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

An Oncologists Perspective on Cancer and Thrombosis

Gary H. Lyman, MD, MPH, FRCP(Edin)Professor of Medicine and Director

Health Services, Effectiveness and Outcomes ResearchDuke University School of Medicine and the

Duke Comprehensive Cancer Center

Oncology Grand Rounds University of North Carolina

Lineberger Comprehensive Cancer CenterApril 21, 2009

Cancer and Venous Thromboembolism (VTE)

• Association recognized since Trousseau’s observation more than 130 years ago1

• Of all cases of VTE, approximately 20% occur in cancer patients.2

• VTE affects 4-20% of cancer patients antemortem but has been reported in up to 50% on postmortem examination.3-4

• Cancer-associated VTE has important clinical and economic consequences5-7

Armand Trousseau

1. Trousseau, Armand. In Clinique Medicale de l'Hôtel-Dieu de Paris, 2nd ed. Paris: J.B. Bailliere et Fils; 1865 2. Lee AY. Br J. Haematol. 2005;128:291-302. 3. Gao S et al: Expert Rev Anticncer Ther 2004; 4: 303-320.

4. Lyman GH et al: J Clin Oncol 2007; 25: 5490-5505. 5. Sorensen HT, et al. N Engl J Med. 2000;343:1846-1850. 6. Prandoni P, et al. Blood. 2002;100:3484-3488. 7. Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

Patients with

cancer: 20%

All deep venous thrombosis and

pulmonary embolism

Pathogenesis: Virchow’s Triad

StasisBed rest and immobility, extrinsic compression of vessel by mass

Blood Components[Hypercoagulability]

Tumors and macrophages produce procoagulants, inflammatory cytokines

Vessel Damage

Direct tumor invasion, indwelling catheters, chemotherapy, erythropoietin, antiangiogenic agents

TumorCells

HemostaticSystem

Procoagulant Activity

CytokinesGrowth Factors

Fibrinolytic Activity

GrowthInvasion

MetastasesAngiogenesis

Kuderer NM et al J Clin Oncol 2009 (in press)

8

7

6

5

4

3

2

1

0

Chemotherapy

Risk of VTE in the cancer population

Remission

Risk of VTE in the general population

Time

Diagnosis

Metastasis

End of lifeHospitalization

Ris

k (

Od

ds R

ati

o)

Risk of VTE Varies Over Natural History of Cancer

Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

Chew, H. K. et al. Arch Intern Med 2006;166:458-464.

• The California Cancer Registry linked to the California Discharge Data, 1993 - 1995.• Among 235,149 cancer cases, 3775 (1.6%) were diagnosed with VTE within 2 years including 463 (12%) at the time cancer and 3312 (88%) subsequently.

Metastatic Disease Local-Regional Disease

VTE within Two years of Cancer Diagnosis

Incidence of VTE in US Patients With and Without Cancer, 1979-1999

1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999

1

0

2

3

4

National Hospital Discharge SurveyNational Hospital Discharge Survey

VTE Inci

dence

(%

)

Cancer

No cancer

Years

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

Risk Factors for VTE in Patients with Cancer

Patient-related factorsPatient-related factors• Older age Older age • GenderGender• Race (higher in African Race (higher in African

Americans, lower in Asians)Americans, lower in Asians)• Patient comorbiditiesPatient comorbidities• History of VTEHistory of VTE

Treatment-related factorsTreatment-related factors• Major surgery Major surgery • Hospitalization Hospitalization • Chemotherapy Chemotherapy • Hormonal therapy Hormonal therapy • Antiangiogenic agentsAntiangiogenic agents• ESAs, ?TransfusionsESAs, ?Transfusions

BiomarkersBiomarkers• Platelet and leukocyte Platelet and leukocyte

countscounts• Tissue factorTissue factor• P-selectinP-selectin• D-dimerD-dimer

Cancer-related factorsCancer-related factors• Site of cancer Site of cancer • Advanced stageAdvanced stage• Initial period after diagnosisInitial period after diagnosis

Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

Risk Factors for VTE in Patients with Cancer

Patient-related factors• Older age • Gender• Race (higher in African

Americans, lower in Asians)• Patient comorbidities• History of VTE

Treatment-related factors• Major surgery • Hospitalization • Chemotherapy • Hormonal therapy • Antiangiogenic agents• ESAs, ?Transfusions

Biomarkers• Platelet and leukocyte

counts• Tissue factor• P-selectin• D-dimer

Cancer-related factors• Site of cancer • Advanced stage• Initial period after diagnosis

• Increased morbidity– Hospitalization– Anticoagulation– Postphlebitic syndrome

• Increased mortality• Increased risk of recurrent VTE• Bleeding complications• Cancer treatment delays• Increased healthcare costs

Important Consequences of VTE in Cancer Patients

• Increased morbidity– Hospitalization– Anticoagulation– Postphlebitic syndrome

• Increased mortality• Increased risk of recurrent VTE• Bleeding complications• Cancer treatment delays• Increased healthcare costs

Important Consequences of VTE in Cancer Patients

• CA Cancer Registry linked to Discharge Data

• Overall Mortality– HR=3.7 [1.3-14.4]

• Multivariate analysis – Stratified by stage– Adjusted for age, race– VTE is a significant

predictor for 1 year mortality for each cancer type

Effect of VTE on Risk of Death Stratified by Stage, Adjusted for Age and Race

Chew, H. K. et al. Arch Intern Med 2006;166:458-464.

VTE in Diffuse Large B-cell Lymphoma

Retrospective review of patients with DLBCL treated 1990-2001

Symptomatic VTE at diagnosis or during initial treatment.

– 27/211 patients (12.8%).

Median survival (years)– Controls: 5.20 [1.80 – 8.60]– VTE: 1.04 [0.75 – 1.33] – P = 0.038

Multivariate Analysis for Mortality*

Komorokji RS et al. Leuk Lymph 2006; 47: 1029-1033

Variable HR P-value

Age 1.02 .014

IPI 1.45 .015

VTE 1.92 .025

* Adjusted for sex, race, and stage

Retrospective review of 70 patients with unsuspected PE found on staging CT

– 2003–2006– VTE, anticoagulation or

multiple cancers excluded

2:1 matching based on– Cancer type– Age– Stage

Unsuspected PE:– Subsegmental: 24.3%– Proximal: 75.7%

Unsuspected PE On Routine Cancer StagingImpact on Survival

HR=1.79 [95% CI: 1.10-2.90; P=0.018]

O’Connell CL et al: ASH 2008

Unsuspected VTE in Cancer Patients Results from Autopsy Series

Consecutive autopsies in 506 cancer patients

Causes of Death, n (%)– Major

– Infection 184 (36%)– Hemorrhage 55 (11%)– VTE 35 (7%)– MI 35 (7%)

– Contributing – Infection 68 (13%)– Hemorrhage (25%)– VTE 91 (18%)– MI 13 (3%)

578 consecutive autopsies

145 cancer patients, n (%)– PE 24 (17%)– Fatal PE 20 (14%)

433 noncancer patients– PE 55 (13%)– Fatal PE 343 (8%)

Author’s conclusions:– 1 in 7 hospitalized cancer

pts died of PE– 60% of fatal PEs occur in

early or limited metastatic disease

Ambrus J et al J Med 1975; 6: 61-64

P<.05

Shen VS et al. South Med J 1980; 73: 841-843

Roswell Park Cancer Institute University of Missouri

Causes of Early Death in Ambulatory Cancer Patients Results from Prospective Study of Series

Patient Population– Prospective study of 4466 patients starting new

chemotherapy– Consecutive patients accrued at 117 US practices – Median followup of 75 days, 141 (3.2%) died.

Causes of Death, n (%)– All 141 (100)– Progression of cancer 100 (70.9)– Thromboembolism 13 (9.2)

– Arterial 8 (5.6)– Venous 5 (3.5)

– Infection 15 (10.6)– Respiratory failure 5 (3.5)– Bleeding 2 (1.4)– Other 9 (6.4)– Unknown 5 (3.5)

Khorana AA et al. J Thromb Haemost 2007; 5: 632-634

Breast Cancer40%

Small Cell Lung5%

Colon Cancer14%

Non-small Cell Lung18%

Ovarian8%

Hodgkin's Lymphoma

2%

Non-Hodgkin's Lymphoma

13%

Distribution of Cancer Type

Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer

ASCO Clinical Practice Guideline

Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

Clinical Questions

1. Should patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized? √

2. Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? √

3. Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis?

