1. Epidemiology of VTE in Patients with Cancer Paolo Prandoni, MD, PhD University of Padua (Italy) ESMO, Stockholm 2008

2. Adapted from Levitan et al, Medicine 1999. 120 117 110 98 81 76 Ovary Brain Pancreas Lymphoma Leukaemia Colon Lung 61 Cancer type 0 20 40 60 80 100 120 140 Rate per 10,000 patients Risk of Thrombosis According to Cancer Type

4. 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 Cancer Methods And Results

5. 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 diagnosis53 fold increase Patients with distant metastasesHigher Risk Cancer patients with thrombophiliaHigher Risk The “MEGA” Study Adapted from Blom et al., JAMA 2005; 293:715-22.

6. 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)

7. Risk Factors For VTE In Patients With Cancer

8. 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.

9. Postoperative DVT in Cancer Patients Kakkar, 197024/59 (41%)38/144(26%) Hills, 19728/16 (50%)7/34(21%) Walsh, 197416/45 (35%)22/217(10%) Rosenberg, 197528/66 (42%)29/128(23%) Pineo, 197910/30 (33%)13/134(10%) Allan, 198331/100 (31%)21/100(21%) Sasahara, 19849/37 (22%)13/53(24.5%) Sue-Ling, 198612/23 (52%)16/62(26%) TOTAL138/376 (37%)159/872(18%) Postoperative DVT CancerNon-cancer

10. Late Postoperative VTE in Cancer Patients OVERALL VTE PROXIMAL DVT PE ENOXACAN II Study, adapted from Bergqvist et al, 2002.

11. 0 2 4 6 8 10 12 14 16 Non-cancerCancer 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

12. Sub Analysis of the Medenox Study OR (95% CI) Previous VTE2.06 (1.10-3.69) Acute infectious disease1.74 (1.12-2.75) Cancer1.62 (0.93-2.75) Age > 75 yrs1.03 (1.00-1.06) Chronic respiratory disease0.60 (0.38-0.92) Adapted from Alikhan et al, Arch Int Med 2004.

13. Predictors of VTE During Hospitalization in Medical Patients OR (95% CI) Trauma < 3 months7.9 (1.1-54.9) Platelet count > 350/nl3.1 (1.4-7.0) Leg edema 3.0 (1.2-7.3) Cancer2.8 (0.8-9.5) Pneumonia2.7 (1.2-5.8) Adapted from Zakai et al, JTH 2004.

14. Venous and Arterial Thrombosis in Cancer Patients During Chemotherapy Weiss, 1981433Breast stage II 22 (5%)0* Goodnough, 1984159Breast stage IV 24 (15%)4 (2.5%) Levine, 1988205Breast stage II 14 (7%)0* Saphner, 19912352Breast 128 (5%)0* * statistically significant Type of Thrombosis ncancer during after chemotherapy

15. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW Development and Validation of a Predictive Model for Chemotherapy-associated Thrombosis Blood 2008

16. Patient CharacteristicRisk Score Site of cancer: stomach, pancreas2 Site of cancer: lung, lymphoma, gynaecologic, bladder, testicular 1 Platelet count > 350,000/mm 3 1 Haemoglobin < 10 g/dl or use of erythropoietin1 Leukocyte count > 11,000/ mm 3 1 Body mass index > 351 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.

17. 0 2 4 6 8 10 12 14 16 TamoxifenTamoxifen + CT Rate of thrombosis (%) p=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

18. 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

19. Venous Thromboembolism And Mortality Associated With Recombinant Erythropoietin And Darbepoetin Administration For The Treatment 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.

20. Overall Mortality Rates

21. VTE Rates

22. Endpoint Total DVT Lokich, 1983Venography 42% Bern, 1990Venography 37% Monreal, 1996Venography 61.7% Verso, 2005Venography18.0% Luciani, 2001Doppler US11.8% Couban, 2005Clinical 4% Reichardt, 2002Clinical 4% Karthaus, 2005Clinical 3.4% Lee, 2006Clinical 4.3% Incidence of CVC-related DVT without Prophylaxis

23. Incidence Of Recurrent VTE In Patients With Cancer

24. 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.

