Cancer-Associated Thrombosis

1. Cancer-Associated Thrombosis Professor Mark Levine, MD, MSc McMaster University Juravinski Cancer Centre Hamilton, Ontario, Canada Guidelines for Treatment

2. Why do we treat proximal DVT? • To improve symptoms • To prevent progression and recurrence • To prevent pulmonary embolism • To prevent post-phlebitic syndrome

3. Why do we treat pulmonary embolism? • To improve symptoms • To prevent pulmonary hypertension • To prevent death

4. Adapted from Barritt and Jordan Lancet 1960. • Patients with pulmonary embolism diagnosed clinically. • Randomized to heparin 10,000 units Q6H x 6 doses plus concurrent nicoumalone for 14 days (target PT 2-3x control) or no treatment.

5. Adapted from Barritt and Jordan Lancet 1960. • In the 1st 35 patients, 0 of 16 anticoagulant patients died compared to 5 of 19 control patients, P=0.036 and 5 additional control patients had recurrent PE based on clinical diagnosis. • 3 minor bleeds on anticoagulant therapy. • Randomization was discontinued and then 38 additional patients were treated with anticoagulants with no adverse outcomes.

6. Initial Therapy: Unfractionated or Low Molecular Weight Heparin?

7. Depolymerisation of UFH UFH Molecular weight = 16,000 Da DEPOLYMERISATION LMWH Molecular weight = 4,500-5,000 Da High affinity for AT III

8. Binds less avidly to plasma proteins, platelets, and cells Dose-independentrenal clearance Good bioavailabilityafter sc injection Experimentally less bleeding Once-daily sc injection Weight-adjusted dosing No laboratory monitoring Less HIT Outpatient therapy Advantages of LMWH over UFH HIT = heparin-induced thrombocytopenia; sc = subcutaneous

9. Initial treatment of VTE LMWH vs UFH Major bleeding(n=3,674) Recurrent thromboembolism(n=3,566) Primary studies Duroux (1991) Hull (1992) Prandoni (1992) Lopaciuk (1992) Simonneau (1993) Lindmarker (1994) Levine (1996) Koopman (1996) Fiessinger (1996) Luomanmaki (1996) Columbus (1997) All studies (FEM) OR 0.57 (P=0.047) OR 0.85 (P=0.28) OR 0.87 (P=0.40) OR 0.71 (P=0.25) All studies (REM) 100 0.01 0.1 1 10 0.01 0.1 1 10 100 FavoursLMWH Oddsratio FavoursUFH FavoursLMWH Oddsratio FavoursUFH Adapted from Gould et al., Ann Intern Med 1999;130:800-9.

10. Initial treatment of VTEOutpatient LMWH vs inpatient UFH Adapted from: 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators. N Engl J Med 1997;337:657-62. 3. Koopman et al., N Engl J Med 1996;334:682-87.

11. Initial treatment of VTE Outpatient LMWH vs inpatient UFH (cont’d) † Significantly fewer hospital days in LMWH group. Adapted from 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators. N Engl J Med 1997;337:657-62. 3. Koopman et al. N Engl J Med 1996;334:682-87.

12. 30 Hazard ratio 3.2 20 Cancer Cumulative proportionrecurrent thromboembolism (%) 10 No cancer 0 0 181 661 1 160 631 2 3 129 602 4 5 6 92 161 7 8 9 73 120 10 11 12 64 115 Time (months) Cancer No cancer Cumulative Incidence of Recurrent VTE During Anticoagulant Therapy Adapted from Prandoni et al., Blood 2002;100:3484-8.

13. 30 Hazard ratio 2.2 20 Cumulative proportionmajor bleeding (%) Cancer 10 No cancer 0 0 181 661 1 170 636 2 3 141 615 4 5 6 102 170 7 8 9 81 127 10 11 12 68 124 Time (months) Cancer No cancer Cumulative Incidence of Clinically Important Bleeding During Anticoagulant Therapy Adapted from Prandoni et al., Blood 2002;100:3484-8.

14. Oral Anticoagulant Therapy in Cancer Patients • Warfarin therapy is complicated: • difficult to maintain tight therapeutic control(anorexia, vomiting, drug interactions). • frequent interruptions for thrombocytopenia and procedures. • venous access difficult. • increased risk of recurrence and bleeding.

