Low-Molecular-Weight Heparins in Cancer:

Thrombosis and Beyond

Outline

•  The problem of thrombosis in the cancer patient – Mechanisms of coagulation activation – Clinical implications

•  Prevention and treatment of venous thromboembolic disease (VTE) in cancer

•  Low-molecular-weight heparins as antineoplastic agents

Blood Coagulation and Cancer

•  Coagulation system is activated in cancer – Cancer is a hypercoagulable state – Cancer treatments (chemotherapy, surgery,

radiation) amplify coagulation activation

•  Implications of coagulation activation in cancer – Thrombosis (arterial and venous) – Enhanced tumor growth – Poor clinical outcomes

Coagulation Balance: Activators

Adapted from Bauer et al. J South Orthop Assoc. 2002;11:197-202.

VIIa

Cellular tissue factor

Ca2+

Xa

XIa

X

II

IX

XIIIa

XI

XII XIIa

Soluble fibrin

Fibrinogen Fibrin (clot)

Xa Va

PL Ca2+

VII

Thrombin IIa

IXa

VIIIa Ca2+ PL

Intrinsic system Extrinsic system

Coagulation Balance: Inhibitors

Soluble fibrin Fibrinogen Fibrin (clot)

Endogenous inhibitors

TM

VIIa

Cellular tissue factor

Ca2+

Xa

TFPI

XIa

PCa PC

PS

X

II

IX

XIIIa

XI

XII XIIa

Xa Va

PL Ca2+

VII IXa VIIIa Ca2+ PL

AT III

Thrombin IIa

Adapted from Bauer et al. J South Orthop Assoc. 2002;11:197-202.

Intrinsic system Extrinsic system

Tumor-induced endothelial cell

activation

Macrophage tissue factor

Mechanisms of Tumor-Mediated Hypercoagulable States

Tumor cell surface tissue factor Other tumor-derived

procoagulants

Tumor-mediated platelet activation and accumulation

Expression of cell surface phospholipids that support

coagulation activation

Malignant Tumor

Thrombosis in Cancer •  Clinically evident in up to 15% of cancer patients •  Discovered post mortem in 20% to 50% of patients with

metastatic cancer

•  May be presenting feature of occult malignancy –  Standardized incidence ratio for cancer 2.3 (2.0–2.7) within

1 year of VTE episode (Sorensen et al. N Engl J Med. 1998;338:1169-1173)

–  10% with idiopathic VTE develop cancer within 2 years (Prandoni et al. N Engl J Med. 1992;327:1128-1133 )

•  Life-threatening complication of advanced cancer –  Second most common cause of death in hospitalized

solid-tumor cancer patients

Cancer and the Natural History of DVT: Outcome After First Episode of All-Cause DVT

8-year follow-up: 355 patients with symptomatic DVT

Death

Recurrent DVT

Post-thrombotic syndrome

(Presumed) no post-thrombotic sequelae

Subsequent new malignancy (idiopathic DVT–Trousseau’s syndrome)

29%

25% 30%

9% 7%

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

Rates of VTE in Different Malignancies

Cancer Site Rate of VTE

per 10,000 Patients

Head/neck 16 Breast 22 Uterus 44 Prostate 55 Noncancer inpatients 57 Lung 61 Liver 69 Colon 76

Levitan et al. Medicine. 1999;78:285-291.

Cancer Site Rate of VTE

per 10,000 Patients

Leukemia 81 Renal 84 Stomach 85 Lymphoma 98 Pancreas 110 Brain 117 Ovary 120

VTE Risk in Cancer: Breast Cancer as an Example

•  Estimated risk in untreated stage I and II disease: ~0.2% in 4 years (~ background risk)

•  Increased risk with chemotherapy/hormonal therapy: ~5% to 8% in 1 year

•  Risk in metastatic disease under treatment ~5% to 8% in 6 months

Smorenburg et al. Haemostatsis. 1999;29(suppl 1):91-97. Lee et al. Semin Thromb Hemost 1999;25:137-145.

