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Epidemiology of VTE in
Patients with Cancer
Paolo Prandoni, MD, PhD
University of Padua (Italy)
ESMO, Stockholm 2008
Risk of Thrombosis According to Cancer Type
140
Rate per 10,000 patients
120
120
Ovary
117
100
110
Brain
98
Pancreas
81
80
76
Lymphoma
61
60
Leukaemia
40
Colon
20
Lung
0
Cancer type
Adapted from Levitan et al, Medicine 1999.
Incidence Of VTE In Patient Hospitalized With Cancer
Methods And Results
• The number of patients discharged with a diagnostic
code for 19 types of malignancies, pulmonary
embolism or deep venous thrombosis from 1979
through 1999 was obtained from the National Hospital
Discharge Survey.
• In patients with any of the 19 malignancies studied,
827 000 of 40 787 000 (2.0%) had VTE, which was
twice the incidence in patients without these
malignancies, 6 854 000 of 662 309 000 (1.0 %).
The “MEGA” Study
Population-based, case-control study of 3220 patients with a first VTE
episode and 2131 control individuals
Adjusted OR of VTE in cancer patients: 6.7 (95% CI, 5.2-8.6)
OR (95% CI)
First 3 months after cancer diagnosis
53 fold increase
Patients with distant metastases
Higher Risk
Cancer patients with thrombophilia
Higher Risk
Adapted from Blom et al., JAMA 2005; 293:715-22.
Incidence of VTE Within 2 Years of Diagnosis
of 5 Different Types of Cancer (235,149 cases)
With regional-stage disease
Adapted from Chew et al, Arch Intern Med 2006.
With metastatic disease
Risk Factors For VTE
In Patients With Cancer
Risk Factors Of Venous Thrombosis
In Cancer Patients
• Surgical procedures
• Prolonged immobilization (hospital stay)
• Chemotherapy
• Adjuvant hormonal therapy
• Administration of erythropoietin
• Central venous catheters
Adapted from: Bennett JAMA. 2008;299(8):914-924; Lyman JCO 2007;25 5490-5505.
Postoperative DVT in Cancer Patients
Postoperative DVT
Cancer
Non-cancer
Kakkar, 1970
24/59
(41%)
38/144
(26%)
8/16
(50%)
7/34
(21%)
Walsh, 1974
16/45
(35%)
22/217
(10%)
Rosenberg, 1975
28/66
(42%)
29/128
(23%)
Pineo, 1979
10/30
(33%)
13/134
(10%)
Allan, 1983
31/100
(31%)
21/100
(21%)
Sasahara, 1984
9/37
(22%)
13/53
(24.5%)
Sue-Ling, 1986
12/23
(52%)
16/62
(26%)
138/376
(37%)
159/872
(18%)
Hills, 1972
TOTAL
Late Postoperative VTE in Cancer Patients
20
16
OVERALL VTE
12
%
PROXIMAL DVT
8
PE
4
0
short course
LMWH
ENOXACAN II Study, adapted from Bergqvist et al, 2002.
long course
LMWH
In Hospital Mortality Rate Due To Pulmonary Embolism
in Immobilized Patients With and Without Cancer
Mortality (%)
16
p=0.05
14
12
14
10
8
6
8
4
2
0
Non-cancer
Adapted from Shen and Pollak, South Med J, 1980.
Cancer
Sub Analysis of the Medenox Study
OR (95% CI)
Previous VTE
2.06 (1.10-3.69)
Acute infectious disease
1.74 (1.12-2.75)
Cancer
1.62 (0.93-2.75)
Age > 75 yrs
1.03 (1.00-1.06)
Chronic respiratory disease
0.60 (0.38-0.92)
Adapted from Alikhan et al, Arch Int Med 2004.
Predictors of VTE During Hospitalization
in Medical Patients
OR (95% CI)
Trauma < 3 months
7.9 (1.1-54.9)
Platelet count > 350/nl
3.1 (1.4-7.0)
Leg edema
3.0 (1.2-7.3)
Cancer
2.8 (0.8-9.5)
Pneumonia
2.7 (1.2-5.8)
Adapted from Zakai et al, JTH 2004.