4. What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? √

5. Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? √


• Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation.

ASCO Recommendations for VTE Prophylaxis in Patients with CancerHospitalized Cancer Patients


Risk of Inpatient VTE By Site of Cancer – Solid Tumor

0

2

4

6

8

10

12

All

Brain

Lung

Stom

ach

Colon

Panc

reas

Other

GI

Ovary

Uterin

e

Rate

(%

)

Khorana et al, J Clin Oncol 2006; 24: 484-490

Discharge database of the University HealthSystem Consortium • 115 U.S. academic medical centers• 66,106 adult neutropenic cancer patients hospitalized 1995 - 2002

Risk of Inpatient VTE by Type of Cancer – Hematologic Malignancies

Perc

en

t (%

)

Account for one-third of all VTE

0

1

2

3

4

5

6

7

All Leukemia NHL Hodgkin Myeloma

NHL=Non-Hodgkin’s lymphoma

Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

VTE Inpatient Risk and Mortality

0

2

4

6

8

10

12

14

1618

20

199519961997199819992000200120022003

Inp

ati

ent

Mort

alit

y (

%)

VTE No VTE

P<0.0001P<0.0001

Khorana AA et al. Cancer 2007; 110: 2339-2346

VTE- patients on chemo VTE-all patients DVT-all patients

PE-all patients

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0

199519961997199819992000200120022003

Rate

of

VTE (

%)

P<0.0001

Discharge database of the University HealthSystem Consortium • 133 U.S. academic medical centers• 1,015,598 adult cancer patients hospitalized 1995 - 2003

VTE: 34,357 (3.4%)PE: 11,515 (1.1%)

Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients

• 3 large, randomized, placebo-controlled, double-blind trials in medical patients at high risk including cancer– MEDENOX (enoxaparin)1 ~ 15%– PREVENT (dalteparin)2 ~5%– ARTEMIS (fondaparinux)3 ~15%

• Screening for asymptomatic DVT with venography or ultrasound

1. Samama MM, et al. N Engl J Med. 1999;341:793-800.

2. Leizorovicz A, et al. Circulation. 2004;110:874-879.

3. Cohen AT, et al. BMJ. 2006;332:325-329.

MEDENOX1

Study RRR Thromboprophylaxis Patients with VTE (%)

14.9

5.5

5.0

2.8

10.5

5.6

1Samama MM, et al. N Engl J Med. 1999;341:793-800.2 Leizorovicz A, et al. Circulation. 2004;110:874-9.3Cohen AT, et al. BMJ 2006; 332: 325-329.

P < 0.001

P = 0.0015

RRR

63%

45%

47%

Placebo

Placebo

Placebo

Enoxaparin 40 mg

Dalteparin 5,000 units

Fondaparinux 2.5 mg

ARTEMIS3

PREVENT2

Anticoagulant Prophylaxis to Prevent Screen-Detected VTEHigh Risk Hospitalized Medical Patients: VTE

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Medenox Prevent Artemis

LMWH

Placebo0.49%

0.16% 0.2%

1.7%

1.1%

Samama MM, et al. N Engl J Med. 1999;341:793-800.Leizorovicz A, et al. Circulation. 2004;110:874-9.Cohen AT, et al. BMJ 2006; 332: 325-329..

Inci

dence

of

Majo

r B

leedin

g (

%)

Study

Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding

1. Routine prophylaxis with an antithrombotic agent is not recommended.

2. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. LMWH or adjusted dose warfarin (INR~1.5) is recommended. • This recommendation is based on extrapolation from

studies of post-operative prophylaxis in orthopedic surgery and a trial of adjusted dose warfarin in patients with breast cancer.

3. Randomized clinical trials evaluating antithrombotic agents in pts with myeloma on thalidomide or lenalidomide are needed.

4. Research is also urgently needed to identify better markers in ambulatory patients with cancer likely to develop VTE.

ASCO Recommendations for VTE Prophylaxis in Patients with CancerAmbulatory Cancer Patients


Prospective Study of Adult Cancer Patients Receiving Systemic Chemotherapy

Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008).

• Prospective observational study conducted at 117 randomly selected US practice sites.

• Data obtained on 4,458 consecutive adult patients initiating a new chemotherapy regimen between March 2003 and February 2006.

• There were no exclusions for age, prior history or comorbidities with nearly 40% of patients age 65 and older.

Time (Days)

1501401301201101009080706050403020100

Pro

po

rtio

n w

ith

VT

E

.04

.03

.02

.01

0.00

Reported Cause of Early Mortality Cancer Patients Starting New Chemotherapy

Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008)

Cause of Death

No VTE

N=4,365

VTE N=9

3

All N=4,4

58

PD 2.1 2.2 2.1

Infection 0.3 0 0.3

PE 0 5.4 0.1

Pulmonary

0.2 0 0.2

Bleeding 0.1 0 0.1

Other vascular

0.2 0 0.2

Unknown 0.3 0 0.3

All 3.2 7.6 3.3

Time (Days)

1501401301201101009080706050403020100

Cu

mla

tive

Su

rviv

al

1.00

.99

.98

.97

.96

.95

.94

.93

.92

.91

.90

[HR=5.48, 95%CI: 2.21-13.61; P<.0001]

VTE

No VTE

RCTs of Thromboprophylaxis in Ambulatory Cancer PatientsWarfarin

• Double-blind, placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancer

• 311 women with metastatic breast cancer on 1st- or 2nd-line chemotherapy

• Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebo

• 1 VTE in warfarin group vs 7 in placebo arm

– 85% risk reduction, P = .03, with no increased bleeding

Levine M, et al. Lancet. 1994;343:886-889.

INR=international normalized ratio

Trial N Treatment Chemo

Duration VTE MajorBleedin

g

FAMOUSSolid tumors(Stage III/IV)

385 DalteparinPlacebo

64% 12 months 2.4%3.3%

0.5%0

TOPIC-IBreast(Stage IV)

353 CertoparinPlacebo

100% 6 months 4%4%

1.7%0

TOPIC-2NSCLC(Stage IV)

547 CertoparinPlacebo

100% 6 months 4.5%†

8.3%3.7%2.2%

PRODIGEGlioma

186 DalteparinPlacebo

- 6-12 months

11%17%

5.1%1.2%

SIDERASSolid Tumors(Stage IV)

141 DalteparinPlacebo/Control

54% Indefinitely 5.9%7.1%

2.9%7.1%

PROTECHTSolid Tumors(Stage III/IV)

1166

Nadroparin 2:1 Placebo

100% < 4 monthswith chemo

1.4%2.9%

0.7%0

1. Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948. 2. Haas SK, et al. J Thromb Haemost. 2005(suppl 1):abstract OR059. 3. Perry JR et al. Proc ASCO 2007. 2011 4. Sideras K et al. Mayo Clin Proc 2006; 81:758-767. 5. Agnelli G et al. Am Soc Hemat Sunday December 7, 2008

RCTs of Thromboprophylaxis in Ambulatory Cancer PatientsLow Molecular Weight Heparin

The PROTECHT StudyRCT of Thromboprophylaxis in Cancer Patients Receiving ChemotherapyDESIGN

Placebo-controlled, double blind, multicenter RCT Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1 1150 patients receiving chemotherapy for locally

advanced or metastatic cancer. Start with new CTX; continue for maximum of 4 m Mean treatment duration: 90 days Primary outcome: clinically detected thrombotic events,

i.e., composite of venous and arterial TE* Main safety outcome: Major bleeding

* deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin

Agnelli G et al: ASH 2009

The PROTECHT StudyRCT of Thromboprophylaxis in Cancer Patients Receiving ChemotherapyRESULTS

• Primary Efficacy Outcome: Any TE Event*– Nadroparin: 16 of 769 (2.1%) – Placebo: 15 of 381 (3.9%) – Relative risk reduction: 47.2%, (interim-adjusted p=0.033)– Absolute risk decrease: 1.8%; NNT = 53.8

• Venous thromboembolism (VTE): – Nadroparin: 11 of 769 (1.4%)– Placebo: 11 of 381 (2.9%) NS

• Major Bleeding: – Nadroparin: 5 (0.7%)– Placebo: 0 (p= 0.177)– Absolute risk increase: 0.7%; NNH = 153.8