Outcome in Cancer With or Without VTE

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

Surv

ival

(% o

f pat

ient

s)

0

50 60 70 80 90

100

10 20 30 40

5 10 20 Years After Diagnosis

15 0

Cancer within 1 yr after VTE Cancer without VTE

Prevention and Treatment of VTE in Cancer

VTE and Cancer: Prevention Challenges •  No markers reliably predict risk •  Thromboprophylaxis must be individualized

–  Extended perioperative thromboprophylaxis is superior –  Central venous catheter thromboprophylaxis

•  LMWH modestly effective –  Warfarin (INR 1.3–1.9) prevents chemotherapy-induced VTE in

breast cancer (Levine et al. Lancet. 1994;343:886-889) –  LMWH prevents VTE in hospitalized medical patients with

cancer (Samama et al. N Engl J Med. 1999;341:793-800) –  Standard prophylactic doses of LMWH may be inadequate for

cancer patients (Alikhan et al. Blood. 2001;98(part 1):266a)

VTE and Cancer: Diagnostic Challenges •  Asymptomatic VTE common

–  ~50% undetected before death

•  D-dimer may be falsely negative –  Due to fibrinolytic defect with cancer (?) –  Rarely negative in noncancer patients with VTE –  Sensitive D-dimer tests required for diagnosis

•  Recurrent VTE common –  28% with cancer; 8% without cancer –  Lower incidence of recanalization of previously affected veins

than in noncancer patients (59% without vs 23% with cancer)

VTE and Cancer: Treatment Challenges •  Cancer treatment–related DVT common

–  Chemotherapy –  Radiotherapy –  Hormonal therapy –  Antiangiogenic drugs (eg, thalidomide + chemotherapy) –  Surgery (3X greater risk of DVT with cancer than without) –  Central venous catheters

•  Bleeding common –  Bleeding lesions, anticoagulants, thrombocytopenia

•  More extensive, harder to treat than in those without cancer

The CORTES Study: Lab Results in Cancer and Noncancer Patients With DVT

Kakkar et al. Blood. 2000;96:449a.

Prothrombin F1.2 (ng/mL) 1.88 1.66 .037

D-dimer (ng/mL) 559 437 .004

Factor XIIa (ng/mL) 2.79 2.42 <.001

TFPI (µ/mL) 159 141 <.001

Marder score at presentation 27 25 .021

Phlebographic response at 3 weeks (%) 37 50 .013

Clinical recurrence at 3 months (%) 8.8 3.3 .007

Cancer (n = 125)

Noncancer (n = 1012) P Parameter

Outpatient SC LMWH, oral AC

Inpatient IV UFH, oral AC

Treatment Options for VTE in Cancer Patients

Outpatient SC UFH, oral AC

IVC filter w/o AC

Inpatient SC LMWH, oral AC

Medical Treatment

Inpatient and/or Outpatient SC LMWH

Doses of Approved LMWHs for the Prevention and Treatment of VTE

Fragmin® (dalteparin) 2500 IU qd 200 IU/kg qd 5000 IU qd (Europe only)

Innohep® (tinzaparin) 75 IU/kg qd 175 IU/kg qd (Europe only)

Lovenox® (enoxaparin) 40 mg qd 1 mg/kg q12h

30 mg q12h 1.5 mg/kg qd

Drug Prevention Treatment

Mousa. Cardiovasc Drug Rev. 2002;20:163-180.

Unfractionated Heparin •  Continuous IV infusion •  Primarily administered in the hospital •  Usually administered by health care

professionals •  Monitoring and dosing adjustments •  Potential for dosing errors •  Risk of thrombocytopenia and

osteoporosis •  Inexpensive, but not cost-effective •  Requires 5–7 days in the hospital

LMWH •  bid or qd subcutaneous injection •  Administered in hospital, office, or home •  Administered by patient, caregiver, or

professional •  No monitoring; fixed or weight-based

dosing •  More precise dosing •  Decreased risk of adverse events •  More cost-effective •  Requires 0–2 days in the hospital •  Possible cancer survival benefit •  Possibly superior to UFH for cancer VTE

Initial Treatment of VTE in Cancer: UFH vs LMWH

Initial VTE Treatment in Cancer and Noncancer Patients: LMWH vs UFH—Results of Meta-Analysis

Major bleeding 0.57† 1.9

Recurrent thromboembolism 0.85 5.4

Overall mortality 0.71† 6.8

Adapted from Hirsh et al. Chest. 2001;119:64S-94S.

