CANCER ASSOCIATED THROMBOSIS. Pankaj Handa Department of General Medicine Tan Tock Seng Hospital

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1 CANCER ASSOCIATED THROMBOSIS Pankaj Handa Department of General Medicine Tan Tock Seng Hospital

2 My Talk Today 1.Introduction 2. Are All Cancer Patients at Risk of VTE? 3. Should All VTE Patients Be Screened For Cancer? 4. Are there any Biomarkers for VTE in Cancer Patients? 5. Risk Stratification of VTE in Cancer Patients. 6. CAT at Tan Tock Seng Hospital. 7. Treatment Options/ ACCP Guidelines

3 TROUSSEAU S SYNDROME 1865 Spontaneous venous thromboembolism in association with clinically occult malignant disease when you are undecided about the nature of the disease of the stomach, when you hesitate among chronic gastritis, simple ulcer, and a carcinoma, a phlegmatia alba dolens occuring in the leg or arm will enable you to assert positively that a cancer is present -Armand Trousseau 1865 lecture in Paris

4 Introduction Thrombosis Cancer : A Double-Edged Sword. Malignancy increases the risk of VTE by a factor of % cancer patients may develop with VTE Development of VTE in a patient with known cancer is the most common presentation, but VTE may precede the diagnosis of malignancy by many months.

5 Introduction Critical oncogenic events Activation of the coagulation cascade Prothrombotic environment VTE Growth and Progression of the Malignancy

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7 Introduction CAT is the 2nd leading cause of death in cancer patients 1-year survival With VTE : Without VTE (12% vs. 36%) In- hospital Mortailty Double in the patients who develop VTE in hospital Significant proportion of cancer patients with VTE have limited cancer disease that in the absence of fatal PE would have been associated with considerably longer survival

8 Introduction Cancer patients are also prone to adverse effects and failure of anticoagulant therapy. Annual risk : recurrent VTE is 21% 27% major bleeding is 12% 13% On warfarin : 2 to 6 times more major bleeding episodes 2 to 3 times more VTE recurrences.

9 2. Are All Cancer Patients At Risk of VTE?

10 Risk Factors for VTE in Cancer Patients

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12 Risk Factors for VTE in Cancer Patients Metastatic disease at the time of diagnosis is the strongest predictor of thromboembolism ( fold higher risk of VTE than patients with localised disease) VTE : chemotherapy three times radiotherapy two times distant metastases six times

13 Annual VTE Risk in Cancer Patient (Solid Tumours) Type of Cancer Localised Metastatic Pancreas 4.2% 20% Stomach 2.5% 10.7% Uterus 0.8% 6.4% Kidney 1.2% 6% Lung 1.1% 5%

14 VTE and Type of Malignancy Type Adjusted Odds Ratio (95%CI) Haematological 28 ( ) Lung 22.2 ( ) Gastrointestinal 20-3 (4.9-83)

15 Risk of VTE in Acutely ILL Ca Patients In hospitalised medical patients with acute illness, cancer is independently associated with a 1.6-fold increase in the risk of VTE In-hospital mortality rate is significantly greater - VTE vs No VTE (OR 2.01; 95% CI ) - localised cancer as well as advanced disease International guidelines recommend the use of prophylaxis with UFH or LMWH for patients with active cancer who are confined to bed in hospital

16 3. Should We Screen All VTE Patients for Cancer?

17 Screening for Occult Malignancy The most appropriate strategy in patients with unprovoked VTE is a thorough history and physical examination, followed by patient-specific laboratory testing and imaging. Routine screening for cancer using extensive investigations in these patients does not appear to provide a survival advantage

18 4. Are There Any Biomarkers For Diagnosis of VTE in Cancer Patients?

19 Candidate Biomarkers Blood Counts: - Platelet count - Leukocyte count - Haemoglobin Tissue Factor Soluble P - selectin D - dimer C reactive protein

20 Candidate Biomarkers Tissue Factor - physiologic initiator of the coagulation cascade, but it appears to play multiple roles in cancer pathogenesis and may be important for angiogenesis in tumors as well. - high levels have been identified in blood of patients to be associated with the risk for VTE

21 Two-Way Biological Relationship Activation of coagulation Growth and Metastatic potential of tumor cells inhibition of the clotting cascade activation or thrombin activity may have antineoplastic effects (LMWH)

22 5. Risk Stratification of VTE in Cancer Patients

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25 6. Cancer Associated Thrombosis At Tan Tock Seng Hospital

