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

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er 1

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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

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d in

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enc

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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

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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