Anticoagulation and cancer

1. Anticoagulation and cancer Not as straightforward as it looks

2. How common is it? • Up to15% estimated clinically apparent • >50% at post-mortem in some tumour types

3. Huntershill hospice study • 298 hospice in-patients with advanced cancer • Screened for lower limb venous obstruction using a light reflection rheograph • 52% DVT • 17% bilateral • 9% symptomatic and confirmed (Doppler and - or V/Q scan)

4. Case history – Mrs D • 42 year old, 2/52 vague abdominal discomfort • Presented with perforated sigmoid carcinoma • Liver metastases at laparotomy • Post-operative PE treated initially with tinzaparin, 10/10/5 warfarin. Tinzaparin stopped • INR 11, recurrent bouts of dyspneoa • Scared, breathless

5. Case history – Mrs P • 72 year old, stomach cancer • Wants to stay at home with daughters popping in • Manages to potter about house • Overnight develops big, uncomfortable right leg • Can’t get out of chair to get to toilet unaided

6. Anticoagulation and cancer • Pathophysiology • Management: problems and solutions • What about prophylaxis? • Draw up a protocol?

7. pathophysiology • 1865: Trousseau - “..a particular condition of the blood which predisposes it to spontaneous coagulation” • Predicted his own death when he developed a left arm thrombosis • Risk is in addition to that from other contributory factors often found such as surgery, immobility, infection, old age

8. Increased risk due to cancer alone • Incidence of VTE higher in cancer vs non-cancer patients in studies of: - surgical patients - non-surgical patients - post-mortem studies • Occult malignancy is 7-8 times more common in patients with VTE with no apparent cause Prandoni P

9. Integral to cancer growth • Patients with cancer and VTE have a 3 fold lower 1 year survival than cancer patients without VTE (multi-factorial) • Evidence suggests activation of coagulation enhances cancer growth and metastasis • Evidence suggests treatment with anticoagulation improves survival (lung cancer) • Current FRAGMATIC trial to repeat these smaller studies (5000U Fragmin vs placebo in lung cancer patients) Simon Noble

11. Coagulation abnormalities • Abnormalities of coagulation are found in over 90% of cancer patients if sensitive indicators are sought • Low-grade activation of coagulation at presentation of malignancy which worsens with progressive disease • Evidence of chronic, low-grade disseminated intravascular coagulation (DIC).

12. Huntershill study (87 patients) • Fibrinogen; 66% raised levels, 4.38g/dl (NR 1.7-3.5) • Fragment 1+2; 71% raised levels, 1.9 nmol/l (NR 0.57 – 1.31) • TAT; 89% raised levels, 10.3 microg/l (NR 1 – 4.1) • Fibrinogen lower in patients with DVT (p = 0.04)

13. Mirrors disease activity • Fibrinogen, platelet count, Fibrino-peptide-A, and D-dimer have all been suggested as useful tumour growth markers but are rather non-specific • Not useful predicting thrombotic events i.e. don’t use D-dimer as a test for DVT in a patient with active cancer (it’ll be raised)

14. Pathophysiology-summary • Secretion of cancer procoagulant/tissue factor by tumour/host cells • Consumption of clotting factors • Compensatory increase in production • Leads to disseminated intravascular coagulation • Platelet activation/thrombocytopenia • Reduced protein C, antithrombin III • Liver dysfunction

15. The upshot… • Thus cancer patients have an increased risk of clotting and bleeding

16. Standard VTE management • Immediate treatment with heparin (usually LMWH) • Whilst commencing warfarin loading (10mg/10mg/5mg) • Loading dose lower in elderly (3mg) • When INR is in therapeutic range stop LMWH (5 days LMWH) • Treat for 3-6 months according to site of VTE

17. Problems with cancer patients • With warfarin: 3 x rate of recurrent VTE despite therapeutic INR • With warfarin: 6.2 x rate of major bleeding • Risks increase with extent of cancer • Risk of VTE persists as long as active cancer persists

18. More problems • Drug interactions • Malnutrition (particularly of Vitamin K) • Vomiting • Liver dysfunction • Poor venous access • Invasive procedures and chemo related thrombocytopenia often require interruption of anticoagulant • Lead to unpredictable and poor anticoagulant control • Lesions liable to bleeding

19. Low molecular weight heparin • renal excretion • few drug interactions • steady, predictable pharmacokinetics from weight adjusted dose • high subcutaneous bioavailability • long half life • no need for monitoring (except platelets initially)

