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Mechanisms of Cancer-Induced Thrombosis: The Interface

Pathogenesis?
Biological significance? Potential importance for cancer therapy?

Pathogenesis of Thrombosis in Cancer – A Modification of Virchow’s Triad

1. Stasis
Prolonged bed rest Extrinsic compression of blood vessels by tumor

Hy p erc oag ul a b il i ty

ss siis Sa Stta

2. Vascular Injury
Direct invasion by tumor Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium

3. Hypercoagulability

Vascular Injury

Tumor-associated procoagulants and cytokines (tissue factor, CP, TNFα, IL-1β, VEGF, etc.) Impaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT, Protein C and S) Enhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and host macrophages

Mechanisms of Cancer-Induced Thrombosis: Clot and Cancer Interface

Pathogenesis? Biological significance? Potential importance for cancer therapy?

Interface of Biology and Cancer
FVII/FVIIa

Tumor Cell
VEGF

TF

Blood Coagulation Activation

THROMBIN

FIBRIN Angiogenesis IL-8 PAR-2

TF

Angiogenesis

Endothelial cells

Falanga and Rickles, New Oncology:Thrombosis, 2005

Activation of Blood Coagulation in Cancer Biological Significance?

Epiphenomenon? Is this a generic secondary event (as in inflammation, where clot formation is an incidental finding) Or, is clotting . . . A Primary Event? Linked to malignant transformation

Mechanisms of Cancer-Induced Thrombosis: Implications

1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy?

VTE and Cancer: Epidemiology
Of all cases of VTE:
About 20% occur in cancer patients Annual incidence of VTE in cancer patients ≈ 1/250

Of all cancer patients:

15% will have symptomatic VTE As many 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

Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

Clinical Features of VTE in Cancer
VTE has significant negative impact on quality of life 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

Bura et. al., J Thromb Haemost 2004;2:445-51

The rate of recurrent venous thromboembolism (VTE) during well-conducted anticoagulation in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) is consistently around 3–5% of patients in the first 3 months following the thrombotic episode. The conditions that have mainly been found to be associated with the risk of recurrent VTE during anticoagulation are active cancer and antiphospholipid syndrome.

Rate of recurrent 3–5% pts in the first 3 months

Main causes active cancer AP syndrome.

Prandoni et al; J Thromb Haemost 2007

The rate of recurrent VTE during well-conducted anticoagulation in patients with DVT or PE is consistently around 3–5% of patients in the first 3 months following the thrombotic episode.

Rate of recurrent 3–5% pts in the first 3 months

other causes
Recurrent VTE during the 3-month course developed in six of the 55 patients (10.9%) with immobility, as compared with 11 of the 322 (3.4%) ambulant patients, leading to a relative risk, adjusted for age, of 2.9 (95% CI: 1.2–7.5).

immobilization 10.9% RR =2,9

Prandoni et al; J Thromb Haemost 2007

DVT and PE in Cancer Facts, Findings, and Natural History
VTE is the second leading cause of death in hospitalized cancer patients1,2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4
1. Ambrus JL et al. J Med. 1975;6:61-64 2. Donati MB. Haemostasis. 1994;24:128-131 3. Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 4. Prandoni P et al. Ann Intern Med. 1996;125:1-7

It has been estimated that 1 in every 7 hospitalized cancer patients who die, do so from pulmonary embolism (PE).

Risk Factors for Cancer-Associated VTE
Cancer
Type
Men: prostate, colon, brain, lung Women: breast, ovary, lung

Stage

Treatments
Surgery
10-20% proximal DVT 4-10% clinically evident PE 0.2-5% fatal PE

Systemic Central venous catheters (~4% generate clinically relevant VTE)

Comorbid Condition and DVT Risk
► Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. ► The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. ► Together, the 8 risk factors accounted for 74% of disease occurrence Heit JAet al Arch Intern Med. 2002. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study
Predicted probability for any venous thromboembolic events (VTE) based on the factors inpatient treatment, prior thrombosis in medical history, thrombosis in family history, chemotherapy, fever and C-reactive protein (CRP), showing the rate of patients with a given number of risk factors as calculated from the total of 507 patients included

Clinical characteristics and management of acute deep vein thrombosis and pulmonary embolism (PE) have been reported to be different in patients with and without cancer. MASTER multicenter registry

A total of 2119 patients were enrolled, of whom 424 (20%) had cancer. The incidence of bilateral lower limb DVT was significantly higher in patients with cancer than in patients without cancer (8.5% versus 4.6%; p<0.01), as were the rates of iliocaval thombosis (22.6% versus 14%; p<0.001), and upper limb deep vein thrombosis (9.9% versus 4.8%; p<0.001).