15. Long-term Anticoagulant Therapy with LMWH • Does not require laboratory monitoring • Once- or twice-daily subcutaneous injection • Effective in warfarin resistance • Potentially less bleeding

16. CANTHANOX Trial • Cancer patients with proximal DVT and/ or PE received initial enoxaparin 1.5 mg/kg subcu daily for at least four days. • Randomized to continue enoxaparin at same dose or warfarin. • Duration of therapy was three months. Adapted from Meyer et al., Arch Intern Med 2002;162,1729.

17. CANTHANOX P=0.09 5 bleeds in LMWH and 12 in Warfarin

18. Dalteparin Dalteparin Cancer patients with acute DVT and/or PE R Dalteparin CLOT Trial Oral anticoagulant DVT, deep vein thrombosis; PE, pulmonary embolism. Adapted from Lee et al., NEJM 2003;349:146-53.

19. CLOT Trial Adapted from Lee et al. CLOT Trial 2003 Group Initial treatment Long-term therapy (5–7 days) (6 months) OAC Dalteparin 200 IU/kg Warfarin or acenocoumarol sc once daily (target INR 2.5) LMWH Dalteparin 200 IU/kg Month 1: dalteparin 200 IU/kg sc once daily Month 2–6: 75–80% of full dose OAC, oral anticoagulant.

20. Baseline Characteristics LMWH OAC N = 338 N = 338 Female gender 179 169 Age, mean (years) 62 63 Outpatient 169 156 Qualifying VTE DVT only 235 230 PE ± DVT 103 108 ECOG score 0 80 63 1 135 150 2 118 122

21. Baseline Characteristics LMWH OAC N = 338 N = 338 Extent of solid tumour 298 308 no evidence 36 33 localised 39 43 metastatic 223 232 Haematological malignancy 40 30 Cancer treatment 266 259 Central venous catheter 46 40 Previous VTE 39 36

22. Risk reduction = 52%P=0.0017 25 20 OAC 15 Probability of recurrent VTE (%) Dalteparin 10 5 0 0 30 60 90 120 150 180 210 Days post-randomization Recurrent VTE Adapted from Lee et al., NEJM 2003;349:146-53.

23. Bleeding Events LMWH OAC P* N = 336 N = 336 Major bleed 19 (5.6%) 12 (3.6%) 0.27 Any bleed 46 (13.6%) 62 (18.5%) 0.093 * Fisher’s exact test

24. Treatment of VTE: Long-term • Long-term LMWH “simplifies” treatment. • In the CLOT trial each patient who received oral anticoagulants had on average 23 INRs performed (maximum 83).

25. What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE LMWH is the preferred choice for the initial treatment. LMWH given for at least six months is preferred for long term. Vitamin K antagonist INR (2-3) when LMWH not available. American Society of Clinical Oncology Guidelines: Treatment of VTE Adapted from JCO 2007;25,5490-505.

26. What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE. After six months, indefinite anticoagulant therapy for selected patients with active cancer e.g. metastases. IVC Filter only in patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite LMWH therapy. Treatment: ASCO Adapted from JCO 2007;25,5490-505.

27. What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE. For CNS malignancy, same therapy as for other cancers. However avoid anticoagulants if active intracranial bleeding, low platelets, etc. For elderly patient with cancer and VTE same approach as for other age groups. Treatment: ASCO 2007 Adapted from JCO 2007;25,5490-505.

28. ESMO Guidelines Initial Therapy Adapted from Ann Oncol 2008.

29. ESMO Guidelines Long Term Adapted from Ann Oncol 2008.

30. Consensus Statement: International Union of Angiology and Union Internationale de Phlebologie Adapted from Int Angiol 2006;25,101-61.

31. So Where are We in 2008? Has there been much research progress since 2003 in terms of treatment of VTE in Cancer?

32. Risk reduction = 52%P = 0.0017 25 20 OAC 15 Probability of recurrent VTE (%) Dalteparin 10 5 0 0 30 60 90 120 150 180 210 Days post-randomization Recurrent VTE Adapted from Lee et al., NEJM 2003;349:146-53.

33. Progress in Treatment? • Can we do better than 8% recurrence at six months? • Has long term LMWH been adopted? • What is the duration of long term treatment? • How should a patient who develops recurrent VTE on LMWH be treated?