26 CAT at Tan Tock Seng Hospital Retrospective 5 year study (Jan 2006-December 2010) Patients discharged with diagnosis of Cancer and Thrombosis Total 93 Age Sex 68.9 years Male(47.31%) Female(52.68%) Race Chinese (79.56 %) Malay (13.97 %) Indian (06.45 %)

27 VTE Association with Type of Cancer Lung Haematological Colon Pancreas Stomach Breast Gall Bladder 5 0

28 VTE : Prevalence BOTH 16% DVT PE BOTH PE 17% DVT 67%

29 Percentage VTE - Deep Vein Thrombosis % % % 11% 8% 14% 0 Proximal Distal Both UL DVT Others No DVT

30 Onset of VTE

31 Axis Title Treatment Only VKA Only LMWH Only IVC VKA + LMWH VKA + IVC LMWH + IVC Nil Axis Title

32 7. Treatment Options for VTE in Cancer Patients

33 Treatment of VTE in Patients with Cancer (A) Initial Treatment LMWHs have become preferred mode of treatment for the initial treatment of VTE in cancer Hettiarachchi RJ, Curr Opin Pul Med, A meta-analysis of studies: UFH vs LMWH. LMWH : at least as safe and effective as UFH : reduced mortality risk in these patients.

34 Treatment of VTE in Patients with Cancer (B) Long-Term Treatment Difficulties with (OAC) Warfarin : Prandoni P; Blood, OAC in patients with cancer( vs without cancer) - two to three-fold increase in recurrent VTE - two to six fold increase in major bleeding Other problems : potential for drug interactions( chemotherapy) poor intestinal absorption altered hepatic function

35 Treatment of VTE in Patients with Cancer Difficulties with (OAC) Warfarin : In patients with cancer receiving warfarin for VTE, the risk of bleeding and recurrent VTE remains high, even when the INR is within the target range. Palareti G; Throb Haemost Bleeding rate is consistently high and is independent of the INR value in patients with cancer. Prandoni P; Blood,2002. At the time of recurrence, the INR value is within or above the target range in a higher proportion of cancer

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37 Treatment of VTE in Patients with Cancer Meta-analysis of 4 studies: - Prolonged treatment with LMWH statistically significant and clinically important 50% reduction in the rate of recurrent VTE (6.5 vs12.6%,rr 0.52, 95% CI ; p=0.001) No significant difference between warfarin and LMWH for the risk of bleeding

38 LMWH :Treatment of VTE in Ca Patients American College of Chest Physicians (ACCP) American Society of Clinical Oncology (ASCO) National Comprehensive Cancer Network (NCCN) The Italian Medical Oncology Society (AIOM) Long-term anticoagulant therapy for patients with DVT and cancer should involve LMWH rather than VKAs. Duration: at least three to six months

39 8. Anticoagulant Treatment and Survival in Cancer Patients

40 Effects of Anticoagulant treatment on Survival in Patients with Cancer Several studies have suggested a link between anticoagulant therapy and improved survival in patients with malignancy. Zacharaski LR;Cancer,1984 a prospective, randomised clinical trial warfarin was associated with significant prolongation of progression-free and overall survival in patients with small-cell lung cancer However, in patients with other types of tumour, warfarin had no effect on survival.

41 Effects of Anticoagulant treatment on Survival in Patients with Cancer Furthermore, subsequent trials of VKAs in patients with cancer have provided conflicting results. Smorenburg SM;Thromb Haemost, a systematic review concluded that there was insufficient evidence that long-term VKA administration provided a survival benefit in patients with cancer Smorenburg SM;Thromb Haemost, 1999 Similar uncertainty surrounds the effect of UFH on survival

42 LMWHs on Survival in Patients with Cancer Hettiarachchi RI. Curr Opin Pulm Med, Ca patients who receive LMWH (vs UFH) for the initial treatment of acute DVT may have prolonged survival Altinbas M. J Thromb Haemost, small-cell lung cancer. - overall survival - significantly prolonged (LMWH + Chemotherapy) - both in patients with extensive / limited disease.