MASTER multicenter registry 8.5% versus 4.6%; p<0.01

Imberti et al 2008

consequently

Venous thromboembolism (VTE) is a frequent complication in cancer patients and represents an important cause of morbidity and mortality.

During the 3-month period, Major bleeding complications developed in twice as many patients with (four of the 55, 7.3%) than without (11 of the 322, 3.4%) prior immobilization,

immobilization Rate of major bleeding 7,3 % pts in the first 3 months No immobilization 3.4%

but the adjusted relative risk was not statistically significant (2.1; 95% CI 0.7–6.5).

RR =2,1

Prandoni et al; J Thromb Haemost 2007

Bleeding Events in CLOT

Dalteparin N=338
Major bleed Any bleed
19 ( 5.6%) 46 (13.6%)

OAC N=335
12 ( 3.6%) 62 (18.5%)

P-value*
0.27 0.093

* Fisher’s exact test
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Treatment of Cancer-Associated VTE
Study Design Length of N Therapy (Months) 6 336 336 3 67 71 80 87 32 36 34 Recurrent VTE (%) 9 17 11 21 6 11 3.4 3.1 6.7 Major Bleeding (%) 6 NS 4 7 16 6 8
0.09

Death (%) 39 41 11 23 23 22
NS

CLOT Trial (Lee 2003) CANTHENOX (Meyer 2002) LITE (Hull ISTH 2003) ONCENOX (Deitcher ISTH 2003)

Dalteparin OAC Enoxaparin OAC Tinzaparin OAC Enox (Low) Enox (High) OAC

0.002

0.09

0.03

3

0.03

NS

NS

6

NS

NS

NR

MASTER multicenter registry

Major bleeding (3.3% versus 1.1%; p=0.001), inhospital treatment (73.3% versus 66.6%; p=0.02) and inferior vena cava filter implantation (7.3% versus 4.1%; p=0.005) were significantly more frequent in patients with cancer, in whom oral anticoagulants were less often used (64.2% versus 82%; p<0.0001).

Imberti et al 2008

consequently

Major bleedings is a frequent complication in cancer patients (than in patient without cancer) and represents an important cause of morbidity and mortality.

1.00 DVT/PE and Malignant Disease

Probability of Death

0.80 0.60 Malignant Disease 0.40 DVT/PE Only 0.20 Nonmalignant Disease 0.00 0 20 40 60 80 100 120140 160 180
Number of Days

Levitan N, et al. Medicine 1999;78:285

As Number Of Cancer Survivors Increases, VTE Rates Increase
4
VTE in Hospitalized Cancer And Noncancer Patients (%)

3,5 3 2,5 2 1,5 1 0,5 0

Cancer Patients

Noncancer Patients

79

81

83

85

87

93

89

91

95

97

YEAR

99

Relative Risk of VTE in Cancer Patients 1 2 3 4 0.5 Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder 1.5 2.5 3.5 4.5

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

60% of cancer patients, have localized cancer or limited metastatic disease that would have allowed for longer survival in the absence of a fatal PE. The incidence of VTE in cancer patients has been described to be approximately 15%, with reported incidence rates ranging from 3.8% to 30.7%.

Does VTE in patients with cancer adversely affect outcome?

Probability of death within 183 days of initial hospital admission in patients with cancer with or without concurrent VTE

However, it is likely to be much higher, because VTE is often asymptomatic or minimally symptomatic and, even when symptoms are present; they are often nonspecific or mistakenly attributed to the underlying malignancy. Especially in patients who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment. Some patients with DVT develop recurrent VTE or bleeding complications mainly during anticoagulant treatment. These complications may occur more frequently if these patients have concomitant cancer.

From a prospective follow-up study arise that in thrombosis patients those with cancer have a higher risk (was 20.7% or a hazard ratio of 3.2 for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer (6.8%). In the same study, the cumulative incidence of major bleeding was 12.4% in patients with cancer and 4.9% in patients without cancer, with a risk ratio of 2.2.
Fig 1. Cumulative incidence of recurrent VTE during anticoagulant therapy.

ANTICOAGULANTS
ACTION AND MONITORING
HEPARIN-AT F XIIa F XIa F IXa F Xa THROMBIN (IIa) PTT Anti Xa levels LMWH WARFARIN F VII

F Xa

F IX F X F II PT/INR

Fig 2. Cumulative incidence of clinically important bleeding during anticoagulant therapy in DVT patients with and without cancer.

