Risk of thrombosis during chemotherapy in cancer patients. Fabio Ciceri, MD Hematology San Raffaele Scientific Institute Milano.

Transcription

1 Risk of thrombosis during chemotherapy in cancer patients Fabio Ciceri, MD Hematology San Raffaele Scientific Institute Milano. Italy

2 Contents 1. definitions 2. biological issues that predispose cancer patients to thrombosis 3. the dimension of thrombosis issue in cancer 4. individual patient risk-assessment of thrombosis 5. prophylactic and treatment measures

3 1- definitions

4 Vascular thrombosis clinical syndromes in cancer patients arterial syndromes venous thromboembolism microangiopathies

5 Arterial thrombotic events Event Category Cardiovascular Cerebrovascular Peripheral vascular Event Terms Acute coronary syndrome; acute myocardial infarction; angina pectoris; angina unstable; cardiac discomfort; coronary artery disease; coronary artery occlusion; coronary artery stenosis; electrocardiogram T wave inversion; myocardial infarction; myocardial ischemia; troponin I increased; troponin increased Aphasia; carotid artery stenosis; cerebellar infarction; cerebral artery stenosis; cerebral infarction; cerebral ischemia; cerebrovascular accident; cerebrovascular insufficiency; dysarthria; hemiparesis; hemiplegia; transient ischemic attack; vertebral artery stenosis Arterial stenosis limb; embolism arterial; extremity necrosis; femoral arterial stenosis; femoral artery occlusion; intermittent claudication; peripheral arterial occlusive disease; peripheral coldness; peripheral ischemia; poor peripheral circulation; Raynaud's phenomenon; subclavian artery stenosis; ischemic ulcer

6 Thrombotic microangiopathies Thrombotic Thrombocytopenic Purpura (TTP) Hemolitic-uremic syndrome (HUS) Malignant Hypertension Scleroderma HELLP Post Transplant Microangiopathy (TAM)

7 VTE: definitions Deep vein thrombosis (DVT) and pulmonary embolism (PE) are collectively known as venous thromboembolism (VTE) Hypercoagulable state is a biological hallmark of cancer, although only rarely results in a clinically relevant intravascular coagulation

8 2- Biology of VTE in cancer

9 Endothelial damage induced by anti-tumor agents Carreras BMT 2011

10 VCAM-I

11 The long pentraxin PTX3 Short pentraxins Long pentraxins PTX3 Protomer 381 aa - 43 Kda N-linked glycosilation site 2 Kda 8 protomers forming an elongated octamer Garlanda, Bottazzi and Mantovani, Annu Rev Immunol 2005; Bottazzi, Doni, Garlanda, Mantovani, Annu Rev Immunol 2010; Inforzato et al., J. Biol. Chem. 2010

12 CELLULAR SOURCES and FUNCTIONS OF PTX3 TLR AGONISTS (LPS. OmpA, CpG..) PRIMARY INFLAMMATORY CYTOKINES (IL-1, TNF) IL-10 OXIDIZED LDL GDF9 FSH, camp, EGF (+ oocyte) PMN Mø MATRIX DEPOSITION and ANGIOGENESIS Interaction with TSG-6 and IaI. Interaction with FGF2 (Garlanda Bottazzi and Mantovani Annu Rev Immunol 2005; Bottazzi Curr Op Immunol 2006) myeloid DC Fibroblasts Decidual stromal cells INNATE IMMUNITY Resistance to A. fumigatus, P. brasiliensis, P. aeruginosa, K. pneumoniae, CMV, Influenza virus... adipocytes PTX3 mesangial cells SMC Endothelium Epithelium Granulosa cells FERTILITY Cumulus oophorus maturation Fertilization Decidualization and placentation Implantation INFLAMMATION Complement modulation through interaction with C1q and Factor H. Interaction with apoptotic cells and P-selectin.

13 PTX3 in human pathology Hischemic heart disease, heart failure (Circulation 2000, 2004) Atherosclerosis (Rolph et al. Arterioscler.Thromb.Vasc. Biol.2002) Small vessel vasculitis, RA (Arthritis Rheum 2001, 2006, Clin. Exp. Immunol. 2000) Sepsis (Mueller et al. Crit. Care Med. 2001) Infections: TBC, Dengue, Influenza, Aspergillosis, Leptospirosis, Meningococcus. Preeclampsia Genetic polymorphisms (TB; pregnancy; P.aeruginosa infection in CF)

14 Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction In 724 patients with MI and ST elevation, PTX3, C reactive protein (CRP), creatinekinase (CK), troponin T (Tn-T), and N-terminal pro-brain natriuretic peptide (NTproBNP) were assayed at entry, 3h and 22h from symptom onset. PTX3, but not CRP or other cardiac biomarkers, predicted 3-month mortality. (Latini R. et al. Circulation 2004)

15 PTX3 (ng/ml) PTX3 maternal levels in relation to severity of preeclampsia *** *** AGA mild PE severe PE ** The severity of the disease correlates with maternal PTX3 levels. The highest PTX3 level was observed in a case of eclampsia. Maternal plasmatic median levels. p<0.001; **p<0.01

