 5 0 0 1 2 3 4
Years
Prandoni et al, Ann Intern Med 1996;125:1-7 1996;125:1-
10
Stages of Chronic Venous Insufficiency 1. 2. 3. 4. 5. Varicose veins Ankle/ leg edema Stasis dermatitis Lipodermatosclerosis Venous stasis ulcer
Progression of Chronic Venous Insufficiency
From UpToDate 2006
11
U.S.A. SURGEON GENERAL: CALL TO ACTION TO PREVENT DVT AND PE
September 15, 2008
100,000-180,000 Deaths/year in USA
12
CTEPH
RECURRENT ACUTE PE
Lang, I. M. NEJM 2004;350:2236-2238 2004;350:2236-
DVT FREE Registry 5,451 patients enrolled prospectively
Consecutive acute DVT di C ti t diagnosed by venous db ultrasonography No exclusions 183 participating sites in the U.S.
Goldhaber SZ, Tapson VF. Am J Cardiol 2004;93:259-262. 2004;93:259-
13
DVT FREE Registry (N= 5,541): TOP 5 Medical Comorbidities 1. 2. 3. 4. 5. Hypertension Immobility Cancer Obesity (BMI > 30) Cigarette Smoking
Am J Cardiol 2004; 93: 259-262 259-
Pivotal VTE Primary Prevention Trials
14
Trials of VTE Prophylaxis in Hospitalized Medical Patients

MEDENOX
(enoxaparin 40 mg) Samama MM, et al. N Engl J Med. , g 1999;341:7931999;341:793-800. (dalteparin 5000 IU) Leizorovicz A, et al. Circulation. 2004;110:8742004;110:874-879. (fondaparinux 2.5 mg) Cohen AT, et al.
PREVENT
ARTEMIS
BMJ 2006; 332: 325.
PREVENTPREVENT- Dalteparin Trial (N= 3,681)

A
multicenter, randomized, controlled study in acutely ill medical patients the incidence in the dalteparin and placebo groups of:

Compared
Any symptomatic VTE y y p Asymptomatic proximal DVT Sudden death
Circulation 2004; 110: 874-879 874-
15
PREVENT Study Design (N= 3,681)

Treatment period Dalteparin D l i
Randomization
Follow-up period No N study d d drug
Placebo Day 14
No study drug Day 90
Day 21 Primary endpoint/ Bilateral leg U/S
Dalteparin 5000 Units SC once daily (12-14 d) (12 Placebo SC once daily (12-14 d) (12-
Primary Efficacy Endpoint: VTE (Day 21)

Dalteparin
N=1518 Placebo N=1473 73 Difference in Incidence (%) Risk Ratio
42
2.77%
95% CI
4.96%
-2.19
-3.57 to -0.81
0.55
0.38 to 0.80
P = 0.0015
Circulation 2004; 110: 874-879 874-
16
Dalteparin Benefit Similar Across Subgroups

Age Gender Cancer Obesity Previous
DVT
Quality Improvement Initiative to Improve VTE Prophylaxis

Randomized
controlled trial to issue or withhold electronic alerts to MDs whose ithh ld l t i l t t MD h highhigh-risk patients were not receiving VTE prophylaxis
Kucher N et al. NEJM 2005; 352: 969
17
Computer Program
We
developed a computer program linked to the patient database that screened the system daily to identify high-risk patients. highpatients. included consecutive high-risk patients highon medical and surgical services who were not receiving DVT prophylaxis prophylaxis.
We
Kucher N et al. NEJM 2005; 352: 969
Definition: High Risk
VTE risk score 4 points:

Cancer Prior VTE Hypercoagulability Major surgery Bed rest Advanced age Obesity HRT/OC
3 (ICD codes) 3 (ICD codes) 3 (Leiden, ACLA) 2 (> 60 minutes) 1 (bed rest order) ( bed rest 1 (> 70 years) 1 (BMI > 29 kg/m2) 1 (order entry)
18
Randomization
VTE risk score > 4 No prophylaxis N = 2,506
INTERVENTION: Single alert N = 1,255
CONTROL No N computer alert l N = 1,251
Kucher N, et al. NEJM 2005;352:969-977 2005;352:969-
19
Baseline Characteristics
Median
age: 62.5 years M di l services: Medical i 83% Surgical services: 17% Comorbidities

Cancer: 80% Hypertension: 34% Infection: 30% Prior VTE: 20%
Kucher N, et al. NEJM 2005;352:969-977 2005;352:969-
Primary End Point

% %Freedom from DVT PE T/
100 98 96 94 92 90 0 30 60 Time (days) 977 976 900 893 90 853 839
Intervention Control
Number at risk Intervention 1255 1251 Control

Kucher N, et al. NEJM 2005;352:969-977
20
Pivotal VTE Treatment Trial l l in Patients with Cancer
Cancer and VTE
3-fold higher recurrence and bleeding, when treating cancer patients (Prandoni. Blood 2002;
100: 3484) 3484)
LMWH Monotherapy halves recurrence, compared with warfarin. FDA approved May 2007
Lee AYY. NEJM 2003; 349:146
21
CLOT Trial
Dalteparin
monotherapy for 6 months was more effective (8 8% vs. 17% recurrence) (8.8% vs than warfarin in 672 cancer patients with DVT. DVT. dose: 200 u/kg daily 1st month month, then 150 u/kg daily.
Dalteparin
Agnes Lee, et al. NEJM 2003; 349:146-153) 349:146-
Dalteparin Reduces VTE Recurrence in Cancer Patients (N = 676)
CLOT TRIAL
NEJM 2003; 349:146-153 349:146-
22
LMWH Monotherapy

Cancer patients with DVT/PE Any ti t h f il A patient who fails warfarin (has f i (h recurrent DVT/PE) despite target INR Difficulty maintaining target INR Poor GI absorption of meds Alopecia or rash from Coumadin Bridging
ACCP VTE Rx in Cancer: Guidelines 8th Edition 1. At least 3 months of LMWH. 2. Then administer LMWH or warfarin as long as the cancer is active. 3. Indefinite duration anticoagulation after 2nd unprovoked VTE. VTE
CHEST 2008; 133: 454S
23
Conclusions
1. Cancer and VTE are closely linked. 2. 2 Cancer increases VTE risk and may be occult when VTE is diagnosed. 3. Cancer patients are at high risk for VTE but receive less prophylaxis than any other at-risk group of hospitalized atpatients. 4. Dalteparin 5,000 U/d is effective for VTE prophylaxis in cancer patients.
Conclusions (Continued)
5. Dalteparin 200 U/kg/day is effective for treatment fo t e tment of acute VTE as te monotherapy without warfarin. 6. NCCN, ASCO, and ACCP guidelines endorse VTE prevention with LMWH and VTE treatment of cancer patients with LMWH alone (monotherapy (monotherapy without warfarin).
24

The Complex Interface of Malignancy, Thrombosis, and Clinical End Points
Faculty: Frederick R. Rickles, MD Notes: Time: 6:50 7:15 p.m.
The Role of the Coagulation Cascade in Malignant Transformation

Can Anticoagulation Affect Cancer Survival?
Professor of Medicine, Pediatrics, Pharmacology and Physiology The George Washington University Washington, DC
25
Disclosures Consultant Genmab, Bayer/Ortho Genmab, Bayer/OrthoMcNeil/J & J, Pharmacyclics, Pharmacyclics, Leo Speakers Bureau Eisai
Interface of Coagulation and Cancer

Tumor cells
Angiogenesis, Basement matrix degradation. degradation Fibrinolytic activities: t-PA, u-PA u-PAR t-PA u-PA, u-PAR, PAI-1, PAI-2
Procoagulant Activities
TFTF-rich MPs
IL-1, TNF-, VEGF
Activation of coagulation
PMN leukocyte
FIBRIN
Platelets Monocyte Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis, 2005; Hematology, ASH Education Book, 2007 Oncology:Thrombosis, Book,
26
Mechanisms of Cancer- Induced CancerThrombosis: Clot and Cancer Interface

1. Pathogenesis?
2. Biological significance?
3. Anticoagulation and cancer survival?
Activation of Blood Coagulation in Cancer

Biological Significance?
Epiphenomenon?
Is this I thi a generic secondary event where i d t h thrombosis is an incidental finding or, is clotting activation . . .
A Primary Event?
Linked to malignant transformation
27
Interface of Clotting Activation and Tumor Biology

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

ClottingClottingdependent ClottingClottingdependent
TF
Thrombin
Fibrin
VIIa
ClottingClottingindependent
Xa
ClottingClottingindependent
ClottingClottingdependent
PARs
Angiogenesis, Tumor Growth and Metastasis
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584
28
In Situ Localization of Tissue Factor in Vascular Endothelium of Human Lung Adenocarcinoma co- localization with vWF co-
Shoji et al, Amer J Pathol 1998;152:399-411
In Situ localization of Tissue Factor in Tumor Vascular Endothelium in Invasive Human Breast Cancer
Contrino et al. Nature Med 1996;2:209-215
29
In Situ Co- Localization of TF and VEGF ComRNA in Lung Adenocarcinoma

H&E
TF
VEGF
Shoji et al. Amer J Pathol 1998;152:399-411
Human melanoma cell lines grown as xenogeneic tumors in SCID mice
TF high producer
TF low producer
Abe K et al. PNAS 1999;96:8663-8668

1999 by The National Academy of Sciences
30
Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor
1. 1 TF regulates VEGF expression in human cancer cell lines 2. Human cancer cells with increased TF are more angiogenic (and, therefore, more t t ti ) i vivo d to hi h metastatic) in i due t high VEGF production
Abe et al Proc Nat Acad Sci 1999;96:8663-8668; Ruf et al Nature Med 2004;10:502-509 1999;96:8663-
Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor
3. The cytoplasmic tail of TF, which contains three serine residues, appears to play a role in regulating VEGF expression in human cancer cells, perhaps by cells mediating signal transduction 4. Thisa and other data on signaling pathways activated by TF/VIIa engagement of PAR-2b and/or thrombin TF/VIIa PARengagement of PAR-1c suggest that clotting PARpathways are directly involved in regulating tumor growth, angiogenesis and metastasis 5. Is this a paradigm shift?
a b c
Abe et al Proc Nat Acad Sci 1999;96:8663-68 1999;96:8663Ruf et al Nature Med 2004;10:502-9 2004;10:502Karpatkin et al Cancer Res 2009;69:3374-81 2009;69:3374-
31
Activation of Blood Coagulation in Cancer and Malignant Transformation

Epiphenomenon vs. Malignant Transformation?
Paradigm Shift (2005)
1. 2.
carcinoma (Boccaccio lab)
MET oncogene induction produces DIC in human liver

(Boccaccio et al Nature 2005;434:396-400) 2005;434:396-
Pten loss and EGFR amplification produce TF activation

and pseudopalisading necrosis through JunD/Activator ProteinProtein-1 in human glioblastoma
(Rong et al Cancer Res 2005;65:1406-1413; Cancer Res 2009;69:2540-9) 2005;65:14062009;69:2540-
(Bratt lab)
3.
K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma; TF and angiogenesis regulation in epithelial tumors by EGFR (ErbB1) relationship to EMTs (Rak lab)
(Yu et al Blood 2005;105:1734-1741; Milson et al Cancer Res 2008;68:10068-76) 2005;105:17342008;68:10068-
Activation of Blood Coagulation in Cancer: Malignant Transformation

1. MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis
MET encodes a tyrosine kinase receptor for hepatocyte

growth factor/scatter factor (HGF/SF)
growth (tissue morphogenesis, angiogenesis and repair) Aberrant execution (e.g. hypoxia-induced hypoxiatranscription) is associated with neoplastic transformation, invasion, and metastasis
Drives physiological cellular program of invasive
Boccaccio et al Nature 2005;434:396-400 2005;434:396-
32

2. Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma
phosphatase activity
Pten = tumor suppressor with lipid and protein
Loss or inactivation of Pten (70-80% of (70glioblastomas) leads to Akt activation and upregulation of Ras/MEK/ERK signaling cascade Ras/MEK/ERK
Rong et al Ca Res 2005;65:1406-1413
Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma Glioblastoma
Glioblastomas characterized histologically by pseudopalisading necrosis pseudopalisading necrosis Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosis Pseudopalisading cells produce VEGF and IL-8 ILand drive angiogenesis and rapid tumor growth TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2)
33
Results: 1. Hypoxia and PTEN loss TF (mRNA, Ag and procoagulant activity); partially reversed with induction of PTEN 2. Both Akt and Ras pathways modulated TF in sequentially transformed astrocytes. 3. Ex vivo data: TF (by IH-chemical staining) in IHpseudopalisades of # 7 human glioblastoma specimens
Pseudopalisading necrosis
H&E
Vascular Endothelium
TF IHC
34
Activation of Blood Coagulation in Cancer: Malignant Transformation Transformation

3. Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis P i A dA i i
Activation of K-ras oncogene and inactivation of p53 tumor Ksuppressor TF expression in human colorectal cancer cells Transforming events dependent on MEK/MAPK and PI3K CellCell-associated and MP-associated TF activity linked to genetic MPstatus of cancer cells TF siRNA reduced cell surface TF expression, tumor growth and angiogenesis TF may be required for K-ras-driven phenotype K-ras-
Yu et al Blood 2005;105:1734-41 2005;105:1734-

Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis
Effect of TF si mRNA on tumor growth in vitro and in vivo
Yu et al Blood 2005;105:1734-41 2005;105:1734-
35

Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis
Matrigel Assay: (D) HCT 116; (E) SI-3 cells vWF immunohistology
Yu et al Blood 2005;105:1734-41 2005;105:1734-
Similar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma and lung cancer cells; accompanied by epithelial-to-mesenchymal transition (EMT) epithelial-toMilsom et al CA Res 2008;68:10068-76 2008;68:10068-
Microparticles
Originatedirectlyfrommembranesurfaceofactivatedor apoptoticcell Express surface antigens derived from parent cell Expresssurfaceantigensderivedfromparentcell Anucleate <1mindiameter Procoagulantactivity mediatedbyTFand/orPS
BurnierLetal.ThrombHaemost 2009;101:439451
36
Cumulative incidence of VTE in cancer patients with (--) (--) /without ( ) circulating TF-bearing microparticles TF-
Zwicker et al. Clin Cancer Res 2009;15:6830-40
Microparticle TF PCA in Cancer Patients VTE
ManlyDA,etal.ThrombRes 2010;125:511512
37
Q: What do these experiments tell us? A: They suggest two things: Tumor cell-derived, TF-rich microparticles cellTF-
(MPs) may be important as a predictive test for VTE All patients with oncogene-d i ti t ith oncogene-driven cancer may need prophylactic anticoagulation
Mechanisms of Cancer- Induced CancerThrombosis: Implications 1. Pathogenesis? 2. Biological significance?
3. Anticoagulation and cancer survival ?
38
Anticoagulants and Survival

Inconclusive evidence to date Experimental data supportive of antitumor effects but exact mechanisms not established Clinical trials provide supportive data for LMWH but are heterogeneous in design and methodology:
Tumour types Stage or course of disease g Treatment history or concurrent cancer therapies LMWH agents Doses and regimens of LMWHs
A Lee ICTHIC, 2010
Survival Effect of Anticoagulants
Kuderer N et al. Cancer 2007;110:1149-60.
39
PROTECHT Study

Multicentre, double-blind, placebo-controlled RCT doubleplaceboAdvanced lung, breast, GI, pancreas, ovary, H+N Nadroparin vs placebo for duration of chemo (up to 4m)
Nadroparin Placebo 381 3.9% 0 4.2% 41%
*1-sided
P-value
NNT/H
No. Patients 1 endpoint: VTE + ATE Major bleeding Death 1-yr mortality
Agnelli et al. Lancet 2009;10:943-949.
769 2.0% 0.7% 4.3% 43%
0.02* 0.18
54 154
Prophylaxis in Pancreatic Cancer

CONKO 004
no treatment
10% 8% 6% 4% 2% 0%
FRAGEM
no treatment
40%
enoxaparin
dalteparin
No survival difference
P=0.6
20%
P<0.0 1
P<0.02
30%
P=0.03
10%
NS
0%
VTE
bleeding
VTE
fatal PE
Gr 3 bleed
Riess et al. ASCO May 2009 and ISTH July 2009. Maraveyas et al. Presented at ESMO 2009.
40
Cancer and Thrombosis

Year 2010 State- of- the- Science Update State- of- the-
Key Questions
1. Does activation of blood coagulation affect the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using coagulation protein targets? 3. Can anticoagulation alter the biology of cancer?
Cancer and Thrombosis

Year 2010 State- of- the- Science Update State- of- the-
Tentative Answers
1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer 2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWHs in cancer patients indicate superiority to oral agents in preventing recurrent VTE; increasing survival (not due to prevention of VTE) not clear
41
LMWH in Cancer
Survival Studies
INPACT (NSCLC, prostate, pancreatic) ( ,p ,p )
nadroparin + chemo vs. chemo bemiparin + chemo vs. chemo tinzaparin + chemo vs chemo dalteparin + chemo vs chemo
A Lee ICTHIC, 2010
ABEL (limited SCLC)
TILT (nonsmall cell lung cancer) (nonsmall
FRAGMATIC (newly diagnosed lung cancer)
Stay tuned !
42

Optimizing Risk Assessment and Management of Cancer Patients at Risk for Venous Thromboembolism (VTE): Reducing DVT Recurrence and Related Complications
Faculty: Craig Kessler, MD Time: 7:15 7:45 p.m.
Notes:
Optimizing Risk Assessment and Management of Cancer Patients at Risk for Venous Thromboembolism (VTE) (VTE)
Reducing DVT Recurrence and Related Complications
Craig Kessler, MD
COI Financial Disclosures

Grant/Research Support: Consultant:
GlaxoSmithKline, sanofi-aventis, GlaxoSmithKline, sanofi-aventis, Eisai sanofi-aventis, sanofi-aventis, Eisai
43
Outline
Guidelines
p patients Performance to date Opportunities for improvement Guidelines for VTE Treatment Performance to date LMWHsWhat Do the Trials, NCCN and LMWHs ASCO Guidelines Teach Us About Duration of Therapy and Patients at Risk?
for VTE prevention in cancer
Recommendations for Venous Thromboembolism P h l i and Th b b li Prophylaxis d Treatment in Patients with Cancer ASCO Clinical Practice Guideline
www.nccn.org NCCN Clinical Practice Guidelines in Oncology Guidelines for supportive Guidelines care the panel of experts includes a medical and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a pharmacist.
44
Importance of Guidelines to Clinical Outcomes

Clinicians armed with appropriate assessments and the best evidence-based practice guidelines evidencecan reduce some of th unpleasant and frequent d f the l t df t sideside-effects that often accompany cancer and chemotherapy treatment, obtain the best possible clinical outcomes, and avoid unnecessary costs.
Statement from Centers for Medicare and Medicaid Services, August 2005
Incidence of VTE in US Patients With Cancer Has Risen Although the Overall Incidence of Cancer Has Not Changed
HighestincidenceofVTE:pancreaticCA(4.3%) LowestincidenceofVTE:oralcavity,orpharynx
Cancer 3 2 1 0 No Cancer
4 VTE Incidence, %
National Hospital Discharge Survey data from 19 types of malignancies from 1979 through 1999 (non-age dependent)
SteinPDetal.AmJMed.2006;119:6068.
1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999
45
Venous Thromboembolism in Cancer Patients

Of all cases of VTE: 20% occur in cancer patients Of all cancer patients: 0.5% 0 5% will have symptomatic VTE As high as 50% have VTE at autopsy Compared to patients without cancer: Higher risk of first and recurrent VTE Higher risk of bleeding on anticoagulants Higher risk of dying VTE may be the presenting sign of occult malignancy 10% with idiopathic VTE develop cancer within 2 years 20% have recurrent idiopathic VTE 25% have bilateral DVT
Lee & Levine. Circulation 2003;107:I17 I21; Bura et. al., J Thromb Haemost 2004;2:445-51 2004;2:445-
Thrombosis and Survival: Likelihood of Death After Hospitalization

(Levitan N, et al. Medicine 1999;78:285)
1.00
Pr robability of Death
0.80 0.60
DVT/PE and M li d Malignant Disease
Malignant Disease
DVT/PE Only y
0.40 0.20 0.00 0 20 40 60
Nonmalignant Disease 80 100 120 140 160 180

Number of Days
46
Cancer and Venous Thromboembolism The Need for Risk Stratification
4.5 4 3.5 3 Rela ativeRisk 2.5 2 1.5 15 1 0.5 0 1
Chemotherapy
EndofLife End of Life
Hospitalization Diagnosis Metastasis
Remission AverageRisk 2 3 Time 4 5 6
VTE in Hospitalized Cancer Patients

7.0 6.0 5.0 RateofVTE(%) 4.0 3.0 2.0 1.0 10 0.0
1995 1996 1997 1998 1999 2000 2001 2002 2003
VTEpatientsonchemotherapy VTEallpatients DVTallpatients PEallpatients p
Years
Cancer2007
47
Effect of Malignancy on Risk of VTE

50 40 30 20 10 0 Lung Brea ast Dista ant metastase es 1 to 3 yea ars nal Gastrointestin 3 to 12 month hs Hematological 0 to 3 month hs 5 to 10 yea ars
28 22.2 20.3 19.8 14.3 4.9 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. nonCA patients 53.5 MEGA=MultipleEnvironmental andGeneticAssessmentcase controlstudy
Adjustedoddsratio
3.6
2.6
1.1
Typeofcancer
Timesincecancerdiagnosis
VTE=venousthromboembolism;CA=cancer;OR=oddsratio.SilverIn:TheHematologist modifiedfromBlomJW,et. al.JAMA. 2005;293:715722.
The Importance of DVT Prophylaxis in Patients With Cancer: ASCO Guidelines

VTE is a leading causes of death in CA, occurring in 4% to 20% pts Hospitalized CA pt and those on chemotx have greatest VTE risk Cancer increased the risk of VTE 4.1-fold 4.1 Chemotherapy increased the risk 6.5-fold 6.5Major risk factors: older age, comorbid conditions, recent surgery or hospitalization, active chemotherapy or hormonal g y p , py therapy All hospitalized CA patients should be considered for prophylaxis
Patients with cancer undergoing surgery should be considered for prophylaxis LymanGH,etal.JClinOncol.2007;25:54905505. LMWH is the preferred drug
> 15 yea ars
48
Updated ASCO Guidelines Hospitalized Patients with Cancer

Role of VTE Prophylaxis Evidence
Multiple RCTs of hospitalized medical patients with subgroups of patients with cancer. The 8th ACCP guidelines strongly recommend (1A) prophylaxis with either lowdose heparin or LMWH for bedridden patients with active cancer.
Patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants (UFH, LMWH, or fondaparinux) in the absence of bleeding or other contraindications to anticoagulation
VOLUME25NUMBER34DECEMBER12007
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
Prophylaxis in Cancer Patients
Cancer patients undergoing surgical procedures: routine thromboprophylaxis that is appropriate for the type of surgery (Grade 1A) Cancer patients who are bedridden with an acute medical illness: routine thromboprophylaxis as for other high-risk medical patients high(Grade 1A) Cancer patients receiving chemotherapy or hormonal therapy: recommend against the routine use of thromboprophylaxis for the primary prevention of VTE (Grade 1C) Cancer patients overall: recommend against the routine use of primary thromboprophylaxis to try to improve survival (Grade 1B)
GeertsWH,etal.Chest.2008;133(6suppl):381S453S.
49
Therapeutic Anticoagulation Treatment for VenousThromboembolismVenousThromboembolism-NCCN Update 2009

The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications s ch the ap cont aindications to such therapy Panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e g cancer surgery patients) high(e.g. continue to receive VTE prophylaxis for up to 4 weeks postpostoperation.
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
Caveats
No randomized controlled trials (RCTs) designed ad hoc for hospitalized medical cancer patients are available Recommendations are based on RCTs of acutely ill medical patients, involving a small proportion of patients with cancer No bleeding data are reported specifically in the subgroup of patients with cancer
50
Anticoagulant Prophylaxis to Prevent Screen-Detected ScreenVTE High Risk Hospitalized Medical Patients
3 large, randomized, placebo-controlled, placebodoubledouble-blind trials in medical patients at high risk including cancer

MEDENOX (enoxaparin)1 ~ 15% PREVENT (dalteparin)2 ~5% ARTEMIS (fondaparinux)3 ~15%
1. Samama MM, et al. N Engl J Med. 1999;341:793-800. 2. Leizorovicz A, et al. Circulation. 2004;110:874-879. 3. Cohen AT, et al. BMJ. 2006;332:325-329.
Screening for asymptomatic DVT with S i f t ti ith venography or ultrasound
Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients
Study
MEDENOX1 P < 0.001
RRR RRR 63%
Thromboprophylaxis Patients with VTE (%) Placebo Enoxaparin 40 mg Placebo Dalteparin 5,000 units Placebo Fondaparinux 2.5 mg 2.8 10.5 5.6 5.5 5.0 14.9
PREVENT2 P = 0.0015
45%
ARTEMIS3
47%
1Samama 2
MM, et al. N Engl J Med. 1999;341:793-800. Leizorovicz A, et al. Circulation. 2004;110:874-9. 3Cohen AT, et al. BMJ 2006; 332: 325-329.
51
Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding
Incidence of Major Bleeding (%) g
1.8 1.6 16 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0
1.7%
1.1%
LMWH
0.49% 0.16% 0 16% 0.2%
Medenox
Prevent
Artemis
Study
Samama MM, et al. N Engl J Med. 1999;341:793-800. Leizorovicz A, et al. Circulation. 2004;110:874-9. Cohen AT, et al. BMJ 2006; 332: 325-329..
EXCLAIM: Extended-duration Enoxaparin ExtendedProphylaxis in High-risk Medical Patients High(MostbenefitseeninLevel1DisabilityPatientswith bedrestorsedentarywithoutBRPsomewithCA)

End points
Outcome, extended prophylaxis, n=2052 (%) Outcome, placebo, n=2062(%) RR reduction (%)
MajorBleeding0.8%0.3% VTE events 2.5 4.0 Symptomatic No Sxs 0.3 2.5 1.1 3.7
38%
0.001 0.004 0.032
73% 34%
(Hull RDetal.AnnInternMed 2010; 153:8)
52
PRODIGE: a randomized placebo-controlled trial of placebodalteparin for primary VTE prophylaxis in newly diagnosed malignant glioma
Reduced VTE for dalteparin 5,000 anti-Xa antiunits qd for 6 mos: 11% vs 17% for placebo Increased ICH: 5.1% vs 1.2% for placebo Both NS significant
PerryJRetal.JTH2010;8;1959
2009 NCCN Guidelines: DVT Prophylaxis

PharmacologicProphylaxis UFH LMWH Pentasaccharide Contraindicationto AnticoagulationTreatment MechanicalProphylaxis SequentialCompressionDevices Sequential Compression Devices CompressionStockings NCCN,NationalComprehensiveCancerNetwork. NCCN.VenousThromboembolicDisease:Version1.2006.Availableat: http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf.
Adult Cancer Inpatient
53
RESULTS: RESULTS: 21 relevant studies (5 randomized controlled trials, 13 observational studies, and 3 surveys) were found. A total of 811 patients were randomized in the 5 randomized controlled trials; 3421 patients participated in the observational studies. ti i t d i th b ti l t di Trauma patients only were enrolled in 4 randomized controlled trials and 4 observational studies. Meta-analysis of 2 randomized controlled trials Metawith similar populations and outcomes revealed that use of compression and pneumatic devices did not reduce the incidence of venous thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90). A range of methodological issues, including bias and confounding variables, make meaningful interpretation of the observational studies difficult. CONCLUSIONS: CONCLUSIONS: The role of mechanical approaches to thromboprophylaxis forfor mechanical thromboprophylaxis in The beneficial role intensive care patients remains uncertain. cancer pts is empiric and derived from benefits seen in surgical studies; No controlled studies in cancer patients
Limbus A et al. Am J Crit Care, 2006;15:402-10
Mechanical thromboprophylaxis in critically ill patients: a systematic review and meta-analysis meta-
VTE Prophylaxis Is Underused in Patients With Cancer

Rate eofAppropriateProphylaxi is,%
100 90 80 70 60 50 40 30 20 10 0
FRONTLINE Surgical FRONTLINE: Medical Stratton Bratzler Rahim DVT FREE
Cancer: FRONTLINESurvey1 3891Clinician Respondents p

Cancer: Surgical
Major Surgery2
52
Major Abdominothoracic Surgery(Elderly)3
ConfirmedDVT (Inpatients)5 Medical Inpatients4
Cancer: Medical
1. KakkarAKetal.Oncologist.2003;8:381388. 2. StrattonMAetal.ArchInternMed.2000;160:334340. 3. BratzlerDWetal.ArchInternMed.1998;158:19091912.
4. RahimSAetal.ThrombRes.2003;111:215219. 5. GoldhaberSZetal.AmJCardiol.2004;93:259262.
54
Despite Evidence, Medical Patients at Risk Remain Unprotected

ENDORSE1
Medical No. of patients At risk for VTE Receiving ACCP Tx 37,356 42% 40% Surgical 30,827 64% 59% No. of patients VTE prophylaxis LMWH UFH
IMPROVE2
United States 3,410 Other Countries 11,746
1852 (54%) 5788 (49%) 476 4 6 (14%) 46 (40%) 4657 717 (21%) 1014 (9%)
1. CohenAT,etal.Presentedat:2007CongressoftheInternationalSocietyonThrombosisand Haemostasis;July612,2007;Geneva,Switzerland. 2. TapsonVF,etal.Chest. 2007;132(3):936945.
Electronic Alerts to Prevent VTE in Hospitalized Patients

100 98 FreedomFromDVT T orPE(%) 96 94 92 90 0 0 No. at Risk
Intervention group Control group 1255 1251 977 976
Interventiongroup
Controlgroup P<.001 300 600

900 893
Days
90
853 839
P<.001bythelogranktestforthecomparisonoftheoutcomebetweengroupsat90days. ReprintedwithpermissionfromKucherN,etal.NEnglJMed.2005;352:969977.
110
55
Ambulatory Patients with Cancer Without VTE Receiving Systemic Chemotherapy: Updated ASCO Guidelines
Routine prophylaxis in ambulatory ti t i i h th is t patients receiving chemotherapy i not recommended due to conflicting trials, potential bleeding, the need for laboratory monitoring and dose adjustment, and the relatively low incidence of VTE. This recommendation is based on nonrandomized trial data and extrapolation from studies of postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose warfarin in breast cancer
Routine prophylaxis with an antithrombotic agents is not recommended except as noted below
LMWH or adjusted dose warfarin (INR ~ 1.5) is recommended in myeloma patients on thalidomide or lenalidomide plus chemotherapy or dexamethasone
VOLUME25NUMBER34DECEMBER12007
Prospective Study of Adult Cancer Patients

Receiving Systemic Chemotherapy
Prospective observational study conducted at 117 randomly selected US practice sites. Data obtained on 4,458 consecutive adult patients initiating a new chemotherapy regimen between March 2003 and February 2006. There were no exclusions for age, prior history or comorbidities with nearly 40% of patients age 65 and older.
P p rtio w V E ro o n ith T
.04
.03
.02
.01
0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 15
Time (Days)
Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008).
56
Reported Cause of Early Mortality Cancer Patients Starting New Chemotherapy

Cause of Death PD Infection PE
NoVTE
1.00 .99 .98
[HR=5.48, 95%CI: 2.21-13.61; P<.0001]
No VTE VTE N=4,365 N=93 2.1 0.3 0 0.2 0.1 0.2 0.3 3.2 2.2 0 5.4 0 0 0 0 7.6
All N=4,458 2.1 0.3 0.1 0.2 0.1 0.2 0.3 3.3
Cumlative Survival
.97 .96 .95 .94 .93 .92 .91 .90 0 10 20 30 40 50 60 70 80
Pulmonary Bleeding
VTE
90 100 110 120 130 140 15
Other vascular Unknown All
Time (Days)
Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008)
RCTs of Thromboprophylaxis in Ambulatory Cancer Patients
Warfarin
DoubleDouble-blind, placebo-controlled RCT demonstrated the placeboy lowy ( 1.3- ) p efficacy of low-intensity warfarin (INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancer 311 women with metastatic breast cancer on 1st- 2nd1st- or 2nd-line chemotherapy Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebo 1.31 VTE in warfarin group vs 7 in placebo arm 85% risk reduction, P = .03, with no increased bleeding
INR=international normalized ratio
Levine M, et al. Lancet. 1994;343:886-889.
57
Low Molecular Weight Heparin in RCTs of Thromboprophylaxis in Ambulatory Cancer Patients

Trial
FAMOUS TOPIC-I
N
385 353
Treatment
Dalteparin Placebo Certoparin Placebo Certoparin Placebo Dalteparin Placebo Dalteparin Placebo/Control Nadroparin 2:1 Placebo
Chemo
64% 100%
Duration
12 months 6 months
VTE
2.4% 3.3% 4% 4% 4.5% 8.3% 11% 17% 5.9% 7.1% 1.4% 2.9%
Major Bleeding
0.5% 0 1.7% 0 3.7% 2.2% 5.1% 1.2% 2.9% 7.1% 0.7% 0
Solid tumors (Stage III/IV) Breast (Stage IV) NSCLC (Stage IV) Glioma
TOPIC-2
547
100%
6 months
PRODIGE SIDERAS
186 141 1166
54% 100%
6-12 months Indefinitely < 4 months with chemo
Solid Tumors (Stage IV) Solid Tumors (Stage III/IV)
PROTECHT
1. Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948. 2. Haas SK, et al. J Thromb Haemost. 2005(suppl 1): abstract OR059. 3. Perry JR et al. Proc ASCO 2007. 2011 4. Sideras K et al. Mayo Clin Proc 2006; 81:758-767. 5. Agnelli G et al. Am Soc Hemat Sunday December 7, 2008
The PROTECHT Study

RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy
DESIGN
PlaceboPlacebo-controlled, double blind, multicenter RCT Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1 1150 patients receiving chemotherapy for locally advanced or metastatic cancer. Start with new CTX; continue for maximum of 4 mos Mean treatment duration: 90 days Primary outcome: clinically detected thrombotic events, i.e., composite of venous and arterial TE* ie TE Main safety outcome: Major bleeding
* deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin Agnelli G et al: Lancet 2009;10, 930
58
The PROTECHT Study

RCT of Thromboprophylaxis in Cancer Patients Receiving Chemotherapy RESULTS
Primary Efficacy Outcome: Any TE Event*

Nadroparin: 16 of 769 (2.1%) Placebo: 1 of 381 (3 9%) 15 f (3.9%) Relative risk reduction: 47.2%, (interim-adjusted p=0.033) (interimAbsolute risk decrease: 1.8%; NNT = 53.8 Nadroparin: 11 of 769 (1.4%) Placebo: 11 of 381 (2.9%) NS Nadroparin: 5 (0.7%) Placebo: 0 (p= 0.177) Absolute risk increase: 0.7%; NNH = 153.8
Venous thromboembolism (VTE):

Major Bleeding:

Agnelli G et al: Lancet 2009;10:930
LMWH halves VTE in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy
PROTECHT All cause thrombothromboembolic events: 2% LMWH vs 3.9% in placebo Major bleeding: 0.7% LMWH vs none in placebo (P=0.18) By the end of study treatment, 33 LMWH deaths vs 16 in placebo group; 48 of these deaths due to CA progression
Agnelli G et al. www.thelancet.com/Oncology Oct 2009
2.1% DVT and 0.8% PE with placebo (N=381 pts)
p=0.02 NNT=53.8
1% DVT and 0.4% PE 0 4% with LMWH (N=769 pts)
Benefits most apparent in those with lung or GI CA (not
59
VTE Incidence In Various Tumors

Oncology Setting
Breast cancer (Stage I & II) w/o further treatment ( g ) Breast cancer (Stage I & II) w/ chemo Breast cancer (Stage IV) w/ chemo NonNon-Hodgkins lymphomas w/ chemo Hodgkins disease w/ chemo Advanced cancer (1-year survival=12%) (1HighHigh-grade glioma Multiple myeloma (thalidomide + chemo) Renal cell carcinoma Solid tumors (anti-VEGF + chemo) (antiWilms tumor (cavoatrial extension)
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
VTE Incidence
0.2% 2% 8% 3% 6% 9% 26% 28% 43% 47% 4%
Arterial Thrombotic Complications of Myeloma VAD(n6,5.9%) TAD(n2,4.5%) PAD(n3,6.4%) PAD (n 3 6 4%)

N=195 ATE=11 5.6%
4developedthrombosis while on VKAs; whileonVKAs; 2onLMWH
Liboureletal.Blood2010;116:2
60
LMWHWarfarinASA LMWH Warfarin ASA 9 3 91418 152431(LDW)
314
PalumboAetal.Leukemia2008;22:414
TheseVTE prophylaxis regimenshavenot beenassessedinany prospective, prospective randomizedtrialand arerecommended basedonanecdotal experience
PalumboAetal. Leukemia2008;22:414 eukemia 008; :4 4
61
VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in Myeloma
NaluriSRetal.JAMA. 2008;300:2277
Tamoxifen and Chemotherapy

705 postmenopeusal women with breast cancer CMF regimen Total thromboembolic events 39 of 54 events occurred during chemotherapy
16 14 12 10 8 6 4 2 0
Rateofthrombosis(%)
p=0.0001
9.6%
1.4% Tamoxifen (n=352) Tamoxifen+CT (n=353)
Pritchard,JClinOnc,1996
62
Treatment of Patients with Established VTE to Prevent Recurrence (continued)

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

Role of VTE Prophylaxis
LMWH is the preferred approach for the initial 5-10 days in cancer patient with established VTE.
Evidence
LMWH for 3-6 months is 36 more effective than vitamin K antagonists given for a similar duration for preventing recurrent VTE.
LMWH for at least 6 months is preferred for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are g g acceptable when LMWH is not available. The CLOT study demonstrated a relative risk reduction of 49% with LMWH vs. a vitamin K antagonist. Dalteparin sodium approved by the FDA for extended treatment of symptomatic VTE to reduce the risk of recurrence of VTE in patients with cancer (FDA 2007)
63
The CLOT Trial Study Schema

Control Group
Dalteparin 200 IU/kg OD Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo
Experimental Group
Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo
5 to 7 days
1 month
6 months
Lee AY, et al. N Engl J Med. 2003;349:146-153.
Results: Symptomatic Recurrent VTE

25 Probab bility of Recurrent VTE, % 20 15 10 5 0 0 30 60 90 120 150 180 210
CLOT Trial:
risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) g log-rank p = 0.002
VKA, 17%
dalteparin, 9%
Days Post Randomization

Lee AY, et al. N Engl J Med. 2003;349:146-153.
64
Results: Bleeding
Dalteparin N=338 Major bleed associated with death critical site* transfusion of > 2 units of RBC or d drop i Hb > 20 g/L in /L Any bleed 19 (5.6%) 1 4 14 VKA N=335 12 (3.6%) 0 3 9 0.09 pvalue 0.27
CLOT Trial:
46 (13.6%) 62 (18.5%)
*intracranial, intraspinal, pericardial, retroperitoneal, intra-ocular, intraarticular Lee AY, et al. N Engl J Med. 2003;349:146-153.
Overall,thesemetaanalysesandclinicaltrialsdonot conclusivelyestablishtheneedfororvalueofprophylaxisof CVCrelatedthrombosisincancerpatients
ChaukiyalPetal.ThrombHaemost2008;99:38
65
Influence of Thrombophilia on Thrombotic Complications of CVADs in Cancer

In10studiesinvolvingmorethan1250cancerpatientswithCVADsvsCA controls: CA+FVLOR=5.18(95%confidenceinterval:3.08.8) CA+G20210AOR=3.95(95%confidenceinterval:1.510.6)
Theattributableriskofcatheterassociatedthrombosisconferredby: FVL13.5% G20210A3.6%
CAVD=centralvenousaccessdevices DentaliF,etal.JTH.2007;5(Suppl2):PS564.
ASCO Recommendations for VTE Prophylaxis in Patients with Cancer
Summary
Patient Group
Recommended
Not Recommended
If bleeding or contraindication to anticoagulation ti l ti Otherwise, no routine prophylaxis
Hospitalized VTE prophylaxis with anticoagulants patients with cancer Ambulatory patients with cancer receiving chemotherapy Patients with cancer undergoing surgery Patients with cancer with established VTE To improve survival Myeloma patients receiving thalidomide or lenalidomide + chemotherapy/ dexamethasone. LMWH or adjusted dose warfarin. Prophylaxis with low-dose UFH or LMWH Prophylaxis with mechanical methods for patients with contraindications to pharmacologic methods Pharmacologic treatment for at least 6 months. Consider continued anticoagulation beyond 6 months in those with active cancer. -
Consider mechanical methods when contraindications to anticoagulation. g -
Not recommended
Lyman GH et al: J Clin Oncol 2007; 25:5490-5505
66
What the ASCO/NCCN Guidelines Do Not Tell Us

What is the role for emerging novel anticoagulant medications? No comparisons with LMWH Is there equivalent safety and efficacy between mq y y menoxaparin and Lovenox? Lovenox? Is there a survival advantage to the use of LMWH in cancer patients? Is there a role for adjunctive statins with anticoagulation in cancer patients? Is there a role for monitoring hypercoagulability markers in cancer patients? i ? How does palliative care influence the survival and VTE incidence data in cancer patients? How should incidental VTE be anticoagulated? anticoagulated? What is the role for retrievable IVC filters in CA patients
67

Risk Stratification Tools to Identify Patients For Primary and Secondary Prevention of VTE in Patients with Malignancy
Faculty: Alok A. Khorana, MD, FACP
Time: 7:45 8:15 p.m.
Notes:
Risk Stratification Tools to Identify Patients for Primary and Secondary Prevention of VTE in the Setting of Malignancy i th S tti f M li
Screening and VTE Risk Assessment Across the Complex Spectrum of Malignant DisordersWhat Disorders Works? What Doesnt?
ViceVice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P. Wilmot Cancer Center University of Rochester Rochester, New York
Disclosures Consultant sanofiaventis, Eisai, Leo Pharma sanofiaventis, f Speakers Bureau sanofiaventis, sanofiaventis, Leo Pharma Grant/Research Support sanofi sanofiaventis
68
VTE in Cancer Patients

Risk assessment for VTE in cancer patients Clinical risk factors Biomarkers Risk assessment tools Implications for thromboprophylaxis I li ti f th b h l i studies Secondary prophylaxis
Risk Factors for VTE

PatientPatient-related factors Older age Race, gender Comorbidities CancerCancer-related factors Site of cancer Advanced stage Ad d t Initial period after diagnosis
Rao et al., in Cancer-Associated Thrombosis. Cancer(Khorana and Francis, Eds) 2007 Eds)
TreatmentTreatment-related factors Hospitalization H i li i Chemotherapy AntiAnti-angiogenics Major surgery ErythropoiesisErythropoiesis-stimulating agents Transfusions
69
VTE and Site of Cancer

Adjusted OR (95% CI)
28 (4-199.7) 22.2 (3.6-136.1) 20.3 (4.9-83) 4.9 (2.3-10.5) 2.2 (0.9-5.4)
Type of cancer
Hematologic Lung GI Breast Prostate
Blom JW et al. JAMA 2005
VTE With Bevacizumab
14 12
Rate of VTE (%)
RR=1.29 (95% CI, 1.03-1.63) 1.03-
13% 9.9 %
10 8 6 4 2 0
Bevacizum ab (n=1,196)
RR=1.38 (95% CI, 1.12-1.70) 1.12-
6.2% 4.2% 4 2%
AllAll-Grade VTE (6 studies)
Control (n=1,08 3)
Bevacizumab Control (n=3,795) (n=3,167)
HighHigh-Grade VTE (13 studies)
However, when corrected for exposure time, RR =1.1 (95% CI, 0.89-1.36)
70
Biomarkers for CancerCancer- Associated VTE

Blood counts
Platelet count Leukocyte count Hemoglobin
D-dimer Soluble P-selectin P Tissue factor C-reactive protein Factor VIII
Incidence of VTE By Quartiles Of PrePre- Chemotherapy Platelet Count

Incidenc Of VTE Over 2.5 Months ce s(%) 6% 5% 4% 3% 2% 1% 0% <250 250-300 300-350 >350 P = 0.005
PrePre-chemotherapy Platelet Counts (x1000)
Khorana AA et al. Cancer 2005
71
Incidence of VTE by Pre-Chemotherapy PreLeukocyte Count

Inciden Of VTE Over 2.4 Months (%) nce
6% 5% 4% 3% 2% 1% 0%
<4.5 (n=342) 4.5-11 (n=3202) 4.5>11 (n=513)
3
P = 0.0008
) PrePre-chemotherapy WBC Counts (x1000/mm
Khorana AA et al. Blood 2008
Incidence of VTE by Type of Leukocyte

Absolute Neutrophil Count
9.0 8.0 7.0 6.0 5.0 4.0 3.0 30 2.0 1.0 0.0
Absolute Monocyte Count

P=0.0001
Propo ortion with VTE
P<0.0001
6.5 4.1 1.8 ANC<=7.7 ANC>7.7 2.0 AMC<=1.2 AMC>1.2
Connolly et al ISTH 2009 Abs 1573
72
Effect of Leukocyte and Platelet Counts on VTE Risk

In the Vienna CATS registry, platelet count >443,000 was associated with VTE (HR3.5) , ( )
Simanek et al, J Thromb Hemost 2009
In the REAL-2 study of advanced GEJ/gastric REALcancers, leukocytosis was associated with VTE during chemotherapy (HR 2 0) 2.0)
Starling et al, J Clin Oncol 2009
Mortality by Pre-chemotherapy PreLeukocyte Count

0.20 0.18 0.16 0 16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 0
Proportion Died
WBC>11x109/L
14.0% (8.9%-21.6%) (8.9%-
WBC< WBC<11x109/L
4.4% (3.2%-6.1%) (3.2%P <0 0001 <0.0001
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Time (Days)
MVA for early mortality: HR 2.0, p = 0.001

Kuderer et al ASH 2008 Connolly et al ISTH 2009, Throm Res 2010
73
Tissue Factor in Cancer: Lack of Standardized Assays

Immunohistochemistry
of tumor specimens
TF
ELISA MP procoagulant activity assay flow cytometry
TF
Impedance-based Impedance-
Tissue Factor Expression and VTE
30 25
Rate of VTE (%)
20 15 10 5 0 LowTF
P = 0.04
HighTF
Khorana AA, et al. Clin Cancer Res. 2007;13:2870-2875.
74
Cumulative Incidence of VTE for Cancer Patients According to TFbearing Microparticles TF
0.6 Cum mulative Incidence of VTE V 0.5 05 0.4 0.3 0.2 0.1 0.0 0 5 10 15 Months 20 25 Log R k P 0 002 L Rank P=0.002
Zwicker J I et al. Clin Cancer Res 2009;15:6830-6840 2009;15:6830-
FRAGEM and TF Biomarker Data

Boxplot of the percentage change of tissue factor antigen in the sera of pancreatic cancer patients in both the control and dalteparin groups
250 200 150 100 50 0 -50 Control Dalteparin
Maraveyas, Maraveyas, et al. Blood Coagul Fibrinolysis 2010
75
TF and Survival In Pancreatic Cancer

Median Survival in pts with TF MP-PCA >2.5 and </=2.5pg/ml. MP-
10 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Proportion surviving
Median survival was 98.5 days for TF >2.5 pg/mL pg/mL vs. 231 days for TF </= 2.5 pg/mL pg/mL p=< 0.0001
0 100 200 300 400 500 600 Days on study <2.5 700 800 900 1000
TF (pg/mL) (pg/mL)
>=2.5
N=117 patients with pancreaticobiliary cancers
Bharthuar et al ASCO GI 2010
D- dimer, F1/2 and VTE in Cancer dimer,

0.25
Cu umulative Risk (probabi ility)
Elevated D-d + F1/2 D0.20
0.15
Elevated F1/2
0.10
Elevated D-dimer D0.05 0 05
Nonelevated D-dimer Noneleva and F1/2

100 200 300 400 500 600 700
Observation Time (Days)

Ay, C. et al. J Clin Oncol; 27:4124-4129 2009
76

VTE in Cancer Outpatients
The overwhelming majority of cancer patients are treated in the outpatient/ambulatory setting p / y g Which patients are most at risk? Which patients will benefit most from prophylaxis?
How do you define high risk?
Level of risk for which prophylaxis is considered acceptable by both patients and oncologists
77
Risk Model
Patient Characteristic
Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) Platelet count > 350,000/mm3 Hb < 10g/dL or use of ESA Leukocyte count > 11,000/mm3 BMI > 35 kg/m2
Score
2 1 1 1 1 1
Risk Model Validation

8% 7% 6% 5% 4% 3% 2% 1% 0% 0.8% 0.3% n=1627 n=842 Intermediate(1-2) n=340 n=149 High(>3) 1.8% 2.0% Development cohort Validation cohort
Rate of VTE over 2.5 mos (%)
7.1%
6.7%
n=734 n=374 Risk Low (0)
78
Vienna CATS Validation
Full data available in 839 patients Median observation time/follow-up: 643 days time/follow-
Number of Events Patients n n (%)

17.7%
Score 3 Score 2
Score 3 Score 2 Score 1 Score 0
96 231 233 279
16 (17%) 25 (11%) 14 (6%) 7 (3%)
9.4%
Score 1
3.8% 1.5%
Score 0
6 months
Ay et al ISTH 2009 Abs
Expanded Risk Score with D- Dimer and sP- selectin sP-
Score 5
30.3%
Score 4
Number of Events Patients n n (%) Score 5 Score 4 Score 3 31 52 137 226 192 201 9 (29%) 10 (19%) 15 (11%) 11 (5%) 13 (7%) 4 (2%)
Score 3 Score 2 Score 1 Score 0
Score 2 Score 1 Score 0
1.0%
6 months
Ay et al ISTH 2009 Abs
79
Risk Score and Short- Term Mortality Shortby VTE Risk Score Categories
1.00
Low L Intermediate
.95
P < 0.0001
Overall Survival
.90
High
.85
.80
.75 0 10 20 30 40 50 60 70 80 90 100 110 12
Time (Days)
Kuderer NM et al. ASH 2008
International Myeloma Working Group Thromboprophylaxis Recommendations

Individual risk factors: obesity (BMI 30), prior VTE, central venous catheter Comorbid risk factors: cardiac disease, chronic renal disease, diabetes, acute infection, immobilization Surgery risk factors: t S i k factors: trauma, general surgery or any anesthesia f t l th i Medications: erythropoietin MyelomaMyeloma-related risk factors: diagnosis, hyperviscosity Myeloma therapy risk factors: multiagent chemotherapy, doxorubicin, high-dose highsteroids Patients with 1 VTE risk factor: Aspirin (81-325 mg daily) (81Patients with 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose fullwarfarin, although less existing supporting data for the latter f i lh hl i i i d f h l Patients receiving thalidomide/lenalidomide concurrently with high-dose highdexamethasone or doxorubicin should receive LMWH thromboprophylaxis Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk factors are present
Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide associated thrombosis in myeloma. Leukemia. 2008 Feb;22(2): 414-23.
80

Rates of VTE in Recent Prophylaxis Studies

Control 35.0
Rate of VTE (%)
LMWH
Aspirin
Warfarin p=0.019 31.0
30.0 30 0 25.0 20.0 15.0 10.0 5.0 50 0.0 PROTECHT N=1165 Myeloma CONKO004 N=930 N=312 FRAGEM N=123
2.9 1.4 p=NS 5.0 6.0 p<0.01 14.5 12.0 5.0
8.0
Agnelli et al Lancet Onc 2009 Palumbo et al ASH 2009 Riess et al ISTH 2009 Maraveyas et al ESMO 2009
81
VTE in Lung Cancer: PROTECHT and TOPIC studies

sVTE LMWH PROTECHT TOPIC-2 All 3.5% 3% 3.2% sVTE Placebo 5% 5.7% 5.5% All VTE LMWH 4% 4.5% 4.3% All VTE Placebo 6.2% 8.3% 7.8%
Major Bleeding LMWH PROTECHT TOPIC-2 All

