Fundamental Research in Oncology and Thrombosis Cancer and thrombosis – a complex relationship lCancer may increase the risk of thrombosis through multiple

Fundamental Research inOncology and Thrombosis

Cancer and thrombosis – Cancer and thrombosis – a complex relationship a complex relationship

Cancer may increase the risk of thrombosis through Cancer may increase the risk of thrombosis through multiple mechanismsmultiple mechanisms1 1

– tumour-induced hypercoagulability, both direct and tumour-induced hypercoagulability, both direct and through expression of tissue factorthrough expression of tissue factor22

– damage to the endotheliumdamage to the endothelium

– venous stasis caused by immobility or bulky tumourvenous stasis caused by immobility or bulky tumour

Idiopathic (no known cause) Idiopathic (no known cause) venous thromboembolism venous thromboembolism (VTE) (VTE) may be a sign of occult malignancymay be a sign of occult malignancy33

VTEVTE is more likely to recur in cancer patients than in is more likely to recur in cancer patients than in those without malignancythose without malignancy44

11Prandoni et al (1999)Prandoni et al (1999)22Kakkar et al (1995)Kakkar et al (1995)

33Prandoni et al (1992)Prandoni et al (1992)44Levitan et al (1999)Levitan et al (1999)


Activation of coagulation in Activation of coagulation in cancer patientscancer patients

0

100

200

300

400

500

600

0

20

40

60

80

100

120

Tissue factor (pg/mL) Factor VIIa (mU/mL) TAT* complex (µg/L)

Control (n=72) Cancer (n=106)

p=0.0006p=0.0002 p=0.0001

0

2

4

6

8

10

*TAT = thrombin-antithrombin

Kakkar et al (1995)Kakkar et al (1995)


Levitan et al (1999)Levitan et al (1999)

120120 117117110110

9898

81817676

OvaryOvary

BrainBrain

PancreasPancreas

LymphomaLymphoma

LeukaemiaLeukaemia

ColonColon

LungLung

6161

Rate of VTE by cancer type Rate of VTE by cancer type

00

2020

4040

6060

8080

100100

120120

140140Rate/10,000 patientsRate/10,000 patients

Thrombosis in cancer patients: Thrombosis in cancer patients: the risk varies with tumour typethe risk varies with tumour type


Incidence of newly diagnosed Incidence of newly diagnosed malignancy in patients with VTEmalignancy in patients with VTE

Incidence of overt cancer Incidence of overt cancer during 2-year follow-up (%)during 2-year follow-up (%)

Prandoni et al (1992)Prandoni et al (1992)

0

2

4

6

8

10

12

14

16

18

20

1.9

17.1

7.6

Secondary venous thrombosis

(n=105)

Idiopathic venous thrombosis

(n=145)

Recurrent idiopathic venous thrombosis

(n=35)

p=0.043

p=0.008


11Baron et al (1998)Baron et al (1998)22Sørensen et al (1998)Sørensen et al (1998)

*SIR, standardised incidence ratio =ratio of observed to expected number of cancers

Registry dataRegistry data

Two large cohort studies have shown an increased Two large cohort studies have shown an increased risk of cancer in patients admitted for VTErisk of cancer in patients admitted for VTE

– Swedish study: incidence of cancer 4.4* x higher Swedish study: incidence of cancer 4.4* x higher than expected within the first yearthan expected within the first year11

– Danish study: incidence of cancer 3* x higher Danish study: incidence of cancer 3* x higher than expected over the first 6 months and 2.2* x than expected over the first 6 months and 2.2* x higher at 1 yearhigher at 1 year22


In-hospital mortality rates In-hospital mortality rates from pulmonary embolism: from pulmonary embolism: cancer vs non-cancercancer vs non-cancer

0

2

4

6

8

10

12

14

16

Non-cancer Cancer

p=0.05

Mortality (%)

Shen and Pollak (1980)Shen and Pollak (1980)


Role of therapeutic Role of therapeutic interventionsinterventions

Therapeutic interventions may increase the risk Therapeutic interventions may increase the risk of VTE in cancer patientsof VTE in cancer patients1,21,2

The risk of VTE in cancer patients undergoing The risk of VTE in cancer patients undergoing surgery is higher than in patients with non-surgery is higher than in patients with non-malignant diseasemalignant disease2,32,3

Chemotherapy increases the risk of VTE, especially Chemotherapy increases the risk of VTE, especially when combined with hormone therapywhen combined with hormone therapy22

Thrombosis rates in patients with indwelling central Thrombosis rates in patients with indwelling central venous catheters but no thromboprophylaxis are venous catheters but no thromboprophylaxis are typically 37–62%typically 37–62%2,3,42,3,4

11Kakkar et al (1970)Kakkar et al (1970)22Kakkar et al (1998)Kakkar et al (1998)33Kakkar et al (1999)Kakkar et al (1999)

44Levine (1997)Levine (1997)