43 LMWHs on Survival in Patients with Cancer Improvement in survival associated with LMWHs may be independent of their anticoagulant effects. Antitumour effects of LMWH: - inhibition of neoangiogenesis - inhibition of tumour-cell-derived heparanase activity, - induction of apoptosis - inhibition of tumour cell adhesion to endothelial cells

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45 LMWHs on Survival in Patients with Cancer Clinical studies conducted so far have produced conflicting results, and evidence for prolonged survival in cancer patients with LMWH comes mainly from post hoc analyses Additional studies conducted in patients with specific cancer types are needed to confirm these preliminary findings Such studies are currently under way in several cancer types including lung, prostate, pancreas, ovary and stomach

46 ACCP Guidelines on VTE in Cancer Patients A. P R O P H Y L A X I S 1. Ambulatory patients receiving chemotherapy. Routine prophylaxis NOT recommended.(1c) 2. Patients with Central Venous Catheters. Routine prophylaxis NOT recommended. (1A) 3. Hospitalised patients with Acute Medical Illness. Routine Thrombo - prophylaxis recommended. (1A)

47 ACCP Guidelines on VTE in Cancer Patients 4. Prophylaxis during Surgery - Routine thrombo-prophylaxis that is appropriate for the type of surgery is recommended (1A) 5. Prophylaxis after discharge - High risk GS patients, including those who have undergone major Ca surgery/ past DVT : Continue LMWH thrombo- prophylaxis x 28/7. (2A) -Similar Gynaecology patients. : Continue LMWH thrombo- prophylaxis x 28/7..(2C)

48 ACCP Guidelines on VTE in Cancer Patients 6. Suggested Regimen for Prophylaxis of VTE - ACCP: No specific recommendation - ASOC: UFH 5000 U TID LMWH: Dalteparin 5000 U OD Enoxaparin 40 mg OD Fondaparinux 2.5 mg OD - NCCN Tinzaparin 4500 U or 75 U/kg OD

49 ACCP Guidelines on VTE in Cancer Patients 7. Mechanical Devices where anticoagulant treatment (ACT) is contraindicated - graduated compression stockings - intermittent pneumatic compression (1A) When the bleeding risk decreases, pharmacological thrombo-prophylaxis be substituted for or added to the mechanical one (1C) Recommendation against the use of IVC filter in trauma patients with acute spinal injury (1C)

50 ACCP Guidelines on VTE in Cancer Patients B. T R E A T M E N T 1. Acute DVT - LMWH : first 3 6 months (1A) - Subsequent LMWH/ VKA therapy indefinitely or until the cancer is resolved 2. Mechanical Devices where ACT is contraindicated - IVC filter (1C) - when the bleeding risk decreases, conventional course of ACT should be given.

51 ACCP Guidelines on VTE in Cancer Patients 3. Treatment similar to that for DVT of the leg is also recommended for DVT of the upper extremity 4. Patients with lower- and upper-extremity DVT may be considered for thrombus removal using catheter-based thrombolytic techniques. 5. Prophylactic or four weeks of intermediate doses of LMWH or UFH should be used in patients with extensive Superficial Vein Thrombosis

52 Take Home Message Patients with cancer are at high risk of thrombosis, and this is an important cause of avoidable mortality in these patients. CAT is associated with : Higher - Mortality - Recurrence of VTE - Bleeding complications These patients present unique challenges that affect the safety and efficacy of antithrombotic therapies.

53 Take Home Message Current data indicate that LMWHs offer several practical advantages for cancer patients, in addition to superior efficacy to OAC without increasing the risk of bleeding. Preliminary data suggest that LMWH administration may be associated with an increase in patient survival

54 THANKS VERY MUCH

55 Treatment of VTE in Patients with Cancer Other important issues of LMWH therapy: - Heparin Induced Thrombocytopaenia (HIT) - Drug Accumulation: Short term Long term

56 LMWH :Treatment of VTE in Ca Patients Heparin Induced Thrombocytopaenia (HIT) Eight studies: Prospective cohorts; 900 patients Not a single episode of HIT. Thrombocytopenia is a common complication in cancer patients receiving chemotherapy Lee; NEJM,2003 For the use of Dalteparin Platelet >100,000/mm 3 Standard Dose 50, ,000 Reduce dose to 3000 IU < 50,000 Stop treatment

57 LMWH :Treatment of VTE in Ca Patients Risk of Drug Accumulation (A) Short Term CLOT trial: - 24 patients receiving dalteparin 200IU/kg once daily - anti-xa measurement at weeks one and four. - at week four, the mean anti-xa level was 1.03 anti-xa units/ml (95% CI ) and did not differ significantly from the value obtained during week one.

58 LMWH :Treatment of VTE in Ca Patients (B) Long Term: Renal impairment is a frequent co-morbid condition in patients having cancer. Renal function may be further impaired as a result of chemotherapy-related nephrotoxicity. Measurement of creatinine clearance is recommended before starting prolonged LMWH

59 LMWH :Treatment of VTE in Ca Patients Tinzaparin may be the most suitable option for patients with moderately impaired renal function. Siguret; Thromb Haemost The results of a study completed in a group of patients with a wide distribution of creatinine clearance indicate that the anti-xa effect of tinzaparin does not increase over 10 days of administration