Verso et al. JTH 2010 online
Major Bleeding Placebo 0% 2.2% 1.7%
1% 3.7% 2.5%
NNT=50 (sVTE) NNT=28 (allVTE) RRR=46% NNH=125
Ongoing Clinical Trials

Study (Agent) Criteria for inclusion* N Endpoints
Asymptomatic and symptomatic VTE DVT, PE, VTErelated death
PHACS -Risk score >=3 (dalteparin x 12 wks) SAVE-ONCO (semuloparin up to 4 mos) -Lung, bladder, GI, ovary -Metastatic or locally advanced
404
3200
-Lung colon pancreas Lung, colon, MicroTEC -Metastatic or (enoxaparin x 6 mos) unresectable -Elevated TF MPs
227
VTE
* All studies enroll patients initiating a new chemotherapy regimen
82

Predictors of Recurrent VTE: Findings from the RIETE Registry
Recurrent PE

Age < 65 (OR 3.0) PE at entry (OR 1 9) 1.9) < 3 months from diagnosis of cancer (OR 2.0) Age < 65 (OR 1.6) < 3 months from diagnosis of cancer (OR 2.4) g
Recurrent DVT

Patients with leukocytosis had increased risk of recurrent VTE and death (OR 2.7)
Trujillo-Santos et al Thromb Haem 2008
83
CLOT Study:
Reduction in Recurrent VTE
25 Probability of Recurrent VTE, % 20 15 10 Dalteparin 5 0 0
Lee et.al. N Engl J Med, 2003;349:146
Recurrent VTE
Risk reduction = 52% p-value = 0.0017
OAC
30
60
90
120
150
180
210
Days Post Randomization
Treatment of CancerCancer- Associated VTE

Study Design
Dalteparin OAC Enoxaparin OAC Tinzaparin OAC Enox (Low) Enox (High) OAC 6 3 3
Length of Therapy
(Months)
6
N
336 336 67 71 80 87 32 36 34
Recurrent VTE (%)

9 17 11 21 6 11 3.4 3.1 6.7
N S
Major Bleeding (%)

6 4 7 16 6
NS
Death (%)
39 41 11 23 23 22
NS
CLOT Trial (Lee 2003)

CANTHENOX (Meyer 2002) LITE (Hull ISTH 2003) ONCENOX (Deitcher ISTH 2003)
0.002
0.0 9
0.0 9
0.03
0.03 8
N S
N S
N S
NR
84
Conclusions
Cancer
patients are clearly at increased risk for VTE but risk varies widely 53% of cancer patients are unaware that they are at high risk for VTE
Yet,
Sousou et al, Ca Inv 2010
High-risk High-
subgroups can be identified based on clinical risk factors and biomarkers recently validated risk model can predict risk of VTE (and mortality) using 5 simple clinical and laboratory variables
Conclusions
LMWH-based prophylaxis is safe and effective in LMWHcertain high-risk settings high
Hospitalized and surgical patients Highly selected cancer outpatients (myeloma, ?pancreas, ?? lung)
Ongoing studies are adopting novel approaches to selecting patients for prophylaxis Clinicians need to conduct baseline and ongoing risk assessment for VTE in cancer patients receiving chemotherapy
85

Program Chairmans Concluding Vision Statement: Current and Near Future Perspectives of VTE Management in the Setting of Malignancy
Faculty: Samuel Z. Goldhaber, MD Program Chairman Time: 8:15 8:30 p.m.
Notes:
VISION STATEMENT
VTE in the Setting of Malignancy
86
Disclosures Research Support: BMS; Boehringer-Ingelheim; Eisai; Johnson Boehringer-Ingelheim; & Johnson, Sanofi-Aventis SanofiConsultant: Boehringer-Ingelheim; Boehringer-Ingelheim; BMS; Eisai; EKOS: Medscape; Medscape; Merck; Pfizer; Sanofi-Aventis Sanofi-
Toward Eradication of InInHospital VTE: The Promise of Prophylaxis VITAE Studies
87
VTE Prophylaxis in 19,958 Medical Patients/9 Studies (Meta- analysis) (Meta-
62% 57% 53%
reduction in fatal PE reduction in fatal or nonfatal PE reduction in DVT
Dentali F, et al. Ann Intern Med 2007; 146: 278-288 278-
VITAE I VITAE I uses a Federal database to model p Hospitalized Medical Patients with VTE. 2 of every 100 hospitalized Medical Service patients suffer VTE. With universal in-hospital prophylaxis, the VTE inrate would be cut by 58%.
Thromb Haemost 2009; 102: 505-510
88
58% Reduction in VTE with Universal Prophylaxis in Hospitalized Medical Patients

40000 35000 30000 25000 20000 15000 10000 5000 0
Current prophylaxis rates
100% prophylaxis
Thromb Haemostas 2009; 102: 505-510
VITAE II VITAE II models the 5-year aftermath of initial 5VTE among these same Hospitalized Medical Patients who were initially stricken. If universal prophylaxis had been utilized initially, the 5-year VTE complication rates of 5death, recurrence, PTS, and CTEPH would have been reduced by 60%.
Thromb Haemost 2009; 102: 688-693 688-
89
VITAE II
Status Quo 100% VTE Prophylaxis
Thromb Haemost 2009; 102: 688-693 688-
Conclusions 1. 2. 3. Electronic alerts can identify hospitalized cancer patients at risk for VTE. Optimal prophylaxis for hospitalized cancer patients is LMWH. When VTE is diagnosed in cancer patients, patients the only FDA-approved LMWH FDAfor Rx as monotherapy without warfarin is dalteparin. dalteparin.
90
Conclusions (Continued) (Continued) 4. ACCP guidelines state that every hospital should develop a formal strategy to p gy prevent VTE. As cancer therapies improve, quality lifelifeyears will be extended. DVT and PE will be mostly prevented in cancer patients, and when necessary to treat, will be managed will LMWH monotherapy. monotherapy.
5. 6. 6
91

Interactive Q &A Discussion Session
Faculty: Faculty Panel Time: 8:30 8:45 p.m.
Notes:
British Journal of Cancer (2010) 102, S17 S23 & 2010 Cancer Research UK All rights reserved 0007 0920/10 $32.00
www.bjcancer.com
Full Paper
Treatment and secondary prevention of venous thromboembolism in cancer

R Coleman*,1 and P MacCallum2

1
Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Whitham Road, Sheff ield S10 2SJ, UK; 2Barts and The London School of Medicine and Dentistry, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
Patients with cancer who develop venous thromboembolism (VTE) are at elevated risk for recurrent thrombotic events, even during anticoagulant therapy. The clinical picture is further complicated because these patients are also at increased risk of bleeding while on anticoagulants. In general, there are four key goals of treatment for VTE: preventing fatal pulmonary embolism (PE); reducing shortterm morbidities associated with acute leg or lung thrombus; preventing recurrent VTE; and preventing the long-term sequelae of VTE (e.g., post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension). A fifth goal minimising the risk for bleeding while on anticoagulation is particularly warranted in patients with cancer. Traditionally, pharmacological treatment of VTE has two phases, with the transition between phases marked by a switch from a rapid-acting, parenterally administered anticoagulant (such as unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux) to an oral vitamin K antagonist (e.g., warfarin). Recent clinical trials of established agents and the advent of new pharmacological options are changing this paradigm. Low-molecular-weight heparin continued for 6 months is more effective than warfarin in the secondary prevention of VTE in cancer patients without increasing the risk of bleeding and is now the preferred treatment option. Given the impact of VTE on short-term and long-term outcomes in patients with cancer, a group of health-care providers based in the United Kingdom gathered in London in 2009 to discuss recent data on cancer-associated thrombosis and to evaluate how these recommendations can be integrated or translated into UK clinical practice. This article, which is the third of four articles covering key topics in cancer thrombosis, focuses on treatment and secondary prevention of VTE in cancer patients. British Journal of Cancer (2010) 102, S17 S23. doi:10.1038/sj.bjc.6605601 www.bjcancer.com & 2010 Cancer Research UK
Keywords: venous thromboembolism; heparin; warfarin
It has been clearly established that patients with cancer have an increased risk of venous thromboembolism (VTE) compared with patients without cancer. Venous thromboembolism, comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is an important cause of morbidity and mortality in cancer patients and its treatment is particularly difficult because standard therapy is less effective in preventing recurrences and causes more bleeding than is the case in non-cancer patients with VTE. The need to perform surgery or invasive procedures in patients with cancer receiving anticoagulants, as well as the frequent presence of thrombocytopenia due to chemotherapy or haematological malignancy, widespread use of in-dwelling central lines, administration of multiple interacting drugs, and varying dietary intake during the course of cancer therapy, all add to the particular challenges faced in VTE treatment. Randomised clinical trials over the past decade have substantially altered the management of VTE in patients with cancer, leading to improved outcomes and quality of life. Unfractionated heparin (UFH) and vitamin K antagonists (e.g., warfarin) have been the mainstay of management of VTE since the mid-twentieth century, followed by the widespread replacement of UFH by low-molecular-weight heparins (LMWH) since the 1990s. The appearance of new classes of oral anticoagulants that directly inhibit specific clotting factor targets, such as thrombin and factor
*Correspondence: Professor R Coleman; E-mail: R.E.Coleman@sheffield.ac.uk
Xa, may further transform the management of VTE in patients with cancer in the years to come. Venous thromboembolism is a major cause of death in patients with cancer receiving chemotherapy (Khorana et al, 2007). Compared with patients without cancer, patients with cancer have a three-fold elevated risk of recurrent DVT or PE, following an initial episode of VTE. For example, in a prospective study, Prandoni et al (2002) observed a 12-month cumulative incidence of recurrent thromboembolism of 20.7% in 181 cancer patients, compared with 6.8% in patients without cancer. Both groups were managed in the same standard manner with initial heparin followed by warfarin. Levitan et al (1999) showed that the cumulative probability of re-admission to the hospital with DVT among patients initially hospitalised for DVT and malignant disease was approximately three-fold higher than those initially hospitalised with DVT alone. A more recent retrospective study, conducted by Elting et al (2004) using medical records from 529 consecutive cancer patients, found an overall rate of recurrence of 17%, ranging to as high as 32% in patients with inferior vena caval (IVC) filters. Similarly, in 2006, Blom et al (2006) found that the risk of VTE within the first 6 months after a first thrombotic event was 18.4/1000/0.5 year, with a 4.6-fold increased risk compared with cancer patients who did not have a thrombotic event in the 6 months after cancer diagnosis. In this study, patients with leukaemia, brain cancer, or cancer of the bladder, ureter, or testes were at highest risk for recurrence. In the RIETE registry of 15 520 consecutive patients with VTE, cancer was present in 20% and was
Treatment and secondary prevention of VTE in cancer R Coleman and P MacCallum
S18 associated with a two-fold increase in the risk of fatal PE within 3 months (Laporte et al, 2008). Risk factors for the recurrence on multivariate analysis were age o65 years or o3 months from cancer diagnosis to VTE (Trujillo-Santos et al, 2008). Those presenting with PE were more likely to have a PE recurrence than those initially presenting with DVT. The clinical picture is further complicated by the fact that patients with cancer are also at increased risk of bleeding during anticoagulant therapy. In the study conducted by Prandoni et al (2002), referred to above, the 12-month cumulative incidence of major bleeding was 12.4% in patients with cancer and 4.9% in patients without cancer a hazard ratio of 2.2. Notably, both recurrence and bleeding were directly related to cancer severity, and could not be explained by over- or under-anticoagulation (Prandoni et al, 2002). Similarly, in the study by Elting et al (2004), the risk of major bleeding during anticoagulant therapy was 12% (Elting et al, 2004). In the RIETE Registry, cancer was independently associated with a 1.7-fold increased risk of major bleeding (Ruiz-Gimenez et al, 2008). Risk factors for bleeding in cancer patients were immobility, metastases, recent bleeding, or creatinine clearance o30 ml min1 (Trujillo-Santos et al, 2008). A number of evidence-based guidelines on the management of VTE in both cancer and non-cancer patients have recently been published (Lyman et al, 2007; Kearon et al, 2008; Torbicki et al, 2008; NCCN, 2009). Given the impact of VTE on short-term and long-term outcomes in patients with cancer and a potential gap between current guidelines and national clinical practice a group of health-care providers based in the United Kingdom gathered in London in 2009 to discuss recent data and guidelines on cancerassociated thrombosis and to evaluate how these recommendations can be translated into best practices for the United Kingdom. This article, which is the third of four articles covering key topics in cancer thrombosis, focuses on treatment and secondary prevention of VTE in the cancer patient. The paper is structured as a brief review of key data and guidelines on acute treatment and secondary prevention of VTE in patients with cancer, followed by an edited transcript of the discussion surrounding these data. see Kearon et al, 2008). The trial that enrolled patients with symptomatic PE (with or without symptomatic DVT), who were randomly allocated to 1.5 days of heparin and 14 days of vitamin K antagonist therapy or no treatment, showed that anticoagulation significantly reduced recurrent PE and mortality. The need for initial treatment with a rapid-acting anticoagulant such as heparin was confirmed in a trial by Brandjes et al (1992). In this study, patients were assigned to either combination therapy (intravenous loading dose of 5000 U heparin, followed by an infusion of 1250 U h1 for a minimum of 7 days, in combination with vitamin K antagonist acenocoumarol) or to acenocoumarol alone (Brandjes et al, 1992). The study was ended early because of an excess of events in the acenocoumarol group (20%) compared with the combined-therapy group (6.7%). Asymptomatic extension of venous thrombus was seen in 39.6% of patients in the acenocoumarol group and in 8.2% of the combination group. Notably, the rate of major bleeding was comparable in the two groups (Brandjes et al, 1992). Although UFH as an initial treatment for VTE is highly effective, it is associated with a number of important limitations, including a short half-life, wide interpatient and intrapatient variability due to pharmacokinetic shortcomings, the need for frequent monitoring, a risk for heparin-induced thrombocytopenia, and, with long-term therapy, osteoporosis (a detailed discussion of the advantages and shortcomings of heparin can be found elsewhere in this supplement). Low-molecular-weight heparins have more predictable pharmacokinetics and greater bioavailability, which permits body-weight-adjusted dosing without the need for laboratory monitoring for most patients. This makes therapy much simpler and allows for outpatient treatment of many patients, reducing hospitalization, and improving their quality of life. A number of clinical studies and meta-analyses have compared the efficacy and safety of body-weight-adjusted LMWH, administered subcutaneously without monitoring, with monitored, doseadjusted intravenous heparin (Quinlan et al, 2004; van Dongen et al, 2004) and found it to be more effective, with reduced major bleeding during initial treatment and overall mortality at follow-up (van Dongen et al, 2004). Individual studies have not specifically assessed the effect of LMWH as initial treatment in patients with cancer. However, a meta-analysis of 14 trials that included cancer subgroup data showed that LMWH was equivalent to UFH for mortality (RR 0.89, 95% CI 0.61 1.27) and for clinically suspected DVT (RR 0.73, 95% CI 0.23 2.28) (Akl et al, 2008). In a post hoc analysis that included all studies that assessed DVT (irrespective of diagnostic strategy), LMWH was superior to UFH (RR 0.72, 95% CI 0.55 0.94). Rates of PE and minor or major bleeding were similar for the two strategies. Data on the subcutaneously administered factor Xa inhibitor, fondaparinux, in the initial treatment of VTE associated with cancer are more limited. Post hoc analyses of the cancer patient subgroups of two randomised trials (Buller et al, 2003, 2004) in which fondaparinux was compared with UFH (for initial treatment of PE) or LMWH (for initial treatment of DVT) suggest broadly similar efficacy and safety (van Doormaal et al, 2009). However, these data require confirmation. In summary, LMWHs, or possibly fondaparinux, are the agents of choice for the initial treatment of most episodes of VTE occurring in patients with cancer. An exception is in the setting of massive PE characterised by shock or hypotension in which UFH remains the preferred mode of anticoagulation, as newer agents have not been properly evaluated and an immediate anticoagulant effect is required.
TREATMENT OF VTE IN CANCER PATIENTS

In general, the goals of VTE treatment can be summarised as follows: (1) preventing fatal PE; (2) reducing short-term morbidities associated with acute leg or lung thrombus; (3) preventing recurrent VTE; (4) preventing the long-term sequelae of VTE (e.g., post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension). Anticoagulant therapy is the mainstay of treatment for VTE. Traditionally, pharmacological treatment of VTE has two phases, with the transition between phases marked by a switch from a parenterally administered anticoagulant with a rapid mechanism of action (e.g., UFH, low-molecular-weight heparin (LMWH), or fondaparinux (a synthetic pentasaccharide with the same antithrombin-dependent inhibition of factor Xa as LMWH)) to an oral vitamin K antagonist (e.g., warfarin). As will be discussed, recent clinical trials of established agents and the advent of new pharmacological options may change this paradigm. In addition to anticoagulants, a number of additional options exist for acute VTE, including systemic thrombolytic therapy, catheter-directed thrombolysis, mechanical thrombectomy, and use of vena caval filters.
Initial treatment of VTE

The use of UFH in the initial treatment of VTE is well established. The first and only trial that compared anticoagulant therapy with no therapy was published in 1960 (Barritt and Jordan, 1960,
British Journal of Cancer (2010) 102(S1), S17 S23
MANAGEMENT OF MASSIVE PE
Massive PE constitutes a medical emergency, and specialised medical advice should be sought. Patients presenting with PE
& 2010 Cancer Research UK
S19 should be clinically risk stratified into high-risk and non-high-risk groups. The former is characterised by systolic hypotension (BPo90 mm Hg) (Torbicki et al, 2008) and carries a short-term mortality of 415% (Torbicki et al, 2008). Pooled data from randomised trials in non-cancer patients suggest a significant reduction in mortality and PE recurrence with systemically administered thrombolytic therapy in this subgroup (Wan et al, 2004). Intravenous heparin should be started immediately (80 U kg1 as a bolus, followed by infusion at the rate of 18 U kg1 h1 and adjusted to keep the activated partial thromboplastin time (aPTT) ratio between 1.5 and 2.5 times control) (Torbicki et al, 2008). Oxygen should be administered if the patient is hypoxic (Torbicki et al, 2008). A number of thrombolytic regimens are approved for PE. In practice, recombinant tissue plasminogen activator (rtPA) is commonly used at a dose of 100 mg over 2 h, or at 0.6 mg kg1 over 15 min (maximum dose 50 mg) if the patient is rapidly deteriorating (Torbicki et al, 2008). In patients in whom thrombolytic therapy is contraindicated (e.g., intracranial bleeding), alternative approaches, depending on local availability and expertise, are surgical pulmonary embolectomy and percutaneous catheter embolectomy and fragmentation (Torbicki et al, 2008). Interruption of therapy is more likely in patients with cancer and, given the slow onset and offset of action of warfarin, this can lead to considerable gaps in anticoagulant coverage (Bick, 2006). In addition to these issues, some evidence suggests that patients with cancer who are receiving warfarin are not only at particular risk for recurrent thromboembolic events but also have an increased risk for bleeding (Prandoni et al, 2002). As a result of the shortcomings of warfarin in cancer patients, the possible benefits of LMWH for prevention of recurrent VTE have been evaluated in a number of randomised trials. The largest of these was the CLOT trial in which, after initial standard LMWH treatment, oral anticoagulation and LMWH (dalteparin) were compared for prevention of recurrent VTE in 672 patients with cancer (Lee et al, 2003). The recurrence rate over 6 months was 9% in the LMWH group compared with 17% in the oral anticoagulant group, a 52% (P 0.002) reduction in favour of LMWH (Figure 2). There were no significant differences in major bleeding or death between the two groups (Lee et al, 2003). In this trial, dalteparin was administered at a full-treatment dose for the first month, followed by a 75% treatment dose for the remaining 5 months (Lee et al, 2003). This regimen is now licensed in the United Kingdom for treatment of VTE in patients with cancer, and a number of systematic reviews and meta-analyses comparing LMWH with oral anticoagulation in the long-term treatment of VTE in patients with cancer have been published (Akl et al, 2008; Noble et al, 2008; Louzada et al, 2009). They show that, compared with oral anticoagulants, LMWH reduces the risk of recurrence by about 50%, with no difference between treatment modalities in major bleeding or mortality. The use of anticoagulation in the thrombocytopenic patient remains challenging. Different options can be considered. For example, the label for dalteparin recommends a reduction in daily dose of 2500 IU if the platelet count falls to 50 100 109/l, until it recovers to X100 109/l, and discontinuation if the platelet count falls to o50 109/l. In a prospective cohort study, 203 patients with metastatic cancer and VTE received LMWH at treatment dose for 1 week (Monreal et al, 2006). The dose was then reduced to 10 000 IU daily, irrespective of weight, for 3 months. The dose was further reduced to 5000 IU daily at platelet counts o50 109/l and to 2500 at counts o10 109/l. Recurrent VTE developed in 9% of patients (fatal in two patients). Five percent had a major bleed (fatal in six patients) (Monreal et al, 2006). Although unsupported by specific data, others have recommended a 50% dose reduction of LMWH if the platelet count is o50 109/l and discontinuation if the platelet count is o20 109/l (Falanga and Rickles, 2007). Consideration should be given to insertion of a vena caval filter if anticoagulation is contraindicated because of thrombocytopenia or active bleeding, but again firm data are lacking. Thus, the optimal approach to management of VTE in this setting is
25 20 15 10 5 0 0 30 301 280 60 90 120 150 Days after randomisation 264 242 235 221 227 200 210 194 180 164 154 210 Dalteparin
Secondary prevention of VTE

Heparins are used in the initial treatment of VTE to provide anticoagulant support during the period of time required to achieve an appropriate international normalised ratio (INR), generally 2.0 3.0, with oral warfarin. In patients without cancer, warfarin is subsequently continued for a period of up to 6 months or longer. The need for anticoagulation beyond the initial period of heparinisation was demonstrated 30 years ago (Hull et al, 1979). Subsequently, a large, multicentre, randomised trial suggested that longer-duration warfarin (6 months) was superior to shortduration therapy (6 weeks). In this study, 902 patients were randomly assigned to receive either 6 weeks or 6 months of oral anticoagulant therapy with a target INR of 2.0 2.85 (Schulman et al, 1995). At 2 years, the rate of recurrence in the 6-week group was 18.1%, compared with 9.5% in the 6-month group (see Figure 1). There was no difference between the groups in mortality or in the rate of major haemorrhage (Schulman et al, 1995). Although warfarin is effective in preventing VTE recurrence, its safe use in cancer patients is complex. Warfarin has more than 200 known drug, food, or botanical interactions that can result in irregular responses to treatment (Bick, 2006). In cancer patients, malnutrition, nausea, vomiting, and diarrhoea may make achieving and maintaining a therapeutic INR with an oral agent challenging. The need for therapeutic monitoring may also present a considerable challenge and/or an undue burden to the patient.
0.2 Cumulative probability of recurrence
Probability of recurrent venous thromboembolism (%)
P = 0.002 Oral anticoagulant
6-week group 0.1 6-month group
0.0 0 2 4 6 8 10 12 14 Months 16 18 20 22 24
No. at risk Dalteparin Oral anticoagulant
336 336
Figure 1 Cumulative probability of recurrent VTE after a first episode, according to duration of anticoagulation with a vitamin K antagonist (Schulman et al, 1995). Copyright r [1995] Massacusetts Medical Society. All rights reserved.
Figure 2 Probability of symptomatic recurrence of VTE among patients with cancer, according to whether they received secondary prophylaxis with dalteparin or oral anticoagulant therapy for acute VTE. Reproduced with permission from Lee et al (2003).
S20 uncertain. In individual circumstances in which there is a clear wish not to interrupt LMWH therapy, it may be reasonable to continue at a slightly reduced dose with platelet support to maintain the count 450 109/l and to reduce to a prophylactic dose, discontinue LMWH, or consider insertion of a vena caval filter if this is not possible. 3-month follow-up, including one fatal event (Monreal et al, 2006). In routine practice, the catheter is commonly removed and the patient is anticoagulated with LMWH in the standard way for VTE in patients with cancer (i.e., with LMWH) for at least 3 months. Whether it is necessary to remove the catheter is unclear. Current recommendations from the National Comprehensive Cancer Network (NCCN) are to remove the catheter if it is not required and anticoagulate for at least 3 months. If the catheter is required and there is no contraindication to anticoagulation, it may be reasonable to leave the catheter in place and anticoagulate for at least 3 months after it is eventually removed. If symptoms worsen while the catheter remains in place or if anticoagulation is contraindicated, the catheter should be removed (NCCN, 2009).
Duration of anticoagulant therapy

The optimal duration of anticoagulant therapy for prevention of recurrent VTE in patients with cancer has not been specifically studied. Guidelines recommend that it should continue as long as the patient has active cancer (Lyman et al, 2007). In practice, this means indefinite treatments in patients with metastases or in those receiving anticancer therapy. However, each patient should be assessed individually in terms of the risk/benefit ratio of continuing vs stopping anticoagulants, life expectancy, quality of life, and patient preference. The CLOT trial data referred to earlier in favour of LMWH over oral anticoagulation did not extend beyond 6 months. It seems likely that the benefit of LMWH would extend beyond this period if continuing anticoagulation is required, but consideration may be given to oral anticoagulant therapy in individual instances.
Therapeutic anticoagulation failure

Therapeutic anticoagulation failure, defined as an extension of DVT, or new DVT, or PE while on therapeutic levels of recommended anticoagulation therapy, is relatively common in patients with cancer (Prandoni et al, 2002). The recurrence rate in the LMWH arm of the CLOT trial was 9%, much higher than would be seen in a non-cancer population of patients with VTE. Management in this setting has not been systematically studied, and the measures taken in practice depend in part on the individual circumstances in which the recurrence took place. Among patients receiving vitamin K antagonist therapy, INR should be assessed and adjusted, if necessary, to a higher INR range after acute therapy with UFH or LMWH (Streiff, 2006). Alternatively, and particularly among patients who experience recurrence despite therapeutic levels of a vitamin K antagonist, long-term LMWH represents a reasonable option. Vena caval filters represent another option in patients with therapeutic anticoagulation failure, particularly in those with VTE who have contraindications to anticoagulant therapy (NCCN, 2009). However, the hypercoagulable state associated with cancer affects all vasculature; thus, regional approaches to preventing recurrent VTE, such as vena caval filters, may not provide adequate protection in these patients (Streiff, 2006). In fact, placement of an IVC filter may be associated with an increased risk for recurrent thromboembolic disease (NCCN, 2009). When a recurrent thrombotic event occurs in a patient receiving heparin (UFH or LMWH), a diagnosis of heparin-induced thrombocytopenia should be considered. Expert advice should be sought, if necessary, for confirmation of diagnosis and provision of non-heparin anticoagulants. More commonly, recurrence represents therapeutic failure. Compliance issues should be considered along with escalation of the dose of LMWH or converting from a once-daily to a twice-daily regimen (NCCN, 2009). For patients receiving a 75 80% maintenance dose of LMWH, this would mean increasing to a treatment dose. For those receiving a treatment dose at the time of recurrence, the dose could be increased by 20 25%. This approach was reported in a recent retrospective cohort study of 70 cancer patients with recurrent VTE despite anticoagulation (67% while on LMWH, 33% while receiving a vitamin K antagonist) (Carrier et al, 2009). Six (8.6%) patients had a second recurrence with this approach. The dose was further escalated by 20 25% in three patients who had a further VTE event at 120% of a therapeutic dose. None of them had a thrombotic recurrence; however, bleeding was seen in 3 out of 70 patients. In conclusion, management of VTE in patients with cancer remains a challenge. Recent data support the use of LMWH both as the initial treatment for VTE and as the preferred option for secondary prevention. It should continue for a minimum of 6 months and longer if the cancer remains active. Both recurrent thrombosis and bleeding remain common problems, and further studies are required to optimise management. The advent of new anticoagulants, many of them oral, will hopefully provide
Prevention of PTS
Post-thrombotic syndrome is a common cause of morbidity following DVT. It occurs in 20 50% of patients overall after symptomatic DVT. Typical features include chronic pain, swelling, heaviness, oedema, and skin changes in the affected limb (Kahn, 2006) and can be difficult to distinguish clinically from recurrent DVT. Use of graduated compression stockings providing an ankle pressure of 40 mm Hg for 2 years has been compared with no mechanical support and shown to reduce the incidence of total and severe PTS by approximately 50% (Brandjes et al, 1997).
Vena caval filters

There is only one open-label randomised trial of IVC filters in patients (mostly without cancer) presenting with VTE (PREPIC, 2005). In this trial, the filters were permanent and all patients received standard anticoagulant therapy. Long-term follow-up suggested that filter insertion was associated with a reduced risk of PE, counter-balanced by an increased risk of DVT, and no overall effect on mortality (PREPIC, 2005). Guidelines on the use of vena caval filters were published by the British Committee for Standards in Haematology (Baglin et al, 2006). The consensus was that there were no strong evidence-based indications for filters but their use should be considered in cases in which anticoagulation is contraindicated, or has to be interrupted within the first month of treatment to allow surgery, or in which there is occurrence of PE despite adequate anticoagulation. In those cases in which anticoagulation is contraindicated, it should be resumed as soon as the contraindication is no longer present, and retrievable filters should be considered in this setting. Such filters should be retrieved within 3 months of insertion where appropriate, or else left in permanently.
Treatment of central venous catheter-related thromboembolism

No randomised, controlled trials have been reported that evaluate the effects of particular therapeutic strategies on the outcomes of central venous catheter (CVC)-related thrombosis. Indeed, both the natural history and management of CVC-related thrombosis have been studied surprisingly little. In the RIETE Registry of 104 patients with cancer and CVC-related thrombosis, 10% of patients presented with symptomatic PE and 4% developed recurrent PE at
S21 significant advances in therapy, although the challenge of providing anticoagulation without increasing the risk of bleeding is likely to remain. Ajay K Kakkar: Dosing presents a major issue with some LMWHs. How do you assess the appropriate de-escalated dose to ensure that the safety profile of the regimen is maintained? LMWH is dosed close to the margin for an increased rate of bleeding, so it is important to be very regimen sensitive when using these agents. John Pasi: Separately, recurrent thrombosis occurring in fully anticoagulated cancer patients is a major issue. Faculty: I agree. Most of the calls I get from the oncology unit are about patients who have had a recurrent event while on anticoagulation. At the moment, there are no good answers, and one has to make a common sense judgment regarding the treatment of these patients. Another key issue is anticoagulation in thrombocytopenic patients. Faculty: Can we discuss duration of therapy? Many believe that patients with advanced disease should stay on indefinite anticoagulation. I want to challenge that, particularly in the typical breast or prostate cancer patient who has a median survival of 35 years. Peter K Maccallum: The current recommendations suggest that indefinite coagulation should be considered. Faculty: But if a patient is in remission, is it safe to stop? I do not know of any physicians who keep cancer patients on anticoagulation for 3 5 years after their first clot. Annie M Young: It does happen in clinical practice. Faculty: I would suggest that even patients with stable disease are at higher risk of VTE than patients without cancer. Peter K Maccallum: There is an opportunity to include this in the consensus statement. If you look at global guidelines, the view is generally that antithrombotic therapy should be continued while there is active cancer or active anticancer therapy. However, there is always a question with breast cancer what should physicians do with patients who are on tamoxifen for 5 years? I think this is a very difficult question, because warfarin is associated with a major risk for bleeding. In my opinion, warfarin at a full anticoagulant dose in such good-prognosis patients is problematic. Faculty: Again, there is some role for discussion with patients. In the clinic, we often ask patients whether bleeding or having another VTE is their biggest worry. For many of them, thrombosis is a significant issue. Ajay K Kakkar: This discussion clearly reflects the real problem of where we are in terms of treatment. We have solid data to guide treatment for the first 6 months, but no real guidance thereafter.
DISCUSSION
Annie M Young: Should we be switching people that are on warfarin to low-molecular-weight heparin? Specifically, how should we manage patients who have had pulmonary emboli, are on warfarin, and have had treatment for cancer? Peter K Maccallum: There are 2 issues. One is probably education of clinicians. We used to get a lot of patients who would come in under the relevant medical team and then be referred to the anticoagulant clinic on warfarin. In my experience, a small proportion of patients are prepared to stay on warfarin, but the majority who are offered LMWH switch. Annie M Young: I do not think outpatients are permitted a choice. Ajay K Kakkar: There are 2 reasons for that. First, dalteparin was not available in the UK until recently for this indication. The second issue is the point you raised. There will be a very large number of people who, beyond 6 months, will be on warfarin, because the general consensus view is that cancer patients with VTE should receive anticoagulant therapy to prevent recurrent thrombosis. Therefore, even in centres that use LMWH for the first 6 months of therapy, they put them on warfarin because they do not want to promote self-injection. There is a study ongoing to evaluate whether 12 months of anticoagulation with LMWH is more effective and as safe as 6 months of treatment. Another complicating factor is the recent availability or imminent availability of newer agents. The studies for these agents will include a small number of cancer patients, and it might be assumed that these agents should also be used in patients with cancer-associated thrombosis. Faculty: Many haematologists are not aware of the issues surrounding anticoagulation for the secondary prevention of VTE, and they tend to keep people on warfarin. There are also many haematologists who keep patients on LMWH, but reduce the dose by 75% at 6 months. Peter K Maccallum: In the absence of evidence, one can have a discussion with the patient to make a decision. There are some patients who are, by the end of the 6 months, unwilling to continue daily injections. Faculty: Another problem is the drug-drug interactions seen with warfarin, particularly in the cancer patient who is undergoing treatment. In many ways, LMWH is easier to use. Faculty: Qualitative data also suggest that warfarin has a negative effect on quality of life in patients with cancer, in part because these patients require frequent venopuncture for monitoring, but also because of the uncertainty and lack of freedom imposed by the monitoring regimen.
CONSENSUS STATEMENT
Following the development of VTE, cancer patients remain at elevated risk for recurrent thrombotic events. Treatment is further complicated by the increased risk of bleeding while on anticoagulants. Acute management of VTE to prevent a fatal pulmonary embolus, as well as reduction in both short-term and long-term
Table 1
Agent Dalteparin sodium
Regimens and contraindications for LMWH in the United Kingdom

Brand name Regimen for secondary prevention Fragmin For extended treatment: 1 K 200 IU kg (max 18 000 IU) s.c. once daily 1 month 1 K Then 150 IU kg (max 18 000 IU) s.c. once daily 5 months (Fragmin PI, 2009)
K K
Key contraindications/cautions in patients with cancer

K K
Enoxaparin sodium Tinzaparin
Clexane Innohep
1.5 mg kg1 once daily for extended prophylaxis (Meyer et al, 2002) 175 U kg1 once daily (Hull et al, 1979)
K K
Patients with cancer undergoing regional anaesthesia (Fragmin PI, 2009) Dose reduction may be warranted in patients with cancer who experience thrombocytopenia or have renal insufficiency (Fragmin PI, 2009) Use with caution in patients with renal or hepatic impairment and in low-weight patients (Clexane PI, 2009) Use with caution in patients with renal impairment
Note that some regimens are based on studies conducted in non-cancer patients.
S22 sequelae of thrombosis, relies on the use of a rapid-acting, parenterally administered anticoagulant such as UFH, LMWH, or fondaparinux (see Table 1). In non-cancer patients, an oral vitamin K antagonist (e.g., warfarin) may be initiated and continued for at least 6 months, with indefinite treatment considered in patients at increased risk of recurrence. In contrast, in patients with VTE and cancer, LMWH is now the preferred approach because of better protection against recurrent thrombosis without increasing the risk of bleeding. It has additional advantages in this population in that it is more flexible in terms of interruption for invasive procedures or thrombocytopenia and avoids the need for close INR monitoring that is essential with warfarin and is particularly challenging in cancer patients. The result is that blood tests and hospital visits can be minimised, thereby improving the quality of life. Warfarin may still be used in cases in which there is a clear patient preference to avoid injections. If the cancer is in remission and there are no additional risk factors for recurrence, anticoagulant therapy can generally be stopped at 6 months. If the cancer remains active or there are ongoing risk factors, consideration should be given to continuing anticoagulation beyond 6 months, after discussing with the patient. Randomised trials have not been conducted beyond this stage in these patients. Low-molecular-weight heparin is likely the option of choice in cases in which the decision is taken to continue anticoagulation, but warfarin is an alternative approach in cases in which this would be preferred by the patient. Massive pulmonary embolus, catheter-related thrombosis, and recurrent VTE despite anticoagulation are clinical scenarios for which evidence on management in the setting of malignancy is limited. However, guidance on treatment, based on the limited evidence, extrapolation from a non-malignant setting, and clinical expertise are provided. Management recommendations are based on the NCCN Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease (NCCN).
Conflict of interest
R Coleman has received lecture fees from Pfizer and grant support from Boehringer Ingelheim. P MacCallum has received consulting fees from Pfizer and Boehringer Ingelheim.
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CLINICAL SCENARIOS
Treatment of limb VTE Acute management * Commence LMWH in preference to UFH Dalteparin 200 U kg1 once daily s.c. Tinzaparin 175 U kg1 once daily s.c. Enoxaparin 1.5 mg kg1 once daily s.c. (alternatively, enoxaparin 1 mg kg1 every 12 h s.c.) * Fondaparinux may be considered Fondaparinux 5 mg (o50 kg); 7.5 mg (50 100 kg); 10 mg (4100 kg) daily s.c. Maintenance treatment * Continue LMWH at 75 80% treatment dose * Alternatively, administer warfarin at a dose to achieve an INR of 2 3 if not on myelosuppressive chemotherapy or complex supportive/concomitant medications * Continue for at least 6 months. Indefinite treatment recommended if active metastatic disease is observed or there is continued exposure to potentially thrombogenic anticancer therapy Anticoagulation contraindicated * Recent central nervous system bleed * Active major bleed (42 U in 24 h) * Platelets o 50 109/l * Severe platelet dysfunction * Known bleeding tendency, e.g., haemophilia * Elevated PT or aPTT above therapeutic target level * Severely limited life expectancy or no palliative benefit * Patient refusal Pulmonary embolus Assess severity, including ECHO or CT angiography if necessary for right heart enlargement. Consider as high risk for death (15%) if systolic BP o90 mm Hg High-risk massive embolus
Oxygen Commence heparin 80 U kg1 and infuse at 18 U kg1 h1 to maintain aPTT between 2.0 and 2.5 (p 16) * Commence thrombolyis with rtPA 100 mg over 2 h or up to 50 mg over 15 min if rapidly deteriorating Uncomplicated * Treat as for VTE
* *
CVC-related thrombosis Preservation of catheter access not essential * Remove line and anticoagulate for 3 months Preservation of catheter access clinically important * Anticoagulate with line in situ and for at least 3 months after removal. Removal of line and reinsertion at a later date may be necessary if symptoms worsen (e.g., recurrent emboli or increasing arm swelling) Vena caval filter placement Contraindications to anticoagulation (p 32) Failure of anticoagulation Non-compliance Documented multiple PE and chronic pulmonary hypertension
Therapeutic anticoagulant failure During vitamin K antagonist therapy * Check compliance * Increase target INR to 3 4 * Change to LMWH * Consider vena caval filter During LMWH therapy * Check compliance * Increase 75 to 80% maintenance dose to full-treatment dose * Consider increase from treatment dose by 20 25% * Convert once-daily to twice-daily administration * Consider vena caval filter
Secondary Prevention of Venous Thromboembolic Events in Patients With Active Cancer: Enoxaparin Alone Versus Initial Enoxaparin Followed by Warfarin for a 180-Day Period
*Steven R. Deitcher, MD, Craig M. Kessler, MD, Geno Merli, MD, James R. Rigas, MD, **Roger M. Lyons, MD, and Jawed Fareed, PhD, for the ONCENOX Investigatorsa
*Section of Hematology and Coagulation Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio; Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; Division of General Internal Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Division of Hematology and Medical Oncology, Dartmouth Medical School, Lebanon, New Hampshire; **U.S. Oncology, San Antonio, Texas; Aventis Pharmaceuticals, Bridgewater, New Jersey; Loyola University Medical Center, Maywood, Illinois.
Summary: This study evaluated enoxaparin alone versus initial enoxaparin followed by warfarin in secondary prevention of venous thromboembolic events in adults with active malignancy. Cancer patients (n = 122) with acute symptomatic venous thromboembolic events were randomly allocated to receive subcutaneous enoxaparin 1.0 mg/kg every 12 hours for 5 days, followed by 1.0 mg/kg daily (group 1a) or 1.5 mg/kg daily (group 1b) for 175 days, or subcutaneous enoxaparin 1.0 mg/kg every 12 hours for at least 5 days and
until a stable international normalized ratio of 2 to 3 was achieved on oral warfarin begun on day 2 and continued to day 180 (group 2). There were no significant differences in major and minor bleeding rates between treatment groups. No bleeding events were intracranial or fatal. Enoxaparin treatment was feasible, generally well tolerated, and effective for a 180-day period in the secondary prevention of venous thromboembolic events in patients with active malignancy. Key Words: EnoxaparinDeep venous thrombosisMalignancy
Venous thromboembolic events (VTEs), including deep venous thrombosis (DVT) and pulmonary embolism, warrant prompt initiation of antithrombotic therapy to prevent thrombus extension, embolization, and early as well as late recurrence. Challenges of VTE management in cancer patients compared with noncancer patients include greater heparin resistance due to excess circulating acutephase proteins, increased recurrence and bleeding rates during standard-intensity oral warfarin
Address correspondence to Steven R. Deitcher, MD, 201 Industrial Road, Suite 310, San Carlos, CA 94070; e-mail: sdeitcher@nuvelo.com.
a
A full list of ONCENOX investigators is given in the Appendix.
Clinical and Applied Thrombosis/Hemostasis Vol. 12, No. 4, October 2006 389-396 DOI: 10.1177/1076029606293692 2006 Sage Publications
therapy, variable nutrition status, greater difficulty maintaining an international normalized ratio (INR) of between 2 and 3 (43.3% time within range compared with 56.9% in noncancer patient controls), and limited venous access to support therapeutic monitoring.1-3 Bleeding during anticoagulation is of particular concern in patients with disease-related and therapy-related thrombocytopenia and cancer that involves the central nervous system. In the setting of acute VTE, the low-molecularweight heparin (LMWH) enoxaparin has been shown to be equally effective and safe for initial anticoagulation compared with unfractionated heparin.4,5 Enoxaparin has the advantage of less nonspecific protein binding, subcutaneous weight-based dosing without the need for monitoring in most cases, and less heparin-induced thrombocytopenia (HIT).6,7 Subcutaneous, weight-based enoxaparin has also
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become a popular warfarin substitute in patients with VTE who have difficult to regulate INRs or have recurrent thrombosis despite an INR of between 2 and 3 (warfarin failure), as is often seen in cancer patients. We performed this study to evaluate patient recruitment, safety, efficacy, and compliance for a 180-day period of enoxaparin alone versus initial enoxaparin followed by warfarin in the secondary prevention of VTE in adult patients with active malignancy. Baseline hemostatic profiling and assessment for inherited hypercoagulable states were performed to partially characterize the pathogenesis of thrombosis associated with cancer. Testing for heparin-associated antibodies was performed to evaluate the risk of HIT in enoxaparinexposed cancer patients who are already prone to thrombocytopenia by virtue of their disease.
PATIENTS AND METHODS This pilot feasibility study was conducted as a randomized, open-label, multidose, active comparator, parallel-design trial. Patients were randomized to receive 1 of 3 treatments. Group 1a received subcutaneous twice-daily enoxaparin (1.0 mg/kg) for 5 days, followed by once-daily enoxaparin (1.0 mg/kg) for 175 days; group 1b received subcutaneous twice-daily enoxaparin (1.0 mg/kg) for 5 days, followed by once-daily enoxaparin (1.5 mg/kg) for 175 days; and group 2 received subcutaneous twice-daily enoxaparin (1.0 mg/kg) for a minimum of 5 days and until achievement of a stable INR between 2 and 3 on oral warfarin begun on day 2 of enoxaparin and continued for a total of 180 days of anticoagulation. Patients were monitored for 7 months from the date of randomization. The primary objectives of this trial were to evaluate the feasibility of recruiting the necessary number of cancer patients (300 evaluable patients) in a 12-month time frame and to evaluate the feasibility of compliance with long-term daily subcutaneous enoxaparin injections in active cancer patients with acute VTE. Compliance was defined as the percentage of enoxaparin or warfarin doses dispensed that were actually taken by the patient. The secondary objectives included an evaluation of the safety of enoxaparin treatment alone (groups 1a and 1b) compared with enoxaparin followed by warfarin treatment (group 2) administered for 180 days to prevent secondary VTE in cancer patients, as determined by assessment of major and minor bleeding rates and serious
adverse events (SAEs). A bleeding event was considered major if it resulted in death, a serious, lifethreatening clinical event requiring hospitalization, transfusion of at least 2 units of packed red blood cells, a fall in hemoglobin of 2 grams or more that was attributable to the bleeding event, a retroperitoneal, intracranial, or intraocular hemorrhage; the need for surgery or decompression of a closed space; or an ecchymosis or hematoma greater than 10 cm in diameter. Another secondary objective was to evaluate the efficacy of VTE treatment with enoxaparin alone (groups 1a and 1b) compared with enoxaparin followed by warfarin treatment (group 2). Efficacy was determined by assessment of objectively confirmed recurrent VTE involving a not previously involved venous segment and symptomatic VTE extension within the same venous segment as the index event during treatment. Baseline testing for acquired and inherited hypercoagulable states was performed on the first day of the study. Testing for the development of heparin-associated antibodies was performed in groups 1a and 1b at each monthly follow-up evaluation. The Hemostasis Research Laboratories of Loyola University Medical Center, Chicago, Illinois, performed all special coagulation testing. To be eligible for enrollment in this study, patients had to be aged 18 years or older, weigh 120 kg or less, and have a functional capacity based on Karnofsky performance scale of 60 or more, or an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 28 based on the most recent performance status before their acute VTE. Patients could be enrolled or randomized within 72 hours of VTE diagnosis and if LMWH or unfractionated heparin had already been initiated as a standard of care therapy. All index VTEs had to be objectively confirmed by appropriate imaging studies. Catheter-associated VTE were not eligible index thrombotic events. Patients had to have active, residual malignancy determined by the presence of measurable disease, persistently elevated tumor markers, metastatic disease after tumor debulking, or histologically or cytologically confirmed cancer. At study entry, a patient could not be a candidate for curative intent surgery. Based on the investigators judgment, all patients had to have an estimated length of survival that would allow for study completion. The study imposed no general or dietary restrictions. Patients were excluded from enrollment if they had an anticipated need for thrombolytic therapy, embolectomy, or placement of a new caval filter,
TREATMENT OF VENOUS THROMBOSIS IN CANCER
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TABLE 1.
Baseline Demographic Characteristics and Index Venous Thromboembolism Diagnosis: Safety Sample Enoxaparin 1.0 mg/kg (n = 31) 62.7 13.4 35-80 6 6 8 11 25 5 0 0 1 (19.4) (19.4) (25.8) (35.5) (80.6) (16.1) (0.0) (0.0) (3.2) Enoxaparin 1.5 mg/kg (n = 36) 64.0 10.7 36-79 3 11 9 13 29 4 1 1 1 (8.3) (30.6) (25.0) (36.1) (80.6) (11.1) (2.8) (2.8) (2.8) Warfarin (n = 34) 64.1 12.4 40-87 7 2 15 10 32 2 0 0 0 (20.6) (5.9) (44.1) (29.4) (94.1) (5.9) (0.0) (0.0) (0.0) Total (N = 101) 63.7 12.0 35-87 16 19 32 34 86 11 1 1 2 (15.8) (18.8) (31.7) (33.7) (85.1) (10.9) (1.0) (1.0) (2.0)
Characteristic Age Mean SD Range Age category (%) 50 years 51-60 years 61-70 years >70 years Race (%) Caucasian Black Asian Hispanic Other Index VTE (%) PE DVT PE and DVT
12 (38.7) 24 (77.4) 7 (22.6)
17 (47.2) 29 (80.6) 10 (27.8)
15 (44.1) 31 (91.2) 13 (38.2)
44 (43.6) 84 (83.2) 30 (29.7)
SD = standard deviation; VTE = venous thromboembolic event; PE = pulmonary embolism; DVT = deep venous thrombosis.
as were those whose active cancer was acute leukemia or a localized cutaneous malignancy. Patients with any contraindication to anticoagulation, including severe liver disease, known nonirradiated intracerebral metastases, deep organ biopsy within 2 weeks, and major surgery within 1 week were excluded. Patients with a baseline INR of 2 or more, known or suspected severe renal insufficiency (creatinine clearance of 30 mL/min or less), history of HIT, history of warfarinassociated skin necrosis, and baseline platelet count of less than 50,000/L were not eligible. Safety evaluations were performed on the safety population defined as all randomized patients who received at least 1 dose of study medication. The intent-to-treat population included all patients in the safety population who had at least 1 follow-up measurement. Descriptive statistics were used to summarize the incidence of major and minor hemorrhagic events and the incidence of recurrent VTE. Statistical analyses were performed using SAS 8.2 (SAS Institute, Cary, SC). All statistical tests performed used 2-sided hypothesis tests at the overall 5% level of significance.
RESULTS In the period from January 26, 2001, to March 28, 2002, 102 patients from 27 sites were recruited. The appropriate institutional review board at each
investigative site approved this study, and all patients signed an approved informed consent form. Each of the 3 treatment arms had approximately equal numbers of subjects: 32 in the enoxaparin 1.0 mg/kg group, 36 in the enoxaparin 1.5 mg/kg group, and 34 in the warfarin group. One subject in the 1.0 mg/kg enoxaparin group did not receive study drug. Of the 101 patients in the safety sample, 91 were included in the intent-to-treat analysis. Nine patients (5 in the 1.0 mg/kg enoxaparin group and 4 in the 1.5 mg/kg enoxaparin group) did not meet full entry criteria and were enrolled after sponsor approval. Table 1 summarizes the baseline demographic characteristics and index VTE diagnosis of the safety population. Most patients in the 1.5 mg/kg enoxaparin group were female (63.9%) and aged 51 years or older (58.3%). In contrast, the 1.0 mg/kg enoxaparin group was 51.6% female and 41.9% were aged 51 years or older. The warfarin group was 47.1% female and younger than those in the enoxaparin groups. Most patients in the 3 treatment arms were diagnosed with DVT, and more patients in the warfarin group had both DVT and pulmonary embolism. Overall, 8.7% of patients had a history of VTE before the study index event. None of these differences were statistically significant. Of the 91 patients in the intent-to-treat population, 49 (53.8%) completed 180 days of study medication. The primary reasons for discontinuation from
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TABLE 2.
Reasons for Patient Withdrawal or Termination Enoxaparin 1.0 mg/kg, n = 32 (%) 1 2 4 0 1 0 3 2 2 0 0 0 0 (3.2) (6.5) (12.9) (0.0) (3.2) (0.0) (9.7) (6.5) (6.5) (0.0) (0.0) (0.0) (0.0) Enoxaparin 1.5 mg/kg, n = 36 (%) 5 3 2 0 0 0 2 7 6 0 0 1 2 (13.9) (8.3) (5.6) (0.0) (0.0) (0.0) (5.6) (19.4) (16.7) (0.0) (0.0) (2.8) (5.6) Warfarin, n = 34 (%) 1 6 1 1 0 0 2 3 2 0 0 1 4 (2.9) (17.6) (2.9) (2.9) (0.0) (0.0) (5.9) (8.8) (5.9) (0.0) (0.0) (2.9) (11.8) Total, N = 101 (%) 7 11 7 1 1 0 7 12 10 0 0 2 6 (6.9) (10.9) (6.9) (1.0) (1.0) (0.0) (6.9) (11.9) (9.9) (0.0) (0.0) (2.0) (5.9)
Withdrawal Reasons Adverse event Progressive disease Study end point Nonpermitted therapy Major protocol violation Lost to follow-up Consent withdrawn Death Malignancy Fatal VTE Fatal hemorrhage Other Other
VTE = venous thromboembolic event.
TABLE 3. Cancer Stage I II III IV Unknown
Cancer Stage at Study Entry: Safety Sample Enoxaparin 1.0 mg/kg, n = 31 (%) 2 2 7 17 3 (6.5) (6.5) (22.6) (54.8) (9.7) Enoxaparin 1.5 mg/kg, n = 36 (%) 0 4 8 24 0 (0) (11.1) (22.2) (66.7) (0) Warfarin, n = 34 (%) 2 1 9 18 4 (5.9) (2.9) (26.5) (52.9) (11.8) Total, N = 101 (%) 4 7 24 59 7 (4.0) (6.9) (23.8) (58.4) (6.9)
the study differed among the treatment groups (Table 2). The discontinuation rate (58.3%) was highest in the enoxaparin group receiving 1.5 mg/kg, with the most common reasons being death (19.4%) and adverse events (13.9%). The lowest discontinuation rate (41.9%) was in the enoxaparin group receiving 1.0 mg/kg. The primary reason (12.9%) for discontinuation in this group was reaching the study end point (recurrent VTE or major hemorrhage). Table 3 summarizes the cancer stage at study entry for the safety population. More subjects in the enoxaparin group receiving 1.5 mg/kg presented with stage IV cancer at the start of the study (66.7%) than in the other groups (54.8% and 52.9% for the 1.0 mg/kg and warfarin groups, respectively). It should be noted that there was a sizeable percentage of subjects with unknown cancer stage in the 1.0-mg/kg enoxaparin (9.7%) and the warfarin (11.8%) groups. More subjects in the 1.5-mg/kg enoxaparin group had also been treated with radiation therapy (38.9%) and chemotherapy (58.3%) than those in the 1.0-mg/kg enoxaparin (32.4% and 55.9%, respectively) and
the warfarin groups (32.3% for both radiation and chemotherapy). Compliance data were available for 98 of 101 treated subjects. The overall compliance rate in the 3 treatment groups averaged 95% throughout the study. Mean overall treatment compliance was slightly lower in the warfarin group (90.1%) than in the 1.0-mg/kg and 1.5-mg/kg enoxaparin groups (97.9% and 97.0%, respectively). Across all visits, 92 patients (91.1%) took 81% to 100% of their study drug. Six subjects (5.9%) took less than 81% of the dispensed drug. Compliance was poorest with warfarin (50% to 100% compliance) and best in the 1.0-mg/kg enoxaparin group (82% to 100% compliance). Few patients experienced objectively confirmed symptomatic extension of their index VTE or true recurrent VTE (Table 4). More intent-to-treat patients in the warfarin treatment arm experienced VTE extension or recurrence than in either of the enoxaparin treatment arms. Three patients (10.0%) in the warfarin group, but only 2 patients in each of the enoxaparin groups (6.9% of 1.0 mg/kg group and 6.3% of 1.5 mg/kg group), experienced
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TABLE 4. VTE Event
Analysis of Venous Thromboembolic Event Recurrence and Symptomatic Extension: Intent-to-Treat Sample Enoxaparin 1.0 mg/kg, n = 29 (%) 1 (3.4) 1 (3.4) 2 (6.9) Enoxaparin 1.5 mg/kg, n = 32 (%) 1 (3.1) 1 (3.1) 2 (6.3) Warfarin, n = 30 (%) 1 (3.3) 2 (6.7) 3 (10.0) Total, N = 91 (%) 3 (3.3) 4 (4.4) 7 (7.7)
Symptomatic extension of index VTEa Recurrent VTEb All VTE
VTE = venous thromboembolic event. a. Extension of the index thrombosis within the same venous segments that were originally involved. b. Detection of new thrombosis within a venous segment not previously involved.
TABLE 5.
Summary of Adverse Events Enoxaparin 1.0 mg/kg, n = 31 (%) 27 3 1 16 19 2 7 (87.1) (9.7) (3.2) (51.6) (61.3) (6.5) (22.6) Enoxaparin 1.5 mg/kg, n = 36 (%) 32 6 0 23 20 4 15 (88.9) (16.7) (0.0) (63.9) (55.6) (11.1) (41.7) Warfarin, n = 34 (%) 29 8 2 17 17 1 11 (85.3) (23.5) (5.9) (50.0) (50.0) (2.9) (32.4) Total, N = 101 (%) 88 17 3 56 56 7 33 (87.1) (16.8) (3.0) (55.4) (55.4) (6.9) (32.7)
Adverse Event Nonserious Treatment-related, nonserious Discontinued due to nonserious AE SAE Minor hemorrhage event Major hemorrhage event Died
AE = adverse event; treatment-related = probably or possibly related to the study drug, in the opinion of the investigator; SAE = serious adverse event.
VTE during anticoagulant treatment. Overall, 3.3% of study subjects experienced a symptomatic VTE extension and 4.4% experienced a new VTE for a total thrombosis event rate of 7.7%. No patient was diagnosed with a new pulmonary embolism during the study. Two patients not in the intent-to-treat sample, 1 in each of the enoxaparin groups, experienced recurrent DVT. Because VTE developed in only a small number of patients in the study, no trends or significance could be observed. There was no effect of age, gender, race, clinical cancer stage, duration of cancer diagnosis, or type of index VTE on the probability that VTE would develop during the 6-month treatment period. Subjects with an ECOG performance status of 2, on the other hand, had a significantly increased risk of experiencing a VTE during the study than did subjects with a score of 0 or 1 (hazard ratio, 7.253; 95% confidence interval, 1.580 to 33.296; P =.011 from proportional hazards model). Table 5 summarizes adverse events for the safety study population. Overall, 87.1% of patients experienced at least 1 nonserious adverse event during the study, and the number of events was evenly distributed among the 3 treatment groups. Approximately half of all study patients experienced at least 1 SAE during the study. The 1.0-mg/kg
enoxaparin and the warfarin groups had similar SAE rates (51.6% and 50.0%, respectively), and the 1.5-mg/kg enoxaparin group had the highest incidence of SAEs (63.9% had at least 1 SAE). More cardiovascular SAEs occurred in the enoxaparin groups than in the warfarin group (6 and 9 versus 0), but the distribution of events in other body systems was nearly even across groups. Only 3 subjects in the study had SAEs that were considered to be possibly or probably related to the study drug: 2 in the warfarin group and 1 in the 1.0-mg/kg enoxaparin group. Overall, 58 patients experienced at least 1 hemorrhagic event (major or minor) during the study. Seven patients experienced at least 1 major hemorrhagic event: 1 in the warfarin group, 2 in the 1.0-mg/kg enoxaparin group, and 4 in the 1.5mg/kg enoxaparin group. All major hemorrhagic events were considered SAEs but were analyzed separately from other adverse events. The incidence and types of adverse events and hemorrhagic events observed with enoxaparin alone versus enoxaparin followed by warfarin were similar to those described in the package inserts and the investigators brochure. Of the 33 deaths during the 7-month observation period, 29 (88%) were attributable to progression of underlying malignancy. Of the remaining 4 subjects,
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TABLE 6.
Molecular Coagulation Studies ONCENOX Subjects, n (%) 66 (92) 6 (8) 0 (0) 71 (99) 1 (1) 0 (0) 42 (58) 24 (33) 6 (8)
Laboratory Test Factor V Leiden Normal Heterozygous Homozygous Prothrombin G20210A Normal Heterozygous Homozygous MTHFR C677T Normal Heterozygous Homozygous
of patients had decreased levels. Anticardiolipin antibody testing showed that 7% had elevated titers of immunoglobulin (Ig)G anticardiolipin antibody, and 3% had elevated titers of IgM anticardiolipin antibody. Of 514 samples tested for anti-heparin-platelet factor 4 antibodies by enzymelinked immunosorbent assay (ELISA), 60 samples from 31 different patients were positive. The titer varied from slightly positive (OD >0.40) to strongly positive (OD >1.00, 10 samples). Seven positive samples were baseline samples. When these 60 samples were tested by 14C serotonin release assay, none were positive.
MTHFR = 5,10-methylene tetrahydrofolate reductase.
DISCUSSION 1 each died of presumed pulmonary embolism (1.0-mg/kg enoxaparin group), VTE (1.0-mg/kg enoxaparin group), cardiac arrest (warfarin group), and heart failure (1.5-mg/kg enoxaparin group). Only 12 patients were discontinued from the study due to death (Table 2). The remainder of the patients who died during the 7-month observation period did so either after study discontinuation for another reason or after completion of the 180-day period of study medication. There were no adverse trends in platelet count during the study. The mean and median values for platelet count were within the normal limits for all 3 groups at all study visits, including at baseline. Thrombocytopenia was reported in 7 patients: 5 in the warfarin group and 1 in each of the enoxaparin groups; however, a causal relationship to study medication was described for only 1 subject in the warfarin group. Mean antifactor Xa activity levels were between 0.44 and 0.73 U/mL over the treatment period in the 1.0-mg/kg enoxaparin group and between 0.59 and 1.04 U/mL in the 1.5-mg/kg enoxaparin group. Overall, 25 samples had antifactor Xa activity levels of more than 2.00 U/mL. Most samples had antifactor Xa activity levels between 0.5 and 1.5 U/mL. Table 6 summarizes the results of molecular coagulation studies performed in the 72 study patients who provided informed consent for such testing. Factor V Leiden, prothrombin G20210A, and homozgous MTHFR C677T prevalence rates were 8%, 1%, and 8% respectively. Table 7 summarizes the results of baseline coagulation studies. In addition, 74 patients underwent antigenic and functional tissue factor pathway inhibitor (TFPI) testing. Antigenic TFPI levels in 27% of tested patients were less than 70 ng/mL. As determined by functional TFPI testing, only 8% This clinical trial was designed as a 3-arm, pilot feasibility study to evaluate patient recruitment, compliance, safety, and efficacy for a 180-day period of treatment with enoxaparin alone versus enoxaparin followed by warfarin in the secondary prevention of VTE in patients with active malignancy. The objective to recruit the necessary number of patients within a 12-month time frame was not met; however, compliance, safety, and efficacy results were available for 102 enrolled patients. The overall compliance rate in the 3 treatment groups was high, averaging 95% throughout the 6month treatment period. Overall, average treatment compliance was slightly higher with enoxaparin alone (97.9% for 1.0-mg/kg and 97.0% for 1.5mg/kg enoxaparin) than with warfarin (90.1%). This indicates that long-term subcutaneous administration of enoxaparin was generally well tolerated by patients. The need for daily subcutaneous injection was not an obvious deterrent to study participation or completion. The antifactor Xa activity levels observed in most patients treated with both doses of enoxaparin were within a range believed to be the desired target range for VTE treatment. The incidence of recurrent VTE in the intentto-treat population was numerically lower with enoxaparin therapy than with initial enoxaparin followed by oral warfarin. No numeric difference in the recurrent VTE rate was observed for the 2 studied once-daily enoxaparin dosages. Although statistical significance was not reached, the cumulative probability of being VTE-free at 6 months was numerically higher for enoxaparin alone than for enoxaparin followed by warfarin therapy. Standard of care included twice-daily subcutaneous administration of enoxaparin at 1.0 mg/kg for a minimum of 5 days, with warfarin therapy started within 48 hours of enoxaparin initiation
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TABLE 7.
Baseline Coagulation Studies Normal Controls > 2.0 > 2.0 95.0 9.5 96.0 8.9 95.0 8.3 135.0 23.8 94.0 7.8 33.7 8.6 32.1 9.6 90.0 4.7 68 13.7 ONCENOX Subjects (range) 2.2 2.6 104.4 82.5 69.3 224.0 111.0 58.2 44.8 93.9 74.0 0.3 (1.3-2.7) 0.2 (1.8-3.2) 21.1 (47-154) 41.4 (4-200) 33.1 (18-172) 83.0 (75.4-556.7) 42.8 (1.0->200) 15.6 (23.9-142.4) 19.6 (3.4-93.5) 15.9 (44.2-139.8) 6.1 (62.5-92.5) % Abnormal 13 1 6 36 56 71 17 36 34 24 27
Laboratory Testa APC-ratio First generation Second generation Antithrombin activity (%) Protein C activity (%) Protein S activity (%) vWF antigen (%) Factor VIII activity (%) dRVVT PAI-1 antigen (ng/mL) TAFI activity (%) TFPI antigen (ng/mL)
APC = activated protein C; vWF = von Willebrand factor; dRVVT = dilute Russells viper venom time; PAI-1 = plasminogen activator inhibitor-1; TAFI = thrombin activatable fibrinolysis inhibitor. a. Data presented as mean standard deviation (range).
with a target INR of 2.5 for 2 consecutive days (range, 2.0 to 3.0).4 This was in accordance with recommendations by the Sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy for the treatment of VTE.9 The observed trend toward greater secondary VTE prevention with long-term enoxaparin compared with warfarin is in line with similar observations with enoxaparin and other LMWHs.10-12 Overall, the incidence, type, and intensity of adverse events observed with enoxaparin administered alone for 6 months in the current study were no more extensive than those described for the standard therapy of enoxaparin followed by warfarin. The higher rate of study discontinuation due to death in the 1.5-mg/kg enoxaparin group may reflect the greater number of patients with stage IV cancer and greater number of patients receiving chemotherapy or radiation therapy in this arm of the study. There were no unexpected adverse events or other clinically significant safety findings that negated the use of long-term enoxaparin therapy as an alternative to oral warfarin. The prevalence rates for factor V Leiden heterozygosity, prothrombin gene G20210A heterozygosity, and homozygous MTHFR C677T did not differ significantly from rates reported for normal populations and are actually numerically less than rates reported for patients with idiopathic VTE.13 Common molecular defects associated with hypercoagulability in general were clearly not the primary determinant of thrombosis in our cancer population. The baseline laboratory characterization reflects the complex and variable nature of the hypercoagulability of malignancy. Acquired
activated protein C resistance based on testing of samples that have not been prediluted with factor V-deficient plasma (first generation) has been described in association with several tumor histologies.14 Combinations of decreased levels of natural anticoagulants (eg, protein C, protein S, and TFPI), increased levels of procoagulant proteins (eg, factor VIII and von Willebrand factor), lupus anticoagulant activity, and increased levels of fibrinolytic inhibitors (eg, plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor) surely contributed to the original development of thrombosis in this population. Nonetheless, the likely ongoing hypercoagulability was adequately neutralized by once-daily enoxaparin at 1.0 mg/kg and 1.5 mg/kg as reflected by low VTE recurrence rates. Ongoing and intermittent thrombocytopenia is often seen in patients with cancer involving the bone marrow and in those receiving cycles of cytotoxic therapy. The development of thrombocytopenia during daily LMWH therapy may raise reasonable concerns about HIT. For this reason, we evaluated patients for the development of heparin-associated antibodies. The detection of such antibodies in 31 enoxaparin-treated patients was not unexpected, because LMWH therapy may result in the generation of these antibodies. However, none of the detected antibodies were functional as determined by serotonin release assay. It seems prudent to recommend against making the diagnosis of HIT in active cancer patients receiving long-term enoxaparin solely from the detection of heparin-associated antibodies by ELISA.
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CONCLUSION This study demonstrated that treatment with enoxaparin was feasible, generally well tolerated, and effective for a 180-day period in the secondary prevention of VTE in patients with active cancer.
Brad Sherrill, Moses Cone Memorial Hospital, Greensboro, NC Juliann Smith, Cancer and Blood Institute of the Desert, Rancho Mirage, CA
REFERENCES ACKNOWLEDGMENT This clinical trial was sponsored by Aventis Pharmaceuticals.