20. Secondary prevention with LMWH vs warfarinLee A et al. NEJM 2003; 349:146-153 • LMWH vs coumarin prospective rct • 8% vs 15.7% recurrent VTE • No significant difference in bleeding • ECOG 3,4 excluded • Study conditions

21. Secondary prevention with LMWH vs warfarin Meyer G et al Arch Int Med 2002; 162; 1729-1735 • LMWH vs coumarin prospective rct • Combined outcome event; major bleeding or recurrent VTE in 3 months • 10% vs 21% • 6/71 warfarin; fatal bleed • 0/67 LMWH; fatal bleed • 17 warfarin all cause deaths vs 8 LMWH deaths • ECOG 3+4 included

22. A common sense approach – use LMWH if… • Advanced disease • Liver metastasis (or other cause of liver dysfunction) • Malabsorption • Likely problem with changing medication regimes • High bleeding risk • The first hint of a problem with warfarin

23. Patients won’t like the injections • Some don’t • Qualitative interviews; palliative care patients on long term LMWH showed minimal problems and some positive feelings about “having the best treatment” and “not being written off”Simon Noble • Many learn to self inject

24. Specific problems • Brain tumour (primary or secondary) • One smallish observational study showed no increase risk of bleeding with tight INR control • Sensible to use LMWH to minimise risk of over-anticoagulation • ! Melanoma and renal tumours are very vascular – reluctant to anticoagulate at all if brain secondaries

25. Specific problems • Actively bleeding lesions (or high risk) • Suggest bd LMWH to even out peaks and troughs • IVC filter • Thrombocytopenia • Weigh up risk and benefits on individual patient • LMWH has least risk of over-anticoagulation • IVC filter

26. IVC filters • Can be very useful if anticoagulation is contraindicated • Long term risk of bilateral leg oedema • Procedure involved • Expense, therefore consider prognosis • Usual judgement is 3 months or more expected prognosis

27. example • 65 yr old nun with endometrial carcinoma • Treated with progestagens • Presented with 3 months h/o progressive breathlessness, can’t walk across room • V/Q multiple PEs • Continuous minor bleeding from tumour (manageable, but increased bleed wouldn’t be)

28. example • Stopped progestagens • Placed IVC filter • Over next 3 months patient’s breathlessness improved to the extent she was now walking down to the shops and back and going out for trips • 14 months did well • Disease progression, leg oedema and died about 18 months after I first saw her

29. summary • Clinical decision making with minimal evidence, but there is some • Important to attempt “decision making” rather than knee jerk reaction • Discuss options with patient if possible to prevent “paternalistic approach” • Often requires a “bespoke regime”

30. Future options? • Oral anti-thrombin agent Ximegalotran • Looked promising, company withdrawn (deaths due to liver disease) • Pentasaccharides and heparinoids • Danaparoid = choice in heparin induced thrombocytopenia

31. What about prophylaxis? • Hickman lines? • Chemotherapy? • Orthopaedic surgery • Abdomino-pelvic surgery • Don’t forget for palliative procedures • Spinal cord compression? • Acute reversible episodes – hypercalcemia? - pneumonia?

32. Prophylaxis in the patients with advanced disease • Still little evidence • Some qualitative data to suggest patient want to be involved in the decision Simon Noble • However, what about the patient who is not going to improve their performance status? (i.e. in bed in hospital, in bed at home) – nothing reversible • Currently we wouldn’t recommend prophylaxis in that situation

33. Risks/benefits • LMWH safer, effective • daily subcutaneous injection but no monitoring needed • Occasionally – IVC filter • ?how long to treat • still individual decision

34. 42 year old, 2/52 vague abdominal discomfort Presented with perforated sigmoid carcinoma Liver metastases at laparotomy Post-operative PE treated initially with tinzaparin, 10/10/5 warfarin. Tinzaparin stopped INR 11, recurrent bouts of dyspneoa Scared, breathless 72 year old, stomach cancer Wants to stay at home with daughters popping in Manages to potter about house Overnight develops big, uncomfortable right leg Can’t get out of chair to get to toilet unaided Case histories – what would you do?

35. Protocol • Literature review – currently underway for secondary and primary prevention as part of APM Science Committee Task Group Noble and Johnson • Prevalence and Pathophysiology • General considerations for cancer patients • Secondary prevention • Primary prevention