Prandoni et al 2002

OAC vs LMWH LMWH vs placebo

CLOT Survival Curves
Overall population
100 90 80 70 60 50 40 30 20 10 0
0 30 60 90 120 150 180 210 240 270 300 330 360 390

Good prognosis population
100

without metastases
Dalteparin

Probability of survival (%)

Probability of survival (%)

90 80 70 60 50 40 30 20 10 0
0 30 60

p=0.62

OAC

Dalteparin OAC

p=0.03

90 120 150 180 210 240 270 300 330 360 390

Days after randomization
Lee, et.al. N Engl J Med, 2003;349:146

Days after randomization

Landmark CLOT Cancer Trial
Reduction in Recurrent VTE
Probability of Recurrent VTE, %
25 20 15 10

Recurrent VTE

Risk reduction = 52% p-value = 0.0017

OAC

Dalteparin
5 0 0 30 60 90 120 150 180 210

Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Days Post Randomization

Famous: Trial Design Kaplan–Meier survival curves for all patients in dalteparin and placebo groups
Kaplan–Meier survival distribution function estimate 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Dalteparin Placebo

The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12%, respectively, for patients receiving placebo (P = .19).

0 190 184

12 85 72

24 36 48 60 72 84 Time from randomisation (months) 30 15 22 9 12 8 5 5 4 2 Dalteparin Placebo

No. at risk:

Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.

Survival Analysis: Good Prognosis Patients
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.0

Kaplan–Meier survival distribution estimate

Dalteparin Placebo

In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P = .03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively.

17 23

29

35

41 47

53

59 65

71

77

83

Time from randomisation (months)

No. at risk:

47 17 55 31

10 9 9 26 22 20

8 13

8 8

5 5

3 5

2 5

0 3

Placebo Dalteparin

Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.

LMWH and Survival: Further Studies (2003)
CLOT
Solid tumor malignancy and acute VTE All patients received dalteparin 200 IU/kg od 5–7 days

R

Dalteparin 1 month 200 IU/kg od 5 months ≅160 IU/kg od Oral anticoagulant 6 months Chemotherapy plus dalteparin 5000 IU od 18 weeks Chemotherapy (cyclophosphamide, epirubicin, vincristine) 18 weeks Nadroparin 2 weeks therapeutic dose 4 weeks 1/2 therapeutic dose Placebo 6 weeks
Lee, et.al. N Engl J Med, 2003;349:146

SCLC study
Small cell lung cancer (SCLC)

R

Patients with responsive limited disease received thoracic radiotherapy

MALT
Solid tumor malignancy

R

Altinbas M, et al. J Thromb Haemost. 2004;2:1-6. Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.

SCLC Study Survival Curves
Overall population
1.0

Good prognosis population
1.0

limited disease

Probability of survival

Probability of survival

0.8

p=0.01

0.8

p=0.007

0.6

0.6

0.4

Dalteparin

0.4

Dalteparin

0.2

0.2

Placebo
0.0 0 5 10 15 20 25 30 35 40 0.0 0

Placebo
5 10 15 20 25 30 35 40

Months after randomization
Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.

Months after randomization

MALT Survival Curves
Overall population
1.0

Good prognosis population
1.0

>6 months survival

Probability of Survival

0.8

Probability of Survival

p=0.021

0.8

p=0.010

0.6

0.6

0.4

0.4

Nadroparin
0.2

0.2

Nadroparin Placebo

Placebo
0.0 0 12 24 36 48 60 72 84 96 0.0 0

12

24

36

48

60

72

84

96

Months after randomization
Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.

Months after randomization

Anti-Tumor Effects of LMWH CLOT 12-month Mortality
Patients Without Metastases (N=150)
100

Probability of Survival, %

90 80 70 60 50 40 30 20 10 0 0 30 60 90 120 150 180

Dalteparin
OAC

HR = 0.50 P-value = 0.03
240 300 360

Days Post Randomization
Lee A, et al. ASCO. 2003

A model for the prediction of symptomatic venous thrombosis after the initiation of chemotherapy, among outpatients with different types of malignancies schedulated by Khorana et al in 2008. Primary site of cancer, platelet count, leukocyte count, hemoglobin level, use of erythropoiesis-stimulating agents, and body mass index were found to be predictive factors. Symptomatic venous thrombotic events were recorded when reported by physicians. Due to this design, the occurrence of asymptomatic thrombotic events could not be assessed.