1. Deitcher SR: Cancer-related deep venous thrombosis. Clinical importance, treatment challenges, and management strategies. Semin Thromb Haemost. 2003;29: 247-258. 2. Luzzatto G, Schafer AI. The prethrombotic state in cancer. Semin Oncol. 1990;17:147-159. 3. Bona RD, Sivjee KY, Hickey AD, Wallace DM, Wajcs SB. The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost. 1995;74:1055-1058. 4. Levine M, Gent M, Hirsch J, Leclerc J, Anderson D, Weitz J, Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334:677-681. 5. Merli G, Spiro TE, Olsson C-G, et al; Enoxaparin Clinical Trial Group. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134:191-202. 6. Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337:688-698. 7. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecularweight heparin or unfractionated heparin. N Engl J Med. 1995;332:1330-1335. 8. Oken, MM, Creech, RH, Tormey, DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 9. Hyers TM, Agnelli A, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001; 119(suppl):176S-193S. 10. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162:1729-1735. 11. Lee AY, Levine MN, Baker RI, et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153. 12. Hull RD, Pineo GF, Mah AF, Brant RF, for the LITE study Investigators. A randomized trial evaluating long-term low-molecular-weight heparin therapy for three months versus intravenous heparin followed by warfarin sodium. Blood. 2002;100:148a (abstract 556). 13. Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hematol. 1997;34:171-187 14. Deitcher SR, Choueiri T, Srkalovic G, Hussein MA. Acquired activated protein C resistance in myeloma patients with venous thromboembolic events. Br J Haematol. 2003; 123:959.
APPENDIX 1. ONCENOX INVESTIGATORS

Wendy Breyer, Central Utah Medical Clinic, Provo, UT Steven R. Deitcher, Cleveland Clinic Foundation, Cleveland, OH Steven Deitelzweig, Oshsner Foundation Hospital, New Orleans, LA Paul Derderian, Community Cancer Care Specialists, Mount Clemens, MI James Fiorica, H. Lee Moffitt Cancer Center, Tampa, FL Charles W. Francis, University of Rochester Medical Center, Rochester, NY David Hanson, Mary Bird Perkins Cancer Center, Baton Rouge, LA Mark Keaton, South Georgia Medical Center, Valdosta, GA Craig Kessler, Georgetown University Medical Center, Washington, DC Pam Khosla, Rush Presbyterian St. Lukes Hospital, Chicago, IL Manish Kohli, University of Arkansas, Little Rock, AR Kapisthalam Kumar, Pasco Hernando Oncology, New Port Richey, FL Edward Libby, University of New Mexico, Albuquerque, NM Eduardo Lim, West Suburban Center for Cancer Care, River Forest, IL Roger Lyons, US Oncology, San Antonio, TX Robert McCroskey, Rainier Oncology Professional Services, Puyallup, WA Rakesh P Mehta, Scott & White Memorial Hospital and . Clinic, Temple, TX Geno Merli, Thomas Jefferson University, Philadelphia, PA Robert Moss, Fountain Valley, CA Joe Muscato, Missouri Cancer Associates, Columbia, MO John Owen, Wake Forest University, Winston-Salem, NC Albert Quiery, Geisinger Medical Center, Danville, PA James R. Rigas, Dartmouth Hitchcock Medical Center, Lebanon, NH William R. Robinson, Don & Sybil Harrington Cancer Center, Amarillo, TX Hussain Saba, James A. Haley VA Hospital, Tampa, FL H. K. Shamasunder, Valley Tumor Medical Group, Lancaster, CA
British Journal of Cancer (2010) 102, S24 S29 & 2010 Cancer Research UK All rights reserved 0007 0920/10 $32.00
www.bjcancer.com
Full Paper
Antithrombotic therapy and survival in patients with malignant disease

AK Kakkar*,1 and F Macbeth2

1
Thrombosis Research Institute and Queen Mary University of London, Emmanuel Kaye Building Manresa Road, London SW3 6LR, UK; 2National Institute for Health and Clinical Excellence, MidCity Place, 71 High Holborn, London WC1V 6NA, UK
A broad range of studies suggest a two-way relationship between cancer and venous thromboembolism (VTE). Patients with cancer have consistently been shown to be at elevated risk for VTE; this risk is partly driven by an intrinsic hypercoagulable state elicited by the tumour itself. Conversely, thromboembolic events in patients without obvious risk factors are often the first clinical manifestation of an undiagnosed malignancy. The relationship between VTE and cancer is further supported by a number of trials and meta-analyses which, when taken together, strongly suggest that antithrombotic therapy can extend survival in patients with cancer by a mechanism that extends beyond its effect in preventing VTE. Moreover, accumulating evidence from in vitro and in vivo studies has shown that tumour growth, invasion, and metastasis are governed, in part, by elements of the coagulation system. On 22 May 2009, a group of health-care providers based in the United Kingdom met in London, England, to examine recent advances in cancer-associated thrombosis and its implications for UK clinical practice. As part of the discussion, attendees evaluated evidence for and against an effect of antithrombotic therapy on survival in cancer. This paper includes a summary of the data presented at the meeting and explores potential mechanisms by which antithrombotic agents might exert antitumour effects. The summary is followed by a consensus statement developed by the group. British Journal of Cancer (2010) 102, S24 S29. doi:10.1038/sj.bjc.6605602 www.bjcancer.com & 2010 Cancer Research UK
Keywords: venous thromboembolism; thrombosis; antithrombotic therapy; cancer survival
As reviewed elsewhere in this supplement, patients with cancer are at increased risk of venous thromboembolism (VTE), not only as a result of extrinsic factors (e.g., immobility, cancer treatment, surgery) but also as a result of an intrinsic hypercoagulable state caused by the tumour itself. Conversely, it has been shown that VTE often heralds an undiagnosed malignancy. Taken together, these data suggest that there is a two-way relationship between cancer and VTE. This link has been clearly established by numerous epidemiological studies; moreover, it has been shown that antithrombotic therapy particularly with heparins may extend survival in patients with cancer. Additional in vitro and in vivo data provide preliminary evidence that elements of the coagulation system itself are critical determinants of cancer growth, invasion, and metastasis. These data suggest that, beyond the intuitively obvious benefit of preventing VTE in patients with cancer, antithrombotic therapies may have a direct antitumour effect, thus prolonging life and perhaps suppressing metastasis. On 22 May 2009, a group of health-care professionals based in the United Kingdom met in London, England, to examine recent advances in cancer-associated thrombosis and its implications for UK clinical practice. As part of the discussion, attendees reviewed clinical and experimental evidence suggesting an effect of antithrombotic therapy on survival in cancer patients. This paper includes a summary of the data presented at the meeting and explores potential mechanisms by which antithrombotic agents
might exert antitumour effects. The summary is followed by a consensus statement developed by the group.
EFFECTS OF ANTITHROMBOTIC THERAPY ON SURVIVAL IN CANCER

A number of clinical trials, of varying quality, have assessed the impact of antithrombotic therapy on cancer outcome. When considered together, the results of these studies suggest that antithrombotic agents including warfarin, unfractionated heparin (UFH), and low-molecular-weight heparins (LMWH) may prolong the survival of patients with malignant diseases. Indirect evidence suggests that warfarin may have an impact on cancer occurrence. A prospective study randomised patients with VTE to either 6 weeks or 6 months of oral anticoagulation; patients were questioned yearly thereafter about any newly diagnosed cancer (Schulman and Lindmarker, 2000). An analysis, conducted after a mean follow-up of 8.1 years, found that cancer was diagnosed in 15.8% of patients who were treated for 6 weeks with oral anticoagulants, compared with 10.3% of those treated for 6 months (OR 1.6; 95% CI 1.1 2.4) (Schulman and Lindmarker, 2000). Notably, the difference between the 6-week and 6-month groups was driven primarily by the occurrence of new urogenital cancers (most commonly prostate cancer), which occurred in 6.7% of the 6-week group and in 2.8% of the 6-month group (Schulman and Lindmarker, 2000). More recently, Tagalakis et al (2007) examined the effect of warfarin in patients with urogenital cancer. This nested, matched case control study included 19 412 new
*Correspondence: Professor AK Kakkar; E-mail: akkakkar@tri-london.ac.uk
Antithrombotic therapy and survival AK Kakkar and F Macbeth
S25 cases of urogenital cancer diagnosed over a 22-year period in Canada (Tagalakis et al, 2007). Four years of warfarin use in the 5-year period immediately preceding the index date was associated with a rate ratio of 0.80; there was a trend towards a decreasing rate ratio for prostate cancer with increasing duration of warfarin use through 5 years (Tagalakis et al, 2007). Although interesting, neither of these studies indicate whether warfarin therapy prevents or merely delays the onset of cancer, nor whether it affects overall mortality. An early trial of warfarin the VA Cooperative Study #75 directly examined the effect of warfarin on survival in patients with cancer. In this study, 431 patients with malignancies were randomised to either warfarin or placebo in addition to their standard cancer treatment (Zacharski et al, 1984). No differences in survival were observed between treatment groups for patients with advanced non-small-cell lung, colorectal, prostatic, or head and neck cancer (Zacharski et al, 1984). A trend towards improved survival was seen in patients with non-small-cell lung cancer after surgical resection or potentially curative radiation therapy. Notably, warfarin was associated with a significant improvement in survival (P 0.018) in a small subset of 50 patients with smallcell lung cancer (SCLC); these patients also had a significantly increased time to disease progression compared with controls (Zacharski et al, 1984). A similar three-arm trial by CALGB (Chahinian et al, 1989) randomised 328 patients with extensive SCLC to a standard chemotherapy regimen (MACC), to the regimen with concurrent warfarin, or to an alternating chemotherapy regimen. The overall response rate was significantly higher in the warfarin arm than in the others (P 0.012), but although there was also a trend towards improved survival, this did not reach statistical significance (Chahinian et al, 1989). Another trial, published by Maurer et al (1997), also attempted to confirm the results of the VA Cooperative Study in limited-stage SCLC patients. As in the previous study, patients were randomised to receive warfarin or no warfarin, in addition to cancer chemotherapy and radiation therapy. There were no significant differences between the warfarin and no-warfarin groups in terms of response rates, survival, failure-free survival, disease-free survival, or patterns of relapse (Maurer et al, 1997). However, the trial was confounded by a protocol amendment after accrual of 179 patients because of pulmonary toxicity with a reduction of the chemotherapy regimen from eight cycles to five cycles (Maurer et al, 1997). Only one study has reported on the effects of UFH on survival. In this study, 277 patients with SCLC were randomised to either receive or not receive dose-adjusted subcutaneous UFH injections for 5 weeks, in addition to chemotherapy (Lebeau et al, 1994). In this study, heparin was associated with improved complete response rates (37 vs 23%; P 0.004); improved median survival (317 days vs 261 days; P 0.01); and better survival rates at 1 year (40 vs 30%), 2 years (11 vs 9%), and 3 years (9 vs 6%) (Lebeau et al, 1994). A subgroup analysis suggested that the effect on survival was only in patients with limited disease. The effect of LMWH on survival has been more extensively studied. An early analysis of two studies, conducted by Green et al (1992), provided initial evidence that mortality was reduced in patients treated with LMWH, compared with those who received UFH. A meta-analysis of trials comparing UFH with LMWH, published in 1996, provided additional evidence that LMWH is associated with reduced mortality in patients with cancer (Siragusa et al, 1996). As expected, both UFH and LMWH were effective in preventing recurrent VTE. An analysis of four studies in patients with cancer found that mortality rates during the 16- to 90-day follow-up period of oral anticoagulant therapy were substantially lower among patients assigned to the LMWH group (12%) compared with the UFH group (26%) (RR 0.33; 95% CI 0.1 0.8; P 0.01) (Siragusa et al, 1996). The mortality rate in patients
without cancer was low and was not significantly different between the two groups. Notably, significant reduction in mortality in cancer patients who received LMWH was not observed during the initial 15 days of treatment. Instead, the majority of deaths occurred after ceasing LMWH or UFH, which suggests that the effect of LMWH in preventing mortality was not because of its antithrombotic effect (Siragusa et al, 1996). A second metaanalysis (1999) also found a striking 57% reduction in mortality with LMWHs compared with UFH in the small subgroup of patients with cancer (Gould et al, 1999). The effect of LMWH on survival in cancer was tested directly in the Fragmin Advanced Malignancy Outcome Study (FAMOUS) (Kakkar et al, 2004). In this study, 385 patients with advanced malignancies (histologically confirmed, advanced stage III or IV disease of the breast, lung, gastrointestinal tract, pancreas, liver, genitourinary tract, ovary, or uterus) were randomly assigned to receive either dalteparin (5000 IU administered once daily) or placebo (Kakkar et al, 2004). There were no restrictions on concomitant use of chemotherapy or radiotherapy. Patients were followed for 1 year for the primary end point of mortality; secondary outcomes included objectively confirmed VTE and bleeding (Kakkar et al, 2004). Rates of symptomatic VTE were low in both the dalteparin (2.4%) and placebo (3.3%) groups; bleeding was seen in 4.7% of dalteparin patients and in 2.7% of placebo patients (Kakkar et al, 2004). At 1 year after randomisation, survival estimates in the dalteparin and placebo groups were 46 and 41%, respectively (P 0.19; Figure 1A). At 2 years, survival rates were 27 and 18% for the dalteparin and placebo groups, respectively, and at 3 years the rates were 21 and 12%, respectively (Kakkar et al, 2004). Post hoc analysis of patients with a better prognosis who survived more than 17 months showed a survival advantage for the dalteparin group (Kakkar et al, 2004). At 2 and 3 years after randomisation, survival in the dalteparin and placebo groups was 78 vs 55% and 60 vs 36%, respectively (P 0.03; Figure 1B). Median survival in the dalteparin group was 43.5 months, compared with 24.3 months in the placebo group (Kakkar et al, 2004). The effect of LMWH on survival in patients with SCLC was evaluated directly in a study conducted by Altinbas et al (2004). In this small study, 84 patients were randomised to receive combination chemotherapy with or without dalteparin (5000 IU once daily during the 18 weeks of combination chemotherapy) (Altinbas et al, 2004). Tumour response rates were substantially higher among patients who received LMWH (69.2%) compared with those who did not (42.5%), but the difference between the two groups was not statistically significant (P 0.07). Median progression-free survival was 10.0 and 6.0 months in the LMWH and noLMWH groups, respectively (P 0.01), with similar improvements in survival with LMWH observed in patients with both limited and extensive disease stages. Overall, the hazard of death was reduced by 44% among patients who received LMWH (P 0.012) (Altinbas et al, 2004). A second recent trial prospectively examined the effect of LMWH on survival in patients with advanced malignancies (Klerk et al, 2005). Patients with metastatic or locally advanced solid tumours who could not be treated curatively were randomly assigned to receive a 6-week course of weight-adjusted nadroparin (administered twice daily during the initial 14 days of treatment and once daily thereafter for an additional 4 weeks) or placebo (Klerk et al, 2005); concomitant chemotherapy or radiotherapy was permitted. The primary end point was all-cause mortality, the secondary end point was major and clinically relevant non-major bleeding (Klerk et al, 2005). At 6 months, survival was 61% among patients randomly allocated to nadroparin, compared with 56% in the placebo group (Klerk et al, 2005). At 12 and 24 months, the corresponding values were 39 vs 27% and 21 vs 11% (Figure 2A) (Klerk et al, 2005). Among all patients, median survival was significantly longer in the
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1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 KaplanMeier survival distribution function estimate Median survival (months) and its 95% CI Dalteparin: 10.8. (9.27, 13.5) Placebo: 9.14 (7.33, 11.5) Delteparin P = 0.19 Placebo
12
24 36 48 60 72 84 Time to event from randomisation (months) 30 15 22 9 12 8 5 5 4 2 Delteparin Placebo
No. at risk 190 85 72 184 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 17 23
KaplanMeier survival distribution function estimate
Delteparin Placebo
Median survival (months) and its 95% CI Dalteparin: 43.5 (33, 52.3) Placebo: 24.3 (22.4, 41.5) P = 0.03
29 35 41 47 53 59 65 71 77 Time to event from randomisation (months) 22 9 20 9 13 8 8 8 5 5 5 3 5 2 3 0
83
No. at risk 55 31 26 47 17 10
Delteparin Placebo
Figure 1 (A) Survival curves for the intent-to-treat population enrolled in the FAMOUS trial; (B) survival curves for the subgroup of patients with better prognosis who survived beyond 17 months after randomisation (Kakkar et al, 2004).
nadroparin group (8.0 months) than in the placebo group (6.6 months; hazard ratio 0.75; 95% CI 0.59 0.96; P 0.021). After adjustment for life expectancy, WHO performance status, concomitant treatment, and type and histology of cancer, the relationship between nadroparin and improved survival remained statistically significant (hazard ratio, 0.76; 95% CI 0.58 0.99) (Klerk et al, 2005). Consistent with the results seen in the FAMOUS trial, the effect of nadroparin on survival was most apparent among patients with a better prognosis at enrollment (defined as an estimated life expectancy of X6 months; Figure 2B) (Klerk et al, 2005). In this group, the hazard ratio was 0.64 (95% CI 0.45 0.90; P 0.010), compared with 0.88 (95% CI 0.62 1.25) in those with a life expectancy of o6 months. Median survival in the good-prognosis group was 15.4 months and 9.4 months for the nadroparin and placebo groups, respectively. There was no significant difference in the rate of major bleeding between the nadroparin group (five events) and the placebo group (one event; P 0.12) (Klerk et al, 2005). In contrast to these data, a trial conducted by Sideras et al (2006) found that LMWH did not influence survival times in patients with advanced cancer. This small study, including 141 participants, initially randomised patients with advanced cancer to treatment with LMWH or saline. Because of low accrual, the placebo injection arm was eliminated and the study became open label, with patients receiving either LMWH plus standard clinical care or standard clinical care alone (Sideras et al, 2006). Median
survival was 10.5 months in the combined standard care and placebo groups and 7.3 months in the combined LMWH arms. When the two arms from the initial, blinded phase of the study were examined, the median survival times were 6.2 months in the LMWH arm and 10.3 months in the placebo arm (Sideras et al, 2006). A recent systematic meta-analysis of randomised trials suggests that LMWH, on balance, improves overall survival in cancer patients, including those with advanced disease (Lazo-Langner et al, 2007). This meta-analysis included four studies, enrolling 898 patients with solid tumours who were randomly allocated to either LMWH or placebo (Lazo-Langner et al, 2007). Three studies used dalteparin (5000 IU daily) for 18 weeks, 1 year, or 2 years; one used 6 weeks of weight-adjusted nadroparin, with a high dose during the first 2 weeks (Lazo-Langner et al, 2007). At 1 year, the pooled results of the studies showed a 30% reduction in the hazard of death in favour of the LMWH group (P 0.05; Figure 3); for patients with less advanced disease, there was a 25% reduction in the hazard of death (P 0.04) (p 731). At 2 years, LMWH reduced mortality in all patients by 43% (P 0.03), and by 41% (P 0.004) in patients with advanced disease. LMWH conferred a statistically significant improvement in survival at both 12 and 24 months (Lazo-Langner et al, 2007). In summary, there is accumulating evidence that anticoagulant therapy may increase survival in some patients with cancer. Further studies are currently ongoing to confirm the effects of anticoagulant therapy in a range of tumour types. The largest of
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1.0 Probability of survival 0.8 0.6 Nadroparin 0.4 0.2 0 0 No. at risk Nadroparin Placebo 1.0 Probability of survival 0.8 Nadroparin 0.6 P = 0.010 0.4 Placebo 0.2 0 0 No. at risk Nadroparin Placebo 12 24 36 48 60 72 84 96 Months after randomisation 79 85 41 31 20 11 12 3 5 3 4 2 3 1 12 24 36 48 60 Months after randomisation 23 12 15 4 7 3 72 84 96 P = 0.021
Placebo
148 154
51 36
4 2
3 1
Figure 2 (A) Probability of survival in all patients with advanced solid malignancy according to assignment to nadroparin or placebo; (B) probability of survival in patients with advanced solid malignancy with a life expectancy of X6 months at enrollment, according to assignment to nadroparin or placebo (Klerk et al, 2005).
Patients with limited and advanced disease or (random) 95% CI One-year mortality Altinbas (2004) Kakkar (2004) Klerk (2005) Sideras (2006) 0.70 (0.49, 1.00) P=0.05 Two-year mortality Altinbas (2004) Kakkar (2004) Klerk (2005) Sideras (2006) 0.57 (0.34, 0.96) P=0.03 0.01 0.1 LMWH better 1 10 100 No LMWH better
Patients with advanced disease or (random) 95% CI
0.75 (0.57, 0.99) P=0.04
0.59 (0.42, 0.84) P=0.004 0.01 0.1 LMWH better 1 10 100 No LMWH better
Figure 3 One- and 2-year mortality in cancer patients randomised to LMWH vs placebo/no intervention (Lazo-Langner et al, 2007).
these is the FRAGMATIC (FRAGMin Added to standard Therapy In patients with lung Cancer) trial (Wales Cancer Trials Unit, 2009), which is currently enrolling patients with pathologically confirmed lung cancer (of all histological types and all stages) who
will be randomly allocated to standard care or standard care plus 6 months of treatment with dalteparin. This trial aims to recruit 2200 patients and is powered to detect a 5% increase in 1-year survival. The GASTRANOX Study (ClinicalTrials.gov, 2009) is enrolling up to
S28 740 patients with advanced gastric cancer who will be randomly allocated to LMWH enoxaparin (1 mg kg1 day1) for 6 months with chemotherapy or chemotherapy alone. The primary end point of the trial is the composite of all-cause mortality and symptomatic VTE. associated with VEGF-induced angiogenesis and venous invasion (Poon et al, 2003), potentially mediated by an interaction with integrin aIIIbI. Moreover, TF-expressing cells seem to be protected from apoptosis induced by serum deprivation and loss of adhesion, suggesting a potential mechanism by which TF may promote metastasis (Versteeg et al, 2004). These data are consistent with the known role of TF in enhancing wound healing, in which it indirectly induces proliferation of human vascular endothelial cells and promotes endothelial cell alignment through the production of thrombin (Carney et al, 1992; Haralabopoulos et al, 1997). Protease-activated receptor-1 (PAR-1) is a receptor for thrombin that is overexpressed in a range of tumour cell lines, particularly metastatic cell lines. Thrombin PAR signalling has been shown to upregulate expression of TF and urokinase plasminogen in prostate cancer, increase invasiveness of breast and pancreatic cell lines, and enhance procoagulant activity in colon cancer (Petralia et al, 2005). Together, it is clear that there is a role for elements of the haemostatic system in cancer progression that extends beyond their role in fibrin generation. These data also suggest mechanisms through which antithrombotic treatments, such as LMWH, may have a direct impact on tumour phenotype, as well as influence survival in patients with cancer, beyond their effect in suppressing VTE.
POTENTIAL MECHANISMS FOR THE EFFECT OF ANTITHROMBOTIC THERAPY ON SURVIVAL IN CANCER

