Cancer and thrombosis – a complex relationship

2. Cancer and thrombosis – a complex relationship • 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)2Kakkar et al (1995)3Prandoni et al (1992)4Levitan et al (1999)

3. Control (n=72) Cancer (n=106) Tissue factor (pg/mL) Factor VIIa (mU/mL) TAT* complex (µg/L) 10 600 120 p=0.0006 p=0.0002 p=0.0001 500 100 8 400 80 6 300 60 4 200 40 2 100 20 0 0 0 *TAT = thrombin-antithrombin Kakkar et al (1995) Activation of coagulation in cancer patients

4. Ovary 120 117 Brain 110 98 Pancreas 81 76 Lymphoma 61 Leukaemia Colon Lung Thrombosis in cancer patients: the risk varies with tumour type Rate/10,000 patients 140 120 100 80 60 40 20 0 Rate of VTE by cancer type Levitan et al (1999)

5. Incidence of newly diagnosed malignancy in patients with VTE Incidence of overt cancer during 2-year follow-up (%) p=0.008 20 17.1 18 16 14 12 p=0.043 10 7.6 8 6 4 1.9 2 0 Secondary venous thrombosis (n=105) Idiopathic venous thrombosis (n=145) Recurrent idiopathic venous thrombosis (n=35) Prandoni et al (1992)

6. Registry data • 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 et al (1998)2Sørensen et al (1998)

7. In-hospital mortality rates from pulmonary embolism: cancer vs non-cancer Mortality (%) 16 p=0.05 14 12 10 8 6 4 2 0 Non-cancer Cancer Shen and Pollak (1980)

8. Role of therapeutic interventions • 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 non-malignant 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)

9. Therapeutic interventionsChemotherapy • Adjuvant breast cancer • Total thromboembolic events • Post-menopausal • 39 of 53 events occurred during chemotherapy Rate of thrombosis (%) 16 p=0.0001 14 12 10 8 6 4 2 0 Tamoxifen Tamoxifen + CMF (n=352) (n=353) Pritchard et al (1996) CMF=cyclophosphamide/methotrexate/fluorouracil

10. Therapeutic interventions Chemotherapy • Stage IV breast cancer • 159 patients 1971–1980 • Five-drug regimen (CMFVP) • Overall incidence = 17.6% Number of patients 30 p=0.05 25 20 15 10 5 0 Thrombosison regimen Thrombosisoff regimen Goodnough et al (1984) CMFVP=cyclophosphamide/methotrexate/fluorouracil/vincristine/prednisone

11. Therapeutic interventionsCentral 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)

12. Rate of fatal PE (%) 1.6 p=0.05 1.6 1.4 • 4-fold increase 1.2 1.0 0.8 0.6 0.4 0.4 0.2 0.0 Patients without cancer(n=1585) Patients with cancer (n=491) International Multicentre Trial (1975)Rahr and Sørensen (1992) Therapeutic interventions Surgery – rate of fatal pulmonary embolism (PE) in patients undergoing surgery

13. Probability of readmission DVT/PE and malignant disease 0.25 Malignant disease 0.20 Nonmalignant disease 0.15 DVT/PE only 0.10 0.05 0.00 0 40 80 120 160 Number of days The risk of recurrence of VTE is increased in cancer patientsProbability of hospital readmission with DVT/PE within 183 days of initial hospital admission Levitan et al (1999)

14. Probability of death DVT/PE and malignant disease 1.00 Malignant disease 0.80 Nonmalignant disease DVT/PE only 0.60 0.40 0.20 0.00 0 40 80 120 160 Number of days Concurrent VTE and cancer increases the risk of deathProbability of death within 183 days of initial hospital admission Levitan et al (1999)

15. Survival (%) 100 Cancer without VTE 80 Cancer at the time of VTE p<0.001 60 40 20 0 0 5 10 15 20 Years after diagnosis Survival rate for patients with a diagnosis of cancer at the time of VTE Sørensen et al (2000)

16. Survival (%) 100 Cancer without VTE 80 Cancer within 1 year after VTE p<0.001 60 40 20 0 0 5 10 15 20 Years after diagnosis Survival rate for patients with a diagnosis of cancer within 1 year after VTE Sørensen et al (2000)

17. FRONTLINE – Rationale • 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

18. FRONTLINE – The first comprehensive global survey of thrombosis and cancer • 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

19. FRONTLINE participation • All medical specialists treating cancer patients are invited to participate in FRONTLINE • surgical oncologists • medical oncologists • radiation oncologists • palliative care specialists • haematologists • oncology nurses

20. 2001 2002 May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar April May Pilot survey ASCO 2001 12/5 LAUNCH and survey roll-out ISTH 20016/7 ECCO 2001 21/10 ASCO 2002 Survey results Data analysis FRONTLINE – Key dates

21. 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

22. References 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.