Cancer and the Heparins

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1 Cancer and the Heparins Wim P Ceelen, MD, PhD, FACS Department of GI Surgery - UZ Gent Senior Clinical Researcher - FWO

2 Overview Mechanisms of cancer induced thrombosis Guidelines for prevention and treatment of VTE in cancer patients Links between heparins and cancer growth Mechanisms Clinical data

3 Armand Trousseau ( ) Je suis perdu, une phlébite qui vient de se déclarer cette nuit ne me laisse plus aucun doute sur la nature de mon mal

4 Incidence of VTE in cancer patients First recognized by Trousseau (1865) Occurs in 4% - 20% of cancer patients Cancer with VTE worse prognosis

5 VTE rate over time in Cancer patients Lyman Cancer 2009

6 VTE within Two years of Cancer Diagnosis Metastatic Disease Local-Regional Disease Chew, H. K. et al. Arch Intern Med 2006;166:

7 Virchow s Triad Stasis Trauma Hypercoaguability Virchow RLK (1856). "Thrombose und Embolie. Gefässentzündung und septische Infektion". Gesammelte Abhandlungen zur wissenschaftlichen Medicin. Frankfurt am Main: Von Meidinger & Sohn. pp

8 What causes hypercoagulability in Cancer Patients? 1. tumor-derived production of pro-coagulants: tissue factor (TF), thrombin, and others 2. Tumor-mediated activation of monocytes, platelets, and endothelial cells 3. Mechanical factors

9 The Extrinsic Coagulation Pathway F7a FX TF FXa FII FIIa (thrombin) Fibrinogen Fibrin

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11 Thromboembolism With Bevacizumab Venous Thromboembolism: Meta-Analysis of RCTs Relative Risk = 1.33 [95% CI: ] Absolute Risk Increase: 2.2% [95% CI: 1.1% - 3.3%] Nalluri, S. R. et al. JAMA 2008;300:

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13 VTE prevention in surgical cancer patients: ASCO recomendations (2007) 1. Major surgery thromboprophylaxis using LMWH. should be commenced preoperatively Mechanical methods may be added, but should not be used as monotherapy 2. Duration: 7 to 10 days postoperatively, or up to 4 weeks in patients undergoing major abdominal or pelvic surgery for cancer with high-risk features.

14 Enoxaparin 40 mg o.d. (n=332) Dalteparin 5000 IU o.d. (n=117) Total DVT (%) 12 20/167 P= /165 Total DVT (%) /63 8 4/54 1 week 4 weeks Bergqvist D et al. N Engl J Med 2002;346: week 4 weeks Rasmussen MS et al. Cancer Treatment Rev 2002;28:141 4

15 VTE prevention in cancer patients undergoing chemotherapy Routine prophylaxis not recommended Exception: myeloma patients treated thalidomide + chemotherapy or dexamethasone Research identifying better markers of ambulatory patients with cancer most likely to develop VTE is urgently needed

16 P = % PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) 2%

17 VTE therapy in cancer patients: ASCO recommendations (2007) Preferred: LMWH during 6 months Indefinite anticoagulant therapy in pts with metastatic disease / chemotherapy (expert opinion) Vena cava filter: only when contraindications to anticoagulant therapy

18 VTE therapy in cancer patients: LMWH or VKA? CLOT study Risk reduction = 52% Lee et al. NEJM 2003

19 LMWH vs VKA Prevention of Recurrent VTE Bleeding Events Mortality Sample Size CANTHANOX At least as effective No difference No difference Calculated a priori ONCENOX Favor LMWH No difference Not Specified Not calculated a priori Main-LITE Favor (12mo) No difference No difference Not calculated a priori CLOT Favor (6mo) No difference No difference Calculated a priori

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22 Overview Mechanisms of cancer induced thrombosis Guidelines for prevention and treatment of TE events in cancer patients Links between heparins and cancer growth Mechanisms Clinical data

23 Anticancer activity of heparins: postulated mechanisms 1. Interference with coagulation cascade (fibrin; TFPI) 2. Interference with binding of adhesion molecules 3. Inhibition of heparanase activity 4. Inhibition of angiogenesis?

24 VEGF,bFGF Heparanase F7a TFPI FX EC Heparins TF Antithrombin FXa FII FIIa (thrombin) Fibrinogen Fibrin

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27 Effect of Heparins on cancer survival: available clinical evidence From VTE therapy trials in cancer patients Subgroup analyses (patients with better prognosis) Hypothesis generating From survival studies in cancer patients without VTE using heparin or LMWH: 4 randomized studies

28 CLOT study subgroup analysis HR 0.50 (95% CI, 0.27 to 0.95; P.03) dalteparin coumarin Lee J Clin Oncol 2005

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30 Anticoagulants, particularly LMWH, significantly improved overall survival in cancer while increasing the risk for bleeding complications. However, given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results

31 The INPACT Study (Improving with Nadroparin the Prognosis in Advanced Cancer Treatment) Patients with cancer of lung, prostate, or pancreas Usual care (n=250) Usual care + Nadroparin *(n=250) Primary endpoint: Mortality

32 Median survival, INPACT study Nadroparin Control 0 P = 0.48

33 Ongoing Randomized Clinical Trials Testing the Effect of LMWH on Survival in Cancer Patients Study LMWH Tumor Type(s) INPACT Nadroparin Advanced prostate, non-small cell lung, pancreatic Principal Investigator H. Buller FOCUS Dalteparin Ovarian A. Lee FRAGMATIC Dalteparin Lung S. Noble ABEL Bemiparin Small cell lung R. Lecumberri TILT Tinzaparin Non-small cell lung (I, II, III-A) G. Meyer & P. Girard GASTRANOX Enoxaparin Gastric (III/IV) A. K. Kakkar INPACT=Improving with Nadroparin the Prognosis in Advanced Cancer Treatment; FOCUS=Fragmin in Ovarian Cancer: Utility on Survival; FRAGMATIC=Fragmin Added to Standard Therapy in Patients with Lung Cancer; ABEL=Adjuvant Bemiparin in Small Cell Lung Carcinoma; TILT=Tinzaparin in Lung Tumors. Courtesy Dr Anna Falanga

34 Conclusions VTE is common in cancer patients, and associated with a worse outcome LMWH is the standard in perioperative prevention and treatment of DVT in cancer patients LMWH s may exert antitumor and/or antiangiogenic effects