The results of individual clinical trials and meta-analyses, on balance, seem to indicate that antithrombotic therapy and particularly LMWH has an effect on survival in patients with cancer. Although this observation is relatively consistent across studies, it is difficult to understand how a short course of LMWH can provide a substantial survival advantage in patients with cancer. Recent data suggest that antithrombotic therapy may have a direct tumour biology-modifying effect. A large number of circulating proteins, usually in inactive form, are involved in the haemostatic cascade. The activation of these factors culminates in the formation of the fibrin network of the clot and is countered by the fibrinolytic cascade, which, when activated, results in thrombus degradation. Cancer itself seems to elicit a systemic hypercoagulable state. Production of a wide range of procoagulant molecules, including tissue factor (TF) and cancer procoagulant (CP), a cysteine protease growth factor, has been demonstrated in patients with cancer, as well as increased levels of procoagulant markers, including TF, activated factor VII (FVIIa), prothrombin-activation peptide, and thrombinantithrombin complexes (a comprehensive review can be found in Petralia et al (2005). Recent evidence suggests that the production of procoagulant molecules in patients with cancer is more than a mere side effect of cancer growth; instead, data suggest that these factors have an integral role in malignancy through eliciting tumour growth, invasion, metastasis, and angiogenesis. These data provide a potential link between the use of anticoagulant therapies and improved survival in patients with cancer. Tissue factor, a cell-surface bound, transmembrane glycoprotein, has been shown to be expressed on a variety of tumours derived from the epithelium. Tissue factor interacts with FVIIa to form the TFVIIa complex the primary activator of coagulation (Petralia et al, 2005). This complex seems to have a role in cell adhesion and migration through the recruitment of actin-binding protein 280 (filamin A), an intracellular protein implicated in cell motility (Ott et al, 1998). In vitro, immobilised ligands for TF specifically support cell adhesion, spreading, and intracellular signalling, suggesting that the interaction between the cytoplasmic domain and filamin A may support tumour cell metastasis and vascular remodelling. Cancer procoagulant is also expressed by a wide range of tumours. It has the ability to initiate the haemostatic cascade directly by activating FX independently of the TFVIIa complex. Tissue factor expression has been shown to dramatically change tumour behaviour. In animal models, overexpression of TF in cancer cells has been shown to significantly upregulate over 40 genes and downregulate nearly 230 genes involved in transcription, translation, intercellular signalling, cell growth, and apoptosis (Wang et al, 2004). Tissue factor expression correlates with histological grade and heralds the transformation from benign to malignant phenotype (Kakkar et al, 1995). Overexpression of TF in experimental models of pancreatic adenocarcinoma enhances in vitro invasion and primary tumour growth (Kakkar et al, 1999). Similarly, overexpression in a mouse sarcoma model resulted in increased levels of proangiogenic vascular endothelial growth factor (VEGF) and suppression of thrombospondin, an antiangiogenic regulatory protein (Zhang et al, 1994). In human breast cancer, TF expression has been shown to correlate with an invasive phenotype and initiation of angiogenesis (Contrino et al, 1996). Tissue factor expression in hepatocellular cancer is strongly
CONSENSUS STATEMENT
Although the association between cancer and an increased risk of thromboembolism is well understood, the evidence that anticoagulant therapy may improve survival in cancer patients has been slow to accumulate. The results of studies have been quite heterogeneous in both the patient population and the anticoagulant used. Many of the studies have also been underpowered to show clinically significant improvements in survival. However, it does seem that there is a beneficial effect even from quite short courses of treatment, and it seems that heparins may be more effective than coumarins, and that this effect may be more marked in patients with better prognosis. The beneficial effects do not seem to come at the expense of a significant risk of adverse effects, haemorrhage in particular. Together, these findings suggest that, although there may be a short-term benefit in preventing thromboembolism in a group of patients at increased risk, there may also be a longer-term effect on the cancer itself. This hypothesis is supported by a number of in vitro and animal studies indicating a link between key factors in the coagulation cascade and tumour growth and metastasis. In addition to continuing investigation of the detailed mechanisms of the complex interactions between growing tumour cells and the coagulation cascade, there are a number of important questions to be answered before routine anticoagulant therapy is integrated into cancer therapy: How large and how consistent is any survival benefit? Which patients (tumour type, stage, prognostic category) are most likely to benefit from therapy? Which anticoagulant is most effective? What duration of treatment is needed? How large is the risk of significant adverse effects? We would therefore urge participation in the ongoing clinical trials and in planning of future studies to make the most of this fascinating and potentially important area of cancer treatment.
Conflict of interest
AK Kakkar has received consulting fees from Bayer, Sanofi-aventis, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Eisai. F Macbeth has received grant support from CRUK and Pfizer.
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Am J Physiol 273: C239 C245 Kakkar AK, Chinswangwatanakul V, Lemoine NR, Tebbut S, Williamson RC (1999) Role of tissue factor expression on tumour cell invasion and growth of experimental pancreatic adenocarcinoma. Br J Surg 86: 890 894 Kakkar AK, Lemoine NR, Scully MF, Tebbutt S, Williamson RC (1995) Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg 82: 1101 1104 Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC (2004) Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 22: 1944 1948 Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller HR (2005) The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23: 2130 2135 Lazo-Langner A, Goss GD, Spaans JN, Rodger MA (2007) The effect of lowmolecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost 5: 729 737 Lebeau B, Chastang C, Brechot JM, Capron F, Dautzenberg B, Delaisements C, Mornet M, Brun J, Hurdebourcq JP, Lemarie E, for Petites Cellules Group (1994) Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer 4: 38 45 Maurer LH, Herndon II JE, Hollis DR, Aisner J, Carey RW, Skarin AT, Perry MC, Eaton WL, Zacharski LL, Hammond S, Green MR (1997) Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. J Clin Oncol 15: 3378 3387 Ott I, Fischer EG, Miyagi Y, Mueller BM, Ruf W (1998) A role for tissue factor in cell adhesion and migration mediated by interaction with actinbinding protein 280. J Cell Biol 140: 1241 1253 Petralia GA, Lemoine NR, Kakkar AK (2005) Mechanisms of disease: the impact of antithrombotic therapy in cancer patients. Nat Clin Pract Oncol 2: 356 363 Poon RT, Lau CP, Ho JW, Yu WC, Fan ST, Wong J (2003) Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma. Clin Cancer Res 9: 5339 5345 Schulman S, Lindmarker P (2000) Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. N Engl J Med 342: 1953 1958 Sideras K, Schaefer PL, Okuno SH, Sloan JA, Kutteh L, Fitch TR, Dakhil SR, Levitt R, Alberts SR, Morton RF, Rowland KM, Novotny PJ, Loprinzi CL (2006) Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clin Proc 81: 758 767 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS (1996) Low-molecularweight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 100: 269 277 Tagalakis V, Tamim H, Blostein M, Collet JP, Hanley JA, Kahn SR (2007) Use of warfarin and risk of urogenital cancer: a population-based, nested case-control study. Lancet Oncol 8: 395 402 Versteeg HH, Spek CA, Richel DJ, Peppelenbosch MP (2004) Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene 23: 410 417 Wales Cancer Trials Unit. FRAGMATIC: a randomised phase III clinical trial investigating the effect of FRAGMin Added to standard Therapy In patients with lung Cancer. http://www.wctu.org.uk/fragh.htm. Accessed 22 September 2009 Wang X, Wang M, Amarzguioui M, Liu F, Fodstad O, Prydz H (2004) Downregulation of tissue factor by RNA interference in human melanoma LOX-L cells reduces pulmonary metastasis in nude mice. Int J Cancer 112: 994 1002 Zacharski LR, Henderson WG, Rickles RR, Forman WB, Cornell Jr CJ, Forcier AJ, Edwards RL, Headley E, Kim S-H, ODonnell JF, ODell R, Tornyos K, Kwaan HC (1984) Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer 53: 2046 2052 Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP (1994) Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 94: 1320 1327
ORIGINAL RESEARCH ARTICLE
Pharmacoeconomics 2006; 24 (6): 593-607 1170-7690/06/0006-0593/$39.95/0 2006 Adis Data Information BV. All rights reserved.
Dalteparin versus Warfarin for the Prevention of Recurrent Venous Thromboembolic Events in Cancer Patients
A Pharmacoeconomic Analysis
George Dranitsaris,1 Mark Vincent2 and Mark Crowther3
1 2 3 Augmentium Pharma Consulting, Toronto, Ontario, Canada London Regional Cancer Centre, London, Ontario, Canada St Josephs Hospital, Hamilton, Ontario, Canada
Abstract
Objective: In a recent randomised trial (CLOT [Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy for long term anticoagulation in cancer patients with venous thromboembolism]), which evaluated secondary prophylaxis of venous thromboembolism (VTE) in cancer patients, dalteparin reduced the relative risk of recurrent VTEs by 52% compared with oral anticoagulation therapy (p = 0.002). A Canadian pharmacoeconomic analysis was conducted to measure the economic value of dalteparin for this indication. Design: The study was conducted from the Canadian healthcare system. The first part of this study utilised the CLOT trial database, from which resource utilisation data were converted into Canadian cost estimates ($Can, year 2005 values). Univariate and multivariate regression analyses were conducted to compare the total cost of therapy between patients randomised to treatment with dalteparin or oral therapy. Health state utilities and treatment preferences were then measured in 24 oncology care providers using the time trade-off technique. Results: When all of the cost components were combined for the entire population (n = 676), patients in the dalteparin group had significantly higher overall costs than the control group ($Can4162 vs $Can2003; p < 0.001). The preference assessment revealed that 23 of 24 respondents (96%) selected dalteparin over warfarin, with an associated gain of 0.157 QALYs. When the incremental cost of dalteparin ($Can2159 per patient) was combined with the QALY gain, the findings revealed that dalteparin was associated with a cost of approximately $Can13 800 (95% CI 12 400, 15 100) per QALY gained. Conclusions: Given the practical advantages of dalteparin in terms of convenience, improved efficacy and the acceptable economic value, this analysis
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suggests that long-term dalteparin therapy is a sound alternative to warfarin for the prevention of recurrent VTEs in patients with cancer.
Over the past decade, considerable cancer supportive care research has been devoted to febrile neutropenia, emesis and anaemia. In contrast, other adverse consequences of cancer such as venous thromboembolism (VTE), manifesting as deep vein thrombosis (DVT) and pulmonary embolism (PE), has received less attention. Compared with noncancer patients, the incidence of VTE has been increasing in cancer patients over the past 10 years and the risk of a recurrent DVT and subsequent PE remains elevated, which may be related to more aggressive chemotherapy and improvements in overall survival.[1,2] In one large epidemiological study, Sallah et al.[3] evaluated VTE in 1041 patients with solid tumours admitted to three major medical centres. The investigators identified 81 patients with VTE for an overall prevalence of 7.8% (95% CI 6.2, 9.4), or one event per 12.8 patients. This high incidence is of concern to oncologists and hospital administrators because the North American and European populations are aging and cancer is a disease that usually occurs later in life.[4] From the perspective of a cancer treatment centre, these changing demographics have resulted in increases in the number of patients seeking treatment. An inability to adequately meet these demands translates into longer patient waiting times and, potentially, suboptimal care. One approach to help oncology centres meet this increased volume would be to identify existing supportive care agents that provide superior efficacy to patients, versus traditional agents, thus reducing unscheduled clinic visits by preventing predictable complications of cancer or its therapy. Thus, in the case of VTE, prolonged warfarin prophylaxis is typically offered to reduce the risk of secondary events such as DVT and PE. However, warfarin
2006 Adis Data Information BV. All rights reserved.
treatment can be problematic because of the potential for drug-drug interactions, and unpredictable anticoagulation levels secondary to liver dysfunction and gastrointestinal dysfunction. The resulting poor quality anticoagulant care can contribute to both bleeding and recurrent VTE.[2] In addition, there is a need to closely monitor patients receiving oral anticoagulation therapy; laboratory monitoring is not only costly but also requires patients to undertake additional hospital or clinic visits. Dalteparin is a low-molecular-weight heparin (LMWH) that has been used for many years for the treatment and prevention of VTE. The advantage of dalteparin over warfarin is the reduced variability in the anticoagulation response, eliminating the need for laboratory monitoring. Dalteparin has been shown to be more effective than oral anticoagulation therapy for the secondary prophylaxis of VTE in patients with cancer, with an overall relative risk reduction of approximately 52%.[5] Furthermore, evidence suggests a survival benefit in cancer patients treated with LMWH versus a non-LMWH control group.[6-8] One of the potential barriers to the use of dalteparin for secondary VTE prophylaxis in cancer patients is its high acquisition cost compared with warfarin, and the need for subcutaneous administration. However, other characteristics of dalteparin such as improved efficacy, a reduced need for patient monitoring and a lower clinical burden should be considered when discussing the cost of therapy. These factors were considered in previous economic evaluations of LMWHs in patients such as those undergoing orthopaedic surgery.[9-11] Therefore, there are two questions that formulary committees have to consider:
Pharmacoeconomics 2006; 24 (6)
Cost Effectiveness of Dalteparin for Preventing VTEs in Cancer
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1. Does the use of dalteparin for secondary prophylaxis of VTE in cancer patients provide good economic value when all of the clinical, economic and patient factors are quantified? 2. How does the economic value of dalteparin compare with other drugs currently used in cancer supportive care? In this study, a pharmacoeconomic analysis was conducted to determine whether dalteparin is an economically reasonable alternative to warfarin from the perspective of the publicly funded Canadian healthcare system. Methods
reach statistical significance (dalteparin = 14%, oral therapy = 19%; p = 0.09). In a post hoc analysis that evaluated various patient subgroups, the occurrence of death at 1 year in patients with no metastatic disease was 20% in the dalteparin group compared with 36% in the oral anticoagulant group (hazard ratio = 0.50; p = 0.03).[6] Based on the CLOT trial,[5] dalteparin was approved by the Canadian regulatory authority as an acceptable agent for long-term secondary prophylaxis of DVT in cancer patients.
Extraction of Resource Utilisation Information from the CLOT Trial Database
Clinical Trial
The clinical trial data for the pharmacoeconomic evaluation were obtained from a multicentre, randomised, nonblind Canadian trial (CLOT [Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy for long term anticoagulation in cancer patients with venous thromboembolism]), which compared dalteparin with oral anticoagulation therapy for the secondary prevention of VTEs in cancer patients.[5] In that study, Lee et al.[5] randomised 676 cancer patients with a newly diagnosed VTE to receive 6 months prophylaxis with subcutaneous dalteparin (200 IU/kg once daily in the first month, then 150 IU/kg once daily from months 2 to 6) or 7 days of dalteparin followed by an oral anticoagulant. During the study period, 27 of 336 (8.0%) patients evaluated in the dalteparin group developed recurrent VTE compared with 53 of 336 (15.8%) patients treated with warfarin (overall 52% relative risk reduction, p = 0.002). In this study, there were no significant differences in major bleeding events between groups (dalteparin = 6%, oral therapy = 4%; p = 0.27).[5] Overall rates of bleeding were higher with warfarin, but the difference did not
The CLOT study database contained healthcare resource use data for 338 patients randomised into each group.[5] In the original trial, two patients from each group were excluded because they did not have a qualifying thrombotic event. In the current analysis, all randomised patients were included. Although the original CLOT trial was not designed to formally collect healthcare resource data for an economic evaluation, important healthcare resource items were collected about each patient on the following variables: (i) dosage and duration of therapy of study drugs; (ii) routine laboratory tests; (iii) patient international normalisation ratio (INR) in the case of warfarin; (iv) patient telephone contact; (v) unscheduled clinical visits; (vi) diagnostic tests relevant for VTE; (vii) blood transfusions; and (viii) the occurrence of bleeding-related events that were possibly or probably due to the study drugs. There were no direct hospital length of stay or individualised treatment data for the management of patients who actually developed recurrent VTEs. Therefore, the Canadian and international literature was used to obtain cost estimates for treating a DVT, PE, fatal PE as well as the following adverse events: heparin-induced thrombocytopenia, haematochezia, haematoma, haematuria, haematemesis, maleana,
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retroperitoneal bleeding, intracranial bleeding and intraperitoneal bleeding.[12-14] Only events of grade III or higher severity were included in the economic analysis (table I). Unless specified, it was assumed that patients developing DVTs were treated in the outpatient setting. Unit costs were obtained from the University Health Network and the Toronto Sunnybrook Regional Cancer Center in Toronto (table I). All costs in the current study were reported in 2005 $Can, and cost estimates from previous years were converted to 2005 dollars using the consumer price index for healthcare as reported by Statistics Canada.[16] The protocol evaluated in the pivotal randomised trial and used in the current analysis was subcutaneous dalteparin 200 IU/kg once daily in the first month, then 150 IU/kg once daily from months 2 to 6. The daily cost of supplies (e.g. syringes) for dalteparin administration was also included in the analysis. Care was used to ensure the patient demographic, clinical and associated outcomes data had been properly linked with the appropriate costs in all randomised patients. The final outcome of this process allowed an overall estimate of resource use and cost between groups.
Design of Pharmacoeconomic Analysis
Treatment Preferences and Health-State Utilities
When the relevant healthcare resources were extracted from the CLOT database (see the Extraction of Resource Utilisation Information from the CLOT Trial Database section), unit cost estimates were applied to each component. A univariate analysis on the overall cost was initially conducted to determine the magnitude of the cost difference between patients treated with dalteparin relative to those who received oral anticoagulation therapy. This cost difference was then used in the subsequent cost-utility analysis to estimate the incremental cost per QALY gained with dalteparin.
The health-related quality-of-life (HR-QOL) values measured in the analysis were patient preferences for alternative health states. The two health states were long-term secondary treatment with warfarin for 6 months to prevent a recurrent VTE, or dalteparin for the same indication and duration. In the current study, QALYs were measured as healthy months equivalence for the time spent in each health state.[17,18] The scores in months were then converted to utility measures between 0 and 1, where 0 represented death and 1 was a state of perfect health or optimal quality of life (QOL). Gains in healthy month equivalence were also converted into QALYs by dividing by 12 months. The ideal population for measuring health-state utilities and treatment preferences would have been cancer patients who had already experienced a VTE and were about to receive extended prophylaxis. However, in this study, a patient surrogate group consisting of 24 oncology nurses and pharmacists with front line clinical experience was used. There is evidence in the oncology literature to suggest that nurses and clinical pharmacists are suitable patient surrogates for objective outcomes, and that utility estimates derived from nurses and pharmacists do not substantially alter the findings of cost-utility studies compared with estimates reported by patients.[19,20] Furthermore, we ensured that the surrogate sample had clinical experience in cancer supportive care, in which VTE management represents an important component. With a sample of 24 respondents, healthy months equivalence was measured with a precision of 1.0 month, with a 95% probability. After informed consent was obtained, each patient surrogate (i.e. healthcare provider) was interviewed. Respondents were presented with information about the natural history of VTEs in cancer, followed by a description of the warfarin and
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Table I. Unit costs used in the economic analysis ($Can, year 2005 values) Parameter Drugs Dalteparin Warfarin (30 days) Diagnostic tests CBC with differential PT/APTT Liver function tests (AST, ALT, ALP, GGTP) Serum creatinine Electrolytes (K, Na, Cl) Urea Bilirubin Albumin Diagnostic tests Compression ultrasonography Lung perfusion scan Pulmonary angiography (four vessels) Contralateral venography CT scan of the lung with contrast CT scan of the lung with without contrast Unscheduled patient contact Telephone consultation Clinic visit Blood transfusions One unit of red blood cells Physical cost of transfusion 305 278 Gordois et al.[13] Dranitsaris[15] 17.10 161b UHN and Schedule of benefits, Ontario, 2002 83.82 each 521.81 each 1108.82 each 521.81 each 87.13 each 116.17 each Diagnostic Imaging Department, UHN Diagnostic Imaging Department, UHN Diagnostic Imaging Department, UHN Diagnostic Imaging Department, UHN Diagnostic Imaging Department, UHN Diagnostic Imaging Department, UHN 10.95 each 7.50 each 5.17 each 5.10 each 5.10 total 3.18 each 8.50 each 5.17 each Biochemistry Department, UHN Biochemistry Department, UHN Biochemistry Department, UHN Biochemistry Department, UHN Biochemistry Department, UHN Biochemistry Department, UHN Biochemistry Department, UHN Biochemistry Department, UHN 22.05/daya 17.36 Pfizer, Canada Outpatient pharmacy, UHN Cost estimate Source
Treatment of venous thromboembolisms and other events Fatal PE Nonfatal PE Outpatient DVT management Inpatient DVT management Heparin-induced thrombocytopenia a 1162 4237 2445 3473 2417
Based on mean weight and duration data reported in the trial and using a dalteparin drug cost of $Can1.56/1000IU for the first 30 days and then $Can1.976/1000IU from day 31 to 125. Drug cost differences were based on variations in drug vial sizes. Cost of supplies for dalteparin administration were also included in the daily cost. Consists of a clinic visit and a partial patient assessment.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CBC = complete blood count; DVT = deep vein thrombosis; GGTP = gamma glutamyl transpeptidase; PE = pulmonary embolism; PT = prothrombin time; UHN = University Health Network.
dalteparin administration protocol. This included information on the method of administration, monitoring requirements and the associated risks and benefits. During the final part of the interview, the clinical outcomes from the CLOT trial were presented. This consisted of the risk for recurrent DVTs, fatal and non-fatal PEs, and major bleeding
events associated with each therapy. The final piece of information presented to respondents was the results of the post hoc subgroup survival analysis, which suggested a potential survival benefit in patients treated with dalteparin.[6] However, respondents were told that this result was derived from a
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post hoc subgroup analysis and the results needed to be confirmed in a prospective study. Respondents were then asked how many months of optimal health they considered being equivalent to the time spent in each of the less than optimal health states described. These measures were used to weigh the duration within each health state by the QOL experienced by a patient living through that time period. The utility value for each health state was based on scores from the interviews. It was defined as the ratio of the equivalent time in optimal health to the months receiving treatment with either dalteparin or warfarin (e.g. 3 healthy months equivalent to 6 treatment months = 0.50). This provided a utility value in the range of 01, where 0 represented death and 1 was a state of optimal health. Printed interview tools were used to facilitate the participants understanding of the time trade-off technique.[17,18] Demographic data were also collected from each participant and consisted of age, years of oncology experience and experience in the man-
agement of cancer patients with VTEs, involvement in guideline development, level of familiarity with the cost of drugs used in cancer and whether or not family members had developed a VTE.
Cost-Utility Analysis
The clinical, economic and QALY estimates were then used to conduct a cost-utility analysis comparing dalteparin and warfarin. The primary outcome was the cost per QALY gained with dalteparin, which was calculated by dividing the difference in cost relative to warfarin therapy (numerator) by the difference in QALYs gained (denominator). Future costs and benefits were not discounted, because of the short time periods involved. However, the stability of the baseline results was tested through a sensitivity analysis. This procedure included re-analysing the data using the upper and lower 95% confidence intervals for costs and health state utilities.
Table II. Patient demographic and clinical characteristics at randomisation in the CLOT (Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy for long term anticoagulation in cancer patients with venous thromboembolism) study[5] Parameter M/F Median age [y] (range) Mean weight [kg] (range) Major illness in past 3 months (%) ECOG score (%) 0 1 2 3 Patient was in hospital (%) Solid tumour with metastatic disease (%) Haematological cancer (%) History of VTE (%) Mean baseline INR Mean baseline platelets (103 mm3) 23.7 39.9 34.9 1.5 50.0 65.9 11.8 11.5 1.1 260.3 18.6 44.4 36.1 0.9 53.9 68.6 8.9 10.6 1.2 250.6 Dalteparin (n = 338) 159/179 64.0 (2286) 73.6 (39132) 51.8 Oral therapy (n = 338) 169/169 64.2 (2889) 74.7 (40128) 59.8
Mean baseline serum creatinine (mg/dL) 0.84 1.0 ECOG = European Cooperative Oncology Group Performance scale; F = female; INR = international normalisation ratio; M = male; VTE = venous thromboembolism.
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Table III. Comparison of healthcare resource utilisation; data from the CLOT (Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy for long term anticoagulation in cancer patients with venous thromboembolism) database[5] Parameter (mean number/patient) Duration of therapy (days) Treatment complianceb (%) Dalteparin (n = 338) 126.3 98.2 Oral therapy (n = 338) 116.9 88.7
a
Mean dose of dalteparin (IU/kg) First 7 days First 30 days Beyond day 30 Routine laboratory monitoring CBC APTT INR measurements (PT) Sodium Potassium Chloride Urea Serum creatinine ALT AST ALP GGTP Bilirubin Albumin Diagnostic tests Compression ultrasonography Contralateral venography Spiral CT scan Lung scan Pulmonary angiography Unscheduled patient contact Telephone consultation Clinic visit Blood transfusions Total RBC units given Total number of transfusions of II units Mean number APTT measurements Mean number INR measurements a b p < 0.001 between treatment groups. 91 27 7.0 0.27 119 40 11.0 1.84 6.9 1.0 6.8 1.1 0.87 0.02 0.11 0.27 0.01 0.85 0.04 0.10 0.26 0.03 4.5 3.4 0.0 4.2 4.2 3.9 4.1 4.2 3.9 3.5 3.9 3.4 3.9 3.7 4.1 3.2 22.0 3.8 3.8 3.4 3.7 4.1 3.4 3.1 3.4 3.0 3.4 3.2 200.6 165.1 200.0 0.0 0.0
Patients in the oral therapy group received dalteparin for a mean of 8 days, as indicated in the protocol.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CBC = complete blood count; GGTP = gamma glutamyl transpeptidase; INR = international normalisation ratio; PT = prothrombin time; RBC = red blood cell.
Statistical Analysis
pare the overall cost between groups (see Multivariate Analysis section). A paired t-test analysis was then utilised to evaluate healthy month equivalence scores and utility estimates for dalteparin and
Demographic data and utility estimates were presented as descriptive statistics as means, medians or proportions. The unpaired t-test was used to com 2006 Adis Data Information BV. All rights reserved.
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Table IV. Treatment-associated clinical outcomes related to resource utilisation Parameter DVT alone Nonfatal PE Fatal PE Hospital admission rate regardless of cause* (%) Hospital admission rate for VTE, bleeding or HIT* (%) Dalteparin (n = 338) 14 8 5 25.1 3.2 Oral therapy (n = 338) 37 9 7 28.5 3.8
Total number of hospital days for VTE, bleeding or HIT 32 40 DVT = deep vein thrombosis; HIT = heparin-induced thrombocytopenia; PE = pulmonary embolism; VTE = venous thromboembolism; * p = not significant between treatment groups.
warfarin. A multivariable regression analysis was also conducted in an exploratory manner to compare the cost of treatment with dalteparin relative to the control group. This included a main effects-only model as well as an evaluation of patient subgroups through the application of interaction effects. The cut-off for significance for all of the statistical procedures was at the p = 0.05 level. All of the statistical analyses were performed using Stata, release 7.0 (Stata Corp., College Station, Texas, USA). Results The results of the economic analysis were based on data from 676 patients randomised to receive extended prophylaxis with dalteparin or oral anticoagulation therapy. As was reported in the original randomised clinical trial,[5] treatment arms were well balanced with respect to demographic, clinical
characteristics and risk factors (table II). Given this balance between groups, it was reasonable to proceed with a comparison of overall resource use whereby a reduction in resource use in one group relative to another would likely be due to efficacy in reducing the recurrence of VTEs and possibly a reduction in the rate of cancer progression. Healthcare resource utilisation data were collected as part of the CLOT trial database. The mean duration of dalteparin therapy in the experimental group was 126.3 days compared with 8 days in the control group (table III). Patients randomised to the oral anticoagulation therapy group received treatment for a mean of 116.9 days. Compliance with anticoagulation therapy was significantly higher in the dalteparin group by approximately 10% (p < 0.001). The utilisation of laboratory tests was comparable between groups, with the exception of
Table V. Comparison of costs between groups ($Can, year 2005 values) Cost parameter (mean) Drug therapya Laboratory monitoring Diagnostic tests Unscheduled patient contact Blood transfusions Treatment of major bleeding events and other complicationsb,c VTE recurrence management Mean cost per patientd (95% CI) a b c d Cost of supplies for dalteparin administration included in the daily cost. NCI grade III or higher that were possibly or probably related to treatment. Costs obtained from Hull et al.,[12] and converted into 2005 values. p < 0.001 between treatment groups. Dalteparin (n = 338) 2852 303 253 286 143 97.5 228 4162 (3910, 4413) Oral therapy (n = 338) 269 437 267 300 208 92.3 429 2003 (1910, 2096)
NCI = National Cancer Institute; VTE = venous thromboembolism.
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100
80 Percentage of contribution
VTE treatment Major bleeding Blood transfusions Patient contact Diagnostic tests Laboratory monitoring Drug therapy
60
40
20
0 Dalteparin Oral therapy Fig. 1. Contributors to the overall cost of dalteparin and warfarin therapy. VTE = venous thromboembolism.
INR measurements, which are required for oral anticoagulation therapy. An average of 22 INRs were measured per patient randomised to oral anticoagulation therapy. Furthermore, there were more unscheduled clinic visits (absolute number = 352 vs 387), telephone consultations, blood transfusions and activated partial thromboplastin time/INR measurements (associated with transfusions) in the warfarin group (table III). The occurrence of VTE-related events was then extracted from the database and compared between groups (table IV). As reported in the original trial, there was a statistically significant reduction in the occurrence of VTEs in patients randomised to the dalteparin group. Overall, there were 23 fewer DVTs and 3 fewer PE events in the dalteparin group. In patients who were receiving therapy in the outpatient setting, there was a hospital admission rate (regardless of cause) of 25.1% in the dalteparin group compared with 28.5% in the control group (p = 0.33). When the cause for the admission was limited to recurrent VTE, bleeding or heparin-induced thrombocytopenia, the rates of hospital ad 2006 Adis Data Information BV. All rights reserved.
mission were 3.2% for dalteparin and 3.8% in the oral therapy group (p = 0.68). Overall, these rates translated to 32 additional hospital days for dalteparin patients and 40 days in the control group (table IV). A cost comparison was then performed using the resource use estimates in tables III and IV along with the unit cost estimates found in table I. Patients randomised to dalteparin had higher costs for drug therapy and for the treatment of major bleeding events (table V). In contrast, the warfarin group had elevated costs for laboratory monitoring, diagnostic tests, unscheduled patient contact, blood transfusions and VTE recurrence management. When all of the costs were considered, patients in the dalteparin group were approximately $Can2159 more costly to treat than patients in the control group (table V). The largest cost contributor in the dalteparin group was drug acquisition, at 67% (vs 13% in the control), while VTE treatment and laboratory monitoring were the largest cost components in the oral anticoagulation therapy group (figure 1).
Treatment Preferences and Health-State Utilities
Treatment preferences and health-state utilities for each outcome were estimated from a sample of 24 oncology healthcare professionals. The mean age of respondents was 44.3 years (range 2462 years) with an average of 8.6 years of direct oncology experience (range 127 years). Furthermore, 17 of 24 (70.8%) participants had direct experience in the treatment of VTEs in cancer patients, with an average length of experience of 6.7 years. In addition, 8.3% of the sample had been involved in the development of practice guidelines/algorithms specific to VTE management over the previous 2-year period. Lack of drug cost knowledge could affect treatment preferences. Respondents were asked to state their knowledge of costs for oncology drugs. The findings revealed that 41.7% and 45.8% of the sample
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Table VI. Cost-effectiveness and cost-utility analysis (all cost-effectiveness ratios were rounded to the nearest hundred) [$Can, year 2005 values] Parameter Utilities Treatment preferences from respondents [n = 24] (%) Mean health month equivalence Mean health state utilitya,b Mean cost per patient Cost-effectiveness analysisc Recurrence of VTE (%) Cost per VTE avoided Cost-utility analysisc QALY gained Cost per QALY gained a b c d e 0.157d (0.114, 0.208) 13 751c,e (12 400, 15 100) Differences that were statistically significant; p < 0.05. A quality-of-life score for a health state between 0 and 1, with 0 = death and 1 = optimal health. In this case, the duration of the health state was 6 months. 95% confidence intervals were crudely estimated using the 95% CI limits for the difference in cost (i.e. in the numerator), while keeping the gains in VTE avoidance and QALYs (i.e. in the denominator) constant. Difference in healthy month equivalence divided by 12 months. Incremental cost of dalteparin divided by gain in QALYs. 8.0 27 700 (24 400, 30 400) 15.8 7.8a 23 (96) 3.94 (3.32, 4.56) 0.66 (0.55, 0.76) 4162 (3910, 4413) 1 (4)a 2.06 (1.55, 2.58) 0.34 (0.26, 0.43) 2003 (1910, 2096) 2159a (1943, 2373) 1.88a (1.37, 2.49) Outcome (95% CI) dalteparin oral therapy difference
VTE = venous thromboembolism.
were very familiar or somewhat familiar, respectively, with the cost of drugs used to treat cancer. The final series of demographic questions focused on respondents family experience with VTEs. The data revealed that 3 of 24 patients (12.5%) had a positive family history for VTEs. Once all of the information had been presented on both treatments, respondents were asked to select their preferred prophylactic intervention. Overall, 23 of 24 (96%) respondents selected dalteparin over warfarin. Healthy month equivalence scores and health state utilities for each alternative were then estimated from the sample. The utility of the dalteparin health state was almost 2-fold higher than treatment with warfarin, indicating a QOL benefit (table VI). These preferences and utility scores for dalteparin were likely due to a combination of factors such as improved efficacy, demonstrated safety profile with extended use and the ability to eliminate continuous laboratory monitoring. Overall, the gain
in healthy month equivalence was approximately 1.88 months with dalteparin, which corresponded to an additional gain of approximately 0.157 QALYs.
Pharmacoeconomic Analysis
Using the differential in the cost and VTE recurrence rate, the initial analysis estimated the incremental cost per VTE avoided with dalteparin. Overall, the use of dalteparin as an alternative to warfarin was associated with an incremental cost of approximately $Can27 700 (95% CI 24 400, 30 400) per VTE avoided (table VI). However, this cost-effectiveness ratio fails to consider the gain in QALYs associated with dalteparin. To provide such information, a cost-utility analysis was performed where the incremental cost of dalteparin ($Can2159) was combined with the 0.157 QALY gain (a gain of 1.88 health months equivalence corresponds to a QALY gain of 1.88 months per 12 months). The findings revealed an incremental cost of $Can13 751 per
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QALY gained, consistent with the hypothesis that dalteparin is a cost-effective intervention in cancer patients at risk for recurrent VTEs (table VI).
Multivariate Analysis
Sensitivity Analysis
A series of one-way sensitivity analyses were then conducted using the 95% CI of the health months equivalent scores (1.37, 2.49) and the cost differential ($Can1943, $Can2373) between the two treatments. Under the worst case scenario, in which the highest cost difference between the two treatments (i.e. $2373) as well as the lowest gain in healthy months equivalence (i.e. 1.37) was used, the cost per QALY gained with dalteparin would be approximately $Can21 000. Under the best case scenario, in which the lowest cost difference (i.e. $Can1943) along with the highest gain in healthy months equivalence (i.e. 2.49) was used, the cost per QALY gained with dalteparin would be cost effective at $Can9400. These findings imply that the cost per QALY gain estimated in the current study was stable, despite reasonable variations in the point estimates.
Table VII. Multivariable regression analysis on overall cost of therapy Variable Intercept Dalteparin group Male Age ECOG 1 ECOG 2 ECOG 3 Interaction effects (vs ECOG 0)a ECOG 1 dalteparin ECOG 2 dalteparin ECOG 3 dalteparin 0.13 0.26 0.71 0.081 0.83 0.29 Parameter estimate 7.65 0.89 0.077 0.003 0.019 0.15 0.24 0.66 0.031 0.001 0.060 0.062 0.24 SEM
The primary objective of the multivariable analysis was to identify patient subgroups in which the use of dalteparin could be potentially cost saving. An initial assessment of the total cost (dependent variable) revealed that it was highly skewed by a small number of high-cost cases. This is a common occurrence in cost of illness studies; usual practice is to log-Normalise the data in this case. The adequacy of the procedure was verified by inspection of the normal plots and application of the Skew test. The residuals from the final models were also examined to ensure that they were Normally distributed. The adjusted R2 is a multivariate regression indicator of model goodness of fit, with a range between 0 and 100%. The final regression model generated an adjusted R2 value of 0.48, suggesting that 48% of the variability observed in the dependent variable was explained by the independent variables retained in the model. The results of the multivariable analysis determined that treatment group, male gender, patient age and performance status at the initiation of therapy were significantly associated with the cost of therapy (table VII).
p-Value <0.001 0.012 0.018 0.74 0.81 0.30
Effect on total cost Overall 2.4-fold increase 8% increase in men Overall decrease with increasing age NS NS NS
0.096 0.002 0.016
NS 23% decrease in dalteparin cost 51% decrease in dalteparin cost
Adjustedb R2 0.48 a The subgroup analysis was relative to an ECOG Performance Scale score of 0, meaning no physical impairment. For example, for ECOG 1 dalteparin = cost of dalteparin in ECOG 1 patients vs ECOG 0 patients who received dalteparin. b Proportion of variability in the dependent variable that is accounted for by the model. ECOG = European Cooperative Oncology Group; NS = not significant; SEM = standard error of the mean.
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A closer examination of the variable for the dalteparin group revealed that, when controlling for the other factors, treatment with dalteparin was approximately 2.4-fold (anti-log of 0.89 = 2.4) more costly than with oral anticoagulation therapy (p < 0.001). The results of the multivariable procedure confirmed those of the univariate analysis, that the cost of treatment with dalteparin was significantly greater than that of warfarin. The negative value for patient age implied that, as patient age increased, overall cost of management decreased. Furthermore, the positive association with male sex and overall cost implied that men accrued more costs than women (table VII). The regression model provided some interesting insight related to the statistically significant and negative interaction effects between patients treated with dalteparin and performance status where progressive cost reductions were observed in poor performance status patients (table VII). The interpretation is that dalteparin-treated patients with a performance status of 2 or 3 (i.e. progressively being more bed ridden) had significantly lower overall management costs than performance status 0 patients (i.e. fully mobile) randomised to the same therapy. As a result, the overall cost differential between dalteparin and warfarin was reduced in poorer performance status patients. Discussion The basic premise of health economic studies predicated on randomised controlled trials is to compare the costs and consequences of alternative pharmaceutical interventions and determine which treatment offers the best value for money. There are several approaches available to evaluate economic efficiency. Decision analysis, or Markov computer modelling, is one of the most commonly used methods for conducting cost-effectiveness analyses. Using this technique, outcomes are typically presented as incremental cost per QALY gained. Even though
invaluable in many situations, the data required to construct valid models are often not available. As a result, analysts are forced to rely on data from multiple sources and invariably have to make important assumptions. Such assumptions are often based on judgment rather than validated data. As an alternative to computer modelling, economic analyses based on actual resource utilisation data collected as part of a prospective randomised trial offers real world information for health policy decision making. In the current analysis, resource utilisation data collected as part of the CLOT study[5] were used to estimate the incremental cost per VTE avoided and QALY gained with dalteparin as an alternative to warfarin. Within the framework of the treatment regimen used in the Canadian-led CLOT trial, the results of the univariate and multivariate economic analyses suggest that patients randomised to receive dalteparin had significantly higher overall costs compared with those treated with warfarin. When the absolute reduction in the VTE rate was compared with the additional expenditure, dalteparin was associated with an incremental cost of approximately $Can27 700 per VTE avoided. However, this estimate fails to consider treatment preferences and the associated patient utility gain secondary to receiving extended prophylaxis with dalteparin, which has several advantages over warfarin, including improved efficacy, potentially enhanced safety, added convenience, and, possibly, a survival advantage in selected patient subgroups. When differences in treatment preferences and health-state utilities were combined with the additional cost, dalteparin was associated with a favourable incremental cost of $Can13 751 per QALY gained. A $Can50 000 cost per QALY has been suggested as a threshold, at or below which new medical interventions should be considered for adoption by healthcare systems because they are considered to have acceptable ecoPharmacoeconomics 2006; 24 (6)
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nomic value.[21] Dalteparin appears to meet this criterion easily. Interestingly, the findings of the current study are consistent with those of Aujesky et al.,[22] who applied decision analysis computer modelling. In that study, the investigators determined that extended prophylaxis with dalteparin would be considered cost effective (i.e. a cost per QALY <$Can50 000) if the daily cost of the drug were reduced to less than $US18 per day for a dose of 200 IU/kg/day (2002 values). As reported by the investigators, the cost in Canada for dalteparin is approximately $US13 per day (2002 values, equivalent to $Can18/day), which would generate a cost per QALY below the $Can50 000 threshold for economic value. The determination of a cost per QALY gained with dalteparin allows an economic value comparison versus other agents used in cancer supportive care. Two agents commonly used in cancer supportive care include recombinant erythropoietin and filgrastim. In one study, which used decision analysis modelling in a stage IV breast cancer population, the incremental cost per QALY gained with prophylactic recombinant erythropoietin was approximately $Can21 000.[23] In another decision analysis conducted in the US, the prophylactic use of filgrastim in breast cancer patients receiving adjuvant chemotherapy was associated with a cost of $Can46 600 per life-year gained (converted to $Can, using an exchange rate of $US1 = $Can1.24, as of May 2005).[24] A comparison with these agents indicates that prophylaxis with dalteparin offers at least comparable value for money. Exploratory multivariable analysis provided some interesting insight into factors contributing to the overall cost of therapy. There was a negative association between increasing age and overall cost of therapy, which could be related to increased cancer-related mortality with advancing age. Statistically significant and negative interaction effects were identified between treatment with dalteparin
and patients who had a baseline ECOG performance status of 2 or 3. These results can be interpreted in the following way. Patients with a baseline performance status of 2 or 3 who were treated with dalteparin required less hospital resources than performance status 0 patients who received the same therapy. Hence, the incremental cost of using dalteparin in such patients would be reduced compared with performance status 0 patients. There are two possible explanations for this phenomenon. Early death in dalteparin patients with performance status of 2 or 3 may have contributed to lower healthcare resource utilisation. However, if this hypothesis was correct, then the same effect should have also been observed in the oral therapy group. Alternatively, immobility, which is associated with a performance status of 2 or 3, has been identified as a risk factor for VTEs.[25] It is tempting to speculate that the use of dalteparin in patients with a poorer performance status may result in a lower cost differential relative to warfarin secondary to reducing the number of recurrent VTEs, compared with a similar group of performance status 0 patients. Nevertheless, it is important to recall that the multivariate analysis was exploratory and that its findings need to be confirmed through a prospective study.
Study Limitations
There are several limitations in this analysis that have to be addressed. Some of the hospital resources such as specific diagnostic tests utilised were protocol driven and may not completely reflect standard practice. These considerations may reduce the generalisability (external validity) of the results to patients outside of the setting created by a randomised trial. Detailed healthcare utilisation data for the management of recurrent VTEs and for the treatment of bleeding events were not available. Therefore, we had to rely on estimates reported in the literature for managing such events in both the hospitalised and outpatient setting. Oncology nurses
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and pharmacists were used as patient surrogates in the utility assessments. Even though respondents had an average of 8.6 years of cancer experience and 70.8% also had VTE management experience, patients are preferable to surrogates. Conclusion This pharmacoeconomic analysis suggests dalteparin, when used for long-term secondary VTE prophylaxis in patients with cancer, is associated with an estimated incremental cost of approximately $Can2159 per patient. When treatment preferences and health-state utility gains were combined with the additional cost, the use of dalteparin for this indication was associated with an incremental cost of $Can13 751 per QALY gained. Given the practical advantages of this drug in terms of safety, improved efficacy, convenience and the acceptable economic profile, it is a clinically and economically sound alternative to warfarin for the prevention of recurrent VTEs in cancer patients. Acknowledgements
The authors would like to express their gratitude to the local investigators who administered the health-utility assessment. This study was funded via a research grant from Pfizer Canada, Inc. to the principal investigator, following an RFP (request for proposal). Once the study had begun, an arms-length approach was taken with the sponsor. The principal investigator retained the right to publish the findings of a study in a journal of his choosing. G. Dranitsaris, M. Vincent and M. Crowther have acted as consultants to Pfizer Canada, Inc. The corresponding author had full access to all the data in the study and final responsibility for the decision to submit the paper. Contribution of each author. G. Dranitsaris: study design, development of data collection instrument, statistical analysis and preparation of manuscript. M. Vincent: study design, development of data collection instrument and contribution to manuscript development and review. Also provided clinical expertise and guidance on the analysis.
M. Crowther: provided clinical expertise and guidance on the analysis. Contributed to the development and review of the manuscript.
References
1. Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107 Suppl. 1: I22-30 2. Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies. Semin Thromb Hemostasis 2003; 29: 247-58 3. Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thromb Haemost 2002; 87: 575-9 4. National Cancer Institute of Canada. Canadian Cancer Statistics 2004. Toronto, 2004 [online]. Available from URL: http:// www.cancer.ca [Accessed 2005 Feb 4] 5. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-53 6. Lee AYY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123-9 7. Klerk CP, Smorenburg SM, Otten HM, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130-5 8. Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol 2004; 22: 1944-8 9. OBrien BJ, Anderson DR, Goeree R. Cost-effectiveness of enoxaparin versus warfarin prophylaxis against deep-vein thrombosis after total hip replacement. CMAJ 1994; 150: 1083-90 10. Haentjens P, De Groote K, Annemans L. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement: a cost-utility analysis. Arch Orthop Trauma Surg 2004; 124: 507-17 11. Botteman MF, Caprini J, Stephens JM, et al. Results of an economic model to assess the cost-effectiveness of enoxaparin, a low-molecular-weight heparin, versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States. Clin Ther 2002; 24: 1960-86 12. Hull RD, Pineo GF, Raskob GE. The economic impact of treating deep vein thrombosis with low molecular weight heparin: outcome of therapy and health economic aspects. Haemostasis 1998; 28 Suppl. 3: 8-16 13. Gordois A, Posnett J, Borris L, et al. The cost effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery. J Thromb Haemost 2003; 1: 2167-74 14. Dranitsaris G, Kahn S, Stumpo C, et al. Pharmacoeconomic analysis of fondaparinux versus enoxaparin for the prevention of thromboembolic events in orthopedic surgery patients. Am J Cardiovasc Drugs 2004; 4: 325-33
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15. Dranitsaris G. The cost of blood transfusions in cancer patients: a reanalysis of a Canadian economic evaluation. J Oncol Pharm Prac 2000; 6: 1-6 16. Statistics Canada [online]. Available from URL: http:// www.statcan.ca [Accessed 2005 Feb 4] 17. Torrance GW. Utility approach to measuring health-related quality of life. J Chronic Dis 1987; 40: 593-600 18. Gafni A. Alternatives to the QALY measure for economic evaluations. Support Care Cancer 1997; 5: 105-11 19. Leung P, Tanock IF, Oza AM, et al. Cost utility analysis of chemotherapy using paclitaxel, docetaxel or vinorelbine for patients with anthracycline-resistant breast cancer. J Clin Oncol 1999; 17: 3082-90 20. Ortega A, Dranitsaris G, Sturgeon J, et al. Cost utility analysis of paclitaxel in combination with cisplatin for patients with advanced ovarian cancer. Gynecol Oncol 1997; 66: 454-63 21. Laupacis A, Feeny D, Detsky AS, et al. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ 1992; 146: 473-81
22. Aujesky D, Smith KJ, Cornuz J, et al. Cost effectiveness of low molecular weight heparin for secondary prophylaxis of cancer related venous thromboembolism. Thromb Haemost 2005; 93: 592-9 23. Martin SC, Gagnon DD, Zhang L, et al. Cost-utility analysis of survival with epoetin-alfa versus placebo in stage IV breast cancer. Pharmacoeconomics 2003; 21: 1153-69 24. Silber JH, Fridman M, Shpilsky A, et al. Modeling the costeffectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer. J Clin Oncol 1998; 16: 2435-44 25. Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107: I9-I16
Correspondence and offprints: George Dranitsaris, Augmentium Pharma Consulting, 283 Danforth Ave, Suite 448, Toronto, Ontario M4K 1N2, Canada. E-mail: george@augmentium.com
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original article
Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer
Agnes Y.Y. Lee, M.D., Mark N. Levine, M.D., Ross I. Baker, M.D., Chris Bowden, M.D., Ajay K. Kakkar, M.B., Martin Prins, M.D., Frederick R. Rickles, M.D., Jim A. Julian, M.Math., Susan Haley, B.Sc., Michael J. Kovacs, M.D., and Michael Gent, D.Sc., for the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators*
abstract
background
From the Departments of Medicine (A.Y.Y.L., M.N.L.) and Clinical Epidemiology and Biostatistics (M.N.L., J.A.J., S.H., M.G.), McMaster University, Hamilton, Ont., Canada; Henderson Research Centre, Hamilton Health Sciences and McMaster University, Hamilton, Ont., Canada (M.N.L., J.A.J., S.H., M.G.); the Department of Medicine, University of Western Australia, Perth, Australia (R.I.B.); Pharmacia Corporation, Peapack, N.J. (C.B.); the Department of Surgical Oncology and Technology, Imperial College, London (A.K.K.); Academic Hospital Maastricht, Maastricht, the Netherlands (M.P.); the Department of Medicine and Pediatrics, George Washington University, Washington, D.C. (F.R.R.); and the Department of Medicine, University of Western Ontario, London, Ont., Canada (M.J.K.). Address reprint requests to Dr. Levine at Hamilton Health Sciences, Henderson Hospital, Rm. 9, 90 Wing, 711 Concession St., Hamilton, ON L8V 1C3, Canada. *Participating investigators and institutions are listed in the Appendix. N Engl J Med 2003;349:146-53.
Copyright 2003 Massachusetts Medical Society.
Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer.
methods
Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months).
results
During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oralanticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group.
conclusions
In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.
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long-term anticoagulation in patients with cancer
he standard treatment for acute venous thromboembolism consists of initial therapy with low-molecular-weight heparin or unfractionated heparin followed by longterm therapy with an oral anticoagulant.1 This approach is highly effective in most patients, but patients with cancer have a substantial risk of recurrent thromboembolism and hemorrhagic complications.2,3 Furthermore, oral anticoagulant therapy is problematic in patients with cancer. Drug interactions, malnutrition, vomiting, and liver dysfunction can lead to unpredictable levels of anticoagulation. Invasive procedures and thrombocytopenia caused by chemotherapy often require interruption of anticoagulant therapy, and poor venous access can make laboratory monitoring difficult. These limitations may contribute to the higher risk of recurrent thromboembolism and bleeding in patients with cancer than in patients without cancer.2,3 Secondary prophylaxis with low-molecularweight heparin may be a more effective and practical alternative to oral anticoagulant therapy. Unlike vitamin K antagonists, low-molecular-weight heparins have predictable pharmacokinetic properties and drug interactions,4 and they can be effective in patients with cancer who have recurrent thromboembolism while receiving warfarin.5-7 Poor gastrointestinal absorption is not a concern with subcutaneously injected low-molecular-weight heparins. The therapeutic dosage is based on the patients weight, and laboratory monitoring is not routinely required. With a rapid onset of action and predictable clearance, they are also convenient for patients who require frequent interruptions of anticoagulant therapy. We performed a multicenter, randomized, openlabel clinical trial to investigate whether the lowmolecular-weight heparin dalteparin is more effective and safer than oral anticoagulant therapy in preventing recurrent thromboembolism in patients with cancer who have acute venous thromboembolism.
treatment for cancer within the previous six months, or recurrent or metastatic cancer. Proximal deepvein thrombosis was diagnosed on the basis of evidence of thrombus in the popliteal or more proximal veins on compression ultrasonography or contrast venography.8 A diagnosis of pulmonary embolism required verification by ventilationperfusion lung scanning, helical computed tomography, or pulmonary angiography.9-11 Patients were excluded if they weighed 40 kg or less, had an Eastern Cooperative Oncology Group (ECOG) performance status score of 3 or 4,12had received therapeutic doses of any heparin for more than 48 hours before randomization, were already receiving oral anticoagulant therapy, had had active or serious bleeding within the previous two weeks, had conditions associated with a high risk of serious bleeding (e.g., active peptic ulcer or recent neurosurgery), had a platelet count of less than 75,000 per cubic millimeter; had contraindications to heparin therapy (e.g., heparin-induced thrombocytopenia) or the use of contrast medium, had a creatinine level that was at least three times the upper limit of the normal range, were pregnant, or could not return to the clinical center for follow-up. At base line, a complete blood count was obtained and the prothrombin time, activated partialthromboplastin time, and serum creatinine and liver enzyme levels were measured. The study protocol was reviewed and approved by the institutional review boards of each participating center. Written informed consent was obtained from all patients.
treatment regimens
methods
study population
Adult patients with active cancer and newly diagnosed, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were eligible. Active cancer was defined as a diagnosis of cancer, other than basal-cell or squamous-cell carcinoma of the skin, within six months before enrollment, any
Patients were assigned to receive subcutaneous dalteparin or an oral anticoagulant. Randomization was stratified according to the clinical center and centralized at the coordinating and methods center at the Henderson Research Centre, Hamilton, Ontario, Canada. The patients assigned to the oral-anticoagulant group received a low-molecular-weight heparin, dalteparin (Fragmin, Pharmacia), initially for five to seven days and a vitamin K antagonist for six months. Dalteparin was supplied in 3.8-ml multidose vials containing 25,000 IU of dalteparin per milliliter. A dose of 200 IU per kilogram of body weight (maximal daily dose, 18,000 IU) was administered once daily. Within 24 hours after randomization, patients in this group also began taking warfarin or acenocoumarol. Warfarin was used in all participating centers except those in the Netherlands and Spain. All doses were adjusted to achieve
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a target international normalized ratio (INR) of 2.5 (therapeutic range, 2.0 to 3.0). Dalteparin was discontinued after a minimum of five days and once the INR had remained above 2.0 for two consecutive days. The INR was measured at least once every two weeks thereafter. The patients assigned to the dalteparin group received 200 IU of dalteparin per kilogram (maximal daily dose, 18,000 IU) from multidose vials once daily for the first month. For the remaining five months, patients were treated with 75 to 83 percent of the full dose (approximately 150 IU per kilogram) with the use of prefilled syringes. These syringes were supplied according to the patients weight: 7500 IU for those weighing 56 kg or less, 10,000 IU for those weighing 57 to 68 kg, 12,500 IU for those weighing 69 to 82 kg, 15,000 IU for those weighing 83 to 98 kg, and 18,000 IU for those weighing 99 kg or more. Patients were instructed to inject the entire contents of one syringe once daily. The practice of measuring the anticoagulant effect against activated factor X was discouraged. The only exception was in the cases of patients in whom clinically significant renal insufficiency developed. Dose adjustment was recommended for patients with thrombocytopenia. Study drug was withheld from patients with a platelet count of less than 50,000 per cubic millimeter and was resumed at the scheduled dose when the count was 100,000 per cubic millimeter or higher. When the platelet count was 50,000 to 99,000 per cubic millimeter, the next lower dose of prefilled syringe was used in the dalteparin group, whereas the target INR was reduced to 2.0 (range, 1.5 to 2.5) in the oral-anticoagulant group. The assigned study treatment was administered at home whenever possible, and it was continued during hospitalization. Patients, family members, or both were taught how to inject the medication, but home care or equivalent nursing services were arranged if necessary.
follow-up
of the signs and symptoms of recurrent thromboembolism, bleeding episodes, and adverse reactions. Patients were instructed to report to the clinic immediately if they had any bleeding or symptoms of recurrent deep-vein thrombosis, pulmonary embolism, or both. All suspected episodes of recurrent thrombosis were investigated with the use of objective tests, according to prespecified diagnostic algorithms.13 All patients were followed until the six-month visit, death, or withdrawal of consent, whichever came first.
outcome measures
During the six-month study period, patients were contacted by telephone every two weeks and were seen in the clinic one week and one, three, and six months after randomization. Each clinic visit included a history taking, physical examination, assessment of compliance, and blood drawing for the calculation of a complete blood count and measurement of liver enzymes and creatinine. Scheduled calls and visits included a standardized assessment
The primary efficacy outcome was the first episode of objectively documented, symptomatic, recurrent deep-vein thrombosis, pulmonary embolism, or both during the six-month study period. Recurrent deep-vein thrombosis was diagnosed if a previously compressible proximal venous segment or segments could no longer be compressed on ultrasonography or if there were constant intraluminal filling defects in two or more projections on venography. Unequivocal extension of the thrombus was required for the diagnosis of recurrence if the results were abnormal on previous testing.8,14,15 Venography was required to confirm distal deep-vein thrombosis. Pulmonary embolism was diagnosed on the basis of a lung scan indicating a high probability of its presence, as indicated by the presence of new or enlarged areas of segmental perfusion defects with ventilationperfusion mismatch; an abnormal perfusion scan with documentation of new or recurrent deep-vein thrombosis; the presence of nonenhancing filling defects in the central pulmonary vasculature on helical computed tomography; a finding of intraluminal filling defects on pulmonary angiography; or evidence of fresh pulmonary embolism at autopsy.9,14,15 Secondary outcome events included clinically overt bleeding (both major bleeding and any bleeding) and death. A bleeding event was classified as major if it was associated with death, occurred at a critical site (intracranial, intraspinal, intraocular, retroperitoneal, or pericardial area), resulted in a need for a transfusion of at least 2 units of blood, or led to a drop in hemoglobin of at least 2.0 g per deciliter.14,15 All suspected events were reviewed by a central adjudication committee whose members were unaware of the patients treatment assignments. Supporting documents, including clinical notes, imaging studies, and the results of laboratory tests, were
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forwarded to the coordinating and methods center for adjudication. All reported episodes that were suggestive of recurrent thrombosis were evaluated and confirmed or rejected as representing recurrence, overt bleeding events were classified as major or minor, and all reported deaths were reviewed to determine the cause of death.
statistical analysis
Table 1. Base-Line Characteristics of the Patients.* Dalteparin Oral Anticoagulant (N=338) (N=338) 6212 179 80 135 118 5 169 169 40 36 39 223 266 33 39 62 46 235 103 6313 169 63 150 122 3 156 182 30 33 43 232 259 42 36 67 40 230 108
Characteristic Mean age (yr) Female sex (no. of patients) ECOG performance score (no. of patients) 0 1 2 3 Hospitalization status (no. of patients) Outpatient Inpatient Hematologic cancer (no. of patients) Solid tumor (no. of patients) No clinical evidence of disease Localized disease Metastatic disease Antineoplastic treatment (no. of patients) Current smoker (no. of patients) History of DVT or PE (no. of patients) Recent major surgery (no. of patients) Central venous catheter (no. of patients) Qualifying thrombotic event (no. of patients) DVT alone PE, with or without DVT
The initial calculation of the sample size was based on an estimated risk of recurrent thrombosis of 20 percent at six months among patients treated with oral anticoagulant therapy. In order to detect a 50 percent reduction in risk with a power of 0.85 and a two-sided alpha of 0.05, it was determined that 70 primary efficacy outcome events were required. In order to adjust for the loss to follow-up from early death, the sample size was increased by 20 percent. A blinded reassessment of the sample size that was specified in the protocol led us to increase the targeted enrollment by an additional 90 patients. Accordingly, we determined that 676 patients would be required. An analysis of efficacy end points was performed according to the intention-to-treat principle and included all randomized patients who had a confirmed, qualifying thrombotic event and active cancer. The primary analysis of efficacy was based on the time from randomization to the first recurrent thromboembolic event. Data on patients without events were censored at the time of the six-month visit or death, whichever occurred first. The risk of recurrence over time was estimated according to the KaplanMeier method, and the treatment groups were compared with use of the two-sided log-rank test.16,17 A Cox proportional-hazards regression model was used to examine the influence of potentially prognostic base-line factors (e.g., age, ECOG status, type of qualifying thrombotic event, and presence or absence of metastases) on the risk of recurrent thromboembolism. Interactions between treatment group and covariates were assessed in the model. Death from all causes was also calculated and compared with use of the KaplanMeier method and the two-sided log-rank test, respectively. Patients who received at least one dose of the study drug were included in the safety analyses. The proportions of patients in each group who had a major bleeding event after the first dose and up to 48 hours after the permanent discontinuation of the study drug were compared with use of a two-sided Fish-
* Plusminus values are means SD. ECOG denotes Eastern Cooperative Oncology Group, DVT deep-vein thrombosis, and PE pulmonary embolism. Eight patients were included in the study before the protocol was amended to exclude patients with an ECOG score of 3 or 4. Antineoplastic treatment included chemotherapy, radiation, and surgery.
ers exact test. Similarly, the proportions of patients in each group with any bleeding were compared. Two investigators designed and developed the original protocol, which was revised and approved by the steering committee. This committee, composed of seven academic members and one representative of the sponsor, was responsible for overseeing the conduct of the study, formulating the statistical-analysis plan, reviewing and interpreting the data, and preparing the manuscript. The central adjudication committee and data-monitoring committee operated independently of the sponsor. The Clinical Trials Methodology Group at the Henderson Research Centre, Hamilton Health Sciences, was responsible for study coordination, data management, statistical analyses, and administrative
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activities. Pharmacia provided funding and the study drug.
Table 2. Sites of Solid Tumors. Dalteparin Oral Anticoagulant (N=298) (N=308) no. of patients Breast Colorectal area Lung Genitourinary tract Gynecologic system Pancreas Brain Other 59 54 40 39 38 13 14 41 49 54 50 47 30 16 13 49
results
study population
Tumor Site
Forty-eight clinical centers in eight countries participated (see the Appendix). Recruitment began in May 1999 and was completed in October 2001. Of the 1303 patients who met the inclusion criteria, 439 also met one or more of the exclusion criteria and were not considered eligible. The three most frequent reasons for exclusion were an ECOG score of 3 or 4 (169 patients), treatment with any heparin for more than 48 hours (107), and an inability to reach the clinical center easily (43). Of the remaining 864 eligible patients, 676 provided written informed consent. Eight patients with an ECOG score of 3 were enrolled before the protocol was amended to exclude patients with such a score. Of the 676 consenting patients, 338 were allocated to receive dalteparin and 338 were assigned to oral anticoagulant therapy, each for six months. Patients in the two groups had similar base-line characteristics (Table 1). Ninety percent of the patients had solid tumors (Table 2), and 67 percent had metastatic disease at the time of randomization.
anticoagulant therapy
Table 3. Primary Efficacy Outcome Events. Oral Dalteparin Anticoagulant (N=336) (N=336) no. of patients Deep-vein thrombosis alone Nonfatal pulmonary embolism Fatal pulmonary embolism Total 14 8 5 27 37 9 7 53
Event
The mean duration of study treatment was 125 days in the dalteparin group and 115 days in the oralanticoagulant group. For patients who did not have an outcome event throughout the study period, the mean duration of study treatment was 170 days in both groups. In the oral-anticoagulant group, the mean (SD) INR was 2.50.75. Using linear interpolation over time, we estimated that the INR was in the therapeutic range 46 percent of the time, below the range 30 percent of the time, and above the range 24 percent of the time.
recurrent venous thromboembolism
Two patients in each group were excluded from the efficacy analysis because they did not have a qualifying thrombotic event: one patient had a thrombosis in an arm vein, one had an asymptomatic thrombus in the leg, and the other two did not have a confirmed pulmonary embolism. Symptomatic, recurrent deep-vein thrombosis, pulmonary embo- bleeding lism, or both occurred in 27 of 336 patients in the Three patients assigned to oral anticoagulant therdalteparin group and 53 of 336 patients in the oral- apy did not receive the study drug and were exclud-
anticoagulant group (Table 3). The hazard ratio for recurrent thromboembolism in the dalteparin group as compared with the oral-anticoagulant group was 0.48 (95 percent confidence interval, 0.30 to 0.77; P=0.002) over the six-month study period (Fig. 1). The KaplanMeier estimate of the probability of recurrent thrombosis at six months was 9 percent in the dalteparin group, as compared with 17 percent in the oral-anticoagulant group. All recurrent deepvein thromboses were proximal. No significant interactions between treatment group and risk factors were detected. Of the 53 thrombotic events in the oral-anticoagulant group, 20 occurred when the INR was below 2.0.
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ed from the safety analyses. Nineteen of 338 patients in the dalteparin group (6 percent) and 12 of 335 patients who received oral anticoagulant therapy (4 percent) had major bleeding (P=0.27). The respective rates of any bleeding were 14 percent and 19 percent (P=0.09). At the time of a major bleeding event, two patients in the dalteparin group had thrombocytopenia. Major bleeding was associated with an INR of more than 3.0 in six patients in the oral-anticoagulant group. In the dalteparin group, one patient died from massive hemoptysis related to metastatic lung cancer and three patients bled at a critical site: one patient with a brain tumor had intracranial bleeding, one patient with prostate cancer had retroperitoneal bleeding, and one patient with lung cancer had pericardial bleeding. In the oral-anticoagulant group, there were no fatal bleeding events and four patients bled at a critical site: two patients, one with breast cancer and one with prostate cancer, had intracranial bleeding, and two patients, one with a brain tumor and one with prostate cancer, had retroperitoneal bleeding.
mortality
25
P=0.002
Probability of Recurrent Venous Thromboembolism (%)
20 Oral anticoagulant 15 10 Dalteparin 5 0 0 30 60 90 120 150 180 210
Days after Randomization No. at Risk

