Cancer and thrombosis –
a complex relationship
Fundamental Research in
Oncology and Thrombosis
 Cancer may increase the risk of thrombosis through
multiple mechanisms1
– tumour-induced hypercoagulability, both direct and
through expression of tissue factor2
– damage to the endothelium
– venous stasis caused by immobility or bulky tumour
 Idiopathic (no known cause) venous thromboembolism
(VTE) may be a sign of occult malignancy3
 VTE is more likely to recur in cancer patients than in
those without malignancy4
1Prandoni
et al (1999)
et al (1995)
3Prandoni et al (1992)
4Levitan et al (1999)
2Kakkar
Activation of coagulation in
cancer patients
Control (n=72)
Tissue factor (pg/mL)
Factor VIIa (mU/mL)
600
120
p=0.0006
500
100
400
80
Fundamental Research in
Oncology and Thrombosis
Cancer (n=106)
TAT* complex (µg/L)
10
p=0.0002
8
p=0.0001
6
300
60
200
40
100
20
2
0
0
0
4
*TAT = thrombin-antithrombin
Kakkar et al (1995)
Thrombosis in cancer patients:
the risk varies with tumour type
Rate/10,000 patients
140
120 117
120
100
80
Fundamental Research in
Oncology and Thrombosis
Ovary
Brain
110
98
Pancreas
81
Lymphoma
76
61
60
Leukaemia
Colon
40
Lung
20
0
Rate of VTE by cancer type
Levitan et al (1999)
Incidence of newly diagnosed
malignancy in patients with VTE
Incidence of overt cancer
during 2-year follow-up (%)
20
18
16
14
12
p=0.043
10
8
6
4
1.9
2
0
Secondary venous
thrombosis
(n=105)
Fundamental Research in
Oncology and Thrombosis
p=0.008
17.1
7.6
Idiopathic venous
thrombosis
(n=145)
Recurrent idiopathic
venous thrombosis
(n=35)
Prandoni et al (1992)
Registry data
Fundamental Research in
Oncology and Thrombosis
 Two large cohort studies have shown an increased
risk of cancer in patients admitted for VTE
– Swedish study: incidence of cancer 4.4* x higher
than expected within the first year1
– Danish study: incidence of cancer 3* x higher
than expected over the first 6 months and 2.2* x
higher at 1 year2
*SIR, standardised incidence ratio =
ratio of observed to expected number of cancers
1Baron
2Sørensen
et al (1998)
et al (1998)
In-hospital mortality rates
from pulmonary embolism:
cancer vs non-cancer
Fundamental Research in
Oncology and Thrombosis
Mortality (%)
16
p=0.05
14
12
10
8
6
4
2
0
Non-cancer
Cancer
Shen and Pollak (1980)
Role of therapeutic
interventions
Fundamental Research in
Oncology and Thrombosis
 Therapeutic interventions may increase the risk
of VTE in cancer patients1,2
 The risk of VTE in cancer patients undergoing
surgery is higher than in patients with nonmalignant disease2,3
 Chemotherapy increases the risk of VTE, especially
when combined with hormone therapy2
 Thrombosis rates in patients with indwelling central
venous catheters but no thromboprophylaxis are
typically 37–62%2,3,4
1Kakkar
et al (1970)
2Kakkar et al (1998)
3Kakkar et al (1999)
4Levine (1997)
Therapeutic interventions
Chemotherapy




Fundamental Research in
Oncology and Thrombosis
Adjuvant breast cancer
Total thromboembolic events
Post-menopausal
39 of 53 events occurred during chemotherapy
Rate of thrombosis (%)
16
14
12
10
8
6
4
2
0
Tamoxifen
(n=352)
p=0.0001
CMF=cyclophosphamide/methotrexate/fluorouracil
Tamoxifen + CMF
(n=353)
Pritchard et al (1996)
Therapeutic interventions
Chemotherapy
 Stage IV breast cancer
 159 patients 1971–1980
 Five-drug regimen (CMFVP)
 Overall incidence = 17.6%
Number of patients
30
Fundamental Research in
Oncology and Thrombosis
p=0.05
25
20
15
10
5
0
Thrombosis
on regimen
Thrombosis
off regimen
CMFVP=cyclophosphamide/methotrexate/fluorouracil/vincristine/prednisone Goodnough et al (1984)
Therapeutic interventions
Fundamental Research in
Oncology and Thrombosis
Central venous access
 Port-A-Cath
 Thromboprophylaxis with
dalteparin 2,500 U vs no therapy
 90 day venography
Thrombosis (%)
70
60
50
40
30
20
10
0
Dalteparin
(n=16)
Control
(n=13)
Monreal et al (1996)
Therapeutic interventions
Surgery – rate of fatal pulmonary embolism
(PE) in patients undergoing surgery
Rate of fatal PE (%) 1.6
1.6
Fundamental Research in
Oncology and Thrombosis
p=0.05
1.4
 4-fold increase
1.2
1.0
0.8
0.6
0.4
0.4
0.2
0.0
Patients with cancer
(n=491)
Patients without cancer
(n=1585)
International Multicentre Trial (1975)
