Fundamental Research in Oncology and Thrombosis Cancer and thrombosis – a complex relationship lCancer may increase the risk of thrombosis through multiple mechanisms 1 –tumour-induced hypercoagulability, both direct and through expression of tissue factor 2 –damage to the endothelium –venous stasis caused by immobility or bulky tumour lIdiopathic (no known cause) venous thromboembolism (VTE) may be a sign of occult malignancy 3 lVTE is more likely to recur in cancer patients than in those without malignancy 4 1 Prandoni et al (1999) 2 Kakkar et al (1995) 3 Prandoni et al (1992) 4 Levitan et al (1999)

Fundamental Research in Oncology and Thrombosis Activation of coagulation in cancer patients Tissue factor (pg/mL)Factor VIIa (mU/mL)TAT* complex (µg/L) Control (n=72)Cancer (n=106) p= p= p= *TAT = thrombin-antithrombin Kakkar et al (1995)

Fundamental Research in Oncology and Thrombosis Levitan et al (1999) OvaryBrain Pancreas Lymphoma Leukaemia Colon Lung 61 Rate of VTE by cancer type Rate/10,000 patients Thrombosis in cancer patients: the risk varies with tumour type

Fundamental Research in Oncology and Thrombosis Incidence of newly diagnosed malignancy in patients with VTE Incidence of overt cancer during 2-year follow-up (%) Prandoni et al (1992) Secondary venous thrombosis (n=105) Idiopathic venous thrombosis (n=145) Recurrent idiopathic venous thrombosis (n=35) p=0.043 p=0.008

Fundamental Research in Oncology and Thrombosis 1 Baron et al (1998) 2 Sørensen et al (1998) *SIR, standardised incidence ratio = ratio of observed to expected number of cancers Registry data lTwo 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 year 1 –Danish study: incidence of cancer 3* x higher than expected over the first 6 months and 2.2* x higher at 1 year 2

Fundamental Research in Oncology and Thrombosis In-hospital mortality rates from pulmonary embolism: cancer vs non-cancer Non-cancerCancer p=0.05 Mortality (%) Shen and Pollak (1980)

Fundamental Research in Oncology and Thrombosis Role of therapeutic interventions lTherapeutic interventions may increase the risk of VTE in cancer patients 1,2 lThe risk of VTE in cancer patients undergoing surgery is higher than in patients with non- malignant disease 2,3 lChemotherapy increases the risk of VTE, especially when combined with hormone therapy 2 lThrombosis rates in patients with indwelling central venous catheters but no thromboprophylaxis are typically 37–62% 2,3,4 1 Kakkar et al (1970) 2 Kakkar et al (1998) 3 Kakkar et al (1999) 4 Levine (1997)

Fundamental Research in Oncology and Thrombosis Therapeutic interventions Chemotherapy lAdjuvant breast cancer lTotal thromboembolic events lPost-menopausal l39 of 53 events occurred during chemotherapy TamoxifenTamoxifen + CMF Rate of thrombosis (%) p= Pritchard et al (1996) (n=352)(n=353) CMF=cyclophosphamide/methotrexate/fluorouracil

Fundamental Research in Oncology and Thrombosis Therapeutic interventions Chemotherapy Goodnough et al (1984) lStage IV breast cancer l159 patients 1971–1980 lFive-drug regimen (CMFVP) lOverall incidence = 17.6% Number of patients p=0.05 Thrombosis on regimen Thrombosis off regimen CMFVP=cyclophosphamide/methotrexate/fluorouracil/vincristine/prednisone

Fundamental Research in Oncology and Thrombosis Monreal et al (1996) Therapeutic interventions Central venous access Thrombosis (%) lPort-A-Cath lThromboprophylaxis with dalteparin 2,500 U vs no therapy l90 day venography Dalteparin (n=16) Control (n=13)

Fundamental Research in Oncology and Thrombosis Therapeutic interventions Surgery – rate of fatal pulmonary embolism (PE) in patients undergoing surgery p=0.05 International Multicentre Trial (1975) Rahr and Sørensen (1992) Patients with cancer (n=491) 1.6 Patients without cancer (n=1585) Rate of fatal PE (%) l 4-fold increase

Fundamental Research in Oncology and Thrombosis DVT/PE only Number of days Probability of readmission Nonmalignant disease Malignant disease DVT/PE and malignant disease Levitan et al (1999) The risk of recurrence of VTE is increased in cancer patients Probability of hospital readmission with DVT/PE within 183 days of initial hospital admission

Fundamental Research in Oncology and Thrombosis DVT/PE only Nonmalignant disease Malignant disease DVT/PE and malignant disease Probability of death Number of days Levitan et al (1999) Concurrent VTE and cancer increases the risk of death Probability of death within 183 days of initial hospital admission

Fundamental Research in Oncology and Thrombosis Survival rate for patients with a diagnosis of cancer at the time of VTE Sørensen et al (2000) Years after diagnosis Cancer without VTE Survival (%) Cancer at the time of VTE p<0.001

Fundamental Research in Oncology and Thrombosis Sørensen et al (2000) Survival rate for patients with a diagnosis of cancer within 1 year after VTE Years after diagnosis Survival (%) Cancer without VTE 20 Cancer within 1 year after VTE p<0.001

Fundamental Research in Oncology and Thrombosis FRONTLINE – Rationale lThe association between venous thromboembolism (VTE) and malignant disease was first recognised by Trousseau in 1865 lYet VTE continues to be a major clinical problem in cancer patients lThere is a lack of international consensus on the prevention and treatment of VTE in cancer patients lFRONTLINE will help to collect data on perceptions and practice and further our understanding

Fundamental Research in Oncology and Thrombosis FRONTLINE – The first comprehensive global survey of thrombosis and cancer lFRONTLINE 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 lThe results of FRONTLINE may help to stimulate further research in this important area

Fundamental Research in Oncology and Thrombosis FRONTLINE participation lAll medical specialists treating cancer patients are invited to participate in FRONTLINE –surgical oncologists –medical oncologists –radiation oncologists –palliative care specialists –haematologists –oncology nurses

Fundamental Research in Oncology and Thrombosis FRONTLINE – Key dates ECCO /10 ASCO 2002 Survey results ISTH /7 ISTH /7 Data analysis Pilot survey LAUNCH and survey roll-out LAUNCH and survey roll-out ASCO /5 May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar April May

Fundamental Research in Oncology and Thrombosis lFor 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) Fax: + 44 (0) or visit : FRONTLINE – The first comprehensive global survey of thrombosis and cancer

Fundamental Research in Oncology and Thrombosis 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.