Dalteparin 336 Oral anticoagulant 336 301 280 264 242 235 221 227 200 210 194 164 154
Figure 1. KaplanMeier Estimates of the Probability of Symptomatic Recurrent Venous Thromboembolism among Patients with Cancer, According to Whether They Received Secondary Prophylaxis with Dalteparin or Oral Anticoagulant Therapy for Acute Venous Thromboembolism. An event was defined as an objectively verified, symptomatic episode of recurrent deep-vein thrombosis, pulmonary embolism, or both during the sixmonth study period. The hazard ratio for recurrent thromboembolism in the dalteparin group as compared with the oral-anticoagulant group was 0.48 (95 percent confidence interval, 0.30 to 0.77; P=0.002 by the log-rank test).
Probability of Death (%)
During the six-month study period, 130 patients died in the dalteparin group and 136 patients died in the oral-anticoagulant group. The respective mortality rates at six months were 39 percent and 41 percent (P=0.53) (Fig. 2). Ninety percent of the deaths in each group were due to progressive cancer.
50 Oral anticoagulant 40 30 20 10 0 0 30 60 90 120 150 180
P=0.53
discussion
In patients with cancer, recurrent thromboembolism complicates management and diminishes the patients quality of life. Our study shows that the risk of symptomatic, recurrent thromboembolism among patients with active cancer is significantly lower with dalteparin therapy than with oral anticoagulant therapy. Although previous trials comparing low-molecular-weight heparins with warfarin for the secondary prophylaxis of venous thromboembolism did not find a difference in the risk of recurrent thrombosis, most of the trials were small and conducted primarily in patients without cancer.18-24 We did not detect a significant difference in the rates of major bleeding or any bleeding between the treatment groups. Given the limitations of crossstudy comparisons, the rates of bleeding in the oralanticoagulant group are consistent with those in previous studies.2,25 However, our rates of major
Dalteparin
210
Days after Randomization No. at Risk

Dalteparin 336 Oral anticoagulant 336 310 301 274 268 248 240 237 220 220 211 206 194
Figure 2. KaplanMeier Estimates of the Probability of Death from All Causes among Patients with Cancer, According to Whether They Received Secondary Prophylaxis with Dalteparin or Oral Anticoagulant Therapy for Acute Venous Thromboembolism. There was no significant difference between the groups (P=0.53 by the logrank test).
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bleeding were lower than those reported in another randomized trial involving patients with cancer; in that study, 7 percent of patients who received lowmolecular-weight heparin and 16 percent of those who received warfarin had major bleeding over a three-month period.18 Differences in the patient population, the INR control, and outcome assessment may explain some of the variations in these results. The open-label design could be a potential source of bias in our trial. We believed that a double-blind design would not be logistically feasible or safe in patients with cancer who had many other serious conditions and who were taking multiple drugs, potentially increasing the risk of drug interactions. We tried to minimize reporting and diagnostic bias by contacting patients in both groups at frequent and regular intervals, using standardized follow-up procedures, using objective tests to evaluate suspected events, and having all suspected outcomes evaluated by a central committee whose members were unaware of the patients treatment assignments. Also, substantial bias related to treatment management is unlikely because the level of INR
control achieved was similar to that in other studies and showed that patients who received oral anticoagulant therapy were treated adequately.2,18 In addition, the mean duration of treatment in patients who did not have any outcome event was the same in the two groups. When we planned the study, there was little information on the optimal dose of low-molecularweight heparin for secondary prophylaxis. We designed a regimen that would provide intensive anticoagulation initially and potentially reduce the risk of anticoagulant-related bleeding over the long term. Practical issues regarding the long-term use of low-molecular-weight heparin include the cost of the drug and the feasibility of self-injection. Longterm self-injection of dalteparin was acceptable to our patients, and it significantly reduced the risk of recurrent venous thromboembolism without increasing the risk of bleeding.
Funded by Pharmacia, Peapack, N.J., which also supplied the study drug. Dr. Lee is the recipient of a New Investigator Award from the Canadian Institutes of Health Research, Drug Research and Development Program; Dr. Levine is the Buffett Taylor Chair in Breast Cancer Research, McMaster University, Hamilton, Ont., Canada; and Dr. Kovacs is an Internal Scholar of the Department of Medicine, University of Western Ontario, London, Ont., Canada.
ap p e n d i x The following investigators and institutions participated in the CLOT Trial: Steering Committee: M. Levine (chair), R. Baker, C. Bowden, M. Gent, A. Kakkar, A. Lee, M. Prins, F. Rickles; External Safety and Efficacy Monitoring Committee: J. Pater (chair), H. Bller, S. Goldhaber; Central Adjudication Committee: J. Ginsberg, J. Hirsh, C. Kearon, G. Thomson, J. Weitz; Coordinating and Methods Center: Clinical Trials Methodology Group, Henderson Research Centre, Hamilton, Ont., Canada J. Julian, S. Haley, A. Ling, B. Rush, T. Finch, L. Bonilla-Escobedo, L. Matthews, J. Windsor, C. Tavormina, H. Nelson, G. Lewis, J. Sicurella; Clinical Centers (the numbers of patients enrolled in each country are given in parentheses) Canada (255): Hamilton Health Sciences, Henderson Hospital, Hamilton, Ont. A. Lee, N. Booker, S. Schmidt; London Health Sciences Centre, London, Ont. M. Kovacs, B. Morrow; Queen Elizabeth II Health Sciences Centre, Halifax, N.S. B. McCarron, S. Pleasance; Toronto General Hospital, Toronto W.F. Brien, S. Boross-Harmer; St. Jospehs Hospital, Hamilton, Ont. J.D. Douketis, T. Schnurr; Montreal General Hospital, Montreal S. Solymoss, B. St. Jacques; Sunnybrook and Womens College Health Sciences Centre, Toronto W. Geerts, K. Code; British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, B.C. S. Chia, S. Monkman; Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ont. A.G.G. Turpie, J. Johnson; Kelowna General Hospital, Kelowna, B.C. J. Sutherland, S. Shori; Australia (144) and New Zealand (16), Australasian Society of Thrombosis and Haemostasis: Royal Perth Hospital, Perth, W.A. R. Baker, J. Smith; Flinders Medical Centre, Bedford Park, S.A. D.W. Coghlan, J.M. Osmond; Prince of Wales Hospital, Randwick, N.S.W. S. Dunkley, B. Chong; Box Hill Hospital, Monash University, Box Hill, Victoria H. Salem, L. Poulton; Westmead Hospital, Westmead, N.S.W. M. Hertzberg, P. Stavros; Auckland Hospital, Auckland P. Ockelford, V. Rolfe-Vyson; St. George Hospital, Kogarah, N.S.W. T.A. Brighton, R. Ristuccia; Royal North Shore Hospital, University of Sydney, Sydney, N.S.W. C.M. Ward, K. Sheather; Royal Adelaide Hospital, Adelaide, S.A. I.N. Olver, T. Marafioti; St. Vincents Hospital, Sydney, N.S.W. D. Ma; Monash Medical Centre, Clayton, Victoria T.E. Gan, A. Cummins; Royal Melbourne Hospital, Parkville, Victoria A. Grigg, E. Cinc; United States (118): University of Southern California, Keck School of Medicine, Los Angeles H. Liebman, I. Weitz; University of Texas, M.D. Anderson Cancer Center, Houston C.P. Escalante, P. Horace; Northwestern University, Chicago D. Green, M. Calimaran; University of North Carolina at Chapel Hill, Chapel Hill S. Moll, S.K. Jones; Arizona Cancer Center, University of Arizona, Tucson A. Stopeck, K. Glennie; Atlanta Veterans Affairs Medical CenterEmory University, Atlanta M. Ribeiro, L. Starke; Cleveland Clinic Foundation, Cleveland S.R. Deitcher; Mt. Sinai Medical Center, New York L. Lipsey; St. Joseph Mercy Oakland, Pontiac, Mich. A. Brady, R. Krishnan; University of Vermont and Fletcher Allen Health Care, Burlington M. Cushman, L. Chassereau; University of Virginia Health System, Charlottesville B.G. Macik, L. Newton; Lovelace Health System, Albuquerque, N.M. A. Tarnower, R.J. Weiler; Newark Beth Israel Medical Center, Newark, N.J. A.J. Cohen, E. White; University of Connecticut, Farmington R. Bona, K. Jennings; Italy (67): Ospedali Riuniti, Bergamo A. Falanga, R. Labianca; Clinica Medica II, University of Padua, Padua P. Prandoni, A. Piccioli, E. Zanon; Angelo Bianchi Bonomi Hemophilia Thrombosis Center, University of Milan and National Cancer Institute of Milan, Milan A.B. Federici, G. Pizzocaro; the Netherlands (41): Academic Medical Center of the University of Amsterdam, Amsterdam S.M. Smorenburg, C.P.W. Klerk; University Hospital Nymegen, Nymegen F. Berkmortel, D.J.T. Wagener; Maasland Hospital, Sittard F.L.G. Erdkamp; St. Elisabeth Hospital, Tilburg C. van der Heul, C. Post; St. Antonius Hospital, Nieuwegein D.H. Biesma; Van Weel Bethesda Hospital, Dirksland C. Kroon, M. Kamphuis van der Poel; Spain (33): Hospital Universitari Germans Trias i Pujol, Badalona E. Davant, M. Monreal; United Kingdom (2): Oldchurch Hospital, Romford M. Quigley; Mount Vernon Cancer Centre, Northwood G.J.S. Rustin, J. Boxall.
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references
1. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl: 176S-93S. 2. Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Buller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078-83. 3. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-8. 4. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-98. [Erratum, N Engl J Med 1997;337:1567.] 5. Walsh-McMonagle D, Green D. Lowmolecular-weight heparin in the management of Trousseaus syndrome. Cancer 1997;80:649-55. 6. Eikelboom JW, Baker RI. Low-molecular-weight heparin for the treatment of venous thrombosis in patients with adenocarcinoma. Am J Hematol 1998;59:260-1. 7. Luk C, Wells PS, Anderson D, Kovacs MJ. Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy. Am J Med 2001;111: 270-3. 8. Lensing AWA, Prandoni P, Brandjes D, et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989;320:342-5. 9. Hull RD, Hirsh J, Carter CJ, et al. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan. Ann Intern Med 1983;98:891-9. 10. Remy-Jardin M, Remy J, Deschildre F, et 19. Hull R, Pineo G, Mah A, Brant R. Long-
al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996; 200:699-706. 11. Qanadli SD, Hajjam ME, Mesurolle B, et al. Pulmonary embolism detection: prospective evaluation of dual-section helical CT versus selective pulmonary arteriography in 157 patients. Radiology 2000;217:447-55. 12. Zubrod CG, Schneiderman M, Frei E III, et al. Appraisal of methods for the study of chemotherapy of cancer in man: comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide. J Chronic Dis 1960;11:7-33. 13. Lee AY, Levine MN. Management of venous thromboembolism in cancer patients. Oncology (Huntingt) 2000;14:40917, 421. 14. The Columbus Investigators. Lowmolecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657-62. 15. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-81. 16. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. 17. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50:163-70. 18. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002;162:1729-35.
term low molecular weight heparin treatment versus oral anticoagulant therapy for proximal deep vein thrombosis. Blood 2000; 96:449a. abstract. 20. Lopaciuk S, Bielska-Falda H, Noszczyk W, et al. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb Haemost 1999;81:26-31. 21. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994;72: 191-7. 22. Veiga F, Escriba A, Maluenda MP, et al. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial. Thromb Haemost 2000; 84:559-64. 23. Das SK, Cohen AT, Edmondson RA, Melissari E, Kakkar VV. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996;20:521-6. 24. Gonzalez-Fajardo JA, Arreba E, Castrodeza J, et al. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the longterm treatment of deep venous thrombosis. J Vasc Surg 1999;30:283-92. 25. Palareti G, Legnani C, Lee A, et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000; 84:805-10.
Copyright 2003 Massachusetts Medical Society.
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VOLUME
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APRIL
2005
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Randomized Comparison of Low Molecular Weight Heparin and Coumarin Derivatives on the Survival of Patients With Cancer and Venous Thromboembolism
Agnes Y.Y. Lee, Frederick R. Rickles, Jim A. Julian, Michael Gent, Ross I. Baker, Chris Bowden, Ajay K. Kakkar, Martin Prins, and Mark N. Levine
From the McMaster University; The Henderson Research Centre, Hamilton, ON, Canada; The George Washington University and the Childrens National Medical Center, Washington, DC; University of Western Australia, Perth, Australia; Pzer Inc, New York, NY; Imperial College, London, United Kingdom; and Academic Hospital of Maastricht, Maastricht, the Netherlands. Submitted March 18, 2004; accepted August 23, 2004. Supported by a New Investigator Award from the Canadian Institutes of Health Research/Rx&D Research Program (A.Y.Y.L). M.N.L. is the Buffett Taylor Chair in Breast Cancer Research, McMaster University, Hamilton, Ontario, Canada. Presented in part as a poster at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors disclosures of potential conicts of interest are found at the end of this article. Address reprint requests to Mark N. Levine, MD, Hamilton Health Science, Henderson Hospital, Room 9, 90 Wing, 711 Concession St, Hamilton, ON L8V 1C3, Canada; e-mail: mlevine@mcmaster.ca. 2005 by American Society of Clinical Oncology 0732-183X/05/2310-2123/$20.00 DOI: 10.1200/JCO.2005.03.133
Purpose Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the inuence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism. Patients and Methods Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups. Results During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P .46). The observed effects of dalteparin on survival were statistically signicantly different between patients with and without metastatic disease (P .02). Conclusion The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these ndings. J Clin Oncol 23:2123-2129. 2005 by American Society of Clinical Oncology
INTRODUCTION
Clinical evidence in support of anticoagulants having an antitumor effect was rst reported in a multicenter, randomized, controlled trial in 1981.1 In the Veterans Affairs Research Service Cooperative Study 75, warfarin was found to be associated with an improvement in median survival in patients
with small-cell lung cancer who were receiving chemotherapy. Similarly, a randomized trial in the same patient population demonstrated a survival advantage for those patients treated with subcutaneous injections of unfractionated heparin.2 However, despite compelling experimental evidence for a pathogenic role of blood coagulation in tumor growth and metastasis,3-6 other studies in patients with
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Lee et al
solid tumors have failed to conrm a survival benet for patients treated with anticoagulants.7-10 More recently, the question of whether anticoagulants can favorably inuence the natural history of cancer has received renewed attention. Randomized controlled trials and meta-analyses of studies that compared low molecular weight heparins with unfractionated heparin for the initial treatment of venous thromboembolism have reported a reduction in the overall mortality of patients with cancer who were randomly assigned to receive a low molecular weight heparin.11-15 Although the reduction in mortality has been consistent across studies and could not be attributed to differences in fatal pulmonary embolism or bleeding, the observation that 5 to 7 days of low molecular weight heparin treatment reduced cancer mortality has been difcult to explain. A plausible biologic mechanism, however, is now emerging from experimental studies that show low molecular weight heparins can inhibit angiogenesis, a process that is critical for tumor growth and metastasis, in a dose-dependent fashion.3,4,16,17 To date, two randomized, placebo-controlled trials designed to evaluate whether low molecular weight heparins can improve survival in patients with advanced or incurable malignancies have been completed.18,19 To examine the inuence of a low molecular weight heparin relative to coumarin derivatives on the survival of cancer patients with venous thromboembolism and to investigate the hypothesis that low molecular weight heparins have a greater impact on survival in cancer patients with limited disease than in those with disseminated cancer, we performed a posthoc analysis of the mortality data in patients with solid tumors who participated in the Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism (CLOT) trial.20
METHODS Study Population The CLOT trial was an international, multicenter, openlabel, randomized trial that evaluated the relative efcacy and safety of dalteparin (Fragmin; Pzer, New York, NY), a low molecular weight heparin, with oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer.20 Briey, patients with cancer and acute venous thromboembolism were randomly assigned to 6 months of treatment with dalteparin alone or dalteparin followed by a coumarin derivative (warfarin or acenocoumarol). In the dalteparin group, patients received dalteparin once daily by subcutaneous injections at 200 U/kg for the rst month followed by approximately 150 U/kg for the subsequent 5 months. In the oral anticoagulant group, patients received dalteparin 200 U/kg once daily for the rst week followed by an oral anticoagulant at doses that maintained the international normalized ratio between 2.0 and 3.0. The primary efcacy outcome was symptomatic, recurrent venous
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thromboembolism up to 6 months and patients were observed for death for up to 12 months. The study showed that dalteparin signicantly reduced the risk of symptomatic, recurrent venous thromboembolism by 52% (P .002) without increasing bleeding. At 6 months, 40% of the patients were dead and a difference in overall mortality between treatment groups was not observed (P .53). Ninety percent of the deaths in both groups were attributed to progressive cancer. Statistical Analysis The analysis was performed according to the intention-totreat principle and based on the time from random assignment to death. The extent of cancer in patients with solid tumors was classied at study enrollment by local investigators as metastatic disease, localized disease without evidence of metastases, and no clinical evidence of active malignancy. Staging according to TNM classication was not required at random assignment. An a priori decision was made by the Steering Committee to combine the two latter patient groups into a single group of patients without metastatic disease for the purpose of this analysis because of the small number of patients in each group. The probability of death during the 12 months after random assignment was estimated according to the Kaplan-Meier method for each treatment group in patients with and without metastatic disease.21 The difference in treatment-related survival within the two subgroups of patients was compared using the two-sided log-rank test.22 Treatment-related survival was also analyzed with the exclusion of patients with specic tumor types if there were statistically signicant imbalances in the number of patients with such tumor types between the treatment groups. Cox proportional hazards regression models were used to adjust the treatment effect on survival for baseline factors for all patients with solid tumors, and for the subgroups with and without metastases. These variables, identied a priori as potentially important predictors, and recorded at the time of randomization, included age (either continuous or by decade), sex, Eastern Cooperative Oncology Group performance status, smoking status (ever v never), qualifying episode of venous thromboembolism (pulmonary embolism v deep vein thrombosis), type of cancer treatment (radiation v none, chemotherapy v none), and major primary tumor site (breast, colorectal, lung, gynecologic, genitourinary, brain, pancreas, and other). Treatment and tumor site were forced into all regression models. Using a manual backward elimination modeling strategy, a variable remained in the model if the associated P value was less than .10 using both the Wald and score tests. The residuals from the nal models were inspected for possible outliers, inuential observations, and unusual patterns. Hazard ratios and their corresponding 95% CIs were estimated in the modeling process. To determine whether there was a difference in the inuence of dalteparin on mortality between patients with and without metastatic disease, the unadjusted hazard ratios were compared using a two-sided z test. A two-sided P value of less than .05 was considered to be statistically signicant. The Clinical Trials Methodology Group at the Henderson Research Centre, Hamilton Health Sciences (Hamilton, ON, Canada) was responsible for data management and statistical analyses. The Steering Committee was responsible for supervising and providing nal approval of these activities and preparation of this article.
Anticoagulants and Cancer Survival
RESULTS
A total of 602 patients with solid tumors were included in the CLOT study and data on their survival at 12 months after random assignment were available for inclusion in the analysis. The baseline characteristics of the 452 patients with metastatic disease and the 150 patients without metastases are provided in Table 1. An assessment of the potential imbalance in each of the prognostic baseline factors between treatment groups was undertaken for each subgroup of patients with and without metastases. No statistically signicant differences were observed between treatment groups for baseline variables in patients with metastatic disease. In the subgroup of patients without metastases, statistically signicantly fewer patients with lung cancer (P .04) were treated with dalteparin than with oral anticoagulant. During the 12-month follow-up period, 174 of 296 patients in the dalteparin group died, compared with 182 of 306 patients in the oral anticoagulant group. The difference was not statistically signicant (P .62; Fig 1). In patients without known metastases, 15 of 75 patients in the dalteparin group and 26 of 75 patients in the oral anticoagulant group died. The Kaplan-Meier estimate of the probability of
Fig 1. Survival in patients with solid tumors. ( ) Oral anticoagulant (OAC); () dalteparin. Log-rank test P .62 (two-sided) for the overall comparison between the treatment groups.
Table 1. Baseline Characteristics of the Patients % Without Metastases % With Metastases
Characteristic Age, years Mean Standard deviation Female sex Current smoker Cancer treatment Qualifying DVT ECOG score 0 1 2 Tumor site Breast Colorectal Lung Gynecologic Genitourinary Brain Pancreas Other
Oral Oral Dalteparin Anticoagulant Dalteparin Anticoagulant (n 75) (n 75) (n 221) (n 231)
death at 12 months was 20% in the dalteparin group, compared with 36% in the oral anticoagulant group (Fig 2). The difference is statistically signicant, with a hazard ratio of 0.50 (95% CI, 0.27 to 0.95; P .03), in favor of dalteparin. Adjusting for baseline prognostic factors did not change the ndings dramatically (adjusted hazard ratio, 0.41; 95% CI, 0.19 to 0.86; P .02). When patients with lung cancer were excluded from the analysis, the hazard ratio remained in favor of dalteparin (unadjusted hazard ratio, 0.63; 95% CI,
61 12 51 5 67 59 41 36 23 29 15 5 5 12 17 4 12
63 12 49 9 67 60 28 45 25 25 13 17 1 21 15 0 7
63 11 59 11 71 73 15 42 43 16 19 16 15 14 1 4 14
62 13 52 13 68 71 15 43 42 13 19 15 13 13 1 7 19 Fig 2. Survival in patients with solid tumors according to the presence or absence of metastatic disease. ( ) Oral anticoagulant (OAC); () dalteparin. For patients without metastatic disease, the hazard ratio was 0.50 (95% CI, 0.27 to 0.95; P .03) for the overall comparison between the treatment groups. For patients with metastatic disease, the hazard ratio was 1.1 (95% CI, 0.87 to 1.4; P .46) for the overall comparison between the treatment groups.
Abbreviations: DVT, deep vein thrombosis; ECOG, Eastern Cooperative Oncology Group. Statistically signicant fewer patients with lung cancer were treated with dalteparin than with oral anticoagulant in the group of patients without metastases (P .04). No statistically signicant differences between treatment groups for baseline factors were detected in patients with metastases.
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0.31 to 1.3; P .19; adjusted hazard ratio, 0.37; 95% CI, 0.17 to 0.83; P .02). In contrast, in patients with known metastatic malignancy, 159 of 221 patients assigned to dalteparin and 156 of 231 patients allocated to oral anticoagulant died. The probability of mortality at 12 months was 72% and 69%, respectively (Fig 2). The hazard ratio in the dalteparin group as compared with the oral anticoagulant group in patients with metastatic disease was 1.1 (95% CI, 0.87 to 1.4; P .46). A comparison of the two hazard ratios of dalteparin to oral anticoagulant between the subgroups of patients with and without metastatic disease was statistically signicant (P .02). In the best-tting regression model, the treatment effect for dalteparin versus oral anticoagulant adjusted for statistically signicant baseline risk factors was 0.43 (95% CI, 0.21 to 0.89; P .02) for patients without metastases, and 1.1 (95% CI, 0.91 to 1.4; P .24) for patients with known metastases. In addition, performance status, smoking, and treatment with chemotherapy were also independent predictors for survival (Table 2).
DISCUSSION
In this subgroup analysis of the CLOT trial, we examined the effect of a low molecular weight heparin dalteparin on the survival of patients with cancer and venous thromboembolism. Although a difference in survival at 12 months was not observed for the entire study population and patients with known metastases, we demonstrated a statistically signicant improvement in overall survival associated with dalteparin, relative to oral anticoagulant therapy, in patients with solid tumors who were not known to have metastatic disease at the time of their thromboembolic event. The 50% relative risk reduction in the 12-month mortality remained signicant after adjusting for known prognostic factors. A higher Eastern Cooperative Oncology Group status and smoking predicted for higher mortality, whereas age, sex, and the type of thrombotic event did not.
The lack of effect on survival in patients with metastatic disease suggests that the mechanisms of action of dalteparin may be dependent on or interact with the stage of cancer or extent of tumor burden. Although our results do not conrm a causal relationship between low molecular weight heparin and inhibition of tumor growth or progression, they are consistent with previous observations from clinical studies, including two recently completed randomized, placebo-controlled trials designed to investigate the inuence of low molecular weight heparin on cancer survival.18,19 In the study by Kakkar et al18 (Fragmin Advanced Malignancy Outcome Study [FAMOUS] trial), which randomly assigned 382 patients with metastatic or advanced solid malignancies to once-daily injections of dalteparin or placebo for 1 year, a survival difference between treatment groups was not observed. The 1-year survival was 45% and 42%, respectively (P .29). However, in those patients who survived beyond 17 months, an improvement in survival was observed in patients who received dalteparin (P .04). In the Malignancy and Low Molecular Weight Heparin Therapy (MALT) trial reported by Klerk et al,19 approximately 300 patients with incurable solid tumors were randomly assigned to the low molecular weight heparin nadroparin or placebo for 6 weeks. A statistically signicant improvement in overall survival was observed for nadroparin relative to placebo. The reduction in mortality was also in favor of nadroparin in the subgroup of patients who were identied as having a life expectancy of greater than 6 months. In all three studies, the use of low molecular weight heparin was associated with improved survival in patients with relatively good prognosis. There are also important differences between our study and these additional trials. First, patients in the abovementioned two studies did not have acute venous thromboembolism at the time of random assignment. Given the strong association between coagulation and tumor biology, the presence of venous thromboembolism could have an
Table 2. Hazard Ratios Based on Multivariable Cox Proportional Hazards Modeling of Clinical Risk Factors for Mortality During Anticoagulant Therapy With Low Molecular Weight Heparin or Oral Anticoagulant Without Metastases Risk Factor Dalteparin versus oral anticoagulants ECOG (0, 1, 2) Smoker (ever v never) Chemotherapy (yes v no) Hazard Ratio 0.4 2.0 2.8 95% CI 0.2 to 0.9 1.2 to 3.3 0.96 to 8.3 P .02 .007 .06 Hazard Ratio 1.1 1.6 1.5 0.8 With Metastases 95% CI 0.9 to 1.4 1.3 to 1.8 1.1 to 2.1 0.6 to 0.95 P .24 .0001 .01 .02
Abbreviations: VTE, venous thromboembolism; ECOG, Eastern Cooperative Oncology Group. Hazard ratios for age, gender, qualifying episode of VTE, and radiotherapy did not meet statistical signicance in either subgroup of patients. Two-sided Wald test. Comparison was also adjusted for major tumor sites (see Statistical Analysis). The hazard ratio for chemotherapy was not statistically signicant in patients without metastases.
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inuence on the effect, if any, of low molecular weight heparins on tumor progression. Second, our patients might have had a poorer prognosis than those in the other trials because cancer patients with venous thromboembolism have a shorter life expectancy than similar cancer patients without thrombosis.23,24 The short life expectancy of our patients with metastatic disease could have limited the detection of a survival benet associated with any therapy. Another difference among the studies is the treatment regimens used in the experimental and control groups. In our study, full therapeutic doses of dalteparin were administered for the rst month followed by 75% of the full dose for 5 months, whereas in the FAMOUS study prophylactic dose of dalteparin was used, and in the MALT study nadroparin was given at therapeutic doses for 2 weeks followed by half of this dose for 4 weeks. Lastly, the CLOT study differs from the FAMOUS and MALT trials in the duration of follow-up. In the latter trials, improvement in overall survival was not observed until at least 1 year after randomization. Therefore, it is possible that a survival benet might become evident in patients with metastatic disease in the CLOT trial with longer follow-up. The major limitation of our analysis is the potential imbalance of prognostic factors between treatment groups. Although our study was a randomized trial, stratication for tumor type and extent of disease was not performed because the primary outcome in the CLOT trial was not survival. In addition, we could not control for differences in previous or concurrent antineoplastic therapy. We did examine the possibility that the difference in the number of patients with lung cancer treated with dalteparin or oral anticoagulant in patients without metastases might have inuenced the ndings. Reanalyzing the results with exclusion of patients with lung cancer also produced a statistically signicant hazard ratio in favor of dalteparin when adjusted for prognostic baseline factors. Lastly, we cannot exclude the possibility that our observations are due to chance and imbalance of unknown prognostic variables. Therefore, the results of this subgroup analysis should be interpreted with caution.25 The mechanisms for a potential antineoplastic effect of low molecular weight heparins remain unknown and will require further investigations in well-designed experimental studies. An antiangiogenic effect is an appealing possibility and is compatible with our observation that a survival benet was evident in patients with limited disease and persisted beyond the administration of the agent.26 It can be hypothesized that in patients with disseminated cancer, tumor-related vasculature is sufciently developed so that an antiangiogenic agent would have minimal impact, whereas impairing the establishment of such vasculature by an antiangiogenic agent could exert an inhibitory effect on tumor growth even beyond the time of drug exposure. Although it has been suggested that the improvement in
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cancer survival associated with low molecular weight heparins observed in previous trials may be due to a reduction in fatal pulmonary embolism as compared with unfractionated heparin, the survival benet beyond the period of low molecular weight heparin administration observed in our study would argue against this hypothesis. A strong association between cancer and thrombosis has been demonstrated consistently in experimental and clinical studies. Our results offer additional evidence that the coagulation system is intrinsically involved in tumorigenesis or tumor progression. Future studies designed to conrm the antitumor effects of low molecular weight heparins and explore the pathophysiological mechanisms are awaited.

Acknowledgment We thank C.P.W. Klerk and H.R. Buller for their help ful review of the manuscript. Appendix The following investigators and institutions participated in the CLOT Trial: Steering Committee: M. Levine (Chair), R. Baker, C. Bowden, M. Gent, A. Kakkar, A. Lee, M. Prins, F. Rickles. External Safety and Efcacy Monitoring Committee: J. Pater (Chair), H. Buller, S. Goldhaber. Central Adjudication Committee: J. Ginsberg, J. Hirsh, C. Kearon, G. Thomson, J. Weitz. Coordinating and Methods Centre: Clinical Trials Methodology Group, Henderson Research Centre, Hamilton, ON, CanadaJ. Julian, S. Haley, A. Ling, Q. Guo, B. Rush, T. Finch, L. Bonilla-Escobedo, L. Matthews, J. Windsor, C. Tavormina, H. Nelson, G. Lewis, J. Sicurella. Clinical Centers (the number of patients contributed from each country follows the country): Canada (225) Hamilton Health Sciences, Henderson Hospital, Hamilton, ONA. Lee, N. Booker, S. Schmidt; London Health Sciences Centre, London, ONM. Kovacs, B. Morrow; Queen Elizabeth II Health Sciences Centre, Halifax, NSB. McCarron, S. Pleasance; Toronto General Hospital, Toronto, ONW.F. Brien, S. Boross-Harmer; St. Josephs Hospital, Hamilton, ONJ.D. Douketis, T. Schnurr; The Montreal General Hospital, Montreal, PQS. Solymoss, B. St. Jacques; Sunnybrook & Womens College Health Sciences Centre, Toronto, ONW. Geerts, K. Code; British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BCS. Chia, S. Monkman; Hamilton Health Sciences, Hamilton General Hospital, Hamilton, ONA.G.G. Turpie, J. Johnson; Kelowna General Hospital, Kelowna, BCJ. Sutherland, S. Shori; Australia (144) and New Zealand (16)Australasian Society of Thrombosis and HemostasisRoyal Perth Hospital, Perth, WAR. Baker, J. Smith; Flinders Medical Centre, Bedford Park, SAD.W. Coghlan, J.M. Osmond; Prince of Wales Hospital, Randwick, NSWS. Dunkley, B. Chong; Box Hill Hospital,
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Monash University, Box HillH. Salem, L. Poulton; Westmead Hospital, Westmead, NSWM. Hertzberg, P. Stavros; Auckland Hospital, AucklandP. Ockelford, V. Rolfe-Vyson; St. George Hospital, Kogarah, NSWT. A. Brighton, R. Ristuccia; Royal North Shore Hospital, University of Sydney, Sydney, NSWC.M. Ward, K. Sheather; Royal Adelaide Hospital, Adelaide, SAI.N. Olver, T. Maraoti; St. Vincents Hospital, Sydney, NSWD. Ma; Monash Medical Centre, Clayton, VICT. E. Gan, A. Cummins; Royal Melbourne Hospital, Parkville, VICA. Grigg, E. Cinc; United States (118) University of Southern California, Keck School of Medicine, Los Angeles, CAH. Liebman, I. Weitz; University of Texas, M.D. Anderson Cancer Center, Houston, TXC.P. Escalante, P. Horace; Northwestern University, Chicago, ILD. Green, M. Calimaran; University of North Carolina at Chapel Hill, Chapel Hill, NCS. Moll, S.K. Jones; Arizona Cancer Centre, University of Arizona, Tucson, AZA. Stopeck, K. Glennie; Atlanta VA Medical Centre/Emory UniversityM. Ribeiro, L. Starke; The Cleveland Clinic Foundation, Cleveland, OHS.R. Deitcher; Mt. Sinai Medical Center, New York, NYL. Lipsey; St. Joseph Mercy Oakland, Pontiac, MIA. Brady, R. Krishnan; University of Vermont & Fletcher Allen Health Care, Burlington, VTM. Cushman, L. Chassereau; University of Virginia Health System, Charlottesville, VAB.G. Macik, L. Newton; Lovelace Health System, Albequrque, NMA. Tarnower, R.J. Weiler; Newark Beth Israel Medical Center, Newark, NJA.J. Cohen, E. White; University of Connecticut, Farmington, CTR. Bona, K. Jennings; Italy (67) Ospedali Riuniti, BergamoA. Falanga, R. Labianca; Clinica Medica II, University of Padua, PaduaP. Prandoni, A. Piccioli, E. Zanon; Angelo Bianchi Bonomi Hemophilia Thrombosis Center, University of Milan and
REFERENCES
1. Zacharski LR, Henderson WG, Rickles FR, et al: Effect of warfarin on survival in small cell carcinoma of the lung: Veterans Administration Study No. 75. JAMA 245:831-835, 1981 2. Lebeau B, Chastang C, Brechot JM, et al: Subcutaneous heparin treatment increases survival in small cell lung cancer: Petites Cellules Group. Cancer 74:38-45, 1994 3. Nash GF, Walsh DC, Kakkar AK: The role of the coagulation system in tumour angiogenesis. Lancet Oncol 2:608-613, 2001 4. Mousa SA: Anticoagulants in thrombosis and cancer: The missing link. Semin Thromb Hemost 28:45-52, 2002 5. Rickles FR, Patierno S, Fernandez PM: Tissue factor, thrombin, and cancer. Chest 124: 58S-68S, 2003 (suppl 3) 6. Rickles FR, Levine MN, Dvorak HF: Abnormalities of hemostasis in malignancy, in Colman RW, Hirsh J, Marder VJ, et al (eds): Hemostsis and Thrombosis. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1131-1152
National Cancer Institute of MilanA.B. Federici, G. Pizzocaro; the Netherlands (41)Academic Medical Center of the University of Amsterdam, AmsterdamS.M. Smorenburg, C.P.W. Klerk; University Hospital Nymegen, NymegenF. v.d. Berkmortel, DJTh Wagener; Maasland Hospital, SittardF.L.G. Erdkamp; St. Elisabeth Hospital, TilburgC. van der Heul, C. Post; St. Antonius Hospital, NieuwegeinD.H. Biesma; Van Weel Bethesda Hospital, DirkslandC. Kroon, M. Kamphuis van der Poel; Spain(33)Hospital Universitari Germans Trias i Pujol, BadalonaE. Davant, M. Monreal; United Kingdom (2)Oldchurch Hospital, Romford, EssexM. Quigley; Mount Vernon Cancer Centre, Northwood, Middlesex G.J.S. Rustin, J. Boxall. Authors Disclosures of Potential Conicts of Interest The following authors or their immediate family members have indicated a nancial interest. No conict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Chris Bowden, Bristol-Myers Squibb. Acted as a consultant within the last 2 years: Frederick R. Rickles, Pharmacia/Pzer; Ajay K. Kakkar, Aventis, Pzer; Agnes Y.Y. Lee, Aventis, LEO Pharma, Pharmacia/Pzer, Sano, Wyeth; Mark N. Levine, Pzer. Performed contract work within the last 2 years: Frederick R. Rickles, Pharmacia/Pzer. Received more than $2,000 a year from a company for either of the last 2 years: Frederick R. Rickles, Pharmacia/Pzer; Ajay K. Kakkar, AstraZeneca, Aventis, Pzer; Agnes Y.Y. Lee, Pharmacia/ Pzer; Chris Bowden, Bristol-Myers Squibb; Mark N. Levine, Pharmacia/Pzer.
molecular-weight versus standard heparin. Lancet 339:1476, 1992 13. Hettiarachchi RJ, Smorenburg SM, Ginsberg J, et al: Do heparins do more than just treat thrombosis? The inuence of heparins on cancer spread. Thromb Haemost 82:947-952, 1999 14. Gould MK, Dembitzer AD, Doyle RL, et al: Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: A meta-analysis of randomized, controlled trials. Ann Intern Med 130:800-809, 1999 15. Lensing AW, Prins MH, Davidson BL, et al: Treatment of deep venous thrombosis with lowmolecular-weight heparins: A meta-analysis Arch Intern Med 155:601-607, 1995 16. Norrby K: Heparin and angiogenesis: A low-molecular-weight fraction inhibits and a highmolecular-weight fraction stimulates angiogenesis systemically. Haemostasis 23:141-149, 1993 (suppl 1) 17. Hejna M, Raderer M, Zielinski CC: Inhibition of metastases by anticoagulants. J Natl Cancer Inst 91:22-36, 1999
7. Maurer LH, Herndon JE, Hollis DR, et al: Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: A Cancer and Leukemia Group B study. J Clin Oncol 15:3378-3387, 1997 8. Levine M, Hirsh J, Gent M, et al: Doubleblind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 343:886-889, 1994 9. Smorenburg SM, Hettiarachchi RJ, Vink R, et al: The effects of unfractionated heparin on survival in patients with malignancy: A systematic review. Thromb Haemost 82:1600-1604, 1999 10. Smorenburg SM, Vink R, Otten HM, et al: The effects of vitamin K-antagonists on survival of patients with malignancy: A systematic analysis. Thromb Haemost 86:1586-1587, 2001 11. Prandoni P, Lensing AW, Buller HR, et al: Comparison of subcutaneous low-molecularweight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 339:441-444, 1992 12. Green D, Hull RD, Brant R, et al: Lower mortality in cancer patients treated with low-
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18. Kakkar AK, Levine MN, Kadziola Z, et al: Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol 22:1944-1948, 2004 19. Klerk CPW, Smorenburg SM, Otten JMMB, et al: Malignancy and low-molecularweight heparin therapy: The MALT trial. Presented at Intl Soc Thromb Haemost XIX International Congress, Birmingham, UK, July 12-18, 2003 20. Lee AY, Levine MN, Baker RI, et al: Lowmolecular-weight heparin versus a coumarin for
the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146-153, 2003 21. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 22. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966 23. Levitan N, Dowlati A, Remick SC, et al: Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those with-
out malignancy: Risk analysis using Medicare claims data. Medicine (Baltimore) 78:285-291, 1999 24. Sorensen HT, Mellemkjaer L, Olsen JH, et al: Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343:1846-1850, 2000 25. Assmann SF, Pocock SJ, Enos LE, et al: Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 355:1064-1069, 2000 26. Boehm T, Folkman J, Browder T, et al: Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404-407, 1997
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Journal of Pathophysiology of Haemostasis and Thrombosis
Mechanisms of Cancer-Induced Thrombosis