Agnelli G et al: ASH 2009

• Active, uncontrollable bleeding• Active cerebrovascular hemorrhage• Dissecting or cerebral aneurysm• Bacterial endocarditis• Pericarditis, active peptic or other GI ulceration• Severe, uncontrolled or malignant hypertension• Severe head trauma• Pregnancy (warfarin)• Heparin-induced thrombocytopenia (heparin,

LMWH) • Epidural catheter placement

ASCO Recommendations for VTE Prophylaxis in Patients with CancerRelative contraindications for anticoagulation


Risk of VTE in Cancer Patients Receiving ThalidomideMeta-analysis of RCTs [Estimates ± 95% CI]

• Search identified 17 RCTs including 3,977 patients• Incidence of VTE

– All Studies: 11.7% [8.1% - 16.5%]• Multiple Myeloma: 17.7% [10.9% - 22.1%]• Solid Tumors: 5.3% [2.1% - 12.8%]

• Relative Risk for VTE– All Studies: 2.4 [1.9 – 3.0], P<.001

• Multiple Myeloma: 3.1 [2.1 – 4.4], P<.001• Solid Tumors: 3.5 [1.1 – 10.6], P=.028

– Prophylaxis (all studies)• No prophylaxis: 3.5 [2.5 – 4.9], P<.001• Prophylaxis: 1.9 [1.4 – 2.5], P<.001

Gray KN et al: ASH 2008

Thromboembolism With BevacizumabArterial Thromboembolism

0

2

4

6

8

10

12

Arterial thromboembolism(ATE)

VTE

Chemotherapy* plus bevacizumab (n=963) Chemotherapy* alone (n=782)

Pooled analysis of 5 clinical trials of bevacizumab in metastatic colorectal, breast, or non-small cell lung cancer (N=1,745)

*Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel

Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:1232-1239.

HR=2.0 (95% CI, 1.05-3.75)P=.031

ATE/V

TE R

ate

(%

)

Nalluri, S. R. et al. JAMA 2008;300:2277-2285.

Relative Risk = 1.33 [95% CI: 1.13 – 1.56]Absolute Risk Increase: 2.2% [95% CI: 1.1% -

3.3%]

Thromboembolism With BevacizumabVenous Thromboembolism: Meta-Analysis of RCTs

Bohlius, J. et al. JNCI 2006 98:708-714

Thromboembolic Complications in Cancer Patients Receiving ESAs

RR TE = 1.67 [1.35 – 2.06]

Hb Stopping Value

ESA Cont RR 95% CI

< 12 g/dL 50 50 (0)

>12 - <13 g/dL 148 141 0.70 0.29, 1.67

>13 - <14 g/dL 1,596 1,290 1.71 1.23, 2.40

>14 - <15 g/dL 1,151 914 1.92 1.22, 3.02

>15 - <16 g/dL 368 303 1.66 1.08, 2.54

(Unclear) 42 39 5.590.71, 43.94

Comparative Effectiveness Review # 3Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment

Khorana, A. A. et al. Arch Intern Med 2008;168:2377-2381.

Retrospective cohort study of cancer pts at 60 US hospitals: 1995 – 2003.

Patients: N = 504,208

RBC trans: 70,542 (14%)

Platelet trans: 15,237 (3%)

RBC transfusions

VTE: 7.2%

ATE: 5.2%

Mortality

1.34 [95% CI:1.29-1.38]

Predictors of Venous ThromboembolismMultivariate Logistic Regression Analysis

1. LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE.

2. LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable for long-term therapy when LMWH is not available.

3. After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer.

4. The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long-term therapy with LMWH.

ASCO Recommendations for VTE Prophylaxis in Patients with CancerPreventing Recurrence in Cancer Patients with Established VTE


0 1 2 3 4 5 6 7 8 9101112Time (months)

0

10

20

30

Recu

rren

t V

TE,

%

Hazard ratio 3.2 [1.9-5.4]Cancer 21%

No Cancer 7%

Prandoni P et al. Blood 2002; 100: 3484-3488.

0 1 2 3 4 5 6 7 8 9 101112

Time (months)

0

10

20

30

Majo

r B

leed

ing

, %

Cancer 12%

No Cancer 5%

Hazard ratio 2.2 [1.2-4.1]

Recurrent VTE and bleeding during anticoagulant treatmentPatients with cancer and venous thrombosis

RCTs of Long-term Treatment in Cancer Patients with VTE: RCTs of LMWH vs. Vitamin K Antagonists in Cancer

1. Meyer G, et al. Arch Intern Med. 2002;162:1729-1735. 2. Lee AY, et al. N Engl J Med. 2003;349:146-153.3. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12:389-396. 4. Hull RD, et al. Am J Med. 2006;119:1062-1072.

Study No.Long-Term Treatment

Recurrent VTE,

%

Major Bleed,

%

Death, %

Meyer1

200271 Warfarin 21.1* 22.7

67 Enoxaparin 1.5 mg/kg 10.5* 11.3

Lee2

2003336 Warfarin 17* 4 41

336 Dalteparin 200/150 IU/kg 9* 6 39

Deitcher3

2006

30 Warfarin 10 2.9 8.8

29 Enoxaparin 1.0 mg/kg 6.9 6.5 6.5

32 Enoxaparin 1.5 mg/kg 6.3 11.1 19.4

Hull4

2006100 Warfarin 10* 7 19

100 Tinzaparin 175 IU/kg 6* 7 20* P < .05

5 to 7 days

Dalteparin 200 IU/kg OD

Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo

Control Group

Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo

Experimental Group

Ran

dom

izati

on

1 month 6 months

The CLOT TrialStudy Schema

Lee AY, et al. N Engl J Med. 2003;349:146-153.

0

5

10

15

20

25

Days Post Randomization

0 30 60 90 120 150 180 210

Pro

babili

ty o

f R

ecu

rren

t V

TE,

%

dalteparin, 9%

VKA, 17%

risk reduction = 52%HR 0.48 (95% CI 0.30, 0.77)log-rank p = 0.002

CLOT Trial:Results: Symptomatic Recurrent VTE


Dalteparin

N=338

VKA

N=335

p-value

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

associated with death 1 0

critical site* 4 3

transfusion of > 2 units of RBC

or drop in Hb > 20 g/L

14 9

Any bleed 46 (13.6%) 62 (18.5%) 0.09

*intracranial, intraspinal, pericardial, retroperitoneal, intra-ocular, intra-articular

CLOT Trial:Results: Bleeding


1. Anticoagulants are not recommended to improve survival in patients with cancer without VTE.

2. People with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies.

ASCO Recommendations for VTE Prophylaxis in Patients with CancerImproving survival in absence of established VTE


Treatment Cancer Citation Rate 1 Rate 2 RR P ValueSCLC Altinbas .487 .700 .696 .476 1.018 .054

Mixed Kakkar .542 .592 .915 .766 1.093 .327

Mixed Klerk .608 .727 .836 .711 .983 .028

Mixed Sideras .603 .600 1.005 .766 1.319 .972

LMWH .88 .79 .98 .015

SCLC Lebeau .601 .698 .862 .724 1.026 .093

UFH .86 .72 1.03 .095

SCLC Chahinian .728 .802 .908 .775 1.063 .233

Breast Levine .382 .403 .948 .719 1.251 .705

SCLC Maurer .242 .278 .869 .608 1.240 .438

NSCLC Zacharski (1) .802 .796 1.008 .875 1.161 .915

SCLC Zacharski (2) .600 .840 .714 .497 1.027 .059

CRC Zacharski (3) .588 .529 1.111 .727 1.697 .625

Prostate Zacharski (4) .357 .300 1.190 .366 3.871 .770

HN Zacharski (5) .850 .667 1.275 .895 1.817 .172

NSCLC (early) Zacharski (6) .143 .300 .476 .137 1.651 .224

Warfarin .94 .85 1.04 .239

Combined .91 .85 .97 .003

0.5 1 2

Anticoagulation

Control

1-Year Overall Mortality by Type of Anticoagulation

Kuderer NM, et al. Cancer. 2007;110:1149-1161

[95% CI]

Systematic Review of Anticoagulants as Cancer Treatment:Impact on Survival

SCLC=small cell lung cancer; NSCLC=non-small cell lung cancer; HN=head and neck; CRC=colorectal cancer