Therapeutic interventionsTherapeutic interventions Chemotherapy Chemotherapy

Adjuvant breast cancer Adjuvant breast cancer Total thromboembolic eventsTotal thromboembolic events Post-menopausalPost-menopausal 39 of 53 events occurred during chemotherapy39 of 53 events occurred during chemotherapy

0

2

4

6

8

10

12

14

16

Tamoxifen Tamoxifen + CMF

Rate of thrombosis (%)

pp=0.0001=0.0001

Pritchard et al (1996)Pritchard et al (1996)(n=352) (n=353)

CMF=cyclophosphamide/methotrexate/fluorouracil


Therapeutic interventions Therapeutic interventions ChemotherapyChemotherapy

Goodnough et al (1984)Goodnough et al (1984)

0

5

10

15

20

25

30

Stage IV breast cancer Stage IV breast cancer 159 patients 1971–1980159 patients 1971–1980 Five-drug regimen (CMFVP)Five-drug regimen (CMFVP) Overall incidence = 17.6%Overall incidence = 17.6%

Number of patientsNumber of patients

pp=0.05=0.05

Thrombosison regimen

Thrombosisoff regimen

CMFVP=cyclophosphamide/methotrexate/fluorouracil/vincristine/prednisone


Monreal et al (1996)Monreal et al (1996)

Therapeutic interventionsTherapeutic interventionsCentral venous accessCentral venous access

Thrombosis (%)Thrombosis (%)

Port-A-CathPort-A-Cath Thromboprophylaxis with Thromboprophylaxis with

dalteparin 2,500 U vs no therapydalteparin 2,500 U vs no therapy 90 day venography90 day venography

0

10

20

30

40

50

60

70

Dalteparin(n=16)

Control(n=13)


Therapeutic interventions Therapeutic interventions Surgery – rate of fatal pulmonary embolism Surgery – rate of fatal pulmonary embolism (PE) in patients undergoing surgery (PE) in patients undergoing surgery

pp=0.05=0.05

International Multicentre Trial (1975)International Multicentre Trial (1975) Rahr and Sørensen (1992)Rahr and Sørensen (1992)

Patients with cancerPatients with cancer(n=491) (n=491)

1.61.6

Patients without cancerPatients without cancer(n=1585) (n=1585)

0.40.4

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

1.21.2

1.41.4

1.61.6Rate of fatal PE (%)Rate of fatal PE (%)

4-fold increase4-fold increase


DVT/PE onlyDVT/PE only

Number of daysNumber of days

Probability of readmissionProbability of readmission

0.050.05

0.000.00

0.100.10

0.150.15

0.200.20

0.250.25

4040 8080 120120 16016000

Nonmalignant Nonmalignant diseasedisease

Malignant diseaseMalignant disease

DVT/PE and DVT/PE and malignant diseasemalignant disease


The risk of recurrence of VTE The risk of recurrence of VTE is increased in cancer patientsis increased in cancer patientsProbability of hospital readmission with DVT/PE Probability of hospital readmission with DVT/PE within 183 days of initial hospital admissionwithin 183 days of initial hospital admission


DVT/PE onlyDVT/PE only

Nonmalignant Nonmalignant diseasedisease

Malignant Malignant diseasedisease

DVT/PE and DVT/PE and malignant diseasemalignant disease

Probability of deathProbability of death

0.200.20

0.000.00

0.400.40

0.600.60

0.800.80

1.001.00

Number of daysNumber of days4040 8080 120120 16016000


Concurrent VTE and cancer Concurrent VTE and cancer increases the risk of deathincreases the risk of deathProbability of death within 183 days of initial Probability of death within 183 days of initial hospital admissionhospital admission


Survival rate for patients Survival rate for patients with a diagnosis of cancer at with a diagnosis of cancer at the time of VTEthe time of VTE

Sørensen et al (2000)Sørensen et al (2000)

0

20

40

60

80

100

Years after diagnosis

0 5 10 15 20

Cancer without VTE

Survival (%)

Cancer at the time of VTE

p<0.001


Sørensen et al (2000)Sørensen et al (2000)

Survival rate for patients Survival rate for patients with a diagnosis of cancer with a diagnosis of cancer within 1 year after VTEwithin 1 year after VTE

0

40

60

80

100

Years after diagnosis

0 5 10 15 20

Survival (%)

Cancer without VTE

20

Cancer within 1 year after VTE

p<0.001

Fundamental Research inOncology and ThrombosisFRONTLINE – RationaleFRONTLINE – Rationale

The association between venous thromboembolism The association between venous thromboembolism (VTE) and malignant disease was first recognised (VTE) and malignant disease was first recognised by Trousseau in 1865by Trousseau in 1865

Yet VTE continues to be a major clinical problem Yet VTE continues to be a major clinical problem in cancer patientsin cancer patients

There is a lack of international consensus on the There is a lack of international consensus on the prevention and treatment of VTE in cancer patientsprevention and treatment of VTE in cancer patients

FRONTLINE will help to collect data on perceptions FRONTLINE will help to collect data on perceptions and practice and further our understandingand practice and further our understanding


FRONTLINE – The first FRONTLINE – The first comprehensive global survey comprehensive global survey of thrombosis and cancerof thrombosis and cancer