Frederick R. Rickles
The George Washington University School of Medicine and Health Sciences Washington, DC 20037, USA
Key Words
Platelets Fibrin Thrombus Murine Atherothrobsis Microcirculation Artery Vessel Wall
independent manner (e.g. thru engagement of protease-activated receptors [PARs]). Targeting blood clotting reactions in cancer may provide a unique approach to cancer treatment.
Copyright 2006 S. Karger AG, Basel
Abstract
Substantial epidemiologic, laboratory, pathologic and clinical evidence supports the historic association between activation of blood coagulation and progression of cancer. The increased risk for venous thromboembolism (VTE) in cancer has been considered an epiphenomenon. However, recent studies from several laboratories have linked more closely malignant transformation (oncogenesis), tumor angiogenesis and metastasis to the generation of clotting intermediates (e.g. tissue factor [TF], factor Xa and thrombin), clotting or platelet function inhibitors (e.g. COX2) or fibrinolysis inhibitors (e.g. plasminogen activator inhibitor, type 1 [PAI-1]). Furthermore, TF, Xa and thrombin may induce important tumor cell signaling cascades in a clotting-dependent and/or clotting-
Introduction
Activation of blood coagulation occurs commonly in patients with cancer and leads to the development of venous thromboembolism (VTE) at an overall rate as high as seven times as often as in age-matched, sex-matched, control subjects (1). The pathophysiology of thrombosis in cancer is complex but can be viewed classically as related to abnormalities of so-called Virchows triad: [1] stasis of the blood; [2] vascular injury; [3] hypercoagulability (or, as described by Virchow, abnormalities of the fixed elements of the blood), the terminology for which has been updated and fits well the situation with many cancer patients (2). Substantial epidemiologic, laboratory, pathoP103
Division of Hematology-Oncology, Department of Medicine, GWU Medical Faculty Associates, 2150 Pennsylvania Ave, NW, Washington, DC 20037, USA Telephone: (202)741-2478 Fax: (202)741-2487Email: kgrickles@comcast.net
logic and clinical evidence supports this important association but, until recently, VTE was thought largely to be an epiphenomenon in cancer. That is, cancer and the treatment of cancer were assumed to be the proximate causes of the increased risk for thrombosis but thrombus formation itself was not considered an intrinsic molecular event in oncogenesis. Recent evidence from several laboratories (3-5), however, has linked more closely malignant transformation, tumor angiogenesis and metastasis to thrombus formation, mediated perhaps by signaling cascades that can be triggered in a clotting-dependent and/or clotting-independent manner. Tissue factor (TF), the ubiquitous activator of blood clotting, has been shown, for example, to induce production of vascular endothelial growth factor (VEGF) in human tumor cells independent of its ability to activate factor Xa-catalyzed conversion of prothrombin (6). The TF-VIIa complex and factor Xa are among known activators of G-protein-coupled protease-activated receptor-2 (PAR-2) in tumor cells, while the TF-VIIa-Xa complex and thrombin efficiently activate PAR-1. Both PARs have been implicated in signaling pathways leading to angiogenesis and metastasis (7-9). The precise role of the cytoplasmic domain of TF, which has been targeted as the likely signaling region of the molecule (perhaps due to the presence of 3 serine residues in the cytoplasmic tail of TF), remains controversial (6,8). Nevertheless, multiple cellsignaling cascades are triggered during the generation of these clotting intermediates that are believed to influence tumor cell migration, adhesion, cell-cell interaction, diapedesis and replication, as well as new vessel growth. Taking advantage of epidemiologic information on the negative impact of activation of blood clotting in cancer patients (10,11), investigators are now exploring with renewed interest the potential that inhibitors of blood clotting can impact on cancer survival. Recently published randomized, controlled trials have documented increased survival in patients with advanced cancer treated with various forms of low-molecular-weight heparin (LMWH) (12-16). While the mechanisms for the salutary effects of anticoagulants on cancer survival have yet to be elucidated, some evidence suggests that various heparin fractions can interfere with a variety of important tumor functions, including, for example: [1] tumor angiogenesis; [2] heparanasemediated extravasation of blood-borne tumor cells; and, [3] interactions between carcinoma mucins and selectins. Targeting blood clotting reactions in cancer may provide a unique approach to treatment. New agents are being developed that can activate clotting selectively only in tumor vessels, thus producing localized infarction and reduction in tumor size (17-20). Other approaches target tumor cell and tumor-associated endothelial cell TF to deliver immuno-toxins or selective inhibitors of tumor growth with specificity to spare the surrounding normal tissue
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(21,22). Both selective activation and inhibition of clotting may prove to be useful adjuncts to traditional therapeutic approaches in cancer patients.
Epidemiology
As noted, cancer significantly increases the risk for VTE and this risk is greatest within the first 3-6 months following the diagnosis of cancer (1). Among all patients in whom the diagnosis of VTE is established, cancer is responsible for approximately 20% of the attributable risk (23) and patients with cancer are at nearly 3 times the risk for recurrence of VTE as are matched control subjects after a first episode (24). Although the absolute risk of VTE in cancer patients remains relatively small (e.g. 0.6% in one large population-based study) (11), cancer patients undergoing surgery have at least a 2-fold increase risk of postoperative thrombosis compared to non-cancer controls undergoing the same procedures (25), and even without the added stress of surgery, the adjusted odds ratio for VTE is nearly 30 in patients with some tumor types (1). Finally, the risk of death due to cancer appears to increase significantly if the diagnosis of VTE is established simultaneously or within the first year (10,11), supporting longstanding experimental data that suggest that thrombus formation provides some biological advantage to the growth and dissemination of cancer (2,26).
Mechanisms of Cancer-Induced Thrombosis (Table 1)
Stasis, vascular injury and hypercoagulability, the 3 parts of Virchows Triad (27), all play roles in the pathogenesis of thrombus formation in cancer patients (Table 1). Some or all of the following, each grouped under one of aspect of the triad, can complicate the course of disease in the cancer patient. STASIS: [1] bed rest; [2] extrinsic compression of blood vessels by tumor; VASCULAR INJURY: [1] direct invasion of vessels by tumor; [2] prolonged use of central venous catheters; [3] endothelial damage secondary to chemotherapy; HYPERCOAGULABILITY:[1] release of tumor-associated procoagulants and cytokines; [2] impaired endothelial cell defense mechanisms and reduction of naturally occurring inhibitors (e.g. antithrombin, protein C or protein S deficiency; activated protein C resistance); [3] increased adhesive interactions between tumor cells, vascular endothelial cells, platelets and host monocyte/macrophages, further enhanced in mucin-secreting tumors (e.g. selectin-mediated). These
and other probable mechanisms for thrombosis in cancer patients have been examined in detail elsewhere (2,26,28). Suffice it to say that the pathogenesis of thrombosis in cancer is complex and most likely involves multiple mechanisms that may differ dramatically from patient to patient. However, until recently, it has been presumed that all of these mechanisms are secondary and have no primary role in the molecular events leading to the development of cancer.
Molecular Pathogenesis of Thrombosis in Cancer Direct Link to Oncogenesis (Table 2)
Boccaccio and her colleagues developed a model for human liver carcinoma by targeting activated human MET oncogene to mouse liver with a lentivrial vector and liverspecific promoter (3). The animals developed slowly, progressive hepatocarcinogenesis, which was preceded and accompanied by a thrombohemorrhagic syndrome ultimately indistinguishable from Trousseaus Syndrome with disseminated intravascular coagulation (DIC). Venous thrombosis in the tail vein of the mouse occurred early and was followed by a progressive coagulopathy and fatal internal hemorrhage. The syndrome was characterized in the animals by elevated blood levels of fibrin d-dimer, a prolonged prothrombin time and a marked reduction of the platelet count (i.e. DIC). Genome-wide expression profiling of hepatocytes expressing the MET oncogene demonstrated impressive upregulation of both the plasminogen activator inhibitor 1 (PAI-1) and cyclooxygenase-2 (COX2) genes with two to three-fold increase in circulating protein levels. Inhibitors of either PAI-1 (XR5118) or COX-2 (Rofecoxib) prevented both laboratory and clinical evidence of DIC in the mice. Based on their observations in this mouse model the investigators postulated a 5-step process (Figure 1), whereby MET induction by hypoxia results in increased expression of the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (step 1), activation of prothrombotic, hemostasis genes (e.g. COX-2 and PAI-1) by MET signaling (step 2) with fibrin nesting of the tumor cells, formation of a fibrin provisional matrix for the tumor (step 3), induction of neo-angiogenesis by the fibrin matrix and other coagulation proteases (step 4) and, finally, scattering of tumor cells with invasion (step 5) (29). Thus, for the first time, experimental evidence has been generated linking directly activation of hemostasis with oncogenesis. Inactivation of the tumor suppressor gene Pten, together with hypoxia, which leads to Akt activation and upregulation of the Ras/MEK/ERK signaling cascade, has
recently been shown to induce TF gene expression in human astrocytoma cell lines (4), an in vitro model for malignant transformation. Cells transformed with Akt showed the greatest incremental increase in hypoxiainduced TF expression and secretion, exhibiting procoagulant activity which was factor VII-dependent and inhibited with anti-TF antibodies. These findings were partially reversed by induction of PTEN. PTEN is inactivated by mutation, promoter methylation, or by other mechanisms in upwards of 80% of human glioblastomas and TF is expressed in >90% of such tumors. In low grade astrocytomas, however, only 10% of tumors express TF and evidence for PTEN inactivation is rarely found. The histopathologic hallmark of high grade astrocytomas (glioblastoma multiforme) is so-called pseudopalisading necrosis, thought to represent a wave of tumor cells actively migrating away from a central hypoxic zone that is created following vascular compromise and associated with intravascular thrombosis. (4). Thus, the finding that pseudopalisading cells produced increased amounts of TF in 7 human glioblastoma specimens further supports the molecular relationship between malignant transformation and clotting activation. Yu and colleagues (5) examined another model of human oncogenesis to test the hypothesis that activation of clotting is a direct result of the molecular transforming events. In the well-described, step-wise model of human colorectal cancer (CRC), in which activation of mutant Kras and subsequent inactivation/loss of p53 drive many interrelated aspects of the malignant phenotype., the authors demonstrated that TF is required for full expression of the K-ras-dependent tumorigenic and angiogenic phenotype of CRC cells in vivo, but not for cellular transformation in vitro.(5) Conversely, activation of K-ras and loss of p53 were both necessary to achieve full expression of TF both on the cell membrane and on the surface of microvesicles shed into the circulation of the mouse. With each subsequent mutation, increasing TF levels were documented in the respective cell lines in vitro and in vivo in the more aggressive tumors produced in SCID mice, which were shown to have acquired a new K-ras mutation. Finally, the investigators showed that TF gene-silencing, small interfering RNA (siRNA) markedly inhibited in vivo tumor growth and angiogenesis in Matrigel plugs in vivo. Thus, 3 different tumor model systems have now provided complimentary evidence that oncogene activation and/or tumor suppressor gene inactivation upregulates blood clotting in vivo (by increasing TF, PAI-1 and COX2), strongly implicating clotting pathways in the basic biology of cancer. Furthermore, this data implies that targeting clotting intermediates might prove to be a rationale strategy for both reducing the thrombotic risk in cancer and, perhaps, impairing tumor growth.
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Targeting Tissue Factor and other Coagulation Intermediates in Cancer Therapy
Two more recent therapeutic approaches, one applied to experimental tumor models and one applied to patients with advanced malignancy, support the rationale for further testing of anticoagulant, anti-tissue factor strategies for treating cancer. One approach utilizes either a modified TF construct to induce local tumor infarction (20), or targets TF in tumor cells and/or tumor vascular endothelium to induce direct tumor lysis (22). This method exploits differential TF expression in tumors and tumor-associated endothelium. Modifications of this therapeutic strategy takes advantage of the high affinity binding of factor VIIa to TF and the differential expression of TF on tumor cells and tumor-associated vascular endothelium (31,32). Along with other endothelial-specific targets, investigators have succeeded in treating effectively experimental tumors by inducing local infarction (17-21) (Table 3). The second approach utilizes a more traditional anticoagulant strategy to reduce the effects of thrombin generation and other clotting intermediates on tumor growth, angiogenesis and metastasis. The first approach, which has been effective, is to deliver a toxic construct that binds to TF in the neoangiogenic vasculature of the tumor, activates local blood coagulation, produces an obstructive thrombus and tumor infarction. Reported most recently by El-Sheikh and colleagues (20), the investigators linked a soluble, truncated form of TF (tTF) to the heparin-binding domain of VEGF, the latter of which targets at least 3 receptors hyperexpressed on tumor endothelium the VEGF receptor, neuropilin 1 and chondroitin 6 sulfate proteoglycan (Table 3). This approach was successful in inducing selective tumor necrosis quite rapidly (5 minutes) after infusion of the construct, together with recombinant factor VIIa, into mice harboring the CT26 colon cancer (20), apparently sparing non-tumor vasculature and avoiding systemic activation of coagulation. Utilizing another modification of this strategy, which is not designed to activate TF in the tumor endothelium but instead targets the genes for TF and VEGF, we have demonstrated regression of human breast tumors in nude mice (Figure 2). We reported the use of synthetic analogs of curcumin, which are potent inhibitors of TF and VEGF expression in both tumor cells and vascular endothelial cells. We demonstrated marked reduction of the expression of both gene products in MDA-MB-231 cells and in other human tumor cell lines, as well as in endothelial cells (22). More recent data demonstrates the feasibility of linking the lead compound among these synthetic analogs to rVIIai to target the tumor endothelium and tumor cells, whereby we achieved upwards of 60% uptake of the labeled complex
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into malignant cells. One or more of these targeting strategies may prove useful in cancer chemotherapy. Of interest, the antiangiogenic rationale, using a factor VIIa cassette for targeting TF in the neoangiogenic endothelium, is currently being tested in Phase II studies of patients with wet macular degeneration (33)
Fig. 2. Regression of human breast tumors in nude mice after treatment with compound 14. MDA-MB-231 (1 x 106 cells) were inoculated int eh flanks of nude mice and tumors were allowed to grow for 3 weeks. Compound 14 was administered by injection near the base of the tumors 3x/wk x 2 weeks. The bar graph demonstrates a dose-dependent decrease in tumor weight after treatment (*p < 0.05; n = 5 mice/group). (Reproduced from reference 22, with permission of the publishers).
The direct anticoagulant strategy of cancer treatment focuses typically on LMWH compounds or other newer anticoagulants. The initial impetus for the use of these drugs was for the treatment and/or prevention of VTE and the studies generally compared their safety and efficacy to unfractionated heparin (UFH). Retrospective analyses of the cancer patient subset in many of the larger trials revealed that patients treated for a short time with relatively low (prophylactic) doses of LMWH, demonstrated a lower 3 month mortality rate than those treated with UFH (34). Based on this type of hypothesis-generating data, a number of randomized controlled trials (RCTs) have been undertaken to test the benefit of LMWH in cancer patients, with and without VTE, and results of 6 studies have been published within the past few years (12-15, 35). In total, 1,787 patients with advanced cancer were randomized to treatment with a LMWH or control (no anticoagulant, placebo, unfractionated heparin or warfarin). While the study designs were different, one common outcome was that in each study, the mortality rate for the patients treated with LMWH was improved. In the two trials in which survival was the primary endpoint, the control group received no anticoagulant treatment and the apriori statistical design was adequate to support the conclusion (14,16), patients treated with LMWH had a significantly prolonged median progression-free survival (p = 0.01) and median survival (p = 0.021), respectively. More well-designed studies are needed but the results of these 6 trials across a broad group of patients with poor prognosis cancers have stimulated renewed interest in the
anticoagulant approach, particularly since the increased survival observed was not due to prevention of fatal pulmonary emboli or other thrombotic complications. Instead, these patients lived longer with their tumors and ultimately died of cancer, lending support to the concept that LMWH affects tumor biology. Less certain is the mechanism(s) by which LMWH effects this change in tumor behavior. As indicated earlier, possible mechanisms include (but are not limited to): [1] inhibition of angiogenesis (Figure 3) (2,26,30,36-38); inhibition of tumor proteases (e.g. heparanase)(39,40); inhibition of selectins (41). It is very likely that these and other mechanisms are impacted by LMWH and are overlapping e.g. inhibition of thrombin generation and thrombin action, for example, likely reduces not only its effects on angiogenesis but also effects of thrombin on cell growth genes, selectin expression, etc. We and others have demonstrated a consistent effect of LMWH on angiogenesis in a variety of in vitro, ex vivo and in vivo models (42). As demonstrated in Figure 4, one preparation of LMWH was quite effective in inhibiting the proliferation of blood vessels in the embryonic chick aortic ring model, and similar effects have been seen in virtually every model of angiogenesis.
Oncogene Activation
Fig. 4. Ex Vivo Angiogenesis. Effect of Low-Molecular-Weight Heparin (Dalteparin/Fragmin; continuous exposure) on chick aortic ring angiogenesis in response to maximal stimulation with EGM-2 complete medium (containing 2% fetal bovine serum, hydrocortisone, human fibroblast growth factor-, vascular endothelial growth factor and insulin-like growth factor-1). This experiment is representative of 3 experiments performed to date with a dose response mean inhibition as follows: 0.1 IU/ml 25%; 1.0 IU/ml - 48% ; 5 IU/ml 75%; 10 IU/ml 80%; all values p < 0.001 compared to controls.
Summary
COAGULATION CASCADE
Clottingdependent
TF
?
Clottingindependent
Thrombin
Clottingindependent
Clottingdependent
Fibrin
LMWH
Clottingdependent
In summary, blood clotting reactions are intimately involved in the biology of cancer, not just rendering the cancer patient susceptible to thrombosis but stimulating tumor growth genes, tumor cell diapedesis, adhesion to the endothelium, angiogenesis, and a host of other processes critical to both primary tumor growth and metastasis. Rational strategies to downregulation of these coagulation pathways may provide a duality of beneficial effect both reduction in thrombosis potential and tumor proliferation.
??
??
PARs
platelet
VEGF
ANGIOGENESIS
TUMOR GROWTH AND METASTASIS
Fig. 3.
Possible Effects of Low-Molecular-Weight Heparins on Tumor Biology. See text for details. (Modified from Reference 30, with permission of the publishers).
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Table 1.
Pathogenesis of Thrombosis in Cancer - Modification of Virchows Triad.
1. 2.
3.
STASIS a. Prolonged bed rest b. Extrinsic compression of blood vessels by tumor VASCULAR INJURY a. Direct invasion by tumor b. Prolonged use of central venous catheters c. Endothelial damage by chemotherapy drugs, tumor-associated cytokines, etc. HYPERCOAGULABILITY a. Release of tumor-associated procoagulants (e.g. tissue factor) from malignant cells and/or inflammatory cells (e.g. macrophages) b. Impaired endothelial defense mechanisms and naturally occurring inhibitors (e.g. protein C, protein S, antithrombin, APC resistance) c. Enhanced adhesive interaction between tumor cells, vascular endothelial cells, platelets and host macrophages (e.g. mucin-secreting adenocarcinomas and leukocyte L-selection and platelet P-selectin)
Table 2.
Oncogene Activation of Blood Coagulation
Oncogene or/ Tumor Suppressor Gene (reference number) MET (5) PTEN (6) K-ras & p53 (7)
Signaling Pathway (s)
Human Tumor
Effect on Coagulation or Vascular Biology (genes regulated) Thrombosis; DIC (PAI-1; COX-2) Thrombosis;necrosis (TF) Angiogenesis (TF; VEGF; TSP-1/2)
Tyrosine kinase receptor Hepatoma (hepatocyte growth factor/ Scatter factor) Ras/MEK/ERK Glioblastoma MEK/MAPK/PI3K Colon Cancer
DIC = disseminated intravascular coagulation; PAI-1 = plasminogen activator inhibitor-1; COX-2 = cyclooxygenase-2; TF=tissue factor; VEGF=vascular endothelial growth factor; TSP=thrombospondin
References
1. Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations and the risk of venous thrombosis. J Amer Med Assoc 2005;293:715-722. 2. Falanga A, Rickles FR. The pathogenesis of thrombosis in cancer. New Oncol: Thrombosis 2005;1:9-16. 3. Boccaccio C, Sabatino G, Medico E, Girolami F, Follenzi A, Reato G, Sottile A, Naldini L, Comoglio PM. The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 2005;434:396-400. 4. Rong Y, Post DE, Pieper RO, Burden DL, Van Meir EG, Brat DJ. PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 2005;65:14061413. 5. Yu JL, May L, Lhotak V, Shahrzad S, Shirasawa S, Weitz JI, Coomber BL, Mackman N, Rak JW. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 2005;105:1734-1741. 6. Abe K, Shoji M, Chen J, Bierhaus A, Danave I, Micko C, Casper K, Dillehay D, Nawroth PP, Rickles FR. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Nat Acad Sci USA 1999;96:8663-8668. 7. Ruf W, Dorfleutner A, Riewald M. Specificity of coagulation factor signaling. J Thromb Haemost 2003;1:1495-1503. 8. Belting M, Dorrell MI, Sandgren S, Aguilar E, Ahamed J, Dorfleutner A, Carmeliet P, Mueller BM, Friedlander M, Ruf W. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 2004;10:502-509. 9. Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 2004;104:2746-2751. 10. Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth R, Rimm AA. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy: risk anlaysis using Medicare claims data. Medicine 1999;78:285-291. 11. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000;343:18461850. 12. von Templehoff GF, Harenberg J, Niemann F, Hommel G, Kirkpatrick CJ, Heilmann L. Effect of low molecular weight heparin (Certoparin) versus unfractinated heparin on cancer survival following breast and pelvic surgery: a prospective randomized, double-blind trial. Int J Oncol 2000;16:815
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13. Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RCN. Low molecular weight heparin, therapy with Dalteparin, and survival in advanced cancer: The Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol 2004;21:1944-1948. 14. Altinbass M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, Cetin M, Soyuer S. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004;2:1266-1271. 15. Lee AYY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005;23:2123-2129. 16. Klerk CPW, Smorenburg SM, Otten H-M, Lensing AWA, Prins MH, Piovella F, Prandoni P, Bos MMEM, Richel DJ, van Tienhoven G, Buller HR. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005;23:2130-2135. 17. Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 1997;275:547-550. 18. Hu Z, Sun Y, Garen A. Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model. Proc Nat Acad Sci USA 1999;96:81618166. 19. Nilsson F, Kosmehl H, Zardi L, Neri D. Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice. Cancer Res 2001;61:711-716. 20. El-Sheikh A, Borgstrom P, Bhattacharjee G, Belting M, Edgington TS. A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment. Cancer Res 2005;65:11109-11117. 21. Hu Z, Garen A. Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer. Proc Nat Acad Sci USA 2001;98:1218012185.
22. Adams BK, Ferstl EM, Davis MC, Herold M, Kurtkaya S, Camalier RF, Hollingshead MG, Kaur G, Sausville EA, Rickles FR, Snyder JP, Liotta DC, Shoji M. Synthesis and biological evaluation of novel curcumin analogs as anticancer and anti-angiogenesis agents. Bioorg Med Chem 2004;12:3871-3883. 23. Heit JA, Silverstein MD, Mohr DN, Petterson TM, OFallon WM, Melton LJ. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Int Med 2002;162:1245-1248. 24. Prandoni P, Lensing AWA, PIccioli A, Bernardi E, Simioni P, Girolami B, Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100;3484-3488. 25. Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. ACTA Haematol (Suppl) 2001;106:6-12. 26. Dvorak HF, Rickles FR. Malignancy and Hemostasis. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 5th edition (Eds. R.W. Colman, J Hirsh, VJ Marder, AW Clowes, and JN George). Lippincott-Raven Publishers, Philadelphia, PA, Chapter 57, 2006;851-873. 27. Virchow R. Weitere Unter-suchungen ber die Verstopgung der Lungenarterie und ihre Folgen. In: Virchow R, ed. Gesammelte Abhandlungen zur wissenschaftlichen Medizin. Meidinger Sohn: Frankfurt am Main, 1856, pp. 227-380. 28. Wahrenbrock M, Borsig L, Le D, Varki N, Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest 2003;112:853-862. 29. Boccaccio C, Comoglio PM. A functional role for hemostasis in early cancer development. Cancer Res 2005;65:8579-8582. 30. Rickles FR, Patierno S, Fernandez PM. Tissue factor, thrombin and cancer. Chest (Supplement) 2003;124:58S-68S. 31. Contrino J, Hair GA, Schmeizl M, Rickles FR, Kreutzer DL. In situ characterization of antigenic and functional tissue factor expression in human tumors utilizing monoclonal antibodies and recombinant factor VIIa as probes. Amer J Pathol 1994;145:1315-1322. 32. Contrino J, Hair GA, Kreutzer DL, Rickles FR. In situ expression of antigenic and functional tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat Med 1996;2:209-215.
33. Bora PS, Hu Z, Tezel TH, Sohn J-H, Kang, SG, Cruz JMC, Bora NS, Garen A, Kaplan HJ. Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration. Proc Nat Acad Sci USA 2003;100:2679-2684. 34. Hettiarachchi RJK, Smorenburg SM, Ginsberg J, Levine M, Prins MH, Buller HR. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb Haemost 1999;82:947-952. 35. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of lowmolecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med 2002;162:1729-1735. 36. Folkman J, Langer R, Linhardt RJ, Haudenschild C, Taylor S. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 1983;221:719-725. 37. Collen A, Smorenburg SM, Peters E, Lupu F, Koolwijk P, Van Noorden C, van Hinsbergh VWM. Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro. Cancer Research 2001;60:6196-6200. 38. Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a lowmolecular-weight heparin. J Thromb Haemost 2003;1:1972-1976. 39. Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparase in cancer metastasis and angiogenesis. J Clin Invest 2001;108:341347. 40. Hasan J, Shnyder SD, Clamp AR, McGown AT, Bicknell R, Presta M, Bibby M, Double J, Craig S, Leeming D, Stevenson K, Gallagher JT, Jayson GC. Heparin octasaccharides inhibit angiogenesis in vivo. Clin Cancer Res 2005;11:8172-8179. 41. Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005;11:7003-7011. 42. Fernandez PM, Chou DS, Aquilina JW, Patierno SR, Rickles FR. Unfractionated heparin (UFH) and a low molecular weight heparin (dalteparin) exhibit antiangiogenic effects using in vitro, ex vivo and in vivo angiogenesis models. Proc Amer Assoc Cancer Res 2003;44:698-699.
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ORIGINAL ARTICLE IN PATIENTS WITH ADVANCED CANCER LOW-MOLECULAR-WEIGHT HEPARIN
Low-Molecular-Weight Heparin in Patients With Advanced Cancer: A Phase 3 Clinical Trial

KOSTANDINOS SIDERAS, MD; PAUL L. SCHAEFER, MD; SCOTT H. OKUNO, MD; JEFF A. SLOAN, PHD; LEILA KUTTEH, MD; TOM R. FITCH, MD; SHAKER R. DAKHIL, MD; RALPH LEVITT, MD; STEVEN R. ALBERTS, MD; ROSCOE F. MORTON, MD; KENDRITH M. ROWLAND, MD; PAUL J. NOVOTNY, MS; AND CHARLES L. LOPRINZI, MD
OBJECTIVE: To prospectively assess whether low-molecularweight heparin (LMWH) provides a survival benefit in patients with advanced cancer. PATIENTS AND METHODS: Between December 1998 and June 2001, we performed a randomized controlled study of patients with advanced cancer. Initially, the study was double blinded and placebo controlled, with the patients receiving daily injections of 5000 U of LMWH or saline. However, because of low accrual midway through the study, the placebo injection arm was eliminated, and the study became open labeled, with patients receiving either LMWH injections plus standard clinical care or standard clinical care alone. The primary study end point was overall survival. RESULTS: Of 141 patients randomized to this clinical trial, 3 dropped out, leaving 138 patients. The median survival time was 10.5 months (95% confidence interval, 7.6-12.2 months) for the combined standard care and placebo groups. The median survival time for the combined LMWH arms was 7.3 months (95% confidence interval, 4.8-12.2 months). These median survival times were not significantly different (log-rank P=.46). The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months, respectively. The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the standard care arm. The rate of severe or life-threatening venous thromboembolism was 6% in the LMWH arms and 7% in the control arms. The rate of severe or life-threatening bleeding was 3% in the LMWH arms and 7% in the control arms. CONCLUSION: This trial was unable to demonstrate any survival benefit for LMWH in patients with advanced cancer.
Mayo Clin Proc. 2006;81(6):758-767

CI = confidence interval; LMWH = low-molecular-weight heparin; NCCTG = North Central Cancer Treatment Group; QOL = quality of life; SDS = symptom distress scale; UFH = unfractionated heparin; ULN = upper limit of normal
Prandoni et al6 performed a trial that compared subcutaneous LMWH with intravenous unfractionated heparin (UFH) in patients with proximal deep venous thrombosis. Fifteen of 85 patients in the LMWH arm and 18 of 85 patients in the intravenous UFH arm had malignant disease. Interestingly, 8 (44%) of the 18 patients with malignant disease treated with UFH had died when the study was reported compared with only 1 (7%) of the 15 treated with LMWH. Green et al7 performed a similar study comparing LMWH vs UFH for the treatment of proximal deep venous thrombosis. In their study, 49 of 219 patients in the UFH group and 46 of 213 patients in the LMWH group had cancer. Fourteen deaths due to cancer occurred in the UFH group compared with only 7 cancer deaths in the LMWH group. Moreover, at least 2 meta-analyses, intended to compare LMWH to UFH for the treatment of deep venous thrombosis, have reported an improved survival in cancer patients treated with LMWH.8,9 Thus, these data suggested that the use of LMWH might improve survival in patients with cancer. A possible association between the hemostatic system and cancer cells has been demonstrated in several experimental and clinical studies.10,11 In one trial, the addition of warfarin to chemotherapy was associated with improved
ow-molecular-weight heparin (LMWH), manufactured by the depolymerization of standard heparin, has excellent bioavailability and a long biological half-life when given subcutaneously.1-3 These factors enable LMWH to be given subcutaneously in a fixed dose, based on body weight, once or twice daily. In addition, this treatment can be administered on an outpatient basis without the need for intravenous lines or laboratory monitoring. Two trials, reported before the development of this current clinical trial, demonstrated that LMWH can be used safely and effectively to treat patients with proximal-vein thrombosis on an outpatient basis.4,5
758 Mayo Clin Proc.
From the Division of Hematology (K.S.), Department of Oncology (K.S., S.H.O., S.R.A., C.L.L.), and Department of Health Sciences Research (J.A.S., P.J.N.), Mayo Clinic College of Medicine, Rochester, Minn; Toledo Community Hospital Community Clinical Oncology Program (CCOP), Toledo, Ohio (P.L.S.); Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa (L.K.); Division of Hematology/Oncology, Mayo Clinic College of Medicine, Scottsdale, Ariz (T.R.F.); Wichita Community Clinical Oncology Program, Wichita, Kan (S.R.D.); Meritcare Hospital CCOP, Fargo, ND (R.L.); Iowa Oncology Research Association CCOP, Des Moines (R.F.M.); and Carle Cancer Center CCOP, Urbana, Ill (K.M.R.). A list of additional participating institutions appears at the end of this article. This study was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-63826, CA-52352, CA-60276, CA-35431, CA-37417, CA-35101, and CA-35195 from the National Cancer Institute, Department of Health and Human Services. Both the low-molecular-weight heparin (dalteparin) and the placebo were provided by Pharmacia & Upjohn, Inc. Address reprint requests and correspondence to Charles L. Loprinzi, MD, Department of Oncology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: cloprinzi@mayo.edu). 2006 Mayo Foundation for Medical Education and Research
June 2006;81(6):758-767
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LOW-MOLECULAR-WEIGHT HEPARIN IN PATIENTS WITH ADVANCED CANCER
survival in patients with small cell lung cancer,12 whereas, in a multicenter study, warfarin demonstrated an improved response rate.13 Additionally, the use of subcutaneous UFH in the perioperative period for patients with resected colorectal cancer was associated with an improved survival over no UFH.14 Lebeau et al15 randomized 277 patients with small cell lung cancer to receive subcutaneous heparin or nothing during the first 5 weeks of chemotherapy. There were more complete responses (37% vs 23%), an improved median survival (317 days vs 261 days), and improved survival rates at 1, 2, and 3 years (40% vs 30%, 11% vs 9%, and 9% vs 6%, respectively) in the patients treated with LMWH. This benefit was seen only in patients with limited stage disease. Although the theoretic mechanism to account for the potentially improved response rate and survival in patients with cancer by modifying the hemostatic system is not clearly evident, several theoretical possibilities exist. One such possibility is a direct interference by anticoagulant agents on the local microthrombus formation and fibrin deposition, which has been hypothesized to protect cancer cells from chemotherapy.12,16,17 Another possibility might be heparins antithrombin properties. Thrombin is known to act as a growth factor and an initiator of DNA synthesis. Thus, interference with thrombin might have antitumor growth effects.18 In addition, heparins, specifically LMWH, have been shown to have direct antigrowth, antiangiogenesis, and antimetastatic effects.19-22 We performed this study to prospectively assess whether LMWH provides a survival benefit in patients with advanced cancer. PATIENTS AND METHODS This study, performed between December 1998 and June 2001, was initially developed as a randomized, doubleblinded, placebo-controlled clinical trial to compare subcutaneous LMWH once daily (dalteparin, Pharmacia & Upjohn, Inc, Kalamazoo, Mich), 5000 U, to placebo injections in patients with advanced incurable cancer. Because of a low accrual rate (after 52 accrued patients) and concerns that the low accrual rate was related to the requirements for placebo injections, the study was modified in February 2000, and the saline placebo injections were eliminated. Then, unblinded LMWH was compared with standard clinical care (with 89 more patients accrued after that point). Patients considered for this protocol had advanced breast cancer and failed first-line chemotherapy, advanced prostate cancer and failed primary hormonal therapy, advanced lung cancer, or advanced colorectal
Mayo Clin Proc.
cancer. Other eligibility criteria included age older than 18 years, Eastern Cooperative Oncology Group performance status of 0 to 2, physician-judged life expectancy of more than 12 weeks, and fulfillment of certain laboratory criteria (white blood cell count, >3500 109/L; platelet count, >150,000 109/L; total bilirubin, <1.5 times the upper limit of normal [ULN]; aspartate aminotransferase, <3 times the ULN; creatinine, <1.5 times the ULN; prothrombin time, <1.5 times the ULN; activated partial thromboplastin time, <1.5 times the ULN). Exclusion criteria included known central nervous system metastasis, a history of heparin-induced thrombocytopenia, current anticoagulation therapy, a known intolerance to heparin, enrollment in a chemotherapy or radiation therapy protocol, and a history of deep venous thrombosis, pulmonary embolism, or a clotted catheter within the past year. However, patients were allowed to receive chemotherapy or radiation therapy if not part of an investigational protocol. Patient evaluations at study initiation included a history and physical examination, blood tests (hematology group, liver and renal function tests, prothrombin time, partial thromboplastin time), and quality-of-life (QOL) questionnaires. For QOL assessments, the single-item visual analog Uniscale23 and a 5-item series of linear analog self-assessment measures developed by the Mayo Cancer Center Statistics Unit24 were used. These questionnaires were supplemented by a 13-item symptom distress scale (SDS), which is one of the longest-standing QOL tools for oncology patients, has been well validated, has been proved to be reliable,25 and is prognostic of survival in patients with cancer.26 Eligible patients were stratified before randomization according to age (>50 years or 50 years), sex, disease site, prior thrombotic episodes, good, bad, or unsure prognostic index scores,27 and current therapy (systemic vs radiation vs both vs none). Protocol therapy consisted of dalteparin, 5000 U subcutaneously once a day (or placebo in the first 52 patients). After study initiation, all patients were to be seen for a history and physical examination monthly for the first year and then every 3 months for 2 years. The QOL questionnaires were to be collected on the same schedule. Patients who received injections (LMWH or placebo) were scheduled to have a hematology group test weekly for the first month, then monthly for the first year, and then every 3 months for 2 years. The study was originally designed as a randomized, placebo-controlled, double-blinded phase 3 trial with 2 treatment arms (placebo and LMWH). The randomization processes applied were handled through the North Central Cancer Treatment Group (NCCTG) Randomization Office. Patients were randomized to each of the 2 treatment
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groups using a dynamic allocation method that incorporated the stratification factors mentioned earlier to balance the marginal distributions.28 The study was monitored in concordance with the NCCTG standard operating procedures, which include biannual review of safety and blinded efficacy by the NCCTG Data Monitoring Committee. The primary study end point was overall survival. Secondary end points included incidence of toxic effects, incidence of thromboembolic events, and changes in QOL measured by the Uniscale, SDS, and linear analog self-assessment. Log-rank testing formed the basis for analysis of the primary end point of survival.29,30 Analysis of the secondary end points was performed by simple comparison of frequency distributions via standard t test or Wilcoxon procedures and Fisher exact test for the ordinal and categorical level variables, respectively. The protocol was originally designed to accrue 265 patients in each of the original 2 treatment arms. This would have provided 80% power to detect a 34% improvement in 12-month median survival using a 2-sided log-rank test. This power calculation assumed a median survival of 12 months using the current standard therapy, a minimum of 18 months of follow-up for each patient, and an level of .05. RESULTS BASELINE CHARACTERISTICS A total of 141 patients were randomized to this clinical trial. Three patients, 1 randomized to blinded LMWH and 2 to unblinded LMWH, dropped out before receiving any protocol therapy. Of the 138 remaining patients, 68 received LMWH (24 initially in the blinded LMWH group and 44 after the placebo arm was eliminated), and 70 patients were in the standard clinical care group (26 initially receiving placebo injections and 44 more after the placebo treatment was discontinued). Of the 26 patients initially receiving placebo injections, 10 were alive by the time of unblinding in February 2000. These 10 patients were told to discontinue the injections and were given the option to stay in the study as controls (standard clinical care) the next time they came in contact with the study personnel. These 10 patients discontinued taking placebo injections anywhere from 2 to 11 months after their study initiation. The protocol accrual was stopped before reaching the prestudy planned accrual goal by the NCCTG Data Monitoring Committee because of a slower than predicted protocol accrual rate, with the knowledge (provided by an interim analysis report) that the patient survival rates were numerically worse on one arm of the blinded study. The distribution of baseline values for all 4 groups is given in
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Table 1, demonstrating that the treatment groups were well balanced. In particular, there seemed to be no difference in the blinded and unblinded LMWH arms in terms of patient characteristics. EFFICACY ANALYSIS: SURVIVAL Kaplan-Meier survival curves, based on the primary disease types, are illustrated in Figure 1, revealing that the patient groups were relatively similar, except that the patients with prostate cancer fared slightly better than the other patient groups. The Kaplan-Meier survival curves for the patients randomized and not randomized to receive LMWH are illustrated in Figure 2, illustrating no significant survival differences. Figure 3 demonstrates survival curves with patients divided into 4 groups based on the treatment arm they were assigned (LMWH vs no LMWH) and whether they were part of the initial double-blinded portion of the study or the latter unblinded portion, again demonstrating no significant survival differences among the 4 arms. Examining survival curves for patients randomized to receive LMWH and those not randomized to receive LMWH for each individual primary disease type did not suggest that LMWH was beneficial in any of these patient subsets. The median survival time was 10.5 months (95% confidence interval [CI], 7.6-12.2 months) for the combined standard care and placebo groups. The median survival for the combined LMWH arms was 7.3 months (95% CI, 4.8-12.2 months). These median survival times were not significantly different (log-rank P=.46). The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months, respectively. The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the standard care arm. When a subpopulation of patients who lived longer than 6 months was examined, no significant differences in survival occurred between the 2 treatment groups (Figure 4). The median survival times in this situation were 16.6 months in the combined LMWH arms and 12 months in the placebo and standard clinical care arms (log-rank P=.46). This slight difference in median survival rates was due to the patients in the unblinded LMWH arm, who tended to survive longer than the patients in the other 3 arms in this subpopulation of patients who lived longer than 6 months. To investigate this issue further, we stratified patients according to a prognostic score using baseline covariates only. This way, treatment or no treatment with LMWH is not directly related to the stratification, and, at least theoretically, a better assessment of the treatment effect in this subgroup can be obtained. When this analysis was performed in the current trial, again no statistically significant difference was observed, and the survival curves were more overlapping.
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TABLE 1. Distribution of Baseline Factors in Randomized Patients* Blinded LMWH (n=24) 64.5 4 (17) 20 (83) 12 (50) 12 (50) 4 (17) 5 (21) 3 (12) 9 (38) 3 (12) 12 (50) 2 (8) 1 (4) 9 (38) 1 (4) 23 (96) 9 (38) 2 (8) 13 (54) 7 (29) 15 (63) 2 (8) 3 (13) 8 (33) 7 (29) 4 (17) 2 (8) 11.8 2.0 20.5 11.0 0.9 0.25 81 50.0 Placebo (n=26) 63.5 4 (15) 22 (85) 11 (42) 15 (58) 5 (19) 7 (27) 2 (8) 8 (31) 4 (15) 12 (46) 0 (0) 2 (8) 12 (46) 1 (4) 25 (96) 10 (38) 2 (8) 14 (54) 8 (31) 15 (58) 3 (12) 2 (8) 12 (46) 5 (19) 6 (23) 1 (4) 11.9 1.8 22.0 10.0 0.8 0.20 83 25.0 Unblinded LMWH (n=44) 68.5 4 (9) 40 (91) 28 (64) 16 (36) 4 (9) 12 (27) 3 (7) 19 (43) 6 (14) 21 (48) 2 (5) 1 (2) 20 (45) 2 (5) 42 (95) 18 (41) 1 (2) 25 (57) 15 (34) 22 (50) 7 (16) 2 (5) 14 (34) 12 (29) 9 (22) 4 (10) 12.1 2.1 22.0 10.5 0.9 0.4 74 50.0 Standard care (n=44) 70.5 4 (9) 40 (91) .09 31 (70) 13 (30) .78 2 (5) 12 (27) 2 (5) 23 (52) 5 (11) .85 23 (52) 1 (2) 1 (2) 19 (43) .58 0 (0) 44 (100) .93 16 (36) 3 (7) 25 (57) .72 14 (32) 20 (45) 10 (23) .96 3 (7) 18 (43) 9 (21) 7 (17) 5 (12) .35 12.7 2.4 .54 21.5 12.5 .50 0.9 0.4 .53 79 50.0 .38 .53 .40 .15 .48 .69 .79 .30 .55 .95 .89 P value (among all 4 groups) .10 .68 P value (LMWH vs none) .38 .95
Baseline factors Median age (y) Age range (y) 33-50 51-86 Sex (%) Male Female Disease site Breast Colon Small cell lung Nonsmall cell lung Prostate Current therapy Systemic Radiation Both None Prior thrombotic event Yes No Prognostic index scores Good Bad Unsure ECOG performance status 0 1 2 Appetite rating Increased Same Slightly reduced Moderately reduced Markedly reduced Hemoglobin (mg/dL) Median IQR Aspartate aminotransferase (U/L) Median IQR Creatinine (mg/dL) Median IQR Uniscale QOL Median IQR
*Values are number (percentage) unless indicated otherwise. ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; LMWH = low-molecular-weight heparin; QOL = quality of life. Stratification factor. Data were available for only 41 and 42 patients in the unblinded LMWH and standard care columns, respectively.
The primary analysis for survival was examined for potential confounding variables by concomitant covariates with use of Cox proportional hazards models (Table 2). Variables included in the modeling process were treatment arm; baseline good, bad, or unsure status; tumor site; and baseline performance score. The adjusted P value for differences between the treatment arms was .25, indicating that covariates did not modify the results of the primary analysis.
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QUALITY OF LIFE The QOL and SDS scores were similar, both at baseline and during the protocol period, in patients randomized to receive LMWH vs those not randomized to receive LMWH. The average baseline patient QOL was 74, indicating a high level of QOL for this patient sample. Thirty-seven and 36 patients in the combined LMWH and placebo or standard clinical care arms, respectively,
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100
Breast Colon
80
Small cell lung Nonsmall cell lung Prostate
Probability of survival (%)
60
P=.02
40
20
0 0 1 2
Time from randomization (y)

No. at risk Breast Colon Small cell lung Nonsmall cell lung Prostate 15 36 10 58 18 6 17 1 14 11 2 2 1 0 0
FIGURE 1. Survival curves for the different study subpopulations.
reported decreases in QOL during the treatment period of a clinically meaningful amount of 10 points on the 100-point scale (where 0 is worst QOL and 100 is best QOL).
The SDS scores indicated that fatigue was a major concern in this patient population. The mean baseline fatigue level was 63 of 100 (where 0 is worst and 100 is best). The other major concerns were pain frequency (mean score,
100 LMWH Placebo or standard care 80
P=.46
60
40
20
0 0 1 2

No. at risk LMWH 68 Placebo or standard care 69 23 28 2 6
FIGURE 2. Survival curves for patients randomized to receive low-molecular-weight heparin (LMWH) vs those randomized to receive placebo or standard care.
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100 Blinded LMWH Placebo injection 80
Unblinded LMWH Standard care
60
P=.78
40
20
0 0 1 2

No. at risk Blinded LMWH Placebo injection Unblinded LMWH Standard care 84 86 44 43 8 11 15 17 2 3 0 3
FIGURE 3. Survival curves for patients randomized to receive blinded low-molecular-weight heparin (LMWH), blinded placebo injections, unblinded LMWH, or standard care alone.
70), insomnia (mean score, 75), pain severity (mean score, 78), bowel dysfunction (mean score, 78), and cough (mean score, 80).
100
TOXIC EFFECTS Table 3 provides information on several toxic effects that might have been considered potentially related to LMWH.
LMWH
80
Placebo or standard care P=.46
60
40
20
0 0.0 0.5 1.0 1.5 2.0 2.5 3.0

No. at risk LMWH Placebo or standard care
37 50
23 27
2 6
FIGURE 4. Survival curves for patients living at least 6 months who were randomized to receive low-molecular-weight heparin (LMWH) vs those randomized to receive placebo or standard care.
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763
TABLE 2. Survival Analyses by Baseline Factors No. of patients 54 8 75 44 71 22 67 5 5 60 15 36 10 58 18 15 122 4 133 82 55 No. of deaths 43 7 63 34 60 19 56 5 3 49 13 31 8 50 11 12 101 2 111 67 46 Median survival time (d) 371 76 230 .02 390 219 222 .04 308 95 312 294 .02 346 319 284 196 479 .88 170 309 .88 371 300 .73 284 332 Log-rank P value .01
Factor Prognostic index score Good Bad Unsure Performance score 0 1 2 Current therapy Systemic Radiation Both None Disease group Breast Colon Small cell lung Nonsmall cell lung Prostate Age group (y) 50 >50 Prior thrombotic events Yes No Sex Male Female
In addition to these factors, more than 100 other less likely related toxic effects were also tabulated in the protocol patients. There was no suggestion that LMWH caused any of these other potential toxic effects. The most prevalent toxic effects observed were fatigue (reported by 48% of LMWH-treated patients and 69% of other patients), anorexia (reported by 43% of LMWH-treated patients and 49% of other patients), and nausea (reported by 31% of LMWH-treated patients and 40% of other patients). With regard to bleeding, 2 (3%) of 68 patients in the LMWH arms and 5 (7%) of 70 patients in the control groups experienced severe, life-threatening, or lethal hemorrhagic complications (grades 3, 4, or 5 toxic effects). One of these patients, who was in the standard clinical care group, died as a direct result of a hemorrhagic stroke. With regard to thrombosis, 6% in the LMWH arms and 7% in the control arms experienced grade 3 to 4 thrombotic complications. DISCUSSION This trial found no survival benefit with use of LMWH in patients with advanced cancer. A similar trial by Kakkar et al31 also found no significant difference in patients treated with LMWH compared with placebo (385 patients; median survival, 10.8 vs 9.1 months; P=.19). In
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contrast, a trial by Klerk et al32 showed a statistically significant difference in patients treated with LMWH vs placebo (302 patients; median survival, 8 vs 6.6 months; P=.02). In the study by Kakkar et al, an analysis was performed in patients with better prognosis (not defined a priori), defined as patients who lived more than 17 months. The patients treated with dalteparin in this subgroup were reported to have had a statistically significant increase in median survival (43.5 months; 95% CI, 33-52.3 months) compared with the placebo group (24.3 months; 95% CI, 22.4-41.5 months). This subpopulation was examined because of the hypothesis that LMWH may be beneficial in patients with less advanced disease and better prognosis because it may simply be too late for LMWH to offer a survival benefit in patients with a short life expectancy. In the study by Klerk et al,32 an a priori specified subgroup of patients with more than 6 months of expected survival was examined, and LMWH therapy appeared to be beneficial (median survival, 15.4 vs 9.4 months; P=.10), as was seen in the whole study population. In the current study, the LMWH group survival rate was numerically better for a similar subgroup of patients (also not defined a priori) who survived at least 6 months (Figure 4), although this difference was not statistically significant. Reanalyzing these data by stratifying patients according to a prognostic score using baseline covariates, a less biased analysis method, again demonstrated no survival benefit for patients with better prognoses. Thus, the results of the current study do not support the theory that LMWH is beneficial for patients with better prognoses. The results of the current trial demonstrated the safety of LMWH in patients with advanced incurable cancers. Low-molecular-weight heparin did not appear to significantly increase the incidence of major bleeding. It is reasonable to ask whether the results of this clinical trial were flawed based on the use of 4 different primary disease types, as opposed to the use of a single, more uniform patient population. Several specific disease sites could have been chosen for study, ranging from a single disease site, such as breast, prostate, colon, or lung cancer, vs all patients with advanced cancer, regardless of the primary tumor type. Likewise, different disease stages, ranging from precancers to widespread incurable metastatic disease, could have been chosen for study. To address potential concerns related to the use of different tumor types and patients receiving different therapies, this issue was studied in some depth before the initiation of this trial. First, several trials that involved use of antianorexia agents across a broad spectrum of cancer pa www.mayoclinicproceedings.com
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TABLE 3. Incidences of Toxic Effects* Blinded LMWH (n=24) 6 (25) 12 (50) 4 (17) 0 (0) 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (4) 0 (0) 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 1 (4) 1 (4) 1 (4) 0 (0) 1 (4) 0 (0) 1 (4) 0 (0) 1 (4) 0 (0) 0 (0) 2 (8) 1 (4) Placebo (n=26) 3 (12) 5 (19) 1 (4) 0 (0) 1 (4) 1 (4) 0 (0) 1 (4) 2 (8) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (4) 1 (4) 1 (4) 0 (0) 1 (4) 0 (0) 1 (4) Unblinded LMWH (n=44) ND ND 6 (14) 2 (5) 2 (5) 0 (0) 1 (2) 0 (0) 1 (2) 0 (0) 0 (0) 0 (0) 1 (2) 1 (2) 1 (2) 1 (2) 0 (0) 4 (9) 1 (2) 1 (2) 0 (0) 0 (0) 1 (2) 1 (2) 0 (0) 2 (5) 0 (0) 2 (5) 0 (0) 1 (2) Standard care (n=44) ND ND 3 (7) 0 (0) .86 2 (5) 1 (2) .23 1 (2) 3 (7) .36 0 (0) 1 (2) .49 0 (0) 1 (2) 0 (0) 0 (0) 0 (0) .77 0 (0) 1 (2) .32 2 (5) 0 (0) .45 2 (5) 1 (2) .51 0 (0) 0 (0) .48 0 (0) 0 (0) 0 (0) 1 (2) .70 2 (5) 2 (5) 1 (2) .94 .99 .70 .93 .50 .55 .13 .75 .79 .26 .75 .99 .50 .30 .05 .35 P value (among all 4 groups) .28 .03 .22 P value (between blinded groups) ND ND .05
Toxic effects Soreness at injection site Bruising at injection site Bruising without thrombocytopenia Mild Moderate Epistaxis Mild Severe Hematuria Mild Moderate Hemoptysis Mild Severe Hemorrhage, CNS Severe Lethal Hemorrhage, other, mild Hemorrhage with grade 3-4 thrombocytopenia Mild Severe Melena Mild Severe Petechiae Mild Moderate Rectal bleeding Mild Moderate Vaginal bleeding Mild Moderate Thrombocytopenia Mild Moderate Severe Life-threatening Thrombosis Severe Life-threatening Transfusion, red blood cells, severe
*Values are number (percentage). CNS = central nervous system; LMWH = low-molecular-weight heparin; ND = not done.
tient subpopulations were examined.33-36 Extensive analysis of these trials indicated that even though the survival curves for the varying disease sites varied, balancing the distributions of disease site across treatment arms allowed for an unbiased evaluation of the effect of each agent under study with regard to survival. To demonstrate the effect of randomization in this experimental environment, the results of an analysis based on 496 patients with advanced disease from lung (40%), gastrointestinal (36%), and other sites (24%), which were accrued to a cancer control protocol involving therapeutic
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agents for anorexia or cachexia, were evaluated.37 The survival curves for the treatment arms (which would not be expected to produce survival differences) had an associated log-rank P=.86. Second, the sample of 496 patients was randomly divided into 2 groups (group A and group B), with no stratification factors being used, and survival curves were generated from these groups. These survival curves overlapped. Subsequently, this was repeated 10,000 times using bootstrapped samples. For each of these 10,000 samples, the question was asked, How often were statistically sig www.mayoclinicproceedings.com 765
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nificant (P.05) survival results seen in the 2 randomly allocated groups? The answer was 5% of the time, exactly what would have been expected by chance alone. When this experiment was repeated using the stratification factors identified in the study protocol, statistically significant (P.05) survival curves were observed 4% of the time, demonstrating only a slight improvement with the use of stratification. Thus, this evidence indicates that it is possible to perform a clinical trial across a known heterogeneous population, especially if stratification is used to remove the potentially confounding effect of any covariate that is strongly related to the primary efficacy end point. An additional reason for using 4 different common primary disease types in the current trial is that it provided a wider net to potentially detect a treatment effect, especially when hypothesis-generating subgroup analyses were performed to explore for a potential benefit in 1 of the primary disease type subgroups. One could argue that it might have been better to pick 1 of the 4 disease types for study because the LMWH might have been efficacious in only 1 of the 4 disease types. If this were the case, then, right up front, investigators opting to choose 1 primary disease type for study would have only a 25% chance of picking the correct disease type. In the development of this trial, the issue of whether to allow concomitant cytotoxic chemotherapy in study patients was also seriously considered. At first glance, it might have seemed preferable to not allow concomitant chemotherapy. With this approach, there would have been no chance of possible detrimental effects of LMWH on chemotherapy because of toxic effects or potential pharmacological interactions. However, LMWH is used in patients receiving concomitant chemotherapy. In addition, experience with more than 2000 patients who have entered NCCTG anorexia or cachexia trials has illustrated that the patients who are no longer receiving chemotherapy have a poorer prognosis than patients who continue to receive chemotherapy at the time of study entry. Thus, patients were allowed to receive concomitant chemotherapy while in this study. Another issue to examine, regarding the validity of the results of this clinical trial, relates to whether the study conclusions are compromised because of the lower than planned patient accrual in this trial. To address this issue, it is first worth noting that the decision of the NCCTG Data Monitoring Committee, made independently from the protocol principle investigators, certainly appeared to be wise. The final sample size of 138 patients provided 46% power to detect a 50% improvement in median survival times. Given the results from this study that indicate a 3.2-month superiority in median survival for patients receiving placebo, the probability is less than 9% of obtaining results
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such as would be observed if LMWH were actually 10% superior in terms of median survival. Hence, despite having stopped the study early, our results minimize the possibility of any real survival advantage due to LMWH. CONCLUSION This trial demonstrated the safety of the administered LMWH in patients with advanced incurable cancer but failed to provide any information to suggest that the LMWH prolonged survival or improved patients QOL.
Additional Participating Institutions. Duluth Community Clinical Oncology Program (CCOP), Duluth, Minn (Daniel A. Nikcevich, MD); Medcenter One Health Systems, Bismarck, ND, Mid Dakota Clinic, Bismarck, ND (Edward Wos, MD); CentraCare Clinic, St Cloud, Minn (Harold E. Windschitl, MD); Sioux Community Cancer Consortium, Sioux Falls, SD (Loren K. Tschetter, MD); Geisinger Clinic and Medical Center CCOP, Danville, Pa (Albert Bernath, MD); Michigan Cancer Consortium, Ann Arbor (Philip J. Stella, MD); Missouri Valley Cancer Consortium, Omaha, Neb (James A. Mailliard, MD).
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The Open Cardiovascular Medicine Journal, 2010, 4, 78-82
Open Access
Cancer-Associated Thrombosis
Mehran Karimi* and Nader Cohan
Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Abstract: Thrombosis is a common complication in patients with cancer and it is estimated that about 20% of patients with cancer experience venous thromboembolism (VTE). This complication is associated with high rate of morbidity and mortality and is sometimes the first manifestation of an occult cancer. The risk profiles and markers involved in cancerassociated thrombosis share similarities with inflammation-induced atherosclerosis and thrombosis. The type of cancer, chemotherapy, surgery, central venous catheters, pre-chemotherapy platelet and leukocyte count are associated with high risk of VTE in cancer patients. Landmark studies demonstrated that effective prophylaxis and treatment of VTE reduced morbidity and increased survival. Low-molecular-weight heparin (LMWH) is preferred as an effective and safe means for prophylaxis and treatment of VTE. It has largely replaced unfractionated heparin and vitamin K antagonists. The advantages of LMWH include increased survival and quality of life, decreased rate of VTE, low incidence of thrombocytopenia. New guidelines for prophylaxis and treatment are now available and prophylaxis is recommended in hospitalized cancer patients and patients undergoing major surgery. Treatment with LMWH should be considered as the first line of therapy for established VTE and to prevent recurrent thrombosis in patients with cancer.
Keywords: Cancer, Thrombosis, Low-molecular-weight heparin. INTRODUCTION Thrombosis, a well-recognized complication of cancer, may be the first manifestation of malignancy and is associated with a high rate of morbidity and mortality [1-4]. This association was first described by Armand Trousseau in 1865 and the condition still often called Trousseaus syndrome [5-7]. The clinical manifestations of thrombosis in cancer vary from venous thromboembolism (VTE) to disseminated intravascular coagulation, which is more commonly seen in hematological malignancies [8]. Venous thromboembolism in patients with cancer may present as a vast range of clinically significant thrombotic complications including deep vein thrombosis, pulmonary embolism, arterial thrombosis, nonbacterial thrombotic endocarditis, superficial thrombophlebitis, catheter-related thrombosis and hepatic venoocclusive disease [9-11]. Certain malignancies, particularly mucin-secreting adenocarcinomas of the ovary, pancreas, stomach, brain tumors and hematological malignancies, are associated with a higher risk of VTE [12-16]. Some conditions are well-known risk factors for increased risk of thrombosis in patients with cancer. Chemotherapy is one of the most important risk factors for increased risk of VTE [10-12]. The strongest clinical relationship between chemotherapy and thrombosis was found in patients with breast cancer receiving chemotherapy [10, 12-15]. In a study by the Eastern Cooperative Oncology Group, VTE was significantly more common in patients with
*Address correspondence to this author at the Hematology Research Center, Nemazee Hospital of Shiraz University of Medical Sciences, Zand st, Shiraz, Iran; Tel/Fax: +98 711 6473239; E-mail: Karimim@sums.ac.ir
breast cancer who underwent chemotherapy and hormonal therapy than in the control group [16]. A high incidence of VTE following chemotherapy was also reported in other cancers [17, 18]. Chemotherapy increased the risk of VTE and recurrent VTE 6-fold and 2-fold, respectively in patients with cancer, and it is estimated that the annual incidence of VTE in cancer patients undergoing chemotherapy is about 10.9% [10]. Surgery is estimated to increase the risk of postoperative VTE about 2-fold in patients with cancer compared to patients without cancer who underwent surgery and was associated with a 3-fold to 4-fold increase in the likelihood of developing pulmonary embolism after surgery [19-21]. In contrast, some studies did not show an increased risk of VTE associated with surgery in patients with cancer [14, 22]. One study that analyzed the effect of neurosurgery on the risk of thrombosis in patients with glioma revealed that these patients were 70% more likely to develope VTE compared to patients who did not undergo surgery [14]. Other risk factors for thrombosis in cancer are central venous catheters, immobilization, oral contraceptive use, trauma, previous vein thrombosis, hormonal therapy, pregnancy, older age, prothrombotic mutations such as factor V leiden and prothrombin 20210A, elevated D-dimer levels, elevated C-reactive protein, elevated soluble P-selectin, body mass index 35 kg/m2, antiphospholipid antibody and several biomarkers such as pre-chemotherapy platelet count over 350 103/L or leukocyte count over 11 103/L [14, 2226]. Also it is noted that risk factors and markers involved in cancer-associated thrombosis, inflammation and atherosclerosis share similarities. Thrombogenic risk factors such as tissue factor reported as a promotion factor for a human
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coronary atherosclerosis plague. In addition, platelets can release pro-inflammatory substances relevant to atherothrombosis. Beside the cardiovascular risk factors including; family history of coronary heart disease, smoking, high cholesterol level, hypertension, age and diabetic mellitus several markers including fibrinogen level, markers of fibrinolytic systems and inflammation markers such as Creactive protein is evaluated as risk factors of cardiovascular disease [27, 28]. The aim of this review was to overview evidence on pathophysiology, prophylaxis and treatment of cancerassociated thrombosis. PATHOPHYSIOLOGY OF CANCER-ASSOCIATED THROMBOSIS The pathophysiology of thrombosis formation and blood coagulation in cancer is complex and reflects different mechanisms that are generally related to the host response to cancer. These mechanisms include activation of the coagulation and fibrinolytic systems, acute phase reaction, inflammation, necrosis and cytokine production [5, 8, 29, 30]. Malignant cells can directly activate blood coagulation by producing tissue factor, cancer procoagulant activity, inflammatory reactions and cytokines [9, 12, 29, 31]. Tissue factor, an important coagulation factor that has been reported in many types of cancers [32], is constitutively expressed on solid malignant cells and acute myelogenous leukemia cells. It has been reported to promote thrombotic state [30, 31, 33]. Cancer procoagulant is a 68-kDa cysteine endopeptidase that can directly activate coagulation factor X. It is released by many tumor cells and its activity promotes thrombosis. It
is also has been shown that cancer procoagulant can cause platelet activation [8, 10, 34, 35]. Malignant cells release various types of cytokines including interleukin (IL)-1, tumor necrosis factor- and vascular endothelial growth factor (VEGF), which have important effects on coagulation. These cytokines can induce tissue factor production by vascular endothelial cells, downregulate thrombomodulin expression, produce plasminogen activator inhibitor-1 and increase endothelial cell adhesion molecule expression. This last effect increases the capacity of the vessel wall to attach leukocytes and platelets, promoting localized clotting factor activation and thrombosis formation [810, 29, 36]. Angiogenesis is an important process in pathophysiology of cancer. VEGF and angiopoietins with their receptors, Flt-1 for VEGF and Tie-2 for angiopoietin, that are the most potent proangiogenic factors are involved in the pathogenesis of cancer. Abnormal levels of VEGF, angiopoietins, IL-6 (an inflammatory cytokine) and soluble P selectin and their receptors are established in breast and other cancers that treatment is effective in reduce levels of these markers [37-39]. Interactions between malignant and endothelial host cells, platelets and leukocytes are another mechanism by which tumor cells promote thrombosis. The attachment of malignant cells can promote thrombosis by activating localized clotting factor, favoring platelet aggregation and activating leukocytes which then release their cytokines [8, 10, 29, 40]. It has also been shown that inflammation induced by cancer can increase acute-phase proteins including fibrinogen, coagulation factor VIII and von Willebrand factor, which can promote thrombosis [9, 41]. Fig. (1) illustrates
Tumor cells
CP, TF
Inflammation and cytokinergic reactions involving TNF-, IL-1, VEGF, fibrinogen, FVIII, vWF
Cells adhesion and interaction: endothelial cells, monocyte/macrophage, T and B lymphocytes interaction, platelet hyperactivation with the release of ADP, thrombin, adhesion molecules
Activation of coagulation
Clot formation
Thrombotic vascular events
Fig. (1). Factors involved in cancer-associated thrombosis.
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the mechanism of thrombosis formation induced by cancer cells. EPIDEMIOLOGY THROMBOSIS OF CANCER-ASSOCIATED
after 3-4 days and its clearance from plasma is slow. Also warfarin may interact with chemotherapeutic agents and foodsinteractions that also make this drug difficult to manage [12]. The CLOT trial (Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) compared the efficacy of LMWH plus dalteparin and oral warfarin in preventing recurrent VTE in patients with cancer. Recurrent VTE was found in 27 of 336 patients in the LMWH group compared to 53 of 336 patients in the warfarin group (hazard ratio 0.48, P=0.002) [55]. Low-molecular-weight heparin and dalteparin reduced the risk of recurrent VTE by 52% compared to warfarin therapy [56]. Unfractionated heparin is also widely used for the treatment and prophylaxis of thrombophylactic events and its efficacy is similar to that of LMWH [56]. A metaanalysis revealed that unfractionated heparin decreased the incidence of deep vein thrombosis and pulmonary embolism by 56% and 58% respectively compared to the control group [57]. The most important limitation of unfractionated heparin is the appearance of heparin-induced thrombocytopenia, which is significantly less frequent with LMWH [9, 29]. Treatment with LMWH led to a significant proportion of improvements in thrombosis and higher survival compared to unfractionated heparin [9]. These benefits make subcutaneous (sc) LMWH the first-line choice for the treatment and prophylaxis of thrombosis in patients with cancer. Randomized trials to test different types of prophylaxis for VTE in patients with cancer showed significantly lower rates of VTE with LMWH compared to unfractionated heparin or a placebo [58-60]. New treatment guidelines from the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) accept prophylaxis for VTE in hospitalized cancer patients in the absence of major bleeding or other contraindications to anticoagulants [50, 61]. Contraindications to anticoagulation according to ASCO guidelines include uncontrollable bleeding, active cerebrovascular hemorrhage, dissecting or cerebral aneurysm, bacterial endocarditis, active peptic or other gastrointestinal ulceration, severe uncontrolled or malignant hypertension, severe head trauma, pregnancy (warfarin), heparin-induced thrombocytopenia and epidural catheter placement. It is recommended that patients undergoing major surgery for cancer should be considered candidates for thrombophylaxis, although routine prophylaxis is not recommended in ambulatory cancer patients without VTE except in patients with myeloma receiving thalidomide or lenalidomide treatment [50]. Low-molecular-weight heparin, dalteparin 5000 units s.c daily, enoxaparin 40 mg s.c daily or fondaparinux 2.5 mg s.c daily is recommended for prophylaxis of VTE in patients with cancer [50, 61, 62]. A randomized clinical trial of combination chemotherapy with LMWH with dalteparin 5000 units once daily for 18 weeks compared to chemotherapy alone in patients with small-cell lung cancer revealed that combination therapy with dalteparin increased disease-free survival (10 months) compared chemotherapy alone (6 months, P=0.01) [63].
It is estimated that about 4-20% of patients with cancer experience venous thrombosis [7, 10, 25, 30, 42, 43] with the annual incidence of 0.5% in cancer patients compared to 0.1% in the general population [25]. In patients with cancer, the risk of VTE is estimated to be 4-fold to 7-fold higher than in patients without cancer [44]. Venous thromboembolism and thrombotic complications are the second most frequent cause of mortality in patients with cancer [10]. Several studies have showed that the incidence of VTE is associated with the duration of the underlying illness. The highest rate of VTE is seen in the initial period after diagnosis [14, 29, 45] and mortality from VTE is highest 1 year after diagnosis [14]. Alcalay et al. showed that the incidence of VTE in patients with colorectal cancer is about 5.0% during the first 6 months after diagnosis, 1.4% during the subsequent 7-12 months and 0.6% 13-24 months after diagnosis [46]. The appearance of venous thrombosis has been clearly associated with metastatic cancer and the stage of cancer [14, 29, 42, 44]. About 10% of patients with idiopathic thrombotic complications are diagnosed with malignancy within a few years after thrombotic events and approximately 40% of them have metastatic cancer at diagnosis [47, 48]. As a result VTE is sometimes the first manifestation of occult cancer [10, 29, 42, 47]. In a study by Monreal et al. the rate of occult cancer in patients with idiopathic VTE was 2.2%-12% [48]. More advanced stages of cancer on initial diagnosis are also related with a higher incidence of VTE [14, 45, 46]. The presence of medical comorbodity has an adverse effect on prognosis and survival in patients with cancer who also have thrombosis [47]. Khorana et al. proposed a simple risk scoring system based on clinical and laboratory variables to predict chemotherapy-associated VTE in patients with cancer [25, 49]. They identified five variables based on the site of cancer, pre-chemotherapy platelet and leukocyte count, hemoglobin level and body mass index. This model predicts a risk of chemotherapy-associated VTE in of about 7% in patients with cancer [25]. PREVENTION AND TREATMENT OF VENOUS THROMBOEMBOLISM IN CANCER Effective prophylaxis and treatment of VTE can reduce morbidity and mortality due to thrombosis. Low-molecularweight-heparin (LMWH) is the first choice for prophylaxis and treatment of acute VTE, having largely replaced unfractionated heparin and oral vitamin K antagonists such as warfarin [50, 51]. Warfarin is a long-term anticoagulant for the prevention and treatment of VTE that is given after initial therapy with unfractionated heparin or LMWH to maintain an international normalized ratio of 2-3 [42, 52]. But warfarin treatment in patients with cancer has several problems that have limited its use. Long-term treatment with warfarin increases the risk of bleeding and recurrent VTE in patients with cancer [47, 53, 54]. Difficulties in dose adjustment also limit its use because the anticoagulant effect may reach to its peak
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CONCLUSIONS Venous thromboembolism is a serious complication and the second most frequent cause of death in patients with cancer. The appearance of VTE reduces survival in cancer patients compared to those without VTE and adversely affects quality of life [14]. It is estimated that thrombosis in patients with cancer increases the risk of death 4-fold to 8fold compared to patients without cancer [47]. Landmark studies showed that anticoagulant therapy and thromboprophylaxis are efficacious and can protect patients from VTE. Based on clinical trial findings, subcutaneous LMWH is the first line therapy for VTE in patients with cancer and has largely replaced unfractionated heparin and vitamin K antagonists. New treatment and prophylaxis guidelines are now available for the management of thrombotic events and these guidelines can decrease complications and morbidity and increase survival and quality of life in patients with cancer. ACKNOWLEDGEMENTS We thank Shirin Parand (Hematology Research Center, Shiraz University of Medical Sciences) and K. Shashok (AuthorAID in the Eastern Mediterranean) for improving the use of English in the manuscript. ABBREVIATIONS CP TF TNF- IL-1 VEGF FVIII vWF ADP = = = = = = = = Cancer procoagulant Tissue factor Tumor necrosis factor- Interleukin-1 Vascular endothelial growth factor Factor VIII Von Willebrand factor Adenosine diphosphate
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Received: November 10, 2009
Revised: November 24, 2009
Accepted: December 11, 2009
Karimi and Cohan; Licensee Bentham Open. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
Original article 1
Weight-adjusted dalteparin for prevention of vascular thromboembolism in advanced pancreatic cancer patients decreases serum tissue factor and serum-mediated induction of cancer cell invasion
Anthony Maraveyasa, Camille Ettelaieb, Hussein Echrisha, Chao Lib, Eric Gardinerc, John Greenmana and Leigh A. Maddena
The aim of the present study was to assess the role of tissue factor and serum-induced cell invasion in patients with advanced pancreatic cancer (APC). A cohort of 39 patients with APC, without thrombosis, receiving chemotherapy, were entered in a randomized controlled trial (ISRCTN U 76464767) of thromboprevention with weightadjusted dalteparin (WAD). A total of 19 patients received WAD, the remaining 20 acting as a control group. Serum from baseline and week 8 was analysed for circulatingtissue factor antigen using ELISA. Circulating-tissue factor antigen rose from 324 pg/ml, [interquartile range (IQR) 282347 pg/ml] to 356 pg/ml, (IQR 319431 pg/ml) in controls (C), and decreased in the dalteparin-treated group (D) from 336 pg/ml (IQR 281346 pg/ml) to 303 pg/ml (IQR 274339 pg/ml). The difference in median percentage change between D and C was statistically signicant [S4.0 (D) vs. 4.7 (C); P U 0.005, n U 39]. Serum-induced cellular invasion of MIA-Paca-2 cells in response to patient serum was studied using a Boyden chamber assay in 30 patients (14 WAD and 16 C). The median percentage change between C and D was signicant [R54.9 (C) vs. S21.9 (D) P U 0.025, n U 30]. There was a weak correlation between BB-tissue factor reduction and cellular invasion reduction (Spearman) [0.384 (P U 0.037, n U 30)]. APC patients treated with WAD have lower tissue factor antigen levels and attenuated induction of cellular invasion in their blood. These assays may provide useful markers to guide appropriate dalteparin (and other low-molecular weight heparin) dosing schedules to optimize anticancer effects of dalteparin in APC. Blood Coagul Fibrinolysis 21:000000 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2010, 21:000000 Keywords: blood-borne tissue factor, dalteparin, low-molecular weight heparin, pancreatic cancer
a Division of Cancer, Postgraduate Medical Institute in Association with Hull York Medical School, bBiomedical Section, Department of Biological Sciences, University of Hull, Hull, UK and cFreelance Statistical Consultant
Correspondence to Dr Leigh A. Madden, Postgraduate Medical Institute, University of Hull, Cottingham Road, Hull HU6 7RX, UK Tel/fax: +44 1482 466031; e-mail: l.a.madden@hull.ac.uk Received 7 December 2009 Revised 15 January 2010 Accepted 14 February 2010
Introduction
Conventionally, the state of aberrant coagulation in cancer relates to the morbidity and mortality that accompanies vascular thromboembolic events (VTEs) and disseminated intravascular coagulation (DIC). One of the malignancies with the greatest burden of VTE is advanced pancreatic cancer (APC) [1,2]. Compelling data, however, have accrued to show that mechanisms we associate with the metastatic process in cancer (e.g. angiogenesis, immune evasion and tissue invasion) are also promoted by coagulation factors [3]. A pivotal molecule would appear to be tissue factor, which facilitates the malignant process at all the abovementioned levels. Tissue factor is a 47 kDa transmembrane glycoprotein that forms a complex with circulating factor VIIa to initiate the extrinsic pathway of coagulation [4]. Direct correlations between elevated tissue factor expression and advanced stages of malignancy have been reported in several types of cancer, including nonsmall cell lung [5], breast [6], pancreatic [7], prostate [8] and colorectal cancer [9] and glioma [10]. Many of these studies have
0957-5235 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
suggested that tissue factor may also play a major role in growth, invasion and dissemination of the tumour cells. Previous research has shown that the expression of tissue factor can promote tumour metastasis in a mouse model of melanoma [11] and enhance primary tumour growth in a pancreatic adenocarcinoma cell line [12]. Clinical studies on APC have shown that tissue factor expression shows a signicant positive correlation with histological grade of the tumour, with 77% of poorly differentiated pancreatic tumours expressing tissue factor compared with only 20% of well differentiated tumours [13]. Furthermore, recently, a correlation of pancreatic cancer tissue factor levels, as assessed immunohistochemically, was found with clinical thrombosis in APC [14]. In contrast to tissue-associated tissue factor, the role of circulating-tissue factor in cancer propagation is unknown. Correlative studies of the circulating component of tissue factor are few. An early report has shown that patients with ovarian cancer have higher levels of serum circulating-tissue factor antigen than normal
DOI:10.1097/MBC.0b013e328338dc49
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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nontumour controls and this was correlated with a worse prognosis [15]. A single case report on a patient with APC and death from DIC demonstrated very high levels of tissue factor, both in the tumour and in the circulation [7]. The central position of tissue factor in promoting the malignant phenotype suggests that inhibition of tissue factor might not only be benecial through reduction of risk of VTE, but also there may be further benet through interference of the cancer-promoting properties of tissue factor. Putative anticancer effects of anticoagulants have been demonstrated in preclinical models [16]. Prominent agents in this respect are the low-molecular weight heparins (LMWHs) [17]. A major mechanism involved in metastasis, and shown in these models to be inhibited by LMWHs, is the ability of cancer cells to migrate and invade through stroma. The use of LMWHs in treating patients with various cancers with a VTE has already been shown to reduce circulating levels of circulating-tissue factor antigen [18]. Here, in patients with pancreatic cancer treated with weight-adjusted dalteparin (WAD) in a primary prevention setting of thrombosis, we present data that, for the rst time, demonstrate reduction in circulating tissue factor-antigen levels and reduction in the induction of in-vitro invasion of pancreatic cancer cells in response to dalteparin-treated patients serum.
Fig. 1
(a) FRAGEM study