Major Bleeding Complications by Type of Anticoagulation

Treatment Cancer Study Rate 1 Rate 2 RR [95% CI] P Value

SCLC Altinbas .000 .000 1.025 .021 50.418 .990

NSCLC Haas (2) .037 .023 1.642 .605 4.453 .325

Mixed Sideras .029 .071 .412 .083 2.051 .261

Mixed Klerk .034 .006 5.203 .615 44.006 .089

Mixed Kakkar .005 .000 2.906 .119 70.874 .492

Breast Haas (1) .017 .000 7.120 .370 136.830 .127

LMWH 1.68 .86 3.27 .128

SCLC Lebeau .007 .007 1.007 .064 15.943 .996

UFH 1.01 .06 15.94 .996

SCLC Zacharski (2) .400 .080 5.000 1.217 20.549 .008

SCLC Maurer .067 .018 3.798 1.091 13.223 .023

SCLC Chahinian .068 .000 12.548 .727 216.606 .023

Prostate Zacharski (4) .571 .200 2.857 .763 10.695 .069

NSCLC (early) Zacharski (6) .524 .250 2.095 .885 4.960 .072

NSCLC Zacharski (1) .323 .071 4.521 2.092 9.768 .000

HN Zacharski (5) .500 .381 1.312 .652 2.642 .443

CRC Zacharski (3) .618 .206 3.000 1.473 6.109 .001

Breast Levine .007 .013 .523 .048 5.709 .588

Warfarin 2.98 2.13 4.16 <.001

Combined 2.59 1.94 3.49 <.001

0.1 0.2 0.5 1 2 5 10

Control Anticoagulation


Kuderer NM, et al. Cancer. 2007;110:1149-1161

Findings• Anticoagulation significantly decreased 1-year overall mortality

with a relative risk of 0.905 [95% CI, 0.847-0.967]; P=.003

Conclusions• Anticoagulants, particularly LMWH, significantly improved

overall survival in cancer patients without VTE while increasing the risk for bleeding complications

• Improved survival with anticoagulation may be dependent on tumor type

• However: given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results

Kuderer NM, et al. Cancer. 2007;110:1149-1161.


Ongoing Randomized Clinical Trials Testing the Effect of LMWH on Survival in Cancer Patients

Study LMWH Tumor Type(s)Principal Investigator

INPACT NadroparinAdvanced prostate,non-small cell lung, pancreatic

H. Buller

FOCUS Dalteparin Ovarian A. Lee

FRAGMATIC Dalteparin Lung S. Noble

ABEL Bemiparin Small cell lung R. Lecumberri

TILT Tinzaparin Non-small cell lung (I, II, III-A) G. Meyer & P. Girard

GASTRANOX Enoxaparin Gastric (III/IV) A. K. Kakkar

INPACT=Improving with Nadroparin the Prognosis in Advanced Cancer Treatment; FOCUS=Fragmin® in Ovarian Cancer: Utility on Survival; FRAGMATIC=Fragmin® Added to Standard Therapy in Patients with Lung Cancer; ABEL=Adjuvant Bemiparin in Small Cell Lung Carcinoma; TILT=Tinzaparin in Lung Tumors.

Courtesy Dr Anna Falanga

Characteristic Development CohortN (%)

Validation CohortN (%)

P value

All 2,701 (100) 1,365 (100) ─

All VTE 60 (2.2) 28 (2.1) .72

Age >65 yr

PS 0-1

BMI >35

1,083 (40.1)

2,473 (91.6)

332 (12.3)

515 (37.7)

1,242 (91)

166 (12.2)

.14

.54

.9

Stage IV

Platelet count≥350,000/mm3

997 (36.9)

604 (22.4)

477 (34.9)

295 (21.6)

.06

.59

ESA

Recent surgery

764 (28.3)

829 (30.7)

358 (26.2)

473 (34.7)

.17

.01

PS=performance status; BMI=body mass index; ESA=erythropoiesis-stimulating agents.

Khorana AA et al. Blood. 2008; 111:4902-4907

Clinical Risk Model for Chemotherapy-associated VTEPatient Characteristics

Characteristic β OR* P-value

Site of cancer Very high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, genitourinary excluding prostate)

1.46

.43

4.3

1.5

Platelet count >350,000/mm3 .6 1.8 .03

Hemoglobin <10 g/dL or use of ESA .89 2.4 .001

Leukocyte count >11,000/mm3 .77 2.1 .008

BMI >35 .9 2.5 .01

*Odds ratio adjusted for stage

.05


Clinical Risk Model for Chemotherapy-associated VTEPredictors of VTE: Multivariate Analysis

Clinical Risk Model for Chemotherapy-associated VTERisk Score Based on Pretreatment Risk Factors

Risk Factors Risk score

1. Site of cancer

a) Very high risk cancer (stomach, pancreas) 2

b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 1

2. Platelet count >350,000/mm3 1

3. Hemoglobin level < 10 g/dL or use of Red cell growth factors

1

4. Leukocyte count >11,000 /mm3 1

5. BMI > 35 kg/m2 1




1. Site of cancer





1


5. BMI > 35 kg/m2 1




1. Site of cancer





1


5. BMI > 35 kg/m2 1


RISK SCORE: Low (0) Intermediate (1-2) High (>3)

n=374 n=842 n=149

Rat

e o

f VT

E (

%)

0%

1%

2%

3%

4%

5%

6%

7%

8%

n=734 n=1,627 n=340

Development cohort

0.3%

2.0%

6.7%

Validation cohort

0%

1%

2%

3%

4%

5%

6%

7%

8%

n=734 n=1,627 n=340

0.8%

1.8%

7.1%Development cohort

0.3%

2.0%

6.7%

Validation cohort

n=374 n=842 n=149

VTE Prediction Risk ScoreChemotherapy – Associated Thrombosis


Venous Thromboembolism

Time (Days)

1201101009080706050403020100

Ven

ous

Thr

ombo

embo

lism

.10

.08

.06

.04

.02

0.00

Low

Intermediate

High

P < 0.001*

P<.001P<.001

P<.001P<.001

*Overall test of significance

Overall Survival

Time (Days)

1201101009080706050403020100

Ove

rall

Sur

viva

l

1.00

.95

.90

.85

.80

.75

Low

Intermediate

High

P < 0.001*

P<.001P<.001

P<.001P<.001


Venous Thromboembolism and Overall Survival by VTE Risk Score Categories

Kuderer NM et al; Blood 2008 (ASH 2008)

Grp

Low IntermedIntermed HighHigh

% 1.2 5.95.9 12.712.7

HR 1.0 3.56[1.91-6.66]

6.89 [3.50-13.57]

Mortality

Trial Design

Phase III, multicenter, randomized controlled trial of primary LMWH thromboprophylaxis in ambulatory cancer chemotherapy patients

Patient Population 400 consenting adult solid tumor

or lymphoma patients starting a new chemotherapy regimen

Considered high risk based on the VTE model, ie, risk score for VTE ≥3

Study Outcomes Primary Outcomes: Symptomatic

and asymptomatic VTE Secondary Outcomes: Overall

mortality, bleeding complications

Correlative Studies Blood for biomarkers and

microarray studies

LMWH prophylaxis NIH trial in cancer outpatientsPhase III Multicenter Trial of Thromboprophylaxis in High Risk Ambulatory Cancer Patients Receiving Chemotherapy

Fig. 1. Study Schema. (R=randomization, H&P=history and physical examination, US=ultrasound, CT=computed tomography scan of the chest). All time points are ± 1 week. Baseline CT up to 4 weeks prior to enrollment will be accepted.

Cancer and Venous ThromboembolismConclusionsConclusions

VTE is a common complication of cancer and cancer treatment and is associated with considerable morbidity, mortality and costs.

The US Surgeon General has recently issued a Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism including new research initiatives to lower the burden of this serious illness.

Hospitalized medical and surgical cancer patients are at increased risk for VTE and should be considered for pharmacologic prophylaxis if no contraindication to anticoagulation is present.

Cancer patients treated for documented VTE should be considered for continued anticoagulation, preferably with LMWH, for up to six months or longer in patients with active malignancy.

Routine thromboprophylaxis of ambulatory cancer patients is not currently recommended.

While results from prospective controlled trials are needed, thromboprophylaxis may be considered in selective high risk settings such as multiple myeloma patients receiving thalidomide or lenalidomide along with chemotherapy and/or dexamethasone.

