Epidemiology of VTE in Patients with Cancer
Paolo Prandoni, MD, PhDUniversity of Padua (Italy)
ESMO, Stockholm 2008
Adapted from Levitan et al, Medicine 1999.
120 117110
98
8176
Ovary
Brain
Pancreas
Lymphoma
Leukaemia
Colon
Lung
61
Cancer type
0
20
40
60
80
100
120
140
Rat
e p
er 1
0,00
0 p
atie
nts
Risk of Thrombosis According to Cancer Type
• 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 %).
Incidence Of VTE In Patient Hospitalized With CancerMethods And Results
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
The “MEGA” Study
Adapted from Blom et al., JAMA 2005; 293:715-22.
With regional-stage disease With metastatic disease
Adapted from Chew et al, Arch Intern Med 2006.
Incidence of VTE Within 2 Years of Diagnosis of 5 Different Types of Cancer (235,149 cases)
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
Kakkar, 1970 24/59 (41%) 38/144 (26%)
Hills, 1972 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%)
TOTAL 138/376 (37%) 159/872 (18%)
Postoperative DVTCancer Non-cancer
Late Postoperative VTE in Cancer Patients
OVERALL VTE
PROXIMAL DVT
PE
0
4
8
12
16
20
%
short courseLMWH
long courseLMWH
ENOXACAN II Study, adapted from Bergqvist et al, 2002.
0
2
4
6
8
10
12
14
16
Non-cancer Cancer
p=0.05
Mortality (%)
Adapted from Shen and Pollak, South Med J, 1980.
8
14
In Hospital Mortality Rate Due To Pulmonary Embolism in Immobilized Patients With and Without 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
Weiss, 1981 433 Breast stage II 22 (5%) 0*
Goodnough, 1984159 Breast stage IV 24 (15%) 4 (2.5%)
Levine, 1988 205 Breast stage II 14 (7%) 0*
Saphner, 1991 2352 Breast 128 (5%) 0*
* statistically significant
Type of Thrombosisn cancer during after
chemotherapy
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW
Development and Validation of a Predictive Model for
Chemotherapy-associated Thrombosis
Blood 2008
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
Risk Factors for Chemotherapy-associated VTE
Low risk: score 0
Intermediate risk: score 1-2
High risk: score < 3
Adapted from Khorana et al. Blood 2008.
0
2
4
6
8
10
12
14
16
Tamoxifen Tamoxifen + CT
Rate of thrombosis (%)
pp=0.0001=0.0001
Adapted from Pritchard et al., J Clin Onc, 1996.
(n=352) (n=353)
1.4%
9.6%
Tamoxifen and Chemotherapy
• 705 postmenopeusal women with breast cancer
• CMF regimen
• Total thromboembolic events
• 39 of 54 events occurred during chemotherapy
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.
Tamoxifen Alone Versus Placebo for Prevention of Breast Cancer: VTE Risk
Venous Thromboembolism And MortalityAssociated With Recombinant Erythropoietin
And Darbepoetin Administration For TheTreatment 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
Endpoint Total DVT
Lokich, 1983Lokich, 1983 Venography Venography 42%42% Bern, 1990Bern, 1990 VenographyVenography 37%37% Monreal, 1996Monreal, 1996 Venography Venography 61.7% 61.7%
Verso, 2005Verso, 2005 VenographyVenography 18.0%18.0%
Luciani, 2001Luciani, 2001 Doppler USDoppler US 11.8%11.8%
Couban, 2005Couban, 2005 ClinicalClinical 4% 4%
Reichardt, 2002Reichardt, 2002 ClinicalClinical 4% 4%
Karthaus, 2005Karthaus, 2005 ClinicalClinical 3.4% 3.4%
Lee, 2006Lee, 2006 ClinicalClinical 4.3% 4.3%
Incidence of CVC-related DVT without Prophylaxis
Incidence Of Recurrent VTE In Patients With Cancer
The Long-term Clinical Course Of Acute Deep Venous Thrombosis
Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH
Ann Intern Med 1996; 125:1-7.
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%)
Pregnancy or childbirth 7/161 (4.3%)
Contraceptives 18/161 (11.2%)
High dose estrogens 7 (2.0%)
Adapted from Ann Intern Med 1996; 125:1-7.
Cumulative Incidence of VTE Recurrences (78/355)
%2FconteThe+cumuPrandoni%1996+AmAnnIntMedtrue125/1/1/Fhttp%3A%annintmed
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
Prandoni P, Lensing AWA, Piccioli A, Bernardi E, Bagatella P, Simioni P, Girolami B, Marchiori A, Scudeller A, Sabbion P, Noventa F, Girolami A
Blood 2002; 100: 3484-88
Cumulative Incidence Of Recurrent Thromboembolism In Patients On Anticoagulant Therapy
20
2 4 6 8 10 12
cancer
%
Months
Risk ratio=3.2; P<0.001
18
10
5
no cancer
Incidence of Recurrent VTE by Cancer Stage
CATEGORIES CANCER NON CANCER RR (95%CI)
Severe (Stage IV) 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)
5
10
15
20
2 4 6 8 10 12
cancer
no cancer
%
Months
HR=2.1; P=0.019
Cumulative Incidence Of Major Bleeding On Anticoagulation Therapy
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 ThromboembolismFindings 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 RecurrentPE, Recurrent DVT, Or Major Bleeding
Incidence Of Cancer In Patients With VTE
Development of Subsequent Cancer
Idiopathic VTE Secondary VTE
Aderka, 1986 9/35 (25.7) 2/48 (4.2)
Monreal, 1988-91-97 8/148 (5.4) 4/718 (0.6)
Prandoni, 1992 11/145 (7.6) 2/105 (1.9)
Ahmed, 1996 3/113 (2.7) 0/83 (0)
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) 0/30 (0)
Schulman, 2000 93/534 (17.4) 18/320 (5.6)
TOTAL 147/1292 (11.4) 37/1587 (2.3)
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
Sorensen, DVT 1737 1372 1.3 (1.21-1.33)
Sorensen, PE 730 556 1.3 (1.22-1.41)
Baron 2509 784 3.2 (3.1-3.4)
Murchison 4441 3469 1.3 (1.25-11.33)
White 596 443 1.3 (1.2-1.5)
SIR = standardized incidence ratio
CancersObserved Expected SIR
Risk of Cancer in Relation to Length of Time
4.0
0-6 m 6-12 m 1-2 y 2-5 y 5-10 y > 10 y
DVT
3.0
2.0
1.0
PE
Adapted from Sorensen et al., NEJM 1998;338:1169-73.
SIR
- S
tan
dar
dize
d in
cid
enc
e r
atio
4.0
2 4 8 166 10 12 14 24222018
Years after hospital admission
0
Adapted from Baron et al., Lancet 1998;351:1077-80.
SIR
- S
tan
dar
dize
d in
cid
enc
e r
atio
3.0
2.0
1.0
Risk Of Cancer By Years After Hospital Admission
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 .
Persist activation Control group
n=111 n=2941
Main Results
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 SurvivalA 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
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