25. Prevalence of Potential risk factors for DVT (N=355) Malignancy58(16.3%) Surgery (< 3 months)68(19.1%) Trauma or fracture62(17.5%) Thrombophilia46(13.0%) Immobilization (> 7 days)52(14.6%) Pregnancy or childbirth 7/161(4.3%) Contraceptives18/161(11.2%) High dose estrogens7(2.0%) Adapted from Ann Intern Med 1996; 125:1-7.

26. Cumulative Incidence of VTE Recurrences (78/355)

27. Risk factors for VTE Recurrences Baseline featuresRR 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

28. 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

29. Cumulative Incidence Of Recurrent Thromboembolism In Patients On Anticoagulant Therapy 20 246810 12 cancer % Months Risk ratio=3.2; P<0.001 18 10 5 no cancer

30. 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)

31. 5 10 15 20 2468 10 12 cancer no cancer % Months HR=2.1; P=0.019 Cumulative Incidence Of Major Bleeding On Anticoagulation Therapy

32. 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)

33. Predicting Recurrences Or Major Bleeding In Cancer Patients With Venous Thromboembolism Findings 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

34. Main Clinical Characteristics Of Cancer Patients Who Did And Did Not Experience Recurrent VTE And Major Bleeding

35. Multivariate Analysis On The Risk To Develop Recurrent PE, Recurrent DVT, Or Major Bleeding

36. Incidence Of Cancer In Patients With VTE

37. Development of Subsequent Cancer Idiopathic VTESecondary VTE Aderka, 19869/35(25.7)2/48(4.2) Monreal, 1988-91-978/148(5.4)4/718(0.6) Prandoni, 199211/145(7.6)2/105(1.9) Ahmed, 1996 3/113(2.7)0/83(0) Hettiarachchi, 199710/155(6.5)3/171(1.8) Rajan, 198813/152(8.6)8/112(7.1) Subirà, 1999 0/10 (0) 0/30 (0) Schulman, 200093/534(17.4)18/320(5.6) TOTAL147/1292(11.4)37/1587(2.3)

38. 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

39. Study Results Sorensen, DVT173713721.3 (1.21-1.33) Sorensen, PE7305561.3 (1.22-1.41) Baron25097843.2 (3.1-3.4) Murchison444134691.3 (1.25-11.33) White 596 443 1.3 (1.2-1.5) SIR = standardized incidence ratio Cancers ObservedExpectedSIR

40. Risk of Cancer in Relation to Length of Time 4.0 0-6 m6-12 m1-2 y2-5 y5-10 y> 10 y DVT 3.0 2.0 1.0 PE Adapted from Sorensen et al., NEJM 1998;338:1169-73. SIR- Standardized incidence ratio

41. 4.0 24816610121424222018 Years after hospital admission 0 Adapted from Baron et al., Lancet 1998;351:1077-80. SIR- Standardized incidence ratio 3.0 2.0 1.0 Risk Of Cancer By Years After Hospital Admission

42. 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

43. 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.

44. Persist activation Control group n=111 n=2941 Main Results Total mortality (/1000 p-yrs)17.19.7 Mortality from all cancers11.35.1 Total digestive cancers8.52.9 Fatal digestive cancers6.31.9 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.

45. 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

46. RESULTS

47. 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

48. 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.

49. 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

50. Incidence Rate Ratios for Prostate, Bladder and Kidney Cancer

51. The Effect Of Low-molecular-weight Heparin On Cancer Survival A Systematic Review And Meta-analysis Of Randomized Trials J Thromb Haemost 2007; 5: 729-37 LAZO-LANGNER A, GOSS GD, SPAANS JN, RODGER MA

52. Pooled Odds Ratio of Death (random-effects model)

53. 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

54. 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

55. 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