Consideration of prophylactic anticoagulation in cancer patients must always balance the risk of VTE with the increased risk of bleeding.

Improved methods for the identification of ambulatory cancer patients at increased risk for VTE and targeted thromboprophylaxis are needed and under active investigation.

Cancer and Venous ThromboembolismConclusionsConclusions

http://www1.istockphoto.com/file_thumbview_approve/2663047/2/istockphoto_2663047_scales_of_justice.jpg

Acknowledgments

Duke University– Nicole Kuderer MD– Thomas Ortel MD– Jeffrey Crawford MD– Eva Culakova PhD– Marek Poniewierski

MD– Debra Wolff, MS PCNP

University of Rochester– Alok Khorana MD

– Charles Francis MD

– Mark Taubman MD

– Rami Komrokji, MD

ASCO VTE Guideline Panel Members– Anna Falanga, Co-

Chair

Just Wait Until Next Year………..

Official Duke University Slide for Presentations at the University of North Carolina

Cancer and ThrombosisWhat to Look For……..

• Cancer Investigation, 2009– Special Issue on Cancer and Thrombosis

• Journal of Clinical Oncology, 2009– Special Issue on Cancer and Thrombosis

• ASCO 2009– Education Session on Cancer and Thrombosis– 3 Chapters in the Education Book

• NHLBI Trials on going at Duke/Rochester and UNC

• ISTH 2009: Boston July 11-16

• 5th International Conference on Thrombosis and Hemostasis: Issues in Cancer, Stresa, Italy, April 23-25, 2010

• Any much more………….

ASCO VTE Guideline Panel Members

Gary H. Lyman, MD, MPH, FRCP (Edin), Co-Chair

Duke University

Anna Falanga, MD, Co-Chair Ospedali Riuiniti, Bergamo, Italy

Daniel Clarke-Pearson, MD University of North Carolina

Christopher Flowers, MD, MS Emory University

Charles W. Francis, MD University of Rochester

Leigh Gates, Patient Representative

University of Colorado

Mohammad Jahanzeb, MD University of Tennessee

Ajay Kakkar, MD, PhD Barts and The London School of Medicine

Alok A. Khorana, MD University of Rochester

Nicole M. Kuderer, MD Duke University

Mark Levine, MD, PhD McMaster University

Howard A. Liebman, MD University of Southern California

David S. Mendelson, M.D. Premiere Oncology

Gary Edward Raskob, PhD University of Oklahoma

Paul A. Thodiyil, MD New York Methodist Hospital

David Trent, MD, PhD Virginia Cancer Center

ASCO VTE Guideline Panel Members

Patient Group Recommended Not Recommended

Hospitalized patients with cancer

VTE prophylaxis with anticoagulants If bleeding or contraindication to anticoagulation

Ambulatory patients with cancer receiving chemotherapy

Myeloma patients receiving thalidomide or lenalidomide + chemotherapy/ dexamethasone. LMWH or adjusted dose warfarin.

Otherwise, no routine prophylaxis

Patients with cancer undergoing surgery

Prophylaxis with low-dose UFH or LMWH

Prophylaxis with mechanical methods for patients with contraindications to pharmacologic methods

Consider mechanical methods when contraindications to anticoagulation.

Patients with cancer with established VTE

Pharmacologic treatment for at least 6 months. Consider continued anticoagulation beyond 6 months in those with active cancer.

-

To improve survival - Not recommended

ASCO Recommendations for VTE Prophylaxis in Patients with CancerSummary


● Retrospective review of 1514 HSCT patients

● Median F/U: 642 days

● Symptomatic VTE: 75 (4.6%)

– Catheter-related: 55 (73%)

● Clinical bleeding: 230 (15.2%)

– Fatal bleeding: 55 (3.6%)

– OR with anticoagulation: 3.1

– OR with VOD: 2.2

Gerber, D. E. et al. Blood 2008;112:504-510

Symptomatic VTE in Hematopoietic Stem Cell Transplantation (HSCT)Implications for VTE Prevention

Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic VTE Hospitalized Medical Patients

• 9 studies with 19,958 patients• Anticoagulant prophylaxis:

– Pulmonary embolism (PE): • RR = 0.43; CI 0.26-0.71• ARD = 0.29%; NNT = 345

– Fatal PE: • RR = 0.38; CI 0.21-0.69• ARD = 0.25%; NNT = 400

– Symptomatic DVT: • RR = 0.47; CI 0.22-1.00• ARD = 0.43%; NNT = 233

– Major bleeding • RR = 1.32; CI 0.73-2.37• ARD = 0.14%; NNH = 714

Dentali F, et al. Ann Intern Med. 2007;146:278-288.

Pulmonary Embolism n=8)

Major Bleeding (n=7)

Risk Factors for Early Mortality in Patients Receiving Cancer Chemotherapy

Kuderer NM, et al. ASCO 2008

Variables Hazard Ratio 95% CI P value

VTE* 3.059 1.309 7.153 .010Patient Demographics Age 1.021 1.004 1.038 .017 ECOG >1 1.287 .830 1.996 .260 Charlson comorbidity index >1 1.338 .911 1.966 .137 Body mass index [kg/m2] .959 .927 .992 .016 Stage IV 2.304 1.509 3.516 <.0001Cancer Type .009 Colorectal 1.666 .765 3.626 .199 Small cell lung cancer 1.530 .609 3.842 .365 Non-small cell lung cancer 3.072 1.590 5.937 .001 Ovary 1.543 .565 4.211 .397 Breast 1.059 .442 2.536 .898 Lymphoma 1.580 .756 3.304 .224Relative Dose Intensity .026 <85% .992 .617 1.595 .973 Unknown 2.071 1.132 3.789 .018Year .039 2003 1.166 .685 1.983 .571 2004 .821 .461 1.464 .505 2005 .300 .100 .898 .031Baseline Laboratory Values WBC >11,000/mm3 1.976 1.331 2.932 .001 Creatinine >1.5 mg/dL 2.214 1.223 4.008 .009 Alkaline phosphatase >120 U/L 1.678 1.146 2.455 .008 Protein <5.5 g/dL 3.194 1.698 6.009 <.0001 Albumin <3.5 g/dL 2.373 1.594 3.532 <.0001

*Time-dependent covariate

Coagulation Proteases in Tumor Biology

Tissue Factor/FVIIa

Factor Xa

Thrombin

Tissue Factor/FVIIa

Factor Xa

Thrombin

Fibrin generation plays additional roles in these processes

Growth

Invasion

Metastasis

Angiogenesis

Growth

Invasion

Metastasis

Angiogenesis

Fibrinogen Kinetics in Cancer Patients

Patients: 25 patients with known advanced or active cancer

Methods: Plasma and urine fractional fibrinogen catabolic rates were estimated

Findings: Significantly shortened fibrinogen survival found in patients with active cancer

Categories N T½ TO* P

Controls 6 3.89

.828<.05All

Cancers25

3.01

1.433

Leukemia 6 3.19

.671 NS

Lymphoma 4 2.88

1.881

<.05

Solid Tumor

15

2.98

1.617

<.05

GI 3 2.52

2.234

<.05

No Chemo 15

3.28 NS

Chemo 10

2.61

*TO= mean turnover in mg/ml/day

Lyman GH et al. Cancer 1978; 41: 1113-1122

• 6 clinics in Holland• 3220 consecutive

patients, 18 to 70 years, with a first DVT or PE

• 2131 control participants (partners of the patients)

Risk of VTE in Cancer Patients by Type of MalignancyPopulation-based, case-control study [MEGA] of risk factors for VTE

Type of Cancer

Adjusted Odds Ratio

(95% CI)

Hematologic 28 (4-199.7)

Lung 22.2 (3.6-

136.1)

Gastrointestinal

20.3 (4.9-83)

Breast 4.9 (2.3-10.5)

Prostate 2.2 (0.9-5.4)

Blom JW, et al. JAMA. 2005;293:715-722.

Risk was greatest in first few months following diagnosis of cancer

Patients with distant metastases and carriers of factor V Leiden mutation were are further increased risk.