Summary OR* Frequency in

UFH Group (%)

*A summary OR <1.0 favors LMWH, a summary OR >1.0 favors UFH †P < .05

Initial VTE Treatment in Cancer Patients: LMWH vs UFH—The CORTES Study

Kakkar et al. Blood. 2000;96:449a.

UFH (n = 41)

LMWH bid (n = 33)

LMWH qd (n = 51)

Phlebographic response (%) 19 46.7 46.3 (P = .03 (P = .03 vs UFH) vs UFH)

Clinical recurrence (%) 17.1 3.0 5.9

(P = .068 vs UFH)

LMWHs Are Dissimilar

•  Dosing differences produce clinical differences

•  Differences in biological effects (potency): – Anti-Xa activity – Anti-IIa activity – TFPI release from vascular endothelium

VTE and Cancer: Anticoagulant Considerations for Secondary Prophylaxis (1)

•  Should continue until cancer treatment is completed and cancer is no longer active (lifelong for many)

•  Warfarin – Requires careful monitoring – Cancer patients have reduced time in therapeutic

INR range • Nutrition, drug interactions, liver metastases

– Bleeding more common in cancer patients – Recurrent VTE more common – Relatively inexpensive drug; expenditures for

monitoring, complications

VTE and Cancer: Anticoagulant Considerations for Secondary Prophylaxis (2)

•  LMWH –  Lower rates of recurrent VTE and major bleeding

than warfarin – More stable anticoagulation; no routine monitoring –  Injection – Osteopenia – Expensive drug; few expenditures for ancillary

services

LMWH vs Oral Anticoagulant in Cancer Patients With VTE

Dalteparin (5–7 days)* + OA (6 mo) (n = 336)

Dalteparin (6 mo)† (n = 336)

Recurrent VTE 17.4% 8.8% .0017 Major bleeding 3.6% 5.6% .27 Cumulative mortality 41% 39% NR

Levine et al. Blood. 2002;100:82a.

672 Evaluable Patients

Randomize

*Dalteparin = 200 IU/kg SC; OA = target INR 2.5 †Dalteparin = 200 IU/kg SC for 1 mo, 150 IU/kg SQ for 5 mo

P Value

Special Considerations in Thrombosis Management

Special Populations: Tinzaparin Levels in Age-Related Renal Insufficiency

B

Ant

i-IIa

(IU

/mL)

Plasma anti-Xa (A) and anti-IIa (B) levels prior to the first injection (day 0) and at peak levels after subcutaneous injection of tinzaparin (175 anti-Xa IU/kg) on days 2, 5, 7, and 10 (n = 30, mean age = 87, mean creatinine clearance = 40.4 mL/min)

Siguret et al. Thromb Haemost. 2000;84:800-804.

A

Ant

i-Xa

(IU/m

L)

Day 0

Day 2

Day 5

Day 7

Day 10

0.8

0.6

0.4

0.2

1.0

0.0

0.4

0.2

0.6

0.0 Day 0

Day 2

Day 5

Day 7

Day 10

Special Populations: Obesity

B

Ant

i-IIa

Act

ivity

(IU

/mL)

Mean (SE) anti-Xa and anti-IIa activity in increased-weight and historical control healthy normal-weight subjects receiving 175 IU/kg tinzaparin via SC injection Hainer et al. Thromb Maemost. 2002;874:817-823.

A

Ant

i-Xa

Act

ivity

(IU

/mL)

1.00

0.75

0.50

0.25

1.25

0.00 36 0 6 12 18 24 30 36 0 6 12 18 24 30

0.4

0.1

0.5

0.0

0.3

0.2

Time (h) Time (h)

Normal-weight (n = 30) Increased-weight (n = 35)

Effects of Heparins on Human Cancer

Perioperative Heparin and Cancer Survival

1.00

0.95

0.90

0.85

0 6

Prop

ortio

n Su

rviv

ing

12 18 24 30 36 Months From Operation

Control

Heparin

Number of cases 163 168

3-year mortality (%) 7.6 12.5 .0005

Disseminated disease mortality (%) 9.2 21.4

(RR: 2.33; 95% CI: 1.33–4.09)

Heparin Control P Value

Kakkar et al. Int J Oncol. 1995;6:885-888.