Venous and Arterial Thrombosis in Cancer Patients
During Chemotherapy
n
Weiss, 1981
433
Type of
cancer
Thrombosis
during
after
chemotherapy
Breast stage II
22 (5%)
0*
Goodnough, 1984 159
Breast stage IV 24 (15%)
4 (2.5%)
Levine, 1988
Breast stage II
14 (7%)
0*
128 (5%)
0*
Saphner, 1991
205
2352
* statistically significant
Breast
Development and Validation of a
Predictive Model for
Chemotherapy-associated Thrombosis
Blood 2008
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW
Risk Factors for Chemotherapy-associated VTE
Patient Characteristic
Risk Score
Site of cancer: stomach, pancreas
2
Site of cancer: lung, lymphoma, gynaecologic, bladder,
testicular
1
Platelet count > 350,000/mm3
1
Haemoglobin < 10 g/dl or use of erythropoietin
1
Leukocyte count > 11,000/ mm3
1
Body mass index > 35
1
Low risk:
Intermediate risk:
High risk:
Adapted from Khorana et al. Blood 2008.
score 0
score 1-2
score < 3
Tamoxifen and Chemotherapy
• 705 postmenopeusal women with breast cancer
• CMF regimen
• Total thromboembolic events
• 39 of 54 events occurred during chemotherapy
Rate of thrombosis (%)
16
14
12
10
8
6
4
1.4%
2
0
Tamoxifen
(n=352)
Adapted from Pritchard et al., J Clin Onc, 1996.
p=0.0001
9.6%
Tamoxifen + CT
(n=353)
Tamoxifen Alone Versus Placebo for Prevention of
Breast Cancer: VTE Risk
Tamoxifen
Placebo
DVT incidence (per year)
0.13 %
0.084 %
PE incidence (year)
0.069%
0.023 %
Adapted from Fisher et al., J Nat Cancer Inst, 1998.
Venous Thromboembolism And Mortality
Associated With Recombinant Erythropoietin
And Darbepoetin Administration For The
Treatment Of Cancer-associated Anemia
JAMA 2008; 299: 914-24
Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA,
Gleason KJ, Barnato SE, Elverman KM, et al.
Overall Mortality Rates
VTE Rates
Incidence of CVC-related DVT without Prophylaxis
Endpoint
Total DVT
Lokich, 1983
Venography
42%
Bern, 1990
Venography
37%
Monreal, 1996
Venography
61.7%
Verso, 2005
Venography
18.0%
Luciani, 2001
Doppler US
11.8%
Couban, 2005
Clinical
4%
Reichardt, 2002
Clinical
4%
Karthaus, 2005
Clinical
3.4%
Lee, 2006
Clinical
4.3%
Incidence Of Recurrent VTE In
Patients With Cancer
The Long-term Clinical Course Of
Acute Deep Venous Thrombosis
Ann Intern Med 1996; 125:1-7.
Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S,
Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH
Prevalence of Potential risk factors for DVT (N=355)
Malignancy
58
(16.3%)
Surgery (< 3 months)
68
(19.1%)
Trauma or fracture
62
(17.5%)
Thrombophilia
46
(13.0%)
Immobilization (> 7 days)
52
(14.6%)
7/161
(4.3%)
18/161
(11.2%)
7
(2.0%)
Pregnancy or childbirth
Contraceptives
High dose estrogens
Adapted from Ann Intern Med 1996; 125:1-7.