The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism

September 15, 2008

Risk Factors for Inpatient VTE: Multivariate Analysis*

Characteristic OR P valueSite of Cancer

Lung

Stomach

Pancreas

Uterine

Brain

1.3

1.6

2.8

2

2.2

<0.001

0.0035

<0.001

<0.001

<0.001

Age > 65 1.1 0.005

Arterial Thromboembolism 1.4 0.008

Major Comorbidities** 1.3-1.6 <0.001

Khorana et al, J Clin Oncol 2006; 24: 484-490

* Adjusted for sex, race, HBP, DM, CHF, hepatic disease (NS)

** lung/renal disease, infection, obesity

VTE Risk and Prevention in Multiple MyelomaChemotherapy ± Thalidomide

Zangari et al: Brit J Haematol 2004; 126: 715-721

Ambulatory Cancer Patients: Prophylaxis in Multiple Myeloma Patients

• Prophylaxis with low-molecular-weight heparin (LMWH) or adjusted dose warfarin (INR~1.5) is recommended in multiple myeloma patients receiving thalidomide or lenalidomide plus chemotherapy or dexamethasone (high VTE risk)

• However:– No RCTs available – Recommendation is based on extrapolation from

nonrandomized trials or randomized studies in other similar high-risk categories

– Well-designed RCTs are urgently needed


VTE Risk and Prevention in Multiple MyelomaMelphalan + Prednisone ± Thalidomide

VTE

• No anticoagulation (first two years):

11/65 (17%)• Enoxaparin 40 mg

QD for four months: 2/65 (3%)(P=.005)

Palumbo A et al: The Lancet 2006; 367: 825-831

Older Age and History of Arterial Thromboembolism

0

4

8

12

16

20

Chemotherapy* plus bevacizumab Chemotherapy* alone (control group)

ATE R

ate

(%

)

Total cohort n=963 bevn=872 ctrl

ATE history + age ≥65 yrn=67 bevn=46 ctrl

ATE history n=89 bevn=59 ctrl

Age ≥65 yr n=339 bevn=279 ctrl

No risk factors

n=602 bevn=490 ctrl

Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:1232-1239.

*Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel

Reduction in thrombosis

Increase in bleeding

http://www1.istockphoto.com/file_thumbview_approve/2663047/2/istockphoto_2663047_scales_of_justice.jpg

5. In patients with central nervous system malignancies and in the elderly, anticoagulation is recommended for established VTE as described for other patients with cancer .

6. Careful monitoring of anticoagulation is necessary to limit the risk of hemorrhagic complications.

7. Anticoagulation should be avoided in the presence of active intracranial bleeding or preexisting bleeding diathesis such as thrombocytopenia (platelet count <50,000/mm3) or coagulopathy.

ASCO Recommendations for VTE Prophylaxis in Patients with CancerPreventing Recurrence in Cancer Patients with Established VTE


• multinational, open-label, randomized study

• treatment period 6 months (or until death)• primary endpoint: symptomatic VTE recurrence• follow-up for survival up to 12 months

The CLOT Trial

RCancer patients with proximal DVT, PE or both

Control Group:dalteparin + VKA

Experimental Group:dalteparin alone


Lee, A. Y.Y. et al. J Clin Oncol; 23:2123-2129 2005

CLOT Trial Results:Survival in Solid Tumor Patients ± metastatic disease

For patients without metastatic disease, the hazard ratio was 0.50 (95% CI, 0.27 to 0.95; P = .03) for the overall comparison between the treatment groups. For patients with metastatic disease, the hazard ratio was 1.1 (95% CI, 0.87 to 1.4; P = .46) for the overall comparison between the treatment groups.

P = 0.62

HR=1.1[.87 to 1.4]; P=.46

HR=0.50[.27 to .95]; P=.03

Mortality and PFS in Univariate Analysis by VTE Risk Score Categories

Outcomes

(at 4 months)

Risk Group

Low N=1,206

Intermed. N=2,709

High N=543

All N=4,458

Overall MortalityRisk (%) 1.2% 5.9% 12.7% 5.6%

HR [+/- CI] 1.0 3.56 [1.91-6.66]

6.89 [3.50-13.57]

-

PFSRisk (%) 93% 82% 72% 84%

HR [+/- CI] 1.0 2.77 [1.97-3.87]

4.27 [2.90-6.27]

-


VTE Risk Score Independent Predictor for: PFSMultivariate Analysis*

VariablesP-

valueHR

95% CI for HR

Lower Upper

VTE Risk Score(1) 0.001

Intermed. Risk Group (II)

<0.001 2.077 1.397 3.086

High Risk Group (III) <0.001 2.344 1.465 3.751

VTE(2) 0.028 2.043 1.079 3.870

Patient Characteristics

Age 0.107 1.008 0.998 1.017

ECOG >1 0.001 1.498 1.175 1.909

Charlson >1 0.047 1.256 1.003 1.574

BMI [kg/m2] <0.001 0.962 0.944 0.981

Stage IV(3) <0.001 1.982 1.567 2.506

Year <0.001 0.792 0.700 0.896

*Adjusted for: Cancer Type, and Relative Dose Intensity

(1) Comparison to low risk group (I) (2) Time-dependent covariate (3) Comparison to stages I-III


Progression-Free Survival

Time (Days)

1201101009080706050403020100

Prog

ress

ion-

Free

Sur

viva

l

1.00

.90

.80

.70

Low

Intermediate

High

P < 0.001* P<.001P<.001

P<.001P<.001

*Overall test of significance*Overall test of significance

Inclusion Criteria: Age 18 years or older

A histologic diagnosis of malignancy (not basal cell or squamous cell);

At planned initiation of a new systemic chemotherapy regimen (including patients starting on first chemotherapy or patients previously treated but starting on a new regimen);

A risk score for VTE ≥3. Any counts meeting criteria drawn within 2 weeks prior to enrollment are considered acceptable.

Exclusion Criteria: Patients will be excluded from the trial if they have any of the following:

– Active bleeding or at high risk of serious bleeding complication in the opinion of the investigator

– Diagnosis of primary brain tumor, multiple myeloma, acute leukemia, chronic myelogenous leukemia or myelodysplastic syndrome

– Planned stem cell transplant– Life expectancy < 6 months– Known allergy to heparin or LMWH– Incapable of daily self-injection– Acute or chronic renal insufficiency with creatinine clearance < 30

mL/min– History of heparin-induced thrombocytopenia– Allergy to contrast agents– Need for anticoagulant therapy– Platelet count < 50,000/mm3– Pregnancy

LMWH prophylaxis NIH trial in cancer outpatients

Falanga A: Cancer Invest 2009; 27: 105-115

Procoagulant activities Fibrinolytic activities

Cytokines and growth factors

Activation of coagulation

Angiogenesis

Extracellular matrix remodeling

Tumor cells

Activation of vascular blood cells

Data from the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files

Control patients, who did not have VTE, were matched by

– cancer type– Sex– Age– year of diagnosis

Survival of Cancer Patients Developing VTECompared to Matched Controls

Cancer with VTE

12%

Cancer w/o VTE

36%

One-Year Mortality

HR = 2.20 [2.05-2.40]P<.0001

Sorensen, H. T. et al. N Engl J Med 2000;343:1846-1850

• Venous Thromboembolism– Relative Risk: 0.64 [95% CI: 0.44 – 0.94]

– Absolute Risk Reduction: 1.8% [95% CI: 0.2% -

3.4%]

• Major Bleeding– Relative Risk: 1.85 [95% CI: 0.93 – 3.68]

– Absolute Risk Increase: 0.9% [95% CI: 0% -

1.8%]

RCTs of Thromboprophylaxis in Ambulatory Cancer PatientsLow Molecular Weight Heparin: Meta-Analysis

Summary Estimates [N=6 RCTs]

Kuderer NM et al: ASCO 2009

VTE Risk Score Independent Predictor for: MortalityMultivariate Analysis

Variables P-value HR* 95% CI for HR

VTE Risk Score(1) 0.028

Intermed. Risk Group (II) 0.025 2.222 1.106 4.464

High Risk Group (III) 0.008 2.926 1.332 6.428

VTE(2) <0.001 4.472 1.928 10.370

Patient Characteristics

Age 0.026 1.018 1.002 1.035

ECOG >1 0.027 1.613 1.055 2.464

Charlson >1 0.014 1.582 1.096 2.284

BMI [kg/m2] <0.001 0.941 0.910 0.973

Stage IV(3) <0.001 2.659 1.755 4.028

Year 0.016 0.771 0.624 0.953

*Adjusted for: Cancer Type, and Relative Dose Intensity

(1) Comparison to low risk group (I) (2) Time-dependent covariate (3) Comparison to stages I-III

Kuderer et al. Oral Presentation ASH 2008

Cancer and Venous ThromboembolismThe Need for Risk Stratification

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

1 2 3 4 5 6

Diagnosis

Chemotherapy

Hospitalization

Remission

End of Life

Metastasis

Average Risk

Time

Rel

ativ

e R

isk

Importance of Guidelines to Clinical Outcomes

“Clinicians armed with appropriate assessments and the best evidence-based practice guidelines can reduce some of the unpleasant and frequent side-effects that often accompany cancer and chemotherapy treatment, obtain the best possible clinical outcomes, and avoid unnecessary costs.”