16 16 Defibrotide By decreasing levels of tissue thromboplastin and increasing tissue factor pathway inhibitor (TFPI) Reducing inflammation By decreasing local cytokine release By blocking tissue factor (TF) expression, the most important activator of the coagulation cascade which may help reduce microvascular fibrin deposition Reducing coagulation/ thrombosis Defibrotide Inducing fibrinolysis By increasing levels of tissue tpa and also reducing PAI-1 levels which have been demonstrated to play a key role in VOD Defibrotide also modulates platelet activity by increasing levels of endogenous prostaglandins (PGI-2 and E-2) 1. Coccheri S & Biagi G. Cardiovasc Drug Rev 1991;9: ; 2. Palmer KJ & Goa KL Drugs 1993;45: ; 3. Falanga A et al. Leukemia 2003;17:

17 Hypercoagulable state activation of thrombin and fibrin formation Procoagulants are released directly by the tumor cell indirectly through the activation of endothelial and inflammatory cells Tissue factor (TF) TF is the physiological initiator of coagulation TF expression varies among different types of cancer and increases with advanced cancer stage TF also has signaling properties and enhance tumor growth, invasion, angiogenesis and hematogenous metastasis

18 2- Biology of VTE in cancer Tissue factor (TF) is a key mediator of clotting, inflammation, tumor progression and angiogenesis

19 Biomarkers of hypercoagulable state

20 3-epidemiology of VTE in cancer

21 Epidemiology of VTE in cancer 4x to 6x increased risk of thrombosis VTE 2% to 8% An optimal strategy for screening for occult cancer in patients with idiopathic VTE has not yet been established; PET CT scanning is the latest promising approach to be investigated Blom, J. W.et al. JAMA 2005 Rondina, M. T. et al. Thrombosis Research 2012 Khorana, A. A. & Connolly, G. C. J Clin Oncol 2009

22 4- VTE individual risk-assessment

23 Risk factors and biomarkers Lyman GH et al J Clin Oncol 2013

24 VTE patient risk-assessment outpatients under chemotherapy Khorana A A et al Blood 2008

25 Rates of VTE according to scores from the risk model 2008 by American Society of Hematology Khorana A A et al. Blood 2008

26 5- VTE prophylaxis and treatment

27 Lyman GH et al J Clin Oncol 2013

28 VTE prophylactic and treatment hospitalized patients Hospitalized patients with active malignancy with acute illness or reduced mobility should receive thromboprophylaxis Patients without additional risk factors may be considered for thromboprophylaxis

29 VTE prophylactic and treatment outpatients Routine pharmacologic thromboprophylaxis is not recommended in cancer outpatients Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients

30 VTE prophylactic and treatment perioperative All patients with malignant disease undergoing major surgery should be considered for pharmacologic thromboprophylaxis Pharmacologic thromboprophylaxis should be continued for at least 7 to 10 days Mechanical methods may be added to pharmacologic thromboprophylaxis but should not be used as monotherapy for VTE prevention

31 VTE treatment The use of oral vitamin K antagonists in patients with cancer is complicated by poor therapeutic control and difficulties in maintaining a therapeutic INR occur due to a variety of reasons These patients are often exposed to interacting drugs, and warfarin bioavailability is unpredictable in cancer patients who may have vomiting, malnutrition or diarrhea The detrimental effect on quality of life from more frequent INR monitoring may be particularly troublesome in the setting of cancer therapy

32 VTE treatment

33 VTE treatment LMWH is preferred for the initial 5 to 10 days of anticoagulation for the patient with cancer with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance < 30 ml/min) LMWH for at least 6 months is preferred because of improved efficacy over VKAs Anticoagulation with LMWH or VKA beyond the initial 6 months may be considered for selected patients with active cancer, such as those with metastatic disease or those receiving chemotherapy

34 Dosing regimens

35 New oral anticoagulants

36 Novel oral anticoagulants Dabigatran, rivaroxaban, apixaban are new factor Xa inhibitors that targets the active site of FXa without requiring antithrombin III Novel oral anticoagulants does not require laboratory monitoring, dietary restrictions, dose adjustment and incur fewer drug-drug interactions Use of novel oral anticoagulants for either prevention or treatment of VTE in patients with cancer is investigational at this time

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38 550 cancer pts

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40 Key points VTE in cancer patients is a relevant clinical issue Cancer tissues express a prothrombotic phenotype. Patients with cancer are at increased risk for VTE but incidence rates are highly variable Patients should be informed about VTE risk and/or treatment and should be involved in their care, including monitoring for bleeding Risk can reliably be predicted using a validated risk-assessment tool Routine thromboprophylaxis is not recommended for patients with ambulatory cancer except in selected high-risk A VTE prophylaxis module should be integrated into hospital admission order sets Venous thromboembolism in patients with cancer should be treated with low-molecular weight heparin initially with extended secondary prophylaxis for at least 4 to 6 months

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42 Jacqueline??

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