Cumulative Incidence of VTE Recurrences (78/355)
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Risk factors for VTE Recurrences
Baseline features
RR
Malignancy (n=58, 16%)
1.72
Thrombophilia (n=46, 13%)
1.44
Recent surgery (n=68, 19%)
0.36
Trauma/fracture (n=62, 17%)
0.51
Recurrent Venous Thromboembolism
And Bleeding Complications During
Anticoagulant Treatment In Patients
With Cancer And Venous Thrombosis
Blood 2002; 100: 3484-88
Prandoni P, Lensing AWA, Piccioli A, Bernardi E, Bagatella P, Simioni P,
Girolami B, Marchiori A, Scudeller A, Sabbion P, Noventa F, Girolami A
Cumulative Incidence Of Recurrent Thromboembolism
In Patients On Anticoagulant Therapy
%
20
cancer
no cancer
18
Risk ratio=3.2; P<0.001
10
5
Months
2
4
6
8
10
12
Incidence of Recurrent VTE by Cancer Stage
CATEGORIES
NON CANCER
RR (95%CI)
54.1%
12.8%
4.6 (2.3-9.0)
Mod. Severe (Stage III) 44.1%
12.8%
5.3 (2.5-10.9)
Less severe (Stage I/II) 14.5%
12.8%
1.9 (0.8-4.2)
Severe (Stage IV)
CANCER
Cumulative Incidence Of Major Bleeding On
Anticoagulation Therapy
% 20
cancer
HR=2.1; P=0.019
no cancer
15
10
5
Months
2
4
6
8
10
12
Incidence Of Major Bleeding By Cancer Stage On
Anticoagulation Therapy
CATEGORIES
CANCER
NON CANCER
RR (95%CI)
Severe (Stage IV)
42.8%
8.6%
4.8 (2.3-10.1)
Mod. severe (Stage III)
19.1%
8.6%
2.5 (0.9-6.7)
Less severe (Stage I/II)
3.4%
8.6%
0.5 (0.1-2.1)
Predicting Recurrences Or Major Bleeding
In Cancer Patients With
Venous Thromboembolism
Findings From The RIETE Registry
Thromb Haemost 2008; 100: 435-9
Trujillo-Santos J, Nieto JA, Tiberio G,
Piccioli A, Di Micco P, Prandoni P, Monreal M
Main Clinical Characteristics Of Cancer Patients Who Did And
Did Not Experience Recurrent VTE And Major Bleeding
Multivariate Analysis On The Risk To Develop Recurrent
PE, Recurrent DVT, Or Major Bleeding
Incidence Of Cancer In Patients
With VTE
Development of Subsequent Cancer
Idiopathic VTE
Aderka, 1986
Secondary VTE
9/35
(25.7)
2/48
(4.2)
8/148
(5.4)
4/718
(0.6)
11/145
(7.6)
2/105
(1.9)
3/113
(2.7)
0/83
Hettiarachchi, 1997
10/155
(6.5)
3/171
(1.8)
Rajan, 1988
13/152
(8.6)
8/112
(7.1)
Subirà, 1999
0/10
(0)
93/534
(17.4)
18/320
(5.6)
147/1292
(11.4)
37/1587
(2.3)
Monreal, 1988-91-97
Prandoni, 1992
Ahmed, 1996
Schulman, 2000
TOTAL
0/30
(0)
(0)
Wide Population-based Studies
•
Sorensen et al, NEJM 1998;338:1169-73
• Baron et al, Lancet 1998;351:1077-80
• Murchison et al, Br J Cancer 2004;91:92-5
• White et al, Arch Intern Med 2005;165:1782-87
Study Results
Cancers
Observed
Expected
Sorensen, DVT
SIR
1737
1372
1.3 (1.21-1.33)
730
556
1.3 (1.22-1.41)
Baron
2509
784
3.2 (3.1-3.4)
Murchison
4441
3469
596
443
Sorensen, PE
White
SIR = standardized incidence ratio
1.3 (1.25-11.33)
1.3
(1.2-1.5)
Risk of Cancer in Relation to Length of Time
SIR- Standardized incidence ratio
4.0
DVT
PE
3.0
2.0
1.0
0-6 m
6-12 m
Adapted from Sorensen et al., NEJM 1998;338:1169-73.