Rahr and Sørensen (1992)
The risk of recurrence of VTE
is increased in cancer patients
Fundamental Research in
Oncology and Thrombosis
Probability of hospital readmission with DVT/PE
within 183 days of initial hospital admission
Probability of readmission
DVT/PE and
malignant disease
Malignant disease
0.25
0.20
Nonmalignant
disease
DVT/PE only
0.15
0.10
0.05
0.00
0
40
80
120
Number of days
160
Levitan et al (1999)
Concurrent VTE and cancer
increases the risk of death
Fundamental Research in
Oncology and Thrombosis
Probability of death within 183 days of initial
hospital admission
Probability of death
DVT/PE and
malignant disease
Malignant
disease
Nonmalignant
disease
1.00
0.80
DVT/PE only
0.60
0.40
0.20
0.00
0
40
80
120
Number of days
160
Levitan et al (1999)
Survival rate for patients with
a diagnosis of cancer at the
time of VTE
Fundamental Research in
Oncology and Thrombosis
Survival (%)
100
Cancer without VTE
Cancer at the time of VTE
80
p<0.001
60
40
20
0
0
5
10
15
Years after diagnosis
20
Sørensen et al (2000)
Survival rate for patients with
a diagnosis of cancer within
1 year after VTE
Fundamental Research in
Oncology and Thrombosis
Survival (%)
100
Cancer without VTE
Cancer within 1 year after VTE
80
p<0.001
60
40
20
0
0
5
10
Years after diagnosis
15
20
Sørensen et al (2000)
FRONTLINE – Rationale
Fundamental Research in
Oncology and Thrombosis
 The association between venous thromboembolism
(VTE) and malignant disease was first recognised
by Trousseau in 1865
 Yet VTE continues to be a major clinical problem
in cancer patients
 There is a lack of international consensus on the
prevention and treatment of VTE in cancer patients
 FRONTLINE will help to collect data on perceptions
and practice and further our understanding
FRONTLINE – The first
comprehensive global survey
of thrombosis and cancer
Fundamental Research in
Oncology and Thrombosis
 FRONTLINE will provide a unique insight into:
– the perceived risk of VTE in cancer patients,
including those with therapeutic interventions,
such as surgery, chemotherapy and central
venous lines
– patterns of practice for thromboprophylaxis and
management of VTE
– possible national and regional variations in
practice
 The results of FRONTLINE may help to stimulate
further research in this important area
FRONTLINE participation
Fundamental Research in
Oncology and Thrombosis
 All medical specialists treating cancer patients
are invited to participate in FRONTLINE
– surgical oncologists
– medical oncologists
– radiation oncologists
– palliative care specialists
– haematologists
– oncology nurses
FRONTLINE – Key dates
2001
Fundamental Research in
Oncology and Thrombosis
2002
May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar April May
ASCO 2001
12/5
Pilot
survey
LAUNCH and survey roll-out
ISTH 2001
6/7
ECCO 2001
21/10
Data analysis
ASCO
2002
Survey
results
FRONTLINE – The first
comprehensive global survey of
thrombosis and cancer
 For further information, or to register for
participation in the FRONTLINE Survey:
FRONTLINE Secretariat:
Medical Action Communications
PO Box 56
Egham
Surrey TW20 8BR
UK
Tel: + 44 (0) 1784 220 220
Fax: + 44 (0) 1784 220 221
Email: frontline.survey@mac-uk.com
or visit: www.frontlinesurvey.net
Fundamental Research in
Oncology and Thrombosis
References
Fundamental Research in
Oncology and Thrombosis
Baron JA et al. Lancet 1998; 351: 1077–80.
Goodnough LT et al. Cancer 1984; 54: 1264–8.
Kakkar AK et al. Lancet 1995; 346: 1004–5.
Kakkar AK et al. BMJ 1999; 318: 1571–2.
Kakkar AK et al. Baillieres Clin Haematol 1998; 11: 675–87.
Kakkar VV et al. Am J Surg 1970; 120: 527–30 .
Levine MN. Thromb Haemost 1997; 78: 133–36.
Levitan N et al. Medicine 1999; 78: 285–91.
Monreal M et al. Thromb Haemost 1996; 75: 251–3.
Prandoni P et al. N Engl J Med 1992; 327: 1128–33.
Prandoni P et al. Haematologica 1999; 84: 437–45.
Pritchard KI et al. J Clin Oncol 1996; 14: 2731–7.
Rahr HB, Sørensen JV. Blood Coagul Fibrinolysis 1992; 3: 451–60.
Shen VS, Pollak EW. Southern Med J 1980; 73: 841–3.
Sørensen HT et al. New Engl J Med 1998; 338: 1169–73.
Sørensen HT et al. New Engl J Med 2000; 343: 1846–50.
An international multicentre trial. Lancet 1975; 2: 45–51.