Heparin for Small Cell Carcinoma of the Lung

Lebeau et al. Cancer. 1994;74:38-45.

281 Evaluable Patients

(+) HEPARIN (n = 138)

(–) HEPARIN (n = 139)

CR (%) 37 23 P = .004 Median survival (days) 317 261 P = .01

Randomize

LMWH for Small Cell Carcinoma of the Lung

Altinbas et al. Proc ASCO. 2001;20:321a.

48 Evaluable Patients

CEV (18 weeks) (n = 25)

CEV (18 weeks) + LMWH (n = 23)

CR and PR (%) 36 78 P = .004 Progression-free 5 9 P = .02 survival (months) (range, 2–13) (range, 4–24)

CEV = cyclophosphamide, epirubicin, vincristine; LMWH = dalteparin

Randomize

LMWH in Malignant Melanoma: A Pilot Study

0 3 6 9 15 18 0.0

20.0

40.0

60.0

80.0

100.0

Months 12 21 24

Stage IV

Stage III

Wojtukiewicz et al. Thromb Haemost. 2003;89:405-406.

Lower symbol: Stage IV melanoma survival estimates with chemoimmunotherapy

Perc

ent S

urvi

ving

LMWH vs UFH: Overall Cancer Survival After Surgery

von Tempelhof et al. Int J Oncol. 2000;16:815-824.

LMWH UFH

1

0.8

0.6

0.4

0.2

0 0 650

Days 1050 Days

2400 Days

Log Rank: P = .006 P = .083

A B

Prob

abili

ty E

stim

ate

LMWH, n = 140 UFH, n = 147

LMWH vs UFH: Survival After Breast Cancer Surgery

von Tempelhof et al. Int J Oncol. 2000;16:815-824.

LMWH UFH

1

0.8

0.6

0.4

0.2

0 0 650

Days 1050 Days

2400 Days

Log Rank: P = .316 P = .726

A B

Prob

abili

ty E

stim

ate

LMWH, n = 94 UFH, n = 91

LMWH vs UFH: Survival After Pelvic Cancer Surgery

von Tempelhof et al. Int J Oncol. 2000;16:815-824.

LMWH

UFH

1

0.8

0.6

0.4

0.2

0 0 650

Days 1050 Days

2400 Days

Log Rank: P = .0139 P = .063

A B

Prob

abili

ty E

stim

ate

LMWH, n = 46 UFH, n = 56

Hull et al. N Engl J Med. 1992;326:975-982. Green et al. Lancet. 1992;339:1476.

Tinzaparin UFH

0

5

10

15

20

25

30

Cancer Noncancer Combined N = 47 N = 49 N = 169 N = 169 N = 216 N = 218

Dea

th R

ate

(%)

P = .557

P =.044

P = .041

12.6%

27%

4.1% 3% 4.6%

9.6%

LMWH vs UFH: Effect on Total and Cancer-Related Mortality

P = .07!warfarin!

LMWH Limitations: •  Stages •  Treatments •  Tumor types (breast

most common)

Meyer et al. Arch Intern Med. 2002;162:1729-1735.

Cancer Mortality According to DVT Treatment

0 20 40 60 80 100 75

80

85

90

95

100

Follow-up (days)

Patie

nts

Aliv

e (%

)

1.5 mg/kg/d enoxaparin vs warfarin × 3 months for cancer

LMWH and Survival in Advanced Cancer: FAMOUS

Kakkar et al. Blood. 2002;100:148a.