Statement from Centers for Medicare and Medicaid Services, August 2005

Candidate Biomarkers

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

Ay C, et al. Blood. 2008;112:2703-2708

Soluble P-Selectin and VTE in Cancer

Rheological effects of increased or increasingred cell mass

Young red cells in circulation augment platelet reactivity (red cell–platelet interaction)

ESAs synergize with TPO to activate platelets (ESA–TPO interactions)

Direct, receptor-mediated effects on endotheliumthat enhance interaction with platelets(ESA–endothelial interactions)

Lancet 2003;362:1265TPO, thrombopoietin

Mechanisms for ESAs to Increase Thrombosis

Venous Thromboembolism and

Thromboprophylaxis

Highlights from ASCO 2009 Advances in Supportive Care

Managing Disease and Treatment-Related Complications

Low-molecular-weight heparin for venous thromboprophylaxis in ambulatory cancer patients: A meta-analysisNicole M. Kuderer, Alok A. Khorana, Charles W. Francis et al

Duke University, Durham, NC; University of Rochester, Rochester, NY

• Literature Search:– Medline, EMBASE, Cochrane

Library, Conference Proceedings, Hand Searching of References

• Major Inclusion Criteria:– RCT of LMWH VTE prophylaxis in

adult ambulatory cancer patients– Treatment Group: LMWH– Control Group: placebo or no Rx

• Major Exclusion Criteria:– Non-cancer patients – Non-randomized trials– Surgery, Catheter trials, or

intraportal heparin infusion– Combination of anticoagulants

Overall

Study name Statistics for each study Relative Risk [95% CI]

Relative Lower Upper Risk limit limit Z-Value p-Value

FAMOUS 0.775 0.211 2.840 -0.385 0.700

TOPIC-1 1.006 0.360 2.808 0.011 0.991

TOPIC-2 0.529 0.251 1.111 -1.681 0.093

PRODIGE 0.659 0.292 1.489 -1.003 0.316

PROTECHT 0.495 0.217 1.132 -1.665 0.096

Sideras 0.824 0.231 2.938 -0.299 0.765

0.642 0.441 0.936 -2.301 0.021

0.1 0.2 0.5 1 2 5 10

Favors Prophylaxis Favors Control


OverallOverall

Study name Statistics for each study Relative Risk [95% CI]


FAMOUS 0.775 0.211 2.840 -0.385 0.700

TOPIC-1 1.006 0.360 2.808 0.011 0.991

TOPIC-2 0.529 0.251 1.111 -1.681 0.093

PRODIGE 0.659 0.292 1.489 -1.003 0.316

PROTECHT 0.495 0.217 1.132 -1.665 0.096

Sideras 0.824 0.231 2.938 -0.299 0.765

0.642 0.441 0.936 -2.301 0.021

0.1 0.2 0.5 1 2 5 10



Overall

Study name Statistics for each study Relative risk [95% CI]


FAMOUS 2.906 0.119 70.874 0.655 0.513

TOPIC-1 7.040 0.366 135.290 1.294 0.196

TOPIC-2 1.607 0.534 4.837 0.844 0.399

PRODIGE 4.394 0.523 36.887 1.364 0.173

PROTECHT5.457 0.303 98.434 1.150 0.250

Sideras 0.412 0.083 2.051 -1.083 0.279

1.846 0.927 3.675 1.744 0.081

0.1 0.2 0.5 1 2 5 10


Major Bleeding

Overall



FAMOUS 2.906 0.119 70.874 0.655 0.513

TOPIC-1 7.040 0.366 135.290 1.294 0.196

TOPIC-2 1.607 0.534 4.837 0.844 0.399

PRODIGE 4.394 0.523 36.887 1.364 0.173

PROTECHT5.457 0.303 98.434 1.150 0.250

Sideras 0.412 0.083 2.051 -1.083 0.279

1.846 0.927 3.675 1.744 0.081

0.1 0.2 0.5 1 2 5 10


Major Bleeding

Overall

Risk - Benefit ComparisonVTE – Prophylaxis with LMWH

Benefit Harm

Venous Thrombosis ARD*

Major Bleeding Events ARD*

All Bleeding Events ARD*1

1.8% ↓ 0.9% ↑ 2.4% ↑↑

*ARD = Absolute Risk Difference

1Kuderer et al. Cancer 2007

Study name Statistics for each study Absolute risk difference [95% CI]

Risk Standard Lower Upper difference error Variance limit limit Z-Value p-Value

FAMOUS -0.006 0.016 0.000 -0.037 0.025 -0.385 0.700

TOPIC-1 0.000 0.021 0.000 -0.040 0.041 0.011 0.991

TOPIC-2 -0.040 0.023 0.001 -0.085 0.006 -1.723 0.085

PRODIGE -0.047 0.047 0.002 -0.139 0.045 -1.002 0.316

PROTECHT -0.015 0.010 0.000 -0.033 0.004 -1.519 0.129

Sideras -0.013 0.042 0.002 -0.095 0.070 -0.300 0.764

-0.018 0.008 0.000 -0.034 -0.002 -2.265 0.023

-0.25 -0.13 0.00 0.13 0.25



Overall

Study name Statistics for each study Absolute risk difference [95% CI]

Risk Standard Lower Upper difference error Variance limit limit Z-Value p-Value

FAMOUS -0.006 0.016 0.000 -0.037 0.025 -0.385 0.700

TOPIC-1 0.000 0.021 0.000 -0.040 0.041 0.011 0.991

TOPIC-2 -0.040 0.023 0.001 -0.085 0.006 -1.723 0.085

PRODIGE -0.047 0.047 0.002 -0.139 0.045 -1.002 0.316

PROTECHT -0.015 0.010 0.000 -0.033 0.004 -1.519 0.129

Sideras -0.013 0.042 0.002 -0.095 0.070 -0.300 0.764

-0.018 0.008 0.000 -0.034 -0.002 -2.265 0.023

-0.25 -0.13 0.00 0.13 0.25



Overall



FAMOUS 2.906 0.119 70.874 0.655 0.513

TOPIC-1 7.040 0.366 135.290 1.294 0.196

TOPIC-2 1.607 0.534 4.837 0.844 0.399

PRODIGE 4.394 0.523 36.887 1.364 0.173

PROTECHT5.457 0.303 98.434 1.150 0.250

Sideras 0.412 0.083 2.051 -1.083 0.279

1.846 0.927 3.675 1.744 0.081

0.1 0.2 0.5 1 2 5 10


Major Bleeding

Overall



FAMOUS 2.906 0.119 70.874 0.655 0.513

TOPIC-1 7.040 0.366 135.290 1.294 0.196

TOPIC-2 1.607 0.534 4.837 0.844 0.399

PRODIGE 4.394 0.523 36.887 1.364 0.173

PROTECHT5.457 0.303 98.434 1.150 0.250

Sideras 0.412 0.083 2.051 -1.083 0.279

1.846 0.927 3.675 1.744 0.081

0.1 0.2 0.5 1 2 5 10


Major Bleeding

Overall

• While ambulatory cancer patients experienced a 36% relative risk reduction in VTE with LMWH, the average absolute risk reduction for VTE was only 1.8%.

• Concern remains about the potential increase in major bleeding with an absolute risk increase in major bleeding of 0.9%.

• Major bleeding was not a primary outcome in any of the studies and were not powered to adequately assess major bleeding.

• Weighing risks and benefits, routine VTE prophylaxis in the general outpatient cancer population cannot be recommended at this time.

• Studies are ongoing to better identify cancer outpatients at increased risk for VTE, in whom prophylaxis may have a more favorable risk-benefit ratio.