FRONTLINE will provide a unique insight into:FRONTLINE will provide a unique insight into:

– the perceived risk of VTE in cancer patients, the perceived risk of VTE in cancer patients, including those with therapeutic interventions, such including those with therapeutic interventions, such as surgery, chemotherapy and central venous linesas surgery, chemotherapy and central venous lines

– patterns of practice for thromboprophylaxis and patterns of practice for thromboprophylaxis and management of VTEmanagement of VTE

– possible national and regional variations in practicepossible national and regional variations in practice

The results of FRONTLINE may help to stimulate further The results of FRONTLINE may help to stimulate further research in this important arearesearch in this important area

Fundamental Research inOncology and ThrombosisFRONTLINE participation FRONTLINE participation

All medical specialists treating cancer patients All medical specialists treating cancer patients are invited to participate in FRONTLINEare invited to participate in FRONTLINE

– surgical oncologistssurgical oncologists

– medical oncologistsmedical oncologists

– radiation oncologistsradiation oncologists

– palliative care specialistspalliative care specialists

– haematologistshaematologists

– oncology nursesoncology nurses


FRONTLINE – Key datesFRONTLINE – Key dates

ECCO 2001ECCO 200121/1021/10

ASCO ASCO 20022002

Survey Survey results results

ISTH 2001ISTH 20016/76/7

Data analysisData analysis

Pilot Pilot surveysurvey

LAUNCH and survey roll-out LAUNCH and survey roll-out

ASCO 2001ASCO 200112/5 12/5

May May Jun Jun Jul Jul Aug Aug Sept Sept Oct Oct Nov Nov DecDec Jan Jan Feb Mar April May Feb Mar April May 20012001 20022002


For further information, or to register for participation in For further information, or to register for participation in the FRONTLINE Survey: the FRONTLINE Survey:

FRONTLINE Secretariat:FRONTLINE Secretariat:

Medical Action Communications Medical Action Communications

PO Box 56PO Box 56

Egham Egham

Surrey TW20 8BRSurrey TW20 8BR

UK UK

TelTel: + 44 (0) 1784 220 220 : + 44 (0) 1784 220 220

FaxFax: + 44 (0) 1784 220 221: + 44 (0) 1784 220 221

EmailEmail: : [email protected]

or visit: www.frontlinesurvey.net

FRONTLINE – The first FRONTLINE – The first comprehensive global survey of comprehensive global survey of thrombosis and cancerthrombosis and cancer


ReferencesReferences

Baron JA et al. Baron JA et al. LancetLancet 1998; 351: 1077–80. 1998; 351: 1077–80.Goodnough LT et al. Goodnough LT et al. CancerCancer 1984; 54: 1264–8. 1984; 54: 1264–8.Kakkar AK et al. Kakkar AK et al. LancetLancet 1995; 346: 1004–5. 1995; 346: 1004–5.Kakkar AK et al. Kakkar AK et al. BMJ BMJ 1999; 318: 1571–2. 1999; 318: 1571–2. Kakkar AK et al. Kakkar AK et al. Baillieres Clin HaematolBaillieres Clin Haematol 1998; 11: 675–87. 1998; 11: 675–87.Kakkar VV et al. Kakkar VV et al. Am J SurgAm J Surg 1970; 120: 527–30 . 1970; 120: 527–30 .Levine MN. Levine MN. Thromb HaemostThromb Haemost 1997; 78: 133–36. 1997; 78: 133–36.Levitan N et al. Levitan N et al. Medicine Medicine 1999; 78: 285–91.1999; 78: 285–91.Monreal M et al. Monreal M et al. Thromb HaemostThromb Haemost 1996; 75: 251–3. 1996; 75: 251–3.Prandoni P et al. Prandoni P et al. N Engl J MedN Engl J Med 1992; 327: 1128–33. 1992; 327: 1128–33.Prandoni P et al. Prandoni P et al. HaematologicaHaematologica 1999; 84: 437–45. 1999; 84: 437–45.Pritchard KI et al. Pritchard KI et al. J Clin OncolJ Clin Oncol 1996; 14: 2731–7. 1996; 14: 2731–7.Rahr HB, Sørensen JV. Rahr HB, Sørensen JV. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1992; 3: 451–60. 1992; 3: 451–60.Shen VS, Pollak EW. Shen VS, Pollak EW. Southern Med JSouthern Med J 1980; 73: 841–3. 1980; 73: 841–3.Sørensen HT et al. Sørensen HT et al. New Engl J MedNew Engl J Med 1998; 338: 1169–73. 1998; 338: 1169–73.Sørensen HT et al. Sørensen HT et al. New Engl J MedNew Engl J Med 2000; 343: 1846–50. 2000; 343: 1846–50.An international multicentre trial. An international multicentre trial. LancetLancet 1975; 2: 45–51. 1975; 2: 45–51.

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Fundamental Research in Oncology and Thrombosis Cancer and thrombosis – a complex relationship lCancer may increase the risk of thrombosis through multiple