Inoperable advanced pancreatic cancer Stratify for PS (90100 vs 6080) and metastatic vs locally advanced*
Randomization 1:1 Single agent Gemcitabine (Burris schedule)

Histology (cytology)-proven **Dalteparing is scheduled for 12 weeks scod daily CLOT investigators dose prophylactically 200 U/kg week 14 and 150 U/kg week 512
Single agent Gemcitabine (Burris schedule) And **Dalteparin (CLOT schedule)
(b) FRAGEM: Patient and Sample flow-chart

Gemcitabine 51 patients randomized Gem+Dalteparin
26 patients
*Clinical report
100%
25 patients
20 patients
*BB-TF (W 0+8)
76% (78%)
19 patients
16 patients
***BB-TF & C-INV#
59%
14 patients
Patients and methods

Patients
*Maraveyas et al., ASCO $ ISTH 2007 **All patients studied for BB-TF ***Comprehensively studied for BB-TF and C-INV #Inadequate sample amount to complete duplicate studies for 9 patients (baseline week 8 or both)
Patients in this report are all involved in a prospectively randomized controlled multicentre national (UK) trial of primary VTE prophylaxis in APC called FRAGEM (Phase II randomized study of chemo-anticoagulation (Gemcitabine_LMWH) vs chemotherapy alone (Gemcitabine) for locally advanced and metastatic pancreatic adenocarcinoma; ISRCTN 76464767; UKCRN 1290). Among other common trial selection criteria, patients with a preexisting VTE or, on active treatment for VTE or for risk of VTE, are excluded. Patients are stratied according to stage (local or metastatic) and Karnofsky performance status (90100 vs. 6080) and then are randomized to either conventional single agent gemcitabine chemotherapy or gemcitabine and therapeutic dose dalteparin (Fig. 1a) [19]. Gemcitabine in both arms is given on a weekly schedule at a dose of 1000 mg/m2 for weeks 17 and weeks 911 [20]. Patients receiving dalteparin commenced treatment 3 days before chemotherapy is initiated and received 200 U/kg of dalteparin daily as a single subcutaneous injection for 4 weeks. Then, for the remainder of the 12-week trial period, the dose was reduced to 150 U/kg [21]. The primary endpoint was to demonstrate a reduction in VTE while on dalteparin.
(a) Randomization protocol and treatment schedule. Dalteparin is scheduled for 12 weeks daily per CLOT investigators dose prophylactically 200 U/kg week 14 and 150 U/kg week 512. (b) Patient and sample flow chart. Maraveyas et al. [19]. All patients studied for BB-tissue factor (BB-TF). Comprehensively studied for BB-TF and cell invasion (C-INV). #Inadequate sample amount to complete duplicate studies for nine patients (baseline or week 8 or both).
A scientic substudy, the results of which are the subject of this report, was designed to probe the potential effects of WAD on circulating-tissue factor antigen and the potential effects on markers of tissue invasion that may become apparent in WAD-treated patients as opposed to pretreatment baseline and the control group. Patient demographics are shown in Table 1.
Table 1
Demographics of patients randomized to the trial

Arm A (n 26) 67 50 73 61 Arm B (n 25) 60 60 68 44
Characteristics Median age (years) Male sex (%) KPS 80100% (%) Stage IV disease (%)
The demographics of 51 patients who had been randomized to the trial when the analysis of the samples was undertaken. KPS, Karnofskys performance status.
Dalteparin for VTE in pancreatic cancer Maraveyas et al. 3
Sampling
Blood samples were collected according to a standard validated protocol to collect and store serum and plasma that is followed by the Hull Trials Unit and conforms to Good Clinical Laboratory Practice (GCLP) requirements for commercial national and international research studies. Blood samples were collected in a research clinic at baseline, weeks 4, 8, 12 (end of study treatment) and 17. Dalteparin had been administered between 18 and 24 h prior to attending clinic and never on the day of the sampling. Samples were coded, aliquoted and stored at 708C until analysis. The laboratory study was undertaken in a blinded fashion and staff were not aware of the treatment allocation of coded samples. From April 2003 to April 2006, 51 patients, subsequent to written informed consent for research serum and plasma samples to be drawn, were randomized into the FRAGEM trial [19]. This report presents data relating to the changes observed between baseline and week 8 in patients for whom appropriate clinical material was collected (Fig. 1b). Week 8 was chosen as the preferred comparator date after a longitudinal study on a limited number of samples showed that beyond this time point, no further increase in the observed effects in serum values was apparent [22]. Baseline samples from four patients with metastatic pancreatic cancer from patients screened for the trial were the biological samples used for the tissue factor inhibition and dalteparin-spiking experiments.
Enzyme-linked immunosorbent assay measurement of serum circulating-tissue factor antigen
substrate (3,30 ,5,5 tetramethylbenzidine; Vector Laboratories Ltd., Peterborough, UK) for 15 min at room temperature. The reaction was quenched by the addition of 2.5 mol/l H2SO4 (100 ml) to the wells and absorbance measured at 450 nm on an Anthos 2010 microplate reader (Anthos Labtec Instruments, Wals, Austria).
Prothrombin time assay
A modied one-stage prothrombin time assay, using dilute recombinant human Innovin tissue factor (Dade Behring, Milton Keynes, Buckinghamshire, UK), was undertaken. This test relies on the activity of the recombinant tissue factor to initiate the coagulation mechanism, whereas the low activity of the 1 in 500 diluted tissue factor allows the values to be signicantly altered by the presence of any endogenous tissue factor. To carry out the assays, 25 mmol/l CaCl2 (100 ml) and the patient plasma (100 ml) were incubated for 30 s before the addition of diluted recombinant human tissue factor (100 ml). The time taken for the clot formation was recorded using a Cascade-M coagulometer (Helena Laboratories, Sunderland, UK). The assay was calibrated and data compared to a NormTrol control plasma (Helena Laboratories). The concentration of supplemented tissue factor was adjusted to produce a clotting time of 60 s 10 using NormTrol control plasma and used as a standard against which, the clotting times from the patients plasma were measured.
Cell culture
The concentration of circulating-tissue factor antigen in the patients sera was measured using tissue factor-specic paired antibody ELISA method (Afnity Biologicals, Ancaster, Canada). The capture antibody was diluted 1/100 in coating buffer (15 mmol/l Na2CO3 buffer, pH 9.6), added (100 ml) to each microtitre plate well and incubated overnight at 48C. The wells were then blocked with 150 mmol/l phosphate-buffered saline (PBS), pH 7.4, containing 1% (w/v) bovine serum albumin (BSA) for 90 min followed by four washes with PBS. Patient sera (100 ml) were added in triplicate to the wells and incubated for 60 min at room temperature to allow capture and then washed carefully four times with PBS. Recombinant tissue factors of known concentrations (American Diagnostica, Stamford, Connecticut, USA) were used to construct a standard curve. The detecting antibody [antitissue factor-horse radish peroxidase (HRP)] was diluted 1/100 in conjugate buffer [100 mmol/l 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer pH 7.4, 10 mmol/l NaCl, 1% (w/v) BSA and 1% (w/v) Tween 20)] and added (100 ml) to each well. The plate was incubated for a further 60 min at room temperature, washed four times with PBS and developed by adding 100 ml of 3,30 ,5,50 tetramethyl benzidine (TMB)
MIA-Paca-2, a human-derived pancreatic cancer cell line, was obtained from the LGC Promochem (Teddington, UK) and maintained in supplemented Dulbeccos modied eagle medium [DMEM; 90% (v/v)], fetal calf serum [10% (v/v)], horse serum [1% (v/v)], containing 1% (v/v) antibiotic/antimycotic solution (Sigma Chemical Company Ltd., Poole, UK). Cells were maintained at 378C under 5% CO2. MIA-Paca-2 cells have low endogenous tissue factor (undetectable in our prothrombin assay) and a low inherent invasiveness.
Investigation of induction of cellular invasion by patient sera
MIA-PaCa-2 cells were used to measure the ability of the patient sera to induce locomotion and cellular invasiveness. Boyden chambers (8 mm pore size) were coated with collagen by adding 50 ml collagen type IV [1 mg/ml (w/v)] to each chamber. The chambers were placed in a 24-well plate and incubated at 378C for 12 h. The excess collagen was then discarded, and the cells were seeded (2 105 cells/well) into the upper compartment of each chamber, on to the collagen, in 250 ml serum-free media. Medium in the base of the well was supplemented with patients serum in duplicate (10% v/v; 250 ml total volume). The plates were incubated at 378C under 5% CO2 for 24 h. Following incubation, the medium was removed from the upper compartment of each chamber
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and the cells on the upper side of the lter chamber were scraped off using a sterile cotton swap. The number of cells that had migrated through the collagen-coated pore was quantied by adding CellTitre Aqueous One reagent (40 ml; Promega Inc., Southampton, UK) to the media, in the lower chamber and the plates, which also included a control containing media but no cells were incubated at 378C for 3 h until a colour change was clearly observed. Finally, 240 ml of each sample was diluted with 360 ml of distilled water in a plastic cuvettes and the absorption values measured against the control sample at 490 nm. The values of absorption were converted to number of cells from a previously prepared standard curve.
Dalteparin-spiking assay and circulating-tissue factor antigen inhibition assay
Results
Serum tissue factor antigen
For these experiments, the baseline serum cancer cellinvasion induction (cellular invasion) was assayed from four patients with APC entered into the trial. Patients with the highest cellular invasion were used to assess any direct inuence of dalteparin on cellular invasion. Samples of sera from patients with increased cellular invasion were placed in the bottom chamber (10% v/v) and supplemented with dalteparin (Fragmin; Pharmacia Ltd., Milton Keynes, UK) over a range of 0100 units/ml (nal concentration). Experiments were in duplicate and repeated twice. To conrm the function of tissue factor in the induction of cell migration, aliquots of patients sera (n 4) with increased cellular invasion were incubated with a range of concentrations (048 mg/ml nal concentrations) of a neutralizing polyclonal antihuman tissue factor antibody (Santa Cruz Biotechnology, Heidelberg, Germany), prior to diluting with base media. The samples were placed in the bottom chambers and assayed using the procedure described above. The rate of cell migration was determined following 24 h incubation.
Statistical analysis
Measurement of circulating-tissue factor antigen in serum obtained from the two cohorts showed comparable values at the start of the investigation with signicant increase from baseline for the control group [n 20; baseline median, 324, interquartile range (IQR) 282347 pg/ml; 8-week treatment, 356, IQR 319431 pg/ml], and a tighter distribution for the dalteparin-treated group when assayed at week 8 [n 19; baseline median, 336 (IQR 281346) pg/ml to a median of 303 (IQR 274339) pg/ml]. The difference in median percentage change from baseline to week 8 was signicant between the groups (4.0 vs. 4.7; P 0.005; Fig. 2). Thirty-ve of the APC patients had high levels of circulating-tissue factor antigen, greater than the approximate normal range for this assay [8].
Prothrombin time assay
A one-step plasma prothrombin time was also done as a measure of the integrity of the extrinsic coagulation pathway of these patients. Measurement of prothrombin time in plasma obtained from the two cohorts showed a slightly lower baseline value for the dalteparin-treated arm at the start of the investigation [median baseline clotting times of 168 (IQR 113192) s and 177 (IQR 128 255) s in the dalteparin-treated and untreated groups, respectively]. At week 8, the dalteparin-treated cohort showed a similar median, though the IQR had increased [median 165 (139222) s], whereas the control group showed no change [median 179 (IQR 127250) s]. The difference in median percentage change between groups was not statistically signicant (P 0.075).
Investigation of induction of cellular invasion by patients sera
Measurement of number of MIA-Paca-2 cells migrated at 24 h showed an increase from baseline to week 8 for the
Fig. 2
Statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, USA). Percentage changes from baseline to week 8 were calculated for circulating-tissue factor antigen levels and proportion of cells migrated. The MannWhitney tests were performed to test for differences in the median percentage change between arms for circulating-tissue factor antigen levels and proportion of cells migrated. The Spearmans rank correlation was used to correlate percentage changes in circulating-tissue factor antigen and proportion of cells migrated. Results are reported on an intention-to-treat analysis. Thus, patients in the control arm who may have been anticoagulated due to development of VTE during the rst 8 weeks of treatment or patients who may have discontinued dalteparin for clinical or personal reasons have not been excluded.
Control 250 200 150 100 50 0 50
Dalteparin
Boxplot of the percentage change of tissue factor antigen in the sera of pancreatic cancer patients in both the control and dalteparin groups.
Fig. 3
Fig. 4
Control 400 300 200 100 0 100
Dalteparin
12000
Number of invasive MIA-Paca-2 cells
10000
8000
6000
4000
2000
Cellular invasion (migration proportion percentage change) of MIAPaCa-2 pancreatic cells in response to patients sera in both the control and dalteparin groups.
0.01
0.1
10
Heparin (U/ml)
Effect of increasing doses of extraneous dalteparin on cellular invasion of MIA-Paca-2 cells in response to patients sera.
control group and a decrease for the dalteparin-treated group. The median value of the proportion of cells migrated was signicantly different (54.9 vs.21.9 P 0.025; Fig. 3) between groups. Spearmans rank correlation of the percentage change in circulating-tissue factor antigen and the proportion of cells migrated in this cohort (n 30) demonstrated a weak correlation 0.384 (P 0.037, n 30)
Dalteparin-spiking and effect on cellular invasion
antineoplastic effects. This is further complicated by the lack of surrogate markers of the antineoplastic effects of the LMWHs or other candidate anticoagulants. The work we report may provide useful methodology in these two areas. Baseline circulating-tissue factor antigen levels were raised above the normal range for this assay in 90% of the study patients. Circulating-tissue factor antigen levels in the control group (nondalteparin) of APC patients rose over the 8-week study; in contrast, the concentrations in the dalteparin-treated patients were even slightly reduced. The percentage change at week 8 compared with baseline was statistically signicant. Moreover, the
Fig. 5
Number of invasive MIA-Paca-2 cells
There was no effect of extraneous dalteparin on the cell locomotion invasion of MIA-Paca-2 cells exposed to serum (n 4) from APC patients (Fig. 4). A test for linear trend in the number of cells migrated with dalteparin level of exposure (U/ml) was made. This was not statistically signicant (P 0.194). However, the data presented in Fig. 4 suggest that there may be a trend for the range of pharmacologically relevant dalteparin concentrations studied (0.011.0 U/ml) and so it is possible that a relationship might be observed with inclusion of more data.
Circulating-tissue factor antigen inhibition and effect on cellular invasion
12000 10000 8000 6000 4000 2000 0 0 4 8 16 24 48
Furthermore, the role of tissue factor in inducing cell invasion was demonstrated by preincubation of patients sera with the antitissue factor polyclonal antibody that showed a clear reduction in MIA-Paca-2 cellular invasion, paralleling the increase in neutralizing antibody (Fig. 5).
Discussion
Among the factors that confound the interpretation of the results of clinical trials in cancer patients receiving LMWHs is the lack of dose and schedule optimization and differentiation of a LMWH-dose schedule that will achieve the maximum thromboprevention benet, compared to one that will deliver the postulated
Anti TF (g/ml)
Incubation of the patients serum with polyclonal antitissue factor antibody demonstrated a dose-dependent inhibitory effect on cell invasiveness of MIA-Paca-2. TF, tissue factor.
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distribution of the tissue factor range in the untreated patients became much wider (outliers in boxplot), whereas that of the patients receiving dalteparin remained relatively narrow (Fig. 2). The proportion of MIA-Paca 2 cells migrating in response to the dalteparin-treated patients serum was reduced compared with the untreated patients. The difference in percentage change at week 8 compared with baseline was statistically signicant. A Spearmans correlation analysis between cellular invasion and BB-tissue factor levels showed a weak but signicant correlation. A number of reasons for this are possible, for example, too small a number of patients studied, variability in in-vivo effect of WAD dosing, the underlying effect of the chemotherapy on the tumour over the 8 weeks, the intention-to-treat type of analysis or any combination of these factors. Also possible is that the net in-vivo effect is mediated by molecular pathways not affected by dalteparin or not related to tissue factor or that the dalteparin dose is not high enough. We show that the in-vitro incubation of patients sera with polyclonal antitissue factor antibody inhibits circulating-tissue factor antigen and results in reduction of cellular invasion properties of these sera. This is a reproducible, dose-dependent, in-vitro effect, which supports the hypothesis that the reduction of circulating-tissue factor antigen in the serum of these patients could be one of the mechanisms that could lead to reduction of cellular invasion. We have recently demonstrated that soluble tissue factor is capable of interacting with the cell surface [23,24] and second that this interaction and subsequent activation of different sets of associated coagulation enzymes results in a diverse set of signalling pathways, which result in proliferation, apoptosis [24] and cell migration [25]. In the present study, tissue factor antigen concentration was determined as a measure of procoagulant activity and prothrombin time was used to assess the functional activity of the extrinsic coagulation pathway. Here, we show that tissue factor, as found in patients sera, has a measurable chemotactic effect on cancer-cell invasiveness that can be modulated by the use of dalteparin. Previously, a signicant correlation (P < 0.0001) has been shown to exist in the concentration of tissue factor antigen and tissue factor activity in atherosclerotic plaques [26]. Furthermore, procoagulant activity has been linked to the amount of tissue factor antigen [27]. The fact that we have used uncharacteristically high doses of dalteparin (weight adjusted) in a primary thromboprophylaxis sense in these patients raises the concern that excess free dalteparin could be responsible for the differences shown between the groups by this assay. The dalteparin-spiking experiment showed no statistically signicant trend effect at the concentration range studied excluding a pharmacological dose-related effect on the assay. However, statistical power was limited and a decrease was observed at 0.01 U/ml, in comparison to the
control (Fig. 4). We have recently shown in cancer cell lines that there may be a direct effect of dalteparin on tissue factor expression through mechanisms as yet not clear (manuscript in preparation). We cannot exclude that the reduction of cellular invasion in vivo is the result of the effect of other molecules induced or reduced by the in-vivo effect of dalteparin such as tissue factor pathway inhibitor (TFPI), which is known to have direct inhibitory effects on cancer-promoting mechanisms [28]. Nor can we say from our work whether lower prophylactic dalteparin doses or different heparin-derived molecules would have similar effects. Collectively, our results demonstrate for the rst time that the level of circulating tissue factor antigen in pancreatic cancer patients, as compared with a contemporaneous unbiased (randomized) control group, and as compared to pretreatment baseline values, can be signicantly controlled through WAD treatment for 8 weeks. We also show that WAD is strongly associated with the reduction in the capacity of patients sera to stimulate cancer cell locomotion and invasion in vitro, a keystone phenotypic feature of cancer progression and metastasis. We suggest that circulating-tissue factor antigen and cellular-invasion-type assays may nd use as surrogate markers of the antimalignant effect of dalteparin and other LMWHs and may inform the appropriate dosing of these agents in the use of LMWH for oncological effects.
Acknowledgement
Eli Lilly provided funding for consumables but had no further role in study design, collection or interpretation of data, preparation or submission of the article.
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as opposed to immunosuppressive in its mechanism of action. To summarize, Flowers et al report the results of the largest prospective and randomized study of ECP in corticosteroid refractory or dependent chronic GVHD. While the primary end point was not demonstrated, the study had numerous strengths, as described above. It remains to be seen whether either earlier institution or longer therapy with ECP improves the outcomes of patients with chronic GVHD. Conict-of-interest disclosure: The author declares no competing nancial interests.
CLINICAL OBSERVATIONS
REFERENCES
1. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood. 2006;107: 3074-3080. 2. Greinix HT, Pohlreich D, Maalouf J, et al. A singlecenter pilot validation study of a new chronic GVHD skin scoring system. Biol Blood Marrow Transplant. 2007;13: 715-723. 3. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graftversus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12: 252-266.
Comment on Ay et al, page 2703
Cancer and thrombosis is a sticky business ---------------------------------------------------------------------------------------------------------------Frederick R. Rickles

THE GEORGE WASHINGTON UNIVERSITY
In this issue of Blood, Ay and colleagues demonstrate that elevated levels of soluble P-selectin are a risk factor for a rst episode of venous thromboembolism in patients with all types of cancer.
plication of the adhesive characteristics of the cells. Several lines of evidence have implicated these aberrant properties in the propensity of cancer cells to induce hypercoagulability and predispose patients with cancer to venous thromboembolism (VTE). Indeed, one of those hyperactive adhesive mechanisms, selectin-ligand binding, has been postulated to be responsible for the association of Trousseau syndrome (migratory thrombophlebitis) with mucin-secreting adenocarcinomas1 (see gure). P-selectin, a member of the selectin family of cell-adhesion receptors, is localized principally in the membranes of platelet -granules and endothelial-cell WeibelPalade bodies. In response to various agonists, P-selectin is translocated to the cell surProposed model for L- and P-selectinmediated, mucin-induced activation and face, where it can function as aggregation of platelets. Yellow circle labeled with L indicates L-selectin ligands on mucins. Blue boxes labeled with P indicate P-selectin ligands, including a receptor and mediate cell carcinoma mucins and PSGL-1 expressed on leukocytes. L-sel indicates adhesion via binding to sev1 with permisL-selectin; P-sel, P-selectin. Reproduced from Wahrenbrock et al eral ligands; the principal sion of the publishers.
t is a well-known fact that cancer cells of various types exhibit abnormal membrane surface properties, often an exaggeration of normal functions, such as vesiculation (or blebbing), shedding of microparticles (MPs), and excessive phospholipid turnover, resulting in further am-
ligand, or counterreceptor, is P-selectin glycoprotein ligand-1 (PSGL-1), which is a heterodimeric mucin expressed on the cell surface of the majority of leukocytes. This interaction, particularly with soluble Pselectin (sP-selectin), may play a critical role in the complex cell-cell adhesive process that results in release of procoagulant-rich (ie, tissue factor [TF] and prothrombinase) MPs from leukocytes, endothelial cells, platelets, and cancer cells.2-4 Leukocyte MPs (and presumably MPs from other sources, eg, cancer cells) can further aggravate the procoagulant state by inducing endothelialcell TF expression.5 Elevated circulating levels of sP-selectin are clearly prothrombotic in the experimental animal4,6 and have been implicated as a risk factor for thrombosis in a number of diseases, including recurrence in patients with a rst episode of unprovoked VTEin the absence of cancer or other known risk factors,7 suggesting perhaps that patients with high levels of sPselectin might benet from longer duration of anticoagulation therapy. Ay and colleagues report a similar ability to predict a rst episode of VTE among patients enrolled in a large, prospective cohort study, the Vienna Cancer and Thrombosis Study. Over a 6-month period of time after the initial diagnosis of cancer, or of progression or recurrence after partial or complete remission, the cumulative probability of symptomatic VTE (documented by objective criteria), was 11.9%, or 3-fold higher in patients with an initial level of sP-selectin greater than the 75th percentile, compared with patients whose levels were below the 75th percentile (3.7%; P .002). Ideally, the investigators would have provided the results of sequential sampling over time, in order to increase the condence in their observations and, perhaps, the relationship of sP-selectin levels to the natural history of VTE. Similarly, a more quantitative, stepwise relationship between levels of sPselectin and risk for VTE would have been reassuring, as would a higher degree of association between known high-risk tumors (eg, pancreatic or brain tumors, etc) and sP-selectin levels. Also missing from this study was the ability to determine the possible relationship of sP-selectin levels with other known markers for hypercoagulability, such as
1 OCTOBER 2008 I VOLUME 112, NUMBER 7
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brin d-dimer levels. Regardless, this study provides the impetus to test the utility of using sPselectin levels for stratication in trials of anticoagulant prophylaxis in cancer patients. Further in the future might come trials of inhibitors of sP-selectin function8 in the prevention of VTE in patients with cancer, selected by virtue of high levels of the circulating protein. Conict-of-interest disclosure: The author declares no competing nancial interests.
REFERENCES
1. Wahrenbrock M, Borsig L, Le D, Varki N, Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest. 2003;112:853862. 2. Celi A, Pellegrini G, Lorenzet R, et al. P-selectin induces the expression of tissue factor on monocytes. Proc Nat Acad Sci U S A. 1994;91:8767-8771.
3. Polgar J, Matuskova J, Wagner DD. The P-selectin, tissue factor, coagulation triad. J Thromb Haemost. 2005;3: 1590-1596. 4. Hrachovinova I, Cambien B, Hafezi-Moghadam A, et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med. 2003;9:1020-1025. 5. Mesri M, Altieri DC. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J Biol Chem. 1999;274: 23111-23118. 6. Andre P, Hartwell D, Hrachovinaova I, Saffaripour S, Wagner DD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Nat Acad Sci U S A. 2000;97:13835-13840. 7. Kyrle PA, Hron G, Eichinger S, Wagner O. Circulating P-selectin and the risk of recurrent venous thrombosis. Thromb Haemost. 2007;97:880-883. 8. Meier TR, Myers DD, Wrobleski SK, et al. Prophylactic p-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation. Thromb Haemost. 2008;99:343-351.
GENE THERAPY
Comment on Shi et al, page 2713
Killing 2 birds with 1 stone ---------------------------------------------------------------------------------------------------------------Edward G. D. Tuddenham

ROYAL FREE HOSPITAL
Bone marrow transplantation with stem cells transgenically modied to express factor VIII in platelets corrects the bleeding tendency in hemophilic mice with neutralizing antifactor VIII antibodies. Or, Why the blind mice of Milwaukee didnt bleed to death after their tails were cut off.
t has been sufciently clear for some years that only 2 problems remain in the eld of inherited bleeding disorders. These problems are easy to state but hard to solve. The rst problem is delivery of the clotting factor in the right amount at the right time; that is to say, a normal level all the time. All that is required to correct the bleeding tendency in single factor deciency is to deliver a normal level of factor, be it VIII, IX, Von Willebrand, or one of the 7 other Roman numeral designated enzymes or cofactors that take part in brin formation. This might seem like a simple proposition given that safe effective preparations of nearly all those proteins are available. Sadly, most of the worlds hemophiliacs have no access to factor replacement and solving this depends on new approaches that have a mainly political dimension. In economically advanced countries, there is now no shortage of most of the factors (factor V is the exception) but getting
patients to adhere to a challenging routine of intravenous injections poses a separate set of problems with largely psychological/social aspects. Many, myself included, consider that all these issues could be solved by gene therapy. Indeed, one of the earliest targets identied as being a sensible target for cure by DNA transfer was hemophilia. Although mice and dogs have now been cured of hemophilia by gene transfer, safe effective procedures for curing human hemophilia have yet to be demonstrated. The second outstanding problem in clinical hemophilia care is that of inhibitory antibodies arising after replacement therapy. Patients who have developed such antibodies become resistant to standard treatment. They either undergo immune tolerance induction therapy, which is extremely expensive and sometimes fails, or
are treated with bypassing agents that are also ruinously costly and not always effective. Patients with persistent inhibitors have shortened life expectancy. In this issue of Blood, Shi et al, in a paper whose title says it all, now present proof of a principle that can solve the inhibitor problem and the delivery problem in one fell swoop for the majority of problem cases, that is to say, those with hemophilia A and antibodies to factor VIII (FVIII). An ingenious transgenic mouse model is used in which a line of mice has been established where FVIII is ectopically expressed in megakaryocytes under the control of a platelet membrane receptor promoter sequence. Platelets formed by the megakaryocytes derived from hematopoietic stem cells of such mice contain FVIII stored in alpha granules along with Von Willebrand factor, the natural carrier for FVIII. This FVIII is both protected from plasma antibodies and released upon platelet activation at sites of vascular injury where haemostatic plugs are forming. With this line of mice on hand, a second line of mice that have had their factor VIII gene knocked out are stimulated to form high titer antibody to FVIII by infusing them with recombinant human B domain deleted FVIII. Subsequently, these mice that mimic human hemophilia A patients with inhibitors are rescued by transplanting them, after lethal irradiation with hematopoietic stem cells, from the mice that make platelets with releasable FVIII stored in platelet alpha granules. After successful engraftment of this modied bone marrow, the mice are no longer apt to bleed to death after minor injury. One can already see the outlines of a feasible clinical approach: Autologous hematopoietic stem cells from a patient with antibodies to FVIII are modied ex vivo with a lentivirus-based FVIII expression cassette under control of the GPIIb alpha promoter and then reinfused after irradiation to a level sufcient to produce partial engraftment. If the level of expression is high enough, it might be worth considering this as a general approach to hemophilia gene therapy. Conict-of-interest disclosure: The author declares no competing nancial interests.
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New Insights Into Cancer-Associated Thrombosis Tarek Sousou and Alok A. Khorana Arterioscler. Thromb. Vasc. Biol. 2009;29;316-320 DOI: 10.1161/ATVBAHA.108.182196
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 Copyright 2009 American Heart Association. All rights reserved. Print ISSN: 1079-5642. Online ISSN: 1524-4636
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://atvb.ahajournals.org/cgi/content/full/29/3/316
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Venous Thromboembolism: Mechanisms, Treatment, and Public Awareness

New Insights Into Cancer-Associated Thrombosis
Tarek Sousou, Alok A. Khorana
AbstractVenous thromboembolism (VTE) is an increasingly frequent complication of anticancer therapy. The underlying mechanisms are not completely understood, but are related in part to oncogene activation and tissue factor (TF) expression. Several risk factors have been identified including site and stage of cancer, patient comorbidities, and specific therapeutic agents. Candidate biomarkers such as blood counts, TF, and P-selectin have recently been identified. A risk model predictive of chemotherapy-associated VTE has been validated. Thromboprophylaxis with low molecular weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux is recommended for hospitalized medical and surgical cancer patients. Long-term anticoagulation with LMWH is safe and effective in reducing recurrent VTE in cancer. The role of thromboprophylaxis in ambulatory cancer patients receiving chemotherapy is an area of active investigation. (Arterioscler Thromb Vasc Biol. 2009;29:316-320.) Key Words: thrombosis risk factors cancer
ancer is a prothrombotic state, and cancer treatments are often complicated by thromboembolism. Venous events are the most common, presenting as either deep venous thrombosis (DVT) or pulmonary embolism (PE), together described as venous thromboembolism (VTE). Indeed, cancer patients account for as much as 20% of the total burden of VTE.1 Arterial events, including stroke and myocardial infarction, are also more prevalent in cancer patients.2 The prothrombotic state of cancer is driven by specific oncogenic events.3,4 Activation of the coagulation cascade appears integrally linked to the processes of tumor growth, metastasis, and angiogenesis. Elegant preclinical studies have shown, for instance, that defects in fibrinogen and platelet activation can decrease metastatic potential.57 This has led to a renewed interest in studying the anticancer effects of interrupting the coagulation cascade. Several other factors have contributed to an increasing awareness of the impact of VTE in cancer. The incidence of VTE in cancer is on the rise.8 Novel anticancer drugs, particularly antiangiogenic agents, may be contributing to this increase.9,10 VTE is the second leading cause of death in cancer patients11 and the most common cause of death in the postoperative period.12 VTE in cancer is associated with a 21% annual risk of recurrent VTE, a 12% annual risk of bleeding complications, requirement for long-term anticoagulation, and interruption of chemotherapy.13,14 This brief review will focus on new insights into the pathophysiology of cancer-associated thrombosis, risk factors and candidate predictive biomarkers for VTE, as well as appropriate strategies for the prevention and treatment of VTE in cancer.
Mechanisms of Thrombosis
The pathophysiology of cancer-associated thrombosis is not entirely understood. Rather than one unifying mechanism, the etiology is likely multifactorial with different factors assuming lesser or greater degrees of importance depending on the clinical setting. Much of the research in this area has focused on the intrinsic properties of tumor cells that lead to a prothrombotic state. The role of tissue factor (TF) has gathered the most attention. TF, a transmembrane glycoprotein, is the prime physiological initiator of coagulation and is expressed in a variety of human cancers, induced by activation of oncogenes or inactivation of tumor suppressor genes.4 Overexpression of TF in tumor cells or elevated TF levels in association with microparticles in the systemic circulation may contribute to systemic hypercoagulability.1519 Much of this work has focused on selected cancers, particularly pancreas, and whether TF is equally important in other cancers remains to be seen. Activation of the MET oncogene has been shown in a mouse model of hepatocarcinogenesis to result in a thrombohemorragic state mediated by upregulation of plasminogen activator inhibitor type 1 (PAI-1) and cyclooxygenase-2 gene activity.3 However, the applicability of this model to other cancers and to the clinical setting is not known. Carcinoma mucins, glycosylated molecules that act as ligands for the selectin family, may also play a role in thrombosis.20 Finally, the role of tumor hypoxia and inflammatory cytokines has also been speculated to contribute to the prothrombotic state in cancer, but firm experimental evidence is awaited.2123 Extrinsic factors are also important but, unfortunately, are not accounted for by the various experimental models dis-
Received January 7, 2009; revision accepted January 15, 2009. From the James P. Wilmot Cancer Center and the Department of Medicine (T.S., A.A.K.), University of Rochester, NY. Correspondence to Alok A. Khorana, MD, 601 Elmwood Ave, Box 704, Rochester, NY 14642. E-mail alok_khorana@URMC.rochester.edu 2009 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.108.182196
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Sousou and Khorana

Table 1.
Older age Female gender Race Higher in blacks Lower in Asians/Pacific Islanders Comorbidities Infection, renal disease, pulmonary disease, obesity Inherited prothrombotic mutations Prior history of VTE Cancer-related factors Primary site of cancer Brain, pancreas, kidney, stomach, lung, gynecologic, lymphoma, myeloma Advanced stage of cancer Initial period after diagnosis of cancer Treatment-related factors Major surgery Hospitalization Cancer therapy Chemotherapy Hormonal therapy Antiangiogenic agents Thalidomide, lenalidomide, bevacizumab Erythropoiesis-stimulating agents Transfusions Central venous catheter Candidate biomarkers Prechemotherapy platelet count Prechemotherapy leukocyte count Tissue factor (TF) High grade of TF expression by tumor cells Elevated TF plasma levels Soluble P-selectin D-dimer C-reactive protein 350 000/mm3 11 000/mm3
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Risk Factors and Candidate Biomarkers for VTE
Patient-related factors
tions for cancer (Table 1). Comorbid conditions such as infection, obesity, anemia, and pulmonary and renal disease particularly add to the risk of VTE.8 The primary site of cancer is an important risk factor, with highest rates observed in patients with brain, pancreas, gastric, kidney, ovary, and lung cancers and hematologic malignancies, particularly lymphomas.8,3234 In a population-based study, the risk of VTE was greatest in the first 3 months after the diagnosis of cancer (OR 53.5, 95% CI 8.6 to 334.3).32 Hospitalization increases the risk of VTE in cancer patients.35 Major surgery has long been known to be associated with an increased risk of VTE; more recent data indicate that this risk extends for a prolonged period after the procedure, with 40% of all VTE events in one registry occurring later than 21 days from surgery.12 Chemotherapy is associated with a 2- to 6-fold increased risk of VTE as compared to the general population.36,37 VTE is also associated with the use of central venous catheters.38 Erythropoiesis-stimulating agents (ESAs) have been found to increase the risk of VTE; unfortunately, red blood cell transfusions may have a similar association.39,40 Novel therapeutics such as the antiangiogenic class of agents are also associated with VTE. Thalidomide and lenalidomidecontaining regimens increase the risk several-fold in patients with myeloma.41 Regimens containing bevacizumab, a monoclonal antibody directed against the proangiogenic vascular endothelial growth factor, are associated with high rates of both arterial and venous events.10,42
Candidate Biomarkers
Research conducted primarily in cancer outpatients has resulted in the identification of novel candidate biomarkers that may be predictive of cancer-associated VTE. In an observational study, VTE occurred in 4% of patients with a prechemotherapy platelet count 350 000/mm3 as compared to 1.25% for those with counts 200 000/mm3 34. An elevated prechemotherapy leukocyte count (defined as 11 000/mm3) was also significantly and independently associated with an increased risk of VTE.43 High grades of TF expression in tumor cells and elevated levels of circulating TF have been associated with the risk of VTE in pancreatic and ovarian cancers.18,19 In a prospective cohort study, elevated levels of soluble P-selectin levels ( 53.1 ng/mL, representing the 75th percentile) were predictive of VTE (HR 2.6, CI 1.4 to 4.9).44 Markers of hemostatic activation, particularly D-dimer, have been observed to be elevated in cancer patients and predictive of recurrent VTE in cancer patients.45 In an observational study of 507 cancer patients, an elevated C-reactive protein ( 400 mg/dL) was associated in multivariate analysis with VTE.35
cussed above. Chemotherapy can result in activation of hemostasis within a few hours of administration.24 This occurs via a variety of mechanisms, including induction of TF in tumor cells25 and monocytes,26 downregulation of anticoagulant proteins such as protein C and S,27,28 damage to vascular endothelium,29 and platelet activation.30 Antiangiogenic agents also contribute to thrombosis, perhaps through endothelial cell and platelet activation.31
A Predictive Risk Model

VTE in cancer is a multifactorial disease that involves various risk factors, as is evident from the preceding discussion. A risk model for chemotherapy-associated VTE has recently been published and is based on scores assigned to 5 predictive variables identified in a development cohort of 2701 ambulatory cancer patients initiating chemotherapy (Table 2).43 The score was then validated in an independent cohort of 1365 patients from the same study. Rates of VTE in the
Risk Factors
Multiple recent studies have evaluated risk factors for VTE in cancer patients in the general population, in hospitalized patients, and in registries of outpatients receiving chemotherapy. Overall, these risk factors for VTE can be categorized according to patient characteristics and comorbidities, malignancy-related characteristics, and therapeutic interven-
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to evaluate the benefit of thromboprophylaxis for cancer outpatients, with varying inclusion criteria and contradictory results.54 56 Data from the most recent and largest study found fewer thromboembolic events (venous and arterial combined) occurred in the nadroparin arm than in the placebo arm (2.0% versus 3.9% P 0.033, NNT 53.8).57 Current guidelines do not recommend prophylaxis for cancer outpatients, although data from more targeted approaches such as the risk model described above are awaited. One exception to this is patients with multiple myeloma receiving thalidomide/lenalidomidebased regimens for whom prophylaxis is recommended with either LMWH or warfarin based on data from nonrandomized studies.50
Table 2. A Validated Predictive Model for Chemotherapy-Associated VTE43

Patient Characteristic Site of cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, bladder, testicular) Prechemotherapy platelet count Hemoglobin Pre-chemotherapy leukocyte count Body mass index 35 kg/m2 350 000/mm3 11 000/mm3 10g/dL or use of red cell growth factors 2 1 1 1 1 1 Risk Score
development and validation cohorts, respectively, were 0.8% and 0.3% in the low-risk category (score 0), 1.8% and 2% in the intermediate-risk category (score 1 to 2), and 7.1% and 6.7% in the high-risk category (score 3) over a median period of 2.5 months.43 Rates of VTE in this high-risk subgroup are comparable to hospitalized patients for whom prophylaxis is safe and effective. The National Heart, Lung, and Blood Institute has recently funded a study of outpatient prophylaxis in cancer patients identified as high-risk based on this model.
Treatment of VTE in Cancer Patients

Warfarin has previously been the standard for chronic anticoagulation but in the cancer population is associated with increased rates of bleeding, recurrent VTE, and dietary and drug-related interactions. In the CLOT trial, 672 cancer patients with documented VTE were randomized to receive either dalteparin or dalteparin followed by a vitamin K antagonist (control group) for a total of 6 months.58 Recurrent VTE at 6 months occurred in 9% of patients in the dalteparin group compared to 17% in the control group. These findings are consistent with data from multiple other smaller studies and a meta-analysis.59 These data have established LMWH for at least 3 to 6 months as the standard of care for treatment of VTE in cancer, as recommended by the ASCO, NCCN, and other guidelines.50,53 The optimal duration of anticoagulation in cancer patients with VTE remains unknown. Given that cancer patients remain at risk for VTE, it is recommended that patients with active cancer be considered for indefinite anticoagulation. It is important to note in this context preclinical and clinical data (albeit conflicting) suggesting that anticoagulants, particularly LMWHs, may impact cancer processes such as angiogenesis and tumor cell adhesion and, therefore, clinical outcomes.60 62
Prevention of VTE
Hospitalized Medical Cancer Patients
Three large randomized controlled trials studied either enoxaparin, dalteparin, or fondaparinux for thromboprophylaxis in acutely ill hospitalized medical patients and reported relative risk reductions in VTE ranging from 45% to 63% with anticoagulation.46 48 Unfortunately, none of these were cancer-specific study populations and cancer patients formed only a minority (ranging from 5% to 15%) of study patients. Furthermore, bleeding complications, a major concern with anticoagulation in cancer, were not separately reported for cancer patients. Unfractionated heparin (UFH) is an acceptable alternative to low-molecular-weight heparins (LMWHs) as thromboprophylaxis in this setting.49 Despite the lack of cancer-specific data, the American Society of Clinical Oncology (ASCO) guidelines recommend that hospitalized cancer patients should be considered for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation.50
Conclusions
Ongoing areas of investigation include understanding the pathophysiology of cancer-associated thrombosis in ways that can impact tumor biology, targeted prophylaxis in cancer outpatients, and studying the impact of anticoagulation on survival in cancer. Although many new beginnings have been made in the field of cancer-associated thrombosis in the past decade, much learning awaits.
Surgical Cancer Patients