ConclusionsVTE – Prophylaxis with LMWH

ASCO Guidelines for Thromboprophylaxis

Hospitalized cancer patients Should be considered candidates for VTE prophylaxis in the

absence of contraindications

Surgical cancer patients All patients undergoing major surgical intervention for

malignant disease should be considered for prophylaxis Prophylaxis should be continued for at least 7-10 days

postoperatively and may be extended into the post discharge period for selected high-risk patients

Ambulatory cancer patients Routine prophylaxis not recommended Exception: Patients receiving thalidomide or lenalidomide with

chemotherapy or dexamethasone

Lyman et al. JCO 2007

ASCO Guidelines for Thromboprophylaxis

Hospitalized cancer patientsShould be considered candidates for VTE prophylaxis in

the absence of contraindications

Surgical cancer patientsAll patients undergoing major surgical intervention for

malignant disease should be considered for prophylaxisProphylaxis should be continued for at least 7-10 days

postoperatively and may be extended into the post discharge period for selected high-risk patients

Ambulatory cancer patients Routine prophylaxis not recommendedException: Patients receiving thalidomide or lenalidomide

with chemotherapy or dexamethasone

Risk Model

Patient Characteristic Score

Site of CancerVery high risk (stomach, pancreas)High risk (lung, lymphoma, gynecologic, GU excluding prostate)

21

Platelet count > 350,000/mm3 1

Hb < 10g/dL or use of ESA 1

Leukocyte count > 11,000/mm3 1

BMI > 35 kg/m2 1

Khorana AA et al. Blood 2008

RISK SCORE: Low (0) Intermediate (1-2) High (>3)

n=374 n=842 n=149

Rat

e o

f VT

E (

%)

0%

1%

2%

3%

4%

5%

6%

7%

8%

n=734 n=1,627 n=340

Development cohort

0.3%

2.0%

6.7%

Validation cohort

0%

1%

2%

3%

4%

5%

6%

7%

8%

n=734 n=1,627 n=340

0.8%

1.8%

7.1%

0.3%

2.0%

6.7%

n=374 n=842 n=149

VTE Prediction Risk ScoreChemotherapy – Associated Thrombosis


Time (Days)

1201101009080706050403020100

Ve

no

us T

hro

mb

oem

bo

lism

.10

.08

.06

.04

.02

0.00

Low

Intermediate

High

P < 0.001*

P<.001

P<.001

*Overall test of significance Time (Days)

1201101009080706050403020100

Ve

no

us T

hro

mb

oem

bo

lism

.10

.08

.06

.04

.02

0.00

Time (Days)

1201101009080706050403020100

Ve

no

us T

hro

mb

oem

bo

lism

.10

.08

.06

.04

.02

0.00

Low

Intermediate

High

P < 0.001*

P<.001

P<.001


Mortality and PFS By VTE Risk Score

Outcomes

Low Risk

N=1,206

Intermediate Risk

N=2,709

High Risk

N=543

All

N=4,458

Mortality

Risk (%) 1.2% 5.9% 12.7% 5.6%

HR [+/- CI] 1.0 3.6 [1.9-6.7] 6.9 [3.5-13.6] -

Progression-free survival

Risk (%) 93% 82% 72% 84%

HR [+/- CI] 1.0 2.8 [2-3.9] 4.3 [2.9-6.3] -

Kuderer NM et al. ASH 2008

PHACS Study

Patients starting chemotherapyRisk score ≥3 R

LMWH prophylaxis x 12 weekswith 4-weekly screening US and start/end CT chest

Observe x 12 weekswith 4-weekly screening US and start/end CT chest

R01 HL095109-01

Sites: Duke, Duke Oncology Network, Univ of Rochester

A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin enoxaparin in patients with advanced

pancreatic cancer: Results of the CONKO 004 trial H. Riess, U. Pelzer, G. Deutschinoff, B. Opitz, M. Stauch, P. Reitzig, S. Hahnfeld,

A. Hilbig, J. Stieler, H. Oettle

Randomization

Response evaluation at least every 12 weeks:VTE, Bleeding, RR, PFS, OS

Primary endpoint

Chemotherapy

Chemotherapy Chemotherapy + Enoxaparin

Chemotherapy + Enoxaparin

Treatment for 3 months: VTE, Bleeding, RR, PFS, OS

E 1 mg/kg/d

E 40 mg/kg/d

until PD

Randomization


Primary endpoint

Chemotherapy



Treatment for 3 months: VTE, Bleeding, RR, PFS, OS

E 1 mg/kg/d

E 40 mg/kg/d

until PD

A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin enoxaparin in patients with advanced

pancreatic cancer: Results of the CONKO 004 trial H. Riess, U. Pelzer, G. Deutschinoff, B. Opitz, M. Stauch, P. Reitzig, S. Hahnfeld,

A. Hilbig, J. Stieler, H. Oettle

Randomization


Primary endpoint

Chemotherapy



Treatment for 3 months: VTE , Bleeding, RR, PFS, OS

E 1 mg/kg/d

E 40 mg/kg/d

until PD

Randomization


Primary endpoint

Chemotherapy



Treatment for 3 months: VTE , Bleeding, RR, PFS, OS

E 1 mg/kg/d

E 40 mg/kg/d

until PD

Favorable results in randomized phase II/III in patients with good PS: with Gem/CDDP or Gem/FA/5-FU and Gem/Cap

Gem/CDDP/5-FU and Gem/FA/5-FU/CDDP with remarkable RR and 1-year OS

Patient allocation according to Karnofsky-PS (KPS) and plasma creatinine level

KPS ≥ 80% + creatinine ≤ ULN KPS 60-70% or creatinine > ULN

Gemcitabine (1000 mg/m2) Gemcitabine (1000 mg/m2)

Folinic acid (100 mg/m2) d1, 8, 15; 29

5-FU (750 mg/m2 24 h CI)

CDDP (30 mg/m2) d1, 8; 22

CONKO-004: Chemotherapy

Results: VTE and Major Bleeding

Observation Enoxaparin

Patients (N) 152 160

VTE (at 3 months)*

Major Bleeding (at 3 months)

9.9%

2.6%

1.2%

3.8%

VTE (at 30.4 months)** 15.5% 5%

Major Bleeding (at 30.4 months) 9.9% 6.3%

Median survival 29 weeks 31 weeks

*p<0.01; **p<0.05

Results: VTE and Major Bleeding


Patients (N) 152 160

VTE (at 3 months)*

Major Bleeding (at 3 months)

9.9%

2.6%

1.2%

3.8%

VTE (at 30.4 months)** 15.5% 5%

Major Bleeding (at 30.4 months) 9.9% 6.3%

Median survival 29 weeks 31 weeks

*p<0.01; **p<0.05

Venous thromboembolic events

EventObservation

N= 162

Enoxaparin

N= 150All

Pulmonary embolism 2 0 2

Proximal leg DVT 9 2 11

Distal leg DVT only 2 0 2

Upper extremity DVT 3 0 3

All (VTE) 16 2 18

All (Patients)* 15 2 17

Results: VTE at 3 Months

Results: Relative VTE rates

0

2

4

6

8

10

12

14

16


Per

cent

(%

)

n=5

n=10

■ Gem

■ GFFC

n=1

n=1

Δ=6.6%;RRR=90%;P=.025

Δ=12.4%;RRR=79%;P=.300


0

2

4

6

8

10

12

14

16


Per

cent

(%

)

n=5

n=10

■ Gem

■ GFFC

n=1

n=1

Δ=6.6%;RRR=90%;P=.025

Δ=12.4%;RRR=79%;P=.300


0

2

4

6

8

10

12

14

16


Per

cent

(%

)

n=5

n=10

■ Gem

■ GFFC

n=1

n=1

Δ=6.6%;RRR=90%;P=.025

Δ=12.4%;RRR=79%;P=.300

Major Limitations• Unusual study design• Non-standard chemotherapy• Chemo allocated by

PS/creat.• Small study: trial stopped

early• Paradoxical major bleeding

results• No information on catheters

Conclusions• Enoxaparin (1mg/kg/day) significantly reduces

VTE • No OS improvement• High overall major bleeding• Unusual study design • Clinical relevance of data?

– Reducing non-PE VTE

– Setting of high major bleeding

• ? Long-term complications:– Osteoporosis

– HIT

CONKO-004: Summary

Documents

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