Based on the predictive factors, patients were classified into low-risk (27%), intermediate-risk (61%), and high-risk (12%) groups. Most thrombotic events (75%) occurred during the first 2 cycles of chemotherapy. In the low-risk group, only 0.6% developed symptomatic venous thrombosis, compared with 1.9% in the intermediate-risk group. These findings suggest that the 88% of the patients in the low- and intermediate-risk groups are unlikely to benefit from prophylactic anticoagulation. Patients in the high-risk group had a nearly 7% risk of developing venous thrombosis during a median follow-up period of 73 days. One may argue whether a 7% risk warrants thromboprophylaxis; 93% of patients in this high-risk group would be treated without any apparent benefit, and moreover, patients with a malignancy have an increased risk of major bleeding during thromboprophylaxis.

To make a balanced decision, the risks and benefits need to be assessed. Unfortunately, data regarding bleeding risk were unavailable in the study by Khorana et al. Similarly, data on prophylactic anticoagulation use was lacking. If one of the investigated factors instigated the use of anticoagulation, and thereby indirectly decreased the risk of venous thrombosis, this would influence the model.

This was a very large study consisting of more than 4000 patients with different types of malignancies. Most patients had an excellent performance status. Only a few patients with less prevalent malignancies strongly associated with venous thrombotic events, such as brain tumors, were included. One has to be careful in generalizing the results to patients with a poor performance status and patients with these less prevalent malignancies, as other predictive models may more closely fit those cases. Khorana et al 2008

Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation. So, patients with DVT who also have cancer seem to be at a higher risk for recurrent venous thromboembolic complications during anticoagulation.

Effect of Malignancy on Risk of Venous Thromboembolism (VTE)
53.5

50 Adjusted odds ratio 40 30 20

• Population-based case-control (MEGA) study • N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects • CA patients = 7x OR for VTE vs. non-CA patients 28 22.2 20.3 19.8 14.3

10 0

4.9 3.6 2.6 1.1

Gastrointestinal

3 to 12 months

Hematological

0 to 3 months

5 to 10 years

Distant metastases

1 to 3 years

Type of cancer

Time since cancer diagnosis

Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715

> 15 years

Breast

Lung

VTE is a major cause of morbidity and mortality in patients with cancer. Hence, it is essential that oncologists and other health providers are able to diagnose DVT and PE accurately and administer effective treatment for these common vascular complications

Falanga et all 2008

Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy.

These risks correlate with the extent of cancer.

The most common situations that increase the thromboembolic risk in cancer patients include immobilization, surgery, chemotherapy with or without adjuvant hormone therapy, and the insertion of central venous catheters

Imberti et al 2008

The clinical presentation of acute VTE is different and often more extensive in cancer patients than in patients free from malignancy. Moreover, the management of the acute phase of VTE is more problematic in cancer patients, especially because of a higher rate of major bleeding and the need for implantation of inferior vena cava filters.

During anticoagulant therapy, cancer patients have a 2- to 4fold higher risk of recurrent VTE and major bleeding complications when compared with non cancer patients

Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed.

The long-term administration of LMWH should be considered as an alternative to anti-vitamin K drugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants. Prolongation of anticoagulation should be considered for as long as the malignant disorder is active. The evidence of lowered cancer mortality in patients on LMWH has stimulated renewed interest in these agents as antineoplastic drugs and raises the distinct possibility that cancer and thrombosis share common mechanisms.

Thromboprophylaxis may prevent the occurrence of venous thrombosis, an important cause of morbidity and mortality among patients with cancer, especially those on active antitumor therapy. Identifying cancer patients at high risk for thrombosis who might benefit from prophylaxis is still a major challenge. The only well-defined high-risk group for which thromboprophylaxis appears to be effective and relatively safe is surgical patients, although prophylaxis is also recommended for acutely ill medical patients. However, a high-risk group of outpatients with cancer remains to be determined, and is a necessary piece of information to obtain before the appropriateness of thromboprophylaxis can be assessed. Doggen 2008

Interface of Biology and Cancer
Tumor cells
Angiogenesis, Basement matrix degradation. Fibrinolytic activities: t-PA, u-PA, u-PAR, PAI-1, PAI-2

Procoagulant Activities

IL-1, TNF-α, VEGF

Activation of coagulation

PMN leukocyte

FIBRIN

Platelets Monocyte Endothelial cells

Falanga and Rickles, New Oncology:Thrombosis, 2005