1-2 y
2-5 y
5-10 y
> 10 y
SIR- Standardized incidence ratio
Risk Of Cancer By Years After Hospital Admission
4.0
3.0
2.0
1.0
0
2
4
6
8
10
12
14
16
18
Years after hospital admission
Adapted from Baron et al., Lancet 1998;351:1077-80.
20
22
24
Increased Incidence Of Neoplasia Of The
Digestive Tract In Men With Persistent
Activation Of The Coagulant Pathway
J Thromb Haemost 2004
Miller GJ, Bauer KA, Howarth DJ, Cooper JA,
Humphries SE, Rosenberg RD
Study Design
• Population-based study
• 3052 middle-aged men, registered with 9 general practices in
England and Scotland
• Annual measurement of prothrombin fragment 1+2 and
fibrinopeptide A for 4 years
• Definition of persistent activation of the hemostatic pathway:
increased values in two consecutive examinations
Adapted from: Miller GJ, Bauer KA, Howarth DJ, Cooper JA, Humphries SE, Rosenberg R Increased Incidence Of Neoplasia
Of The Digestive Tract In Men With Persistent Activation Of The Coagulant Pathway. J Thromb Haemost 2004 .
Main Results
Persist activation
n=111
Control group
n=2941
Total mortality (/1000 p-yrs)
17.1
9.7
Mortality from all cancers
11.3
5.1
Total digestive cancers
8.5
2.9
Fatal digestive cancers
6.3
1.9
Adapted from: Miller GJ, Bauer KA, Howarth DJ, Cooper JA, Humphries SE, Rosenberg R Increased Incidence Of Neoplasia
Of The Digestive Tract In Men With Persistent Activation Of The Coagulant Pathway. J Thromb Haemost 2004.
The Risk Of A Second Cancer After
Hospitalisation For Venous
Thromboembolism
Br J Cancer 2005
Sorensen HT, Pedersen L, Mellemkjaer L,
Johnsen SP, Skriver MV, Olsen JH, Baron JA
RESULTS
Incidence Of Cancer After Prophylaxis
With Warfarin Against Recurrent
Venous Thromboembolism
N Engl J Med 2000
Schulman S, Lindmarker P,
for the Duration of Anticoagulation Trial
Cumulative Probability of Newly Diagnosed Cancer
Adapted from Schulman S, Lindmarker P, for the Duration of Anticoagulation Trial Incidence Of Cancer
After Prophylaxis With Warfarin Against Recurrent Venous Thromboembolism. N Engl J Med 2000 .
Use Of Warfarin And Risk Of Urogenital
Cancer: A Population-based, Nested
Case-control Study
Lancet Oncology 2007; 8: 395–402
Tagalakis V, Tamim H Blostein
M, Collet JP, Hanley JA, Kahn SR
Incidence Rate Ratios for Prostate, Bladder and Kidney Cancer
The Effect Of Low-molecular-weight
Heparin On Cancer Survival
A Systematic Review And
Meta-analysis Of Randomized Trials
J Thromb Haemost 2007; 5: 729-37
LAZO-LANGNER A, GOSS GD,
SPAANS JN, RODGER MA
Pooled Odds Ratio of Death (random-effects model)
Conclusions (1)
• There is a strong association between cancer and venous
thromboembolism
• The risk of VTE is highest in the first months after the diagnosis of
cancer, in patients with advanced disease, and in those with
thrombophilia
• Among factors that increase the risk of VTE in cancer patients are
prolonged immobilization (hospital stay), surgical procedures,
adjuvant hormonal therapy, central venous catheters, chemo and
radiotherapy, and the administration of erythropoietin
Conclusions (2)
• Cancer patients with advanced disease and
associated VTE have a relatively high risk of recurrent
VTE after stopping anticoagulation
• Cancer patients have a relatively high risk of recurrent
VTE and major bleeding during anticoagulation
• This risk is more pronounced during the first weeks of
treatment and increases with cancer severity
Conclusions (3)
• The risk for occult cancer in patients with idiopathic
venous thromboembolism approximates 10%
• This risk is particularly high in the first months after
VTE diagnosis, then declines but remains higher than
in controls for at least 10 years