Placebo (n = 181) Dalteparin (n = 185)

0

10

20

30

40

50

12 24 36

Perc

enta

ge S

urvi

ving

P = .29

42 45

27

19 13

21

Months From Randomization

Patients with advanced cancer and without VTE treated for 1 year with placebo or LMWH

P = .04

LMWH and Survival in Advanced Cancer: FAMOUS

Placebo (n = 47) Dalteparin (n = 53)

0

20

40

60

80

100

24 36

Perc

enta

ge S

urvi

ving

56

77

59

37

“Good-prognosis” patients

Months From Randomization Kakkar et al. Blood. 2002;100:148a.

•  Angiogenesis •  Proteases •  Growth factors •  Coagulation factors •  Oncogene expression

•  Immune system •  Differentiation and apoptosis

Heparin

Inhibits Stimulates

Heparin Effect in Cancer

LMWH and Growth Factor–Induced Angiogenesis

Mousa. Semin Thromb Hemost. 2002;28:45-52.

Antiangiogenic effect of tinzaparin in VEGF-induced angiogenesis in the CAM model Chick Chorioallantoic Membrane Model

of Human Colon Cancer

Control Tinzaparin Treated

Antiangiogenic effect of tinzaparin on colon carcinoma–induced angiogenesis in the chick chorioallantoic membrane (CAM) model

LMWH and Angiogenesis

Mousa. Semin Thromb Hemost. 2002;28:45-52.

LMWH and Angiogenesis Effect of tinzaparin on tumor growth in the

CAM-tumor implant model

Control

Treated Mousa. Semin Thromb Hemost. 2002;28:45-52.

Colon Cancer Fibrosarcoma

LMWH and Tumor-Induced Thrombocytopenia and Metastasis

Mousa. Semin Thromb Hemost. 2002;28:45-52.

Baseline

Plat

elet

Cou

nt

Platelet count

Melanoma Melanoma + Tinzaparin (10 mg/kg)

Tum

or N

odul

es

Lung tumor formation

Melanoma Tinzaparin (10 mg/kg),

1 Day

Tinzaparin (10 mg/kg),

14 Days

0

40

10

50

20

60

30

0

600

800

1000

200

400

1200

TFPI in Thrombosis and Cancer Dual pathways of action

TFPI TF/VIIa

Procoagulant Effects

Noncoagulant Effects

Thromboembolism Inflammation, Angiogenesis

TFPI

Anti–TF/VIIa/Xa

TFPI Biologic Actions

Cell adhesion molecule

modulation

Antiangiogenesis Cytoprotection/ Anti-inflammation

Antiplatelet TFPI

Anticoagulation

Distribution of TFPI

LDL

TFPI

TFPI

HDL

TFPI

Proteoglycan

Endothelial Cell

Platelet TFPI

Monocyte Macrophage

TFPI

TFPI H

eparin

Comparative Pharmacodynamics of TFPI Release by LMWHs

0 120 240 360 600 720 40

80

120

160

200

240

Time (min)

TFPI

(ng/

mL)

480

Dalteparin Enoxaparin Tinzaparin

Dose: 100 U/kg IV

Future Directions

Superiority of LMWH vs UFH for Cancer

•  Greater inhibition of – Angiogenesis, heparin-binding growth factors, key

enzymes (Xa, thrombin, heparinase)

•  Greater stimulation of TFPI release

•  Greater protection of platelets (ie, less thrombocytopenia)

Advantages of LMWH vs UFH for Prospective, Randomized Cancer Trials

•  Predictable pharmacokinetics

•  Ease of administration – Self-injected, outpatient, no routine monitoring –  Improved quality of life

•  Safety –  Less HIT, bleeding, osteoporosis

•  Potentially superior anticancer effect

Challenges for Cancer Clinical Trials With LMWH

•  Prospective, randomized trials are needed

•  Cancer-outcome end point is essential

•  Must be controlled for – Tumor type – Stage – Performance status – Treatment

Low-Molecular-Weight Heparins in Cancer: Summary

•  Excellent antithrombotic activity – May be superior to UFH for initial treatment of

cancer-associated VTE – May be superior to oral anticoagulants for secondary

prophylaxis

•  Significant anticancer activity – Multiple possible anticancer mechanisms – Well-designed clinical trials needed to define role in

cancer treatment