Multiple clinical trials have established the safety and efficacy of thromboprophylaxis in the perioperative period for cancer patients undergoing major surgical procedures. More recently, two studies (including one cancer-specific study) have suggested that extending the duration of postoperative LMWH prophylaxis for 2 to 4 weeks after hospital discharge reduces the incidence of late venographic VTE.51,52 Both the ASCO and the National Comprehensive Cancer Network (NCCN) guidelines support either UFH, LMWH, or fondaparinux in the surgical cancer patient for VTE prophylaxis and suggest using prolonged prophylaxis in high-risk patients.50,53
Sources of Funding
Dr Khorana is supported by grants from the National Cancer Institute K23 CA120587, the National Heart, Lung, and Blood Institute 1R01HL095109-01, and the V Foundation.
Ambulatory Cancer Patients

The treatment of cancer has now primarily moved to the outpatient setting. Several clinical trials have been conducted
Disclosures
A.K. has received research funding from sanofi-aventis. Eisai, and Bristal Myers Squibb as well as speakers fees and consulting fees from sanofi-aventis and Eisai.
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21. Varki A. Trousseaus syndrome: multiple definitions and multiple mechanisms. Blood. 2007;110:1723. 22. Denko NC, Giaccia AJ. Tumor hypoxia, the physiological link between Trousseaus syndrome (carcinoma-induced coagulopathy) and metastasis. Cancer Res. 2001;61:795798. 23. Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res. 2001;102:V215V224. 24. Weitz IC, Israel VK, Waisman JR, Presant CA, Rochanda L, Liebman HA. Chemotherapy-induced activation of hemostasis: effect of a low molecular weight heparin (dalteparin sodium) on plasma markers of hemostatic activation. Thromb Haemost. 2002;88:213220. 25. Paredes N, Xu L, Berry LR, Chan AK. The effects of chemotherapeutic agents on the regulation of thrombin on cell surfaces. Br J Haematol. 2003;120:315324. 26. Walsh J, Wheeler HR, Geczy CL. Modulation of tissue factor on human monocytes by cisplatin and adriamycin. Br J Haematol. 1992;81: 480 488. 27. Rogers JS II, Murgo AJ, Fontana JA, Raich PC. Chemotherapy for breast cancer decreases plasma protein C and protein S. J Clin Oncol. 1988;6: 276 281. 28. Woodley-Cook J, Shin LY, Swystun L, Caruso S, Beaudin S, Liaw PC. Effects of the chemotherapeutic agent doxorubicin on the protein C anticoagulant pathway. Mol Cancer Ther. 2006;5:33033311. 29. Cwikiel M, Eskilsson J, Albertsson M, Stavenow L. The influence of 5-fluorouracil and methotrexate on vascular endothelium. An experimental study using endothelial cells in the culture. Ann Oncol. 1996;7: 731737. 30. Togna GI, Togna AR, Franconi M, Caprino L. Cisplatin triggers platelet activation. Thromb Res. 2000;99:503509. 31. Kuenen BC, Levi M, Meijers JC, Kakkar AK, van Hinsbergh VW, Kostense PJ, Pinedo HM, Hoekman K. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol. 2002;22:1500 1505. 32. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005; 293:715722. 33. Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thromb Haemost. 2002;87:575579. 34. Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 2005;104:28222829. 35. Kroger K, Weiland D, Ose C, Neumann N, Weiss S, Hirsch C, Urbanski K, Seeber S, Scheulen ME. Risk factors for venous thromboembolic events in cancer patients. Ann Oncol. 2006;17:297303. 36. Heit JA, Silverstein MD, Mohr DN, Petterson TM, OFallon WM, Melton LJ III. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160: 809 815. 37. Blom JW, Vanderschoot JP, Oostindier MJ, Osanto S, van der Meer FJ, Rosendaal FR. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost. 2006;4:529 535. 38. Lee AY, Levine MN, Butler G, Webb C, Costantini L, Gu C, Julian JA. Incidence, risk factors, and outcomes of catheter-related thrombosis in adult patients with cancer. J Clin Oncol. 2006;24:1404 1408. 39. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708 714. 40. Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA, Lyman GH. Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch Intern Med. 2008;168:23772381. 41. Zangari M, Anaissie E, Barlogie B, Badros A, Desikan R, Gopal AV, Morris C, Toor A, Siegel E, Fink L, Tricot G. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98:1614 1615. 42. Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, Bergsland E, Ngai J, Holmgren E, Wang J, Hurwitz H. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:12321239.
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prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4:2384 2390. Wagman LD, Baird MF, Bennett CL, Bockenstedt PL, Cataland SR, Fanikos J, Fogarty PF, Goldhaber SZ, Grover TS, Haire W, Hassoun H, Jahanzeb M, Leung LL, Linenberger ML, Millenson MM, Ortel TL, Salem R, Smith JL, Streiff MB. Venous thromboembolic disease. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2006;4: 838 869. Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Stewart D, et al. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994;343:886 889. Haas S, Kakkar AK, B K-M. Prevention of venous thromboembolism with low molecular weight heparin in patients with metastatic breast or lung cancer-results of the TOPIC studies. ISTH. 2005. Perry JR, Rogers L, J L. A phase III randomized placebo-controlled trial of thromboprophylaxis using dalteparin LMWH in patients with newly diagnosed malignant glioma. J Clin Oncol. 2007. Agnelli G, Gussoni G, Bianchini C, Verso M, Tonato M. A randomized double-blind placebo-controlled study on nadroparin for prophylaxis of thromboembolic events in cancer patients receiving chemotherapy: The PROTECHT Study. American Society of Hematology Annual Meeting. San Francisco, California: Blood. 2008. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146 153. Akl EA, Barba M, Rohilla S, Terrenato I, Sperati F, Muti P, Schunemann HJ. Low-Molecular-Weight Heparins are superior to Vitamin K Antagonists for the long term treatment of venous thromboembolism in patients with cancer: a Cochrane systematic review. J Exp Clin Cancer Res. 2008;27:21. Khorana AA, Sahni A, Altland OD, Francis CW. Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight. Arterioscler Thromb Vasc Biol. 2003;23:2110 2115. Kuderer NM, Khorana AA, Lyman GH, Francis CW. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer. 2007;110:1149 1161. Fritzsche J, Simonis D, Bendas G. Melanoma cell adhesion can be blocked by heparin in vitro: Suggestion of VLA-4 as a novel target for antimetastatic approaches. Thromb Haemost. 2008;100:1166 1175.
43. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis [see comment]. Blood. 2008;111:4902 4907. 44. Ay C, Simanek R, Vormittag R, Dunkler D, Alguel G, Koder S, Kornek G, Marosi C, Wagner O, Zielinski C, Pabinger I. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). [see comment]. Blood. 2008;112:27032708. 45. Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G. The role of D-dimer and residual venous obstruction in recurrence of venous thromboembolism after anticoagulation withdrawal in cancer patients. Haematologica. 2005;90:713715. 46. Samama MM, Cohen AT, Darmon J-Y, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie A, Graham W, Nadine. A Comparison of Enoxaparin with Placebo for the Prevention of Venous Thromboembolism in Acutely ILL Medical Patients. The N Engl J Med. 1999;341:793 800. 47. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110:874 879. 48. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AG, Egberts JF, Lensing AW. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006; 332:325329. 49. Mismetti P, Laporte-Simitsidis S, Tardy B, Cucherat M, Buchmuller A, Juillard-Delsart D, Decousus H. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost. 2000;83:14 19. 50. Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, Kakkar A, Kuderer NM, Levine MN, Liebman H, Mendelson D, Raskob G, Somerfield MR, Thodiyil P, Trent D, Francis CW. American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490 5505. 51. Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le MoigneAmrani A, Dietrich-Neto F. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975980. 52. Rasmussen MS, Jorgensen LN, Wille-Jorgensen P, Nielsen JD, Horn A, Mohn AC, Somod L, Olsen B. Prolonged prophylaxis with dalteparin to
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REVIEW ARTICLE
Thromboembolism in Gastrointestinal Cancers

Eric D. Tetzlaff, Jonathan D. Cheng, Jaffer A. Ajani
The link between thromboembolism and cancer has been recognized for over 100 years. Venous thromboembolism (VTE) is associated with considerable morbidity in patients with cancer, with emerging research also indicating a detrimental effect on survival. Investigations aimed at improving outcomes for patients with cancer have focused on the role of low molecular weight heparin in primary and secondary prevention of VTE and in improving patient survival. Important fundamental questions remain unanswered, however, and a significant line of research needs to be dedicated to investigating VTE in GI cancers. The effect of VTE on survival needs to be clarified, as does the role of anticoagulation in this patient population. Opportunities for additional research include investigating methods to identify patients at risk of developing VTE and developing new strategies and therapeutic interventions to reduce the morbidity and mortality associated with VTE. This review focuses on the current understanding of VTE related to gastrointestinal cancers and directions of interest in research specific to GI cancers and VTE.
Gastrointest Cancer Res 2:267272. 2008 by International Society of Gastrointestinal Oncology
ABSTRACT
E.D. Tetzlaff, MHS, PA-C; J.D. Cheng, MD: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania J.A. Ajani, MD: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
Submitted: September 22, 2008 Accepted: November 14, 2008
rmand Trousseau was the first to describe the association between cancer and thrombosis when he reported cases of migratory thrombophlebitis in patients with cancer in 1867.1 Over 125 years later, the association between cancer and thrombosis has been well established.24 The prothrombotic state generated by malignancy is multifactorial. Several molecular and cellular etiologies have been proposed, with some of the most intriguing hypotheses including expression of tissue factor by tumor cells, factor X-activating cysteine protease, and procoagulant microparticles derived from platelets, endothelial cells, and leukocytes.5,6 Research on thromboembolism in patients with cancer has focused on improving the primary and secondary prevention of venous thromboembolism (VTE) and assessing the detrimental effect of VTE on survival and quality of life. This review summarizes the current understanding of VTE in gastrointestinal (GI) cancers and implications for future research in this area.
INCIDENCE
Gastrointestinal (GI) cancers are associated with a high incidence of thromboembolic events. In a review of over 1 million
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Medicare patients hospitalized with a diagnosis of malignancy, GI cancers (pancreas, stomach, liver, colon, rectum) were among the top 10 cancers with the highest rate of deep vein thrombosis (DVT) or pulmonary embolism (PE) out of 18 cancers 2 reported (Table 1). In addition, the risk of cancer within 1 year after idiopathic DVT or PE is elevated for pancreatic cancer, gastric cancer, esophageal cancer, colorectal cancer, and primary liver cancer.4,7 Such retrospective data do not, however, provide sufficient information on the effects of treatment, disease stage, and use of anticoagulation for primary prophylaxis on thromboembolism risk. In a prospective series of 2,482 patients treated in clinical trials at Memorial Sloan-Kettering Cancer Center during a 2-year period, Asmis et al found a rate of VTE of 8.6% among GI cancer patients, compared with 3.3% in patients 8 with non-GI cancers (P < .0001). The reported incidence of VTE varies widely based on the location of the primary GI tumor, disease stage, and other factors. Although there appears to be increased awareness of the relationship between thrombosis and cancer, the reporting of VTE in prospective series and clinical trials remains inconsistent.
Advanced Disease Although the general perception is that VTE is common in the palliative chemotherapy setting, rates have not been well defined in prospective clinical trials. The reported overall rate of VTE has been as high as 71% in patients with advanced pancreatic cancer treated with chemotherapy,9 although rates are infrequently reported in phase III trials.1014 In gastric cancer, the reported rate of VTE ranges from 5.3% to 25.5% in phase II clinical trials, with few 1519 phase III data being available. Reported rates for VTE during palliative therapy for other GI cancers include colorectal cancer, 0.4% to 19.4%; hepatocellular carcinoma, 1.4% to 4%; and bile duct and gallbladder 20 cancer, 2% to 16.7%. 24 It is likely that the true rate of VTE is in the range of 10% to 20% for patients with GI cancers in advanced stages, with the highest rates in cancers of the pancreas, stomach, and colon. In the future, with more advanced imaging technology, it is likely that reported rates of VTE will
Address correspondence to: Eric Tetzlaff, MHS, PAC, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: (215) 214-4228; Fax: (215) 728-3639; E-mail: eric.tetzlaff@fccc.edu.
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increase albeit in the setting of increased reporting of asymptomatic VTE with unknown clinical significance. Nevertheless, it is important that diligent reporting of thromboembolic events be undertaken and maintained so that a better understanding of the natural history of this phenomenon can be gained. Localized Disease The reporting of VTE has been even less consistent in clinical trials in patients with localized GI cancers. Recent adjuvant and preoperative phase III trials for gastroesophageal cancer have not reported the rate of VTE during treatment or during the perioperative period.25,26 In a small phase II trial, a retrospective analysis, and a brief communication, reported rates of VTE for localized gastroesophageal cancer were 6.1% to 16% in patients treated with chemoradiotherapy and 30% in patients treated with preoperative biochemotherapy.18,27,28 The rates of VTE in adjuvant and preoperative therapy trials for most other GI cancers are equally under-reported, with the exception of colon cancer. In the MOSAIC trial, which investigated two different chemotherapy regimens for adjuvant therapy in stage II and III colorectal cancer, the rate of VTE among patients who received at least 29 one cycle of chemotherapy was 6.1%. The effort at reporting VTE has been duplicated in other recent phase III trials in adjuvant therapy for colorectal cancer.30,31 Thus, the risk of VTE during adjuvant therapy for GI cancers currently is not well defined. Trial investigators should be encouraged to report VTE as part of their original publication or in publications of correlative studies. It would be beneficial for younger investigators to seize an opportunity to fill the gaps in knowledge about VTE in GI cancers by adopting such reporting as a routine part of the reporting of trial results.
Table 1. Risk analysis using Medicare claims data. Rate of DVT/PE Rank out Per 10,000 of 18 patients malignancies
110 85 76 69 62 43 3 5 8 9 10 15
Cancer
Pancreas Stomach Colon Liver Rectal Esophagus
Abbreviations: DVT = deep vein thrombosis; PE = pulmonary embolism. From Levitan et al.2
Table 2. Reported risk factors for development of VTE in cancer38-45

Clinical Stage Advanced > localized Location of Primary Tumor Histology Adenocarcinoma > squamous-cell carcinoma Mucinous > nonmucinous Chemotherapy Agents Cisplatin > oxaliplatin Irinotecan Vascular Epithelial Growth Factor Inhibitors Bevacizumab (arterial thrombotic events) Erythropoiesis-Stimulating Agents Darbepoetin Erythropoetin Radiotherapy Surgery Medical Comorbidities Number of conditions Procoagulant Factors Tissue factor Plasminogen activator inhibitor-1 Cancer procoagulant Hereditary Risk Factors Factor V Leiden Prothrombin 2021A mutations
RISK FACTORS
The risk factors for the development of VTE can be divided into intrinsic and extrinsic factors. More data on risk factors are available for pancreatic cancer than for other GI cancers. In a study by Blom et al in 202 patients with pancreatic cancer, patients with tumors of the corpus and cauda of the pancreas had a 2- to 3-fold increased risk
of VTE compared with tumors located in the caput.32 In addition, presence of distant metastasis increased the risk of VTE 2-fold (hazard ratio [HR] 1.9, 95% confidence interval [CI] 0.75.1). Other intrinsic tumorrelated risk factors may include high levels of tissue factor expression, platelet aggregation induced by tumor cells, high levels of plasma plasminogen activator inhibitor-
1, and elevated levels of other proteins activated in the coagulation cascade.3235 With regard to extrinsic factors, Blom et al also determined that receiving chemotherapy (adjusted HR 4.8) and the 30-day postoperative period (adjusted HR 4.5) were associated with increased risk for VTE. Patients receiving radiotherapy and those with mucinous adenocarcinomas of the pancreas did not appear to be at greater risk for VTE. Other series have confirmed that the location of the primary pancreatic tumor affects the risk of VTE, while challenging the notion that mucinous adenocarcinomas are not associated with in36,37 creased risk. It is expected that surgery and the presence of metastatic disease would increase the risk of VTE in patients with pancreatic cancer, since both conditions contribute to Virchows classic triad of venous stasis, vessel wall damage, and an increased hypercoaguable state. Surgical trauma can lead to vessel wall damage while the presence of metastatic disease can lead to venous stasis due to vessel obstruction from tumor or adenopathy or decreased patient mobility. However, it is not clear why radiation therapy does not appear to increase the risk of VTE to the same degree as chemotherapy. One explanation could be the selection bias of patients for radiation therapy; patients with lower disease burden and better performance status are selected for aggressive local therapy, and these factors might be associated with lower overall risk for VTE. Fewer data are available on intrinsic and extrinsic risk factors for VTE in other GI cancers. However, it is likely that risk factors reported for pancreatic tumors and other solid tumors are applicable to other GI cancers, as well. These variables include treatment with cytotoxic chemotherapy, angiogenesis inhibitors, erythropoietin stimulating agents and endocrine/metabolic agents, presence of metastatic disease, number of medical comorbidities, tumor histology, presence of central venous catheters, and compression or obstruction of vessels by tumors or adenopathy (Table 2).3845
MORBIDITY AND MORTALITY

VTE is associated with considerable morbidity. Patients who develop clinically relevant DVT may suffer from many direct
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adverse effects of thromboembolism, such as peripheral edema, pain, chronic venous insufficiency, and pulmonary hypertension. In addition, anticoagulation therapy for thromboembolism can be a significant burden. The development of VTE in patients with advanced cancer complicates symptom management and the already daunting challenge of maintaining a patients quality of life. The morbidity of VTE further underscores the necessity to dedicate additional research not only toward prevention and management of VTE, but also toward maintaining or improving quality of life in patients with concurrent malignancy and thromboembolism. Recognition of the effect of VTE on mortality in patients with GI cancers is just now emerging. Tetzlaff et al reported that patients with advanced gastric cancer treated in clinical trials had a significantly shorter median survival if they developed VTE before or during protocol chemotherapy compared with patients who never developed VTE (3.9 months vs. 8.7 months, 46 P = .007). In a study in 198 patients with localized gastroesophageal cancer, these investigators also found that patients developing VTE before or during chemoradiotherapy had a significantly decreased median survival compared with patients without VTE (17.7 months vs. 32 months, P = .014). The development of VTE was an independent prognostic factor for overall survival in multivariate analysis.18 The negative effect of VTE on survival has also been demonstrated in colorectal cancer and pancreatic cancer. In a retrospective analysis of two merged databases in California including 68,142 colorectal cancer patients, it was shown that VTE was a significant predictor of death within 1 year of cancer diagnosis for patients with local and regional stage colorectal cancer 38 (HR 1.5 for both). In what appears to be the first randomized trial to report the effect of VTE on survival in colorectal cancer, Mandal et al found that the development of VTE in 203 patients with metastatic disease had a negative effect on 47 survival. This finding remained significant after adjusting for age, disease site, and treatment schedule in multivariate analysis (HR 1.6, 95% CI 1.02.5). In 227 patients with unresectable pancreatic cancer, Mandal et al found that
VTE during treatment was associated with a decrease in progression-free survival (HR 2.59, 95% CI 1.693.97) and overall survival (HR 1.64, 95% CI 1.042.58).48 VTE during chemotherapy remained a significant prognostic factor after multivariate analysis. A second series reported by Zawin et al supports the observation that VTE is a poor prognostic factor.9 In this series, a high rate of VTE (71% overall) was found among 21 chemotherapy-nave patients with advanced pancreatic cancer enrolled in a phase II trial; median survival was 8 months for patients with VTE compared with 21 months for patients without VTE. Two series in gastroesophageal cancer did not show a detrimental effect of VTE on 17,49 survival. It should be noted that one study, in which 12 (25%) of 47 patients developed VTE, was not powered to detect a difference in survival.17 The second series49 included patients with catheter-related thrombosis in the overall rate of VTE, which may have limited the ability of the investigators to detect a detrimental effect on survival. It could be the case that VTE that develops as a result of malignancy is a more accurate manifestation of aggressive tumor biology and thus associated with increased mortality, whereas VTE related to central venous catheters might be a manifestation of vascular trauma and endothelial reactivity that does not reflect tumor biology. The role that VTE plays in patient survival merits further attention. Available data suggests that VTE is generally a poor prognostic factor for patients with cancer. It is unclear, however, whether the effect of VTE on survival is a direct reflection of aggressive tumor biology or rather related to the development and complications of VTE. If the latter is true, one strategy that might improve outcomes is selective anticoagulation for patients thought to be at increased risk for the development of VTE. Alternatively, if the development of VTE represents aggressive tumor biology, it may be possible to target anticancer therapy at the up-regulated pathway that leads to hypercoagulation and thrombosis eg, with heparins. In animal models, heparins have been shown to inhibit cancer cell adhesion, proliferation, migration, and invasion, providing a rationale for further investigation of their use in preventing VTE.50
ANTICOAGULATION AND SURVIVAL

Anticoagulation is recommended for patients with cancer and thromboembolism for the secondary prevention of recurrent thrombosis. In patients with cancer, anticoagulation with low molecular weight heparin (LMWH), unfractionated heparin, or vitamin K antagonists is often prescribed. Initial studies examining anticoagulation in patients with cancer focused on recurrent thrombosis and bleeding risks as end points. However, post hoc and subgroup analyses and meta-analyses from these trials have suggested that anticoagulation may have a beneficial effect on survival in patients with cancer and a history of thrombosis.5155 These findings remain controversial, though, since the reports of benefit involve heterogeneous cohorts of patients with differing primary tumors, stage of disease, and current treatment. Several prospective trials have examined the effect of anticoagulation on survival in patients without a history of thrombosis. In a study by Klerk et al, 302 patients with advanced solid tumors were randomized to 6 weeks of treatment with 56 daily nadroparin or placebo. Patients were allowed to receive concomitant anticancer therapy at the discretion of the treating physician. The median survival was significantly longer in the nadroparin arm (8.0 months) compared with the placebo arm (6.6 months) (HR 0.75, 95% CI 0.59 0.96, P = .02). The survival difference remained significant after adjusting for performance status, histology, concomitant treatment, and life expectancy. In contrast, the Fragmin Advanced Malignancy Outcome Study (FAMOUS trial), a randomized, double-blind, multicenter trial with the primary end point of mortality at 1 year, found no survival benefit with anticoagulation treatment.57 In the FAMOUS trial, 385 patients with advanced solid tumors and no history of thrombosis received daily injections of dalteparin (5,000 IU) or placebo. There was no difference in survival at 1 year from randomization between the dalteparin group and the placebo group (10.8 months vs. 9.14 months, P = .19). In a post-hoc analysis, dalteparin improved median survival by 19.2 months in patients with a good prognosis and who had survived greater
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than 17 months from randomization compared with placebo patients in the same category. However, this analysis was not defined a priori and represented only 26% of the intention-to-treat population. In a smaller phase III trial, 141 patients with advanced cancer were randomized to standard clinical care plus LMWH or stan58 dard care alone. Median survival did not differ between the two groups in the intention-to-treat population, in the subgroup of patients with a favorable prognosis (patients that survived longer than 6 months), or in subgroups based on disease site. LMWH did not increase the rate of toxic effects for patients nor was it able to improve patients quality of life. A meta-analysis was performed to determine the potential effect of LMWH on survival in patients with advanced cancer, including the three trials discussed above plus a trial reported by Altinbas et al.59,60 The meta-analysis suggested that LMWH plus standard therapy improved survival at 1 and 2 years with odds ratios of 0.70 (95% CI 0.491.00, P = .05) and 0.57 (95% CI 0.42 0.84, P = .03), respectively.60 In addition, LMWH was not associated with an increased risk of bleeding. The effect of anticoagulation on survival has been examined according to specific disease sites, as well. In a small randomized study in small-cell lung cancer, 84 patients received chemotherapy alone (cyclophosphamide/epirubicin/vincristine) or the same chemotherapy regimen with 59 dalteparin (5,000 IU daily). The duration of anticoagulation was limited to the 18 weeks of chemotherapy. At a median follow up of 10 months, there was a significant difference in median survival in favor
of the patients treated with chemotherapy plus dalteparin vs. chemotherapy alone (10 months vs. 6 months, P = .01). Progression-free survival was also significantly longer in patients treated with dalteparin, and a nonsignificant trend in improvement in response rate was reported. The findings of this study are similar to other small studies in lung cancer, suggesting a benefit for treatment with heparin or coumarin derivatives.6163 At this time, insufficient evidence exists to support initiation of anticoagulation therapy in the absence of thromboembolism. Still, continued research is warranted in the subgroups of patients in which a suggestion of benefit has emerged. Initiating well-designed trials in locally advanced cancers of specific sites would be a rational approach to defining the potential utility of anticoagulation therapy, and such trials should be of interest to both patients and researchers. The potential benefit of anticoagulation on survival in GI cancers cannot be defined from the data discussed above, since only a minority of the patients included in those trials had GI cancers. It is thus fortunate that a number of studies are actively recruiting patients to help answer this important clinical question (Table 3). Preliminary safety results have been presented from randomized phase II and III trials examining nadroparin, enoxaparin, or dalteparin in combination with chemotherapy in GI cancers. Three trials in pancreatic cancer have reported that LMWH in combination with gemcitabine was safe, but efficacy data are not yet mature.6466 Results from these trials and others in solid tumors are pending.
CONCLUSION
A significant line of research needs to be dedicated to investigation of thromboembolic phenomena in GI cancers. The effect of VTE on survival continues to be clarified. As well, the role of anticoagulation on the survival of patients with GI cancers also remains to be defined. Opportunities for additional research include investigation of methods to identify patients at risk for the development of VTE, as well as investigation of strategies and therapeutic interventions to reduce the morbidity and mortality of VTE. In addition, more convenient anticoagulation therapy schedules (daily/ weekly) and routes (oral) are needed to improve the management of VTE while minimizing toxicity and reducing monitoring requirements.
REFERENCES
1. 2. Trousseau A, Bazire PV, Cormack JR: Lectures on Clinical Medicine. London, R. Hardwicke, 1867 Levitan N, Dowlati A, Remick SC, et al: Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore), 78: 285291, 1999 Sorensen, HT, Mellemkjaer L, Olsen JH, et al: Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343:1846 1850, 2000 Sorensen HT, Mellemkjaer L, Steffensen FH, et al: The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 338:11691173, 1998 Furie B, Furie BC: Cancer-associated thrombosis. Blood Cells Mol Dis 36:177181, 2006 Furie B, Furie BC: Mechanisms of Thrombus Formation. N Engl J Med 359:938949, 2008 Carrier M, Le Gal G, Wells PS, et al: Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 149:323333, 2008
3.
4.
5. 6. 7.
Table 3. Ongoing and completed trials of low molecular weight heparin in gastrointestinal cancers Study Identifier*
NCT00718354 NCT00312013
Patient population
Gastric cancer Pancreatic cancer Prostate cancer Lung cancer Colorectal cancer Breast cancer Lung cancer Prostate cancer
Treatment
Standard CT enoxaparin Standard CT nadroparin Standard CT dalteparin
Trial status
Recruiting Recruiting
Phase
IIIb III
Primary end point

Overall survival Death due to all causes at study end Overall survival
NCT00003674
Completed
III
Abbreviations: CT=chemotherapy. *www.clinicaltrials.gov
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8. Asmis TR, Templeton M, Trocola R, et al: Incidence and significance of thromboembolic events (TE) in patients with gastrointestinal (GI) and non-GI malignancies on systemic cytotoxic therapy. J Clin Oncol 25:18S, 2007 (abstr 9049) Zawin M, Camputaro C, Rahman Z, et al: Multirow detector CT detection of subclinical visceral and pulmonary thrombosis in advanced pancreatic cancer is an adverse prognostic indicator. Proc Am Soc Clin Oncol 22: 2003 (abstr 1419) 21. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539 1544, 2007 22. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:23352342, 2004 23. Iyer RV, Gibbs J, Kuvshinoff B, et al: A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: a single-institution prospective study. Ann Surg Oncol. 14:32023209 2007 24. Knox JJ, Hedley D, Oza A, et al: Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 23:23322338, 2005 25. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 355:1120, 2006 26. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725730, 2001 27. Shah MA, Ilson D, Kelsen DP: Thromboembolic events in gastric cancer: high incidence in patients receiving irinotecan- and bevacizumabbased therapy. J Clin Oncol 23:25742576, 2005 28. Ilson DH, Bains M, Kelsen DP, et al: Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer. J Clin Oncol 21:29262932, 2003 29. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:23432351, 2004 30. Andre T, Colin P, Louvet C, et al: Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 21:28962903, 2003 31. Saltz LB, Niedzwiecki D, Hollis D, et al: Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 25:34563461, 2007 32. Blom JW, Osanto S, Rosendaal FR: High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients. Eur J Cancer 42:410414, 2006 33. Andren-Sandberg A, Lecander I, Martinsson G, et al: Peaks in plasma plasminogen activator inhibitor-1 concentration may explain thrombotic events in cases of pancreatic carcinoma. Cancer 69:28842887, 1992 34. Khorana AA, Ahrendt SA, Ryan CK, et al: Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Re 13:28702875, 2007 35. Khorana AA, Fine RL: Pancreatic cancer and thromboembolic disease. Lancet Oncol 5:655 663, 2004 36. Mao C, Domenico DR, Kim vations on the developmental consequences of pancreatic carcinoma. Findings of 154 Surg 130:125 134, 1995 K, et al: Obserpatterns and the exocrine adenoautopsies. Arch
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37. Pinzon R, Drewinko B, Trujillo JM, et al: Pancreatic carcinoma and Trousseau's syndrome: experience at a large cancer center. J Clin Oncol 4:509514, 1986 38. Alcalay A, Wun T, Khatri V, et al: Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol 24:11121118, 2006 39. Bennett CL, Silver SM, Djulbegovic B, et al: Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914 924, 2008 40. De Cicco M: The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol 50:187196, 2004 41. Rooden CJ, Tesselaar ME, Osanto S, et al: Deep vein thrombosis associated with central venous catheters a review. J Thromb Haemost 3:24092419, 2005 42. Scappaticci FA, Skillings JR, Holden SN, et al: Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99:12321239, 2007 43. Tesselaar M, Steeghs N, Rosendaal F, et al: Incidence of thrombosis in gastro-esophageal cancer: a cohort study of 761 patients. J Clin Oncol 22:14S, 2004 (abstr 8218) 44. Hussain S, Singh M, Shi R, et al: Megestrol acetate increases the incidence of deep venous thrombosis in patients with non small cell lung cancer. J Clin Oncol. 24:18S, 2006 (abstr 18510) 45. Blom JW, Doggen CJ, Osanto S, et al: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293:715722, 2005 46. Tetzlaff ED, Correa AM, Baker J, et al: The impact on survival of thromboembolic phenomena occurring before and during protocol chemotherapy in patients with advanced gastroesophageal adenocarcinoma. Cancer 109: 1989 1995, 2007 47. Mandala M, Barni S, Isa L, et al: Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: findings from the GISCAD-Alternating schedule study. J Clin Oncol 26:15S, 2008 (abstr 20502) 48. Mandala M, Reni M, Cascinu S, et al: Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Ann Oncol 18:16601665, 2007 49. Starling N, Rao S, Norman AR, et al: Analysis of thromboembolic events (TEs) in the REAL-2 randomised controlled (RCT) study of four chemotherapy regimens for the treatment of oesophagogastric (OG) cancers. 2007 Gastrointestinal Cancers Symposium, Orlando, FL;l 2007 (abstr 74) 50. Smorenburg SM, Van Noorden CJF: The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev 53:93 106, 2001 51. Lyman GH, Khorana AA, Falanga A, et al:
10. Burris HA 3rd, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:24032413, 1997 11. Kindler HL, Niedzwiecki D, Hollis D, et al: A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB). J Clin Oncol 25:18S, 2007 (abstr 4508) 12. Louvet C, Labianca R, Hammel P, et al: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:35093516, 2005 13. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960 1966, 2007 14. Philip PA, Benedetti J, Fenoglio-Preiser C, et al: Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J Clin Oncol 25:18S, 2007 (abstr 4509) 15. Cunningham D, Starling N, Rao S, et al: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:3646, 2008 16. Dank M, Zaluski J, Barone C, et al: Randomized phase 3 trial of irinotecan (CPT-11) + 5FU/folinic acid (FA) vs CDDP + 5FU in 1st-line advanced gastric cancer patients. J Clin Oncol 23:16S, 2005 (abstr 4003) 17. Shah MA, Ramanathan RK, Ilson DH, et al: Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 24:5201 5206, 2006 18. Tetzlaff ED, Correa AM, Komaki R, et al: Significance of thromboembolic phenomena occurring before and during chemoradiotherapy for localized carcinoma of the esophagus and gastroesophageal junction. Dis Esophagus 2008 May 2 [Epub ahead of print] 19. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991 4997, 2006 20. Barbare JC, Bouche O, Bonnetain F, et al: Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol 23:43384346, 2005
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American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 25:54905505, 2007 52. von Tempelhoff GF, Harenberg J, Niemann F, et al: Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: a prospective randomized double-blind trial. Int J Oncol 16:815-824, 2000 53. Lee AYY, Rickles FR, Julian JA, et al: Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23:21232129, 2005 54. Lee AY, Levine MN, Baker RI, et al: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146153, 2003 55. Ferretti G, Bria E, Giannarelli D, et al: Lowmolecular-weight heparin versus oral anticoagulant therapy for the long-term treatment of symptomatic venous thromboembolism: is there any difference in cancer-related mortality? J Clin Oncol 23:7248 7250, 2005 56. Klerk CPW, Smorenburg SM, Otten H-M, et al:
The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23:21302135, 2005 57. Kakkar AK, Levine MN, Kadziola Z, et al: Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). J Clin Oncol 22:19441948, 2004 58. Sideras K, Schaefer PL, Okuno SH, et al: Lowmolecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clin Proc 81:758 767, 2006 59. Altinbas M, Coskun HS, Er O, et al: A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2:12661271, 2004 60. Lazo-Langner A, Goss GD, Spaans JN, et al: The effect of low-molecular-weight heparin on cancer survival. A systematic review and metaanalysis of randomized trials. J Thromb Haemost 5:729737, 2007 61. Chahinian AP, Propert KJ, Ware JH, et al: A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 7:9931002, 1989
62. Lebeau B, Chastang C, Brechot JM, et al: Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer 74:3845, 1994 63. Zacharski LR, Henderson WG, Rickles FR, et al: Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: Final Report of VA cooperative study # 75. Cancer 53:20462052, 1984 64. Voorthuizen TV, Vervenne WL, Van Daalen EH, et al: A randomized phase II study comparing gemcitabine plus nadroparine versus gemcitabine in patients with locally advanced or metastatic pancreatic carcinoma: The GEMFRAX trial. J Clin Oncol. 24:18S, 2006 (abstr 4112) 65. Pelzer U, Hilbig A, Stieler J, et al: A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy (PROSPECT CONKO 004). J Clin Oncol 24:18S, 2006 (abstr 4110) 66. Maraveyas A, Holmes M, Lofts F, et al: Chemoanticoagulation versus chemotherapy in advanced pancreatic cancer (APC): results of the interim analysis of the FRAGEM trial. J Clin Oncol. 25:18S, 2007 (abstr 4583)
Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
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American Journal of Therapeutics 15, 512515 (2008)
Cost-effectiveness of Dalteparin Versus Unfractionated Heparin as Venous Thromboembolism Prophylaxis in Malignant Gynecologic Surgery
William E. Wade, Pharm D, FASHP, FCCP* and William J. Spruill, Pharm D, FASHP, FCCP
Venous thromboembolic events (VTEs) are serious complications that may occur in the patient undergoing surgery for gynecologic malignancies. The American College of Chest Physicians recommends unfractionated heparin or lowmolecular weight heparin as prophylaxis for deep vein thrombosis and pulmonary embolism in this patient population. Cost-effectiveness analyses comparing unfractionated heparin 3 times a day versus once daily dalteparin using published efcacy and safety data demonstrate cost savings if dalteparin were routinely utilized as VTE prophylaxis. Sensitivity analyses support this nding at the upper end of the range of reported proximal DVT, nonfatal pulmonary embolism, and major bleeding incidences. These ndings should be viewed as preliminary, and institutions are encouraged to perform their own cost-effectiveness studies in this patient population. Keywords: venous thromboembolic events, dalteparin, heparin, cost-effectiveness, gynecologic malignancy
INTRODUCTION
Venous thromboembolic events (VTEs) are major causes of morbidity and mortality in patients undergoing surgery for gynecologic malignancies. Deep vein thrombosis (DVT) occurs in approximately 38% of this population, and pulmonary embolism (PE) is a leading cause of postoperative death in patients at highest risk.1 Additionally, intraoperative bleeding is a major concern in these patients. The American College of Chest Physicians recommends lowmolecular weight heparin (LMWH) .3400 units/d or unfractionated heparin (UFH) 5000 units every 8 hours as prophylaxis in these patients.2 The purpose of the current study is to perform a cost analysis on the use of the LMWH,
Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Athens, GA. *Address for correspondence: Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Athens, GA 30602. E-mail: bwade@mail.rx.uga.edu 1075-2765 2008 Lippincott Williams & Wilkins
dalteparin, versus UFH in patients undergoing surgical intervention for gynecologic malignancy using published efcacy and safety data.
MATERIALS AND METHODS

A PubMed literature search was conducted to identify all published English language studies evaluating either UFH or LMWH as DVT and/or PE prophylaxis in patients undergoing surgical intervention for gynecologic malignancies. Preferred studies included prospective, randomized trials. Studies reported as abstracts were excluded due to limited information provided, and no attempt was made to identify unpublished studies regarding this subject matter. To be included in the current study, efcacy trials had to report the following data: types and numbers of patients evaluated; prophylaxis regimen used; duration of prophylaxis; and incidences of total DVT, proximal DVT, and nonfatal PE and major bleeding (MB) episodes observed. Data were pooled and averaged when
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more than 1 study was identied evaluating a specic prophylactic regimen. Cost-effectiveness3,4 analyses were performed to compare the relevant costs and consequences of the identied prophylaxis regimens from an institutional perspective in 1000 patients over a 5-day period. A societal perspective was utilized for costs. A therapy is considered more cost effective if it has a favorable corresponding cost relative to competing alternatives. To make this determination, incremental cost-effectiveness ratios (ICERs) were calculated.4 Incremental costs are the additional costs one program or treatment option imposes over another and compares them with any additional effect, benet, or outcome produced by a selected treatment. These calculations were made by dividing the difference in all costs associated with the identied prophylactic regimens by the difference in thromboembolic events avoided with each regimen. The outcome of this computation represents the number of dollars saved per thromboembolic event avoided if 1 regimen were routinely used as DVT prophylaxis over the other in this patient population. Literaturereported values of costs discounted at 3% per year to reect 2007 US dollars utilized in these calculations are found in Table 1.5 The cost for heparin 5000 units subcutaneously every 8 hours for 5 days plus an appropriate dispensing fee is US $135 per patient.6 The cost of dalteparin 5000 units subcutaneously daily for 5 days plus an appropriate dispensing fee is US $195 per patient.6 Simple sensitivity analyses combined with analysis of extremes were performed to determine the robustness of the ICER calculations.7 Sensitivity analyses are commonly performed on economic evaluations for the purpose of determining the soundness of study conclusions. These analyses consist of mathematical manipulations of variables used in performing the cost-effectiveness calculations over a plausible range. If study results do not vary signicantly over the range of values of the study variables, condence in the study results can be expressed. Simple sensitivity analyses are extremely effective in determining the generalizability of study results. Analysis of extremes considers upper
and lower cost estimates and the upper and lower effectiveness of treatment options being compared to determine the best case and worst case therapeutic modalities. Variables evaluated in these analyses in the current study include drug costs and the range of literature-reported incidences of proximal DVT, nonfatal PE, and MB. A nal cost calculation performed in this study was cost per death averted with UFH or dalteparin prophylaxis versus no prophylaxis. The literature reports a fatal PE rate of 1% to 5% in the absence of prophylaxis in patients at very high risk for this complication.8 We assumed an average rate of 2.5% for study purposes. The cost per death averted was calculated by dividing the cost of providing prophylaxis to 1000 patients by the number of patients expected to die if they did not receive prophylaxis.
RESULTS
A total of 11 studies evaluating either UFH or LMWH as DVT prophylaxis following surgery for gynecologic malignancies were identied. Eight of these studies did not report results in a format that could be used in our analysis. Fricker et al9 compared calcium heparin 5000 units 2 hours before surgery followed by 5000 units every 8 hours with Fragmin (dalteparin) 2500 anti-Xa units 2 hours before surgery followed by an additional dose 12 hours later and then 5000 anti-Xa units daily. Both regimens were continued for 10 days. Suspected DVT was conrmed by venography, whereas clinically suspected PE was conrmed by lung scintigraphy and arterial gazometry. Thirty-two patients received heparin, and 28 patients received Fragmin. No patients in either group developed a DVT, whereas no patients in the Fragmin group and 2 patients in the calcium heparin group developed nonfatal PE (without evidence of DVT). Two patients in the Fragmin group and 1 in the UFH group experienced MB. Clarke-Pearson et al10 compared low-dose heparin with intermittent pneumatic calf compression (IPC) as DVT prophylaxis. Patients were randomly assigned to
Table 1. Literature-reported costs averaged and discounted to 2007 US dollars. Maxwell et al5 (2000), in $ Dx and Tx PDVT Dx and Tx PE Tx MB 3869 5278 1500 Etchells et al12 (1999), in $ 1990 3600 2000 Gould et al13 (1999), in $ NR 6187 1245 Discounted value used in current study (2007), in $ 3640 6296 1985
NR = not reported; Dx and Tx = diagnosis and treatment; PDVT = proximal DVT.
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receive heparin (n = 107) 5000 units subcutaneously every 8 hours 1 day before surgery followed by 5000 units every 8 hours for 7 postoperative days or until ambulating or discharged, or IPC (n = 101) initiated at induction of anesthesia and continued for 5 days or until ambulating or discharged. Suspected DVT was conrmed by ascending venography while signs and symptoms of PE were further evaluated by ventilation perfusion lung scanning and pulmonary arteriography. Three patients in the UFH group and 1 in the IPC group developed a proximal DVT, whereas no patients in either group developed a nonfatal PE. MB was experienced by 3 patients in the UFH group with no patients receiving IPC developing this complication. Maxwell et al11 studied IPC versus dalteparin 2500 units subcutaneously beginning 12 hours before surgery, 2500 units 12 hours later, followed by 5000 units daily for 5 days or until discharged. Real-time duplex and color Doppler ultrasound imaging were used for DVT assessment. Of the 211 study subjects, 2 experienced proximal DVT in the dalteparin group and 1 in the IPC group. No patients developed nonfatal PE. Four dalteparin subjects experienced MB in the postoperative period. In the current study, we performed a cost analysis based on the efcacy and safety data obtained from the 3 above-mentioned trials. Percentage occurrence values for complications used for calculations in this study from the dalteparin trials included proximal DVT 1.9%, nonfatal PE 0%, and MB 5.6%. Values used for the UFH arm included proximal DVT 2.7%, nonfatal PE 1.8%, and MB 3.5%. Total costs in the analyses included cost of the drugs; cost of diagnosing and managing proximal DVT and nonfatal PE; and costs of treating MB events for the 2 groups. Cost calculations were based on a cohort of 1000 patients. Table 2 lists total costs for each regimen evaluated.
Incremental cost-effectiveness calculations demonstrate that if dalteparin 5000 units daily were routinely used as prophylaxis in this patient population, $6961.60 would be saved for each thromboembolic event averted over UFH 5000 units every 8 hours. Sensitivity analyses demonstrate that UFH would produce a cost savings of $5142.89 over dalteparin at the lower range of VTEs and MB events, whereas dalteparin would produce a $7630.20 per patient savings over UFH at the upper range of reported VTE and MB events, supporting the ndings of the original ICER calculation. At the lower range of reported incidences of complications, sensitivity analysis demonstrates that if the cost of dalteparin was reduced to $97 per day, dalteparin would produce cost savings over UFH. Cost per death avoided was $5400 for UFH and $7800 for dalteparin.
DISCUSSION
By applying the rates of VTEs and complications noted in the Fricker et al, Clarke-Pearson et al, and Maxwell et al studies to our population of 1000 patients, we have examined the nancial impact of UFH versus dalteparin as VTE prophylaxis in patients undergoing surgery for gynecologic malignancy. In our costing analysis, we elected to include only VTEs that would be routinely detected and treated in a clinical setting. Subsequently, only costs associated with proximal DVT and nonfatal PE were evaluated. Distal vein thrombosis was excluded, as these tend to be asymptomatic and in clinical practice would not commonly be treated. This resulted in cost savings when daily dalteparin is compared with 3-times a day UFH. It is of interest to note that the dalteparin patients in these studies had a slightly higher incidence of bleeding complications than those receiving UFH. Considerable extra costs may incur because of this complication. The results of the sensitivity analysis show the robustness of our incremental cost ratio as dalteparin produces cost savings at the upper ends of the extremes tested when compared with UFH. However, this was not the case at the lower end of VTE and MB episodes evaluated. Limitations to the current study are recognized. Few studies have been published in which VTE prophylaxis in this patient population has been reported in the format allowing for economic assessment of therapy. Additionally, the sample sizes in these publications were small. Although the preferred study type for evaluating efcacy and safety of a product is a randomized trial, not all studies t this model. Clearly, the results of our study must be viewed as preliminary, and large-scale randomized trials are needed to evaluate
Table 2. Costs utilized in the ICER calculations (1000 patients). Dalteparin 5000 units daily $195,000 69,160 0 111,160 $375,320 $375.32
UFH 5000 units every 8 hours Drug costs (includes dispensing fee) Dx and Tx DVT Dx and Tx PE Treatment MB Total costs Cost per patient $135,000 98,280 113,328 63,520 $410,128 $410.13
Dx and Tx = diagnosis and treatment.
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515 7. Armstrong E. Sensitivity analysis. In: Grauer D, Odom T, Osterhaus J, et al, eds. Pharmacoeconomics and Outcomes: Applications for Patient Care. Kansas City, MO: American College of Clinical Pharmacy; 2003:231242. 8. Clagett GP, Anderson FA Jr, Heit J, et al. Prevention of venous thromboembolism. Chest. 1995;108(Suppl 4): 312S334S. 9. Fricker JP, Vergnes Y, Schach R, et al. Low-dose heparin versus low-molecular weight heparin (Kabi 2165, Fragmin) in the prophylaxis of thromboembolic complications of abdominal oncological surgery. Eur J Clin Investig. 1988; 18:561567. 10. Clarke-Pearson DL, Synan IS, Dodge R, et al. A randomized trial of low-dose heparin and intermittent pneumatic calf compression for the prevention of deep venous thrombosis after gynecologic oncology surgery. Am J Obstet Gynecol. 1993;168:11461154. 11. Maxwell GL, Synan I, Dodge R, et al. Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial. Obstet Gynecol. 2001;98:989995. 12. Etchells E, McLeod RS, Geerts W, et al. Economic analysis of low-dose heparin vs the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism after colorectal surgery. Arch Intern Med. 1999;159:1221 1228. 13. Gould MK, Dembitzer AD, Doyle RL, et al. Lowmolecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med. 1999;130:789799.
efcacy, safety, and costs of various LMWH formulations as DVT and PE prophylaxis in this population. Individual institutions may wish to conduct their own studies using institution-specic costs of drug therapy and treatment of complications to determine the most cost-effective agent for DVT prophylaxis in patients experiencing gynecologic malignancies.
REFERENCES
1. Crandon AJ, Koutts J. Incidence of post-operative deep vein thrombosis in gynaecological oncology. Aust N Z J Obstet Gynaecol. 1983;23:216219. 2. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004; 126(Suppl 3):338S400S. 3. Eisenberg JM. Clinical economics. A guide to the economic analysis of clinical practices. JAMA. 1989;262:28792886. 4. Lee J, McLaughlin-Miley C, Chatteron ML. Cost-effectiveness analysis. In: Grauer D, Odom T, Osterhaus J, et al, eds. Pharmacoeconomics and Outcomes: Applications for Patient Care. Kansas City, MO: American College of Clinical Pharmacy; 2003:133145. 5. Maxwell GL, Myers ER, Clarke-Pearson DL. Costeffectiveness of deep venous thrombosis prophylaxis in gynecologic oncology surgery. Obstet Gynecol. 2000;95: 206214. 6. Anonymous. Red Book. Montvale, NJ: NJ Thomson Healthcare; 2007:434, 461.

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Dear Healthcare Colleague: Welcome and thank you for participating in the New Frontiers and Evolving Paradigms

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Supported by an independent educational grant from Eisai, Inc.

CMEducation Resources, LLC

New Frontiers and Evolving Paradigms

in Cancer and Thrombosis

A Year 2010 Milestone Summit

New Frontiers and Evolving Paradigms in Cancer and Thrombosis

Welcome and Program Overview

We Request That You PLEASE FILL OUT

COURSE SURVEY AND EVALUATION

Alok A. Khorana, MD, FACP

The Complex Interface of Malignancy, Thrombosis, and Clinical End Points

Alok A. Khorana, MD, FACP

Interactive Q&A and Discussion Session

More than 100 questions answered by experts and investigators

A Year 2010 Milestone Summit

New Frontiers and Evolving Paradigms in C i Cancer And Thrombosis A d Th b i

Program Chairman Samuel Z. Goldhaber, MD

New Frontiers and Evolving Paradigms in Cancer and Thrombosis

As Number of Cancer Survivors Increase, VTE Rates Increase

Stein PD, et al. Am J Med 2006; 119: 60-68

VTE Risk and Cancer Type: Solid and Liquid

Stein PD, et al. Am J Med 2006; 119: 60-68

Rate of PE Diagnosis is Increasing in the USA

200,000 200 000

1999 2000 2001 2002 2003 2004 2005

Hospital Costs are Skyrocketing

CHEST 2009; 136: 983-990 983-

DVT: Ominous Sequellae

Prandoni et al, Ann Intern Med 1996;125:1-7 1996;125:1-

Progression of Chronic Venous Insufficiency

From UpToDate 2006

U.S.A. SURGEON GENERAL: CALL TO ACTION TO PREVENT DVT AND PE

September 15, 2008

100,000-180,000 Deaths/year in USA

Lang, I. M. NEJM 2004;350:2236-2238 2004;350:2236-

DVT FREE Registry 5,451 patients enrolled prospectively

Goldhaber SZ, Tapson VF. Am J Cardiol 2004;93:259-262. 2004;93:259-

Am J Cardiol 2004; 93: 259-262 259-

New Frontiers and Evolving Paradigms in Cancer and Thrombosis

Pivotal VTE Primary Prevention Trials

Trials of VTE Prophylaxis in Hospitalized Medical Patients

BMJ 2006; 332: 325.

PREVENTPREVENT- Dalteparin Trial (N= 3,681)

Any symptomatic VTE y y p Asymptomatic proximal DVT Sudden death

Circulation 2004; 110: 874-879 874-

PREVENT Study Design (N= 3,681)

Follow-up period No N study d d drug

No study drug Day 90

Day 21 Primary endpoint/ Bilateral leg U/S

Primary Efficacy Endpoint: VTE (Day 21)