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