Armand Trousseau (1801-1867)• 1. First to associate thrombosis and malignancy.• 2. First to suggest screening for malignancy in recurrent or idiopathic thromboembolic disease.• 3. First to suggest that the pathophysiology was not mechanical obstruction, but a change in the character in the coagulation system itself.• 4. First to suggest the association may be integral to the cancer growth itself. – Khorana AA. J. Thrombosis & Haemostasis, 2003
January 1, 1867 • “Peter, I am lost, the phlebitis that has just appeared tonight leaves me no doubt about the nature of my illness.” • He died six months later of gastric cancer.
Risk of DVT and PE in Patients With Cancer 20% of cancer patients develop VTE at some point during their illness 20% of VTE occurs in cancer patients – Heit, 2005; Prandoni et al, 2005; Hillen, 2000. Pulmonary embolism represents 1/7 of deaths in hospitalized cancer patients in early studies. – Pruemer J. Am. J. Health Syst. Pharm. 62:S4- 6, 2005. 4
Thrombosis at Time of Cancer Diagnosis Associated With Worse Prognosis• 1 year survival rate for patients with advanced cancer: • Presented with VTE: 12% • Presented without VTE: 36% • Sorensen H et al. N Engl J Med, 2000
Effect of Malignancy on the Risk of VenousThrombosis Depending on the Duration Between Diagnosis of Cancer and Venous ThrombosisRedrawn from Blom JW, et al. JAMA 2005;293(6):715-722.
Causes of death in 4466 cancer patients receiving outpatient chemotherapy Cause of Death N (%) All 141 (100) Progression of cancer 100 (70.9) Thromboembolism 13 (9.2) Arterial 8 (5.6) Venous 5 (3.5) Infection 13 (9.2) Respiratory failure 5 (3.5) Bleeding 2 (1.4) Aspiration pneumonitis 2 (1.4) Other 9 (6.4) Unknown 5 (3.5)Khorana AA et al. JTH 5: 632–634, 2007.
Venous Thrombosis Increases Mortality andLength Of Stay at MSKCC By About 3-Fold. 25 Overall Mortality Rate (%) Overall mean LOS (Days) 20 Mortality Rate with VTE (%) Mean LOS With VTE (Days) 15 10 5 0 2002 2003 2004 2005 2006 2007
Identification of Malignancy After Episode of Thrombosis Study Idiopathic Secondary Odds Ratio Thrombosis ThrombosisMeta-Analysis 50/668 19/1100 4.3 of 7 Studies (7.5%) (1.7%)(1986-1998) •Likelihood of finding an occult malignancy is much greater after an unprovoked VTE than a secondary VTE.
Should We Screen For Cancers In Patients With Idiopathic VTE?• Idiopathic thrombosis: 7.5% - 10% diagnosed with cancer within 1-2 years.• 40-60% of patients already have metastatic disease when their cancer becomes clinically evident,• Likelihood of finding early, curable cancers that present with thromboembolic disease when cancer is only detectable by aggressive work-up is small.• Recommend appropriate routine cancer screening for age & sex, i.e. colonoscopy, prostate exam, mammography, pap and pelvic exam, etc.• Follow-up work-up indicated only if initial History/Physical and routine labs suggest specific site.
Risk of Venous Thrombosis per Type of Malignancy Adjusted Odds Ratio (95% CI) No Malignancy 1.00 Lung 22.2 (3.6-136.1) All Hematological Cancer 28.0 (4.0-199.7) GI 20.3 (4.9-83.0) Breast 4.9 (2.3-10.5) Brain 6.7 (1.0-45.4) Skin 3.8 (1.1-12.9) ENT 1.6 (0.4-6.4)Blom JW, et al. JAMA 2005;293(6):715-722.
VTE In Cancer• Virtually all cancers, solid tumor and hematologic malignancies, are associated with thrombotic risk.• The thrombotic risk appears to be related to the nature of the specific tumor, and not simply tumor burden or advanced stage of disease.• Most VTE occur “early” and not as a pre- morbid event.
Virchow’s Triad: Pathophysiology Of Thrombosis Altered blood Altered blood vessel wall flow/venous stasis Increase in bloodCancer coagulability
Coagulation And Vascular Factors Contribute to Cancer Associated Thrombosis• 1. Tissue Factor: – Tumor cells directly produce and release Tissue Factor. – Tissue Factor circulates in microparticles and may result in systemic thrombotic risk.• 2. Platelets: – Early literature suggested role of platelets adhesion/metastasis of malignant cells.• 3. Endothelial cell damage. – Following endothelial cell damage, blood is exposed to a thrombogenic surface. – Antiangiogenic agents target endothelial cells.
TF Expression is Markedly Increased inPancreatic Cancer, Compared With Normal Pancreatic Epithelium.• Nitori N. et al. Clin. Canc. Res. 11, 2531-2539, 2005
TF Expression Predicts Poor Survival In Resected Pancreatic Cancer Patients. All cancer patients With Lymph node involvement Few deaths related to VTE. Therefore, poor prognosis associated with increased TF expression is largely independent of thrombosis. Nitori N. et al. Clin. Canc. Res. 11, 2531-2539, 2005
Tissue Factor/Coagulation And Cancer Progression• Activation of oncogene/inactivation of tumor suppressor gene results in cellular transformation and TF expression as parallel pathways. – MET, RAS, P53, PTEN, HIF-1 have been shown to regulate the expression of TF and other coagulation- related factors. – Boccaccio and Comoglio. JCO. 27:4827-4833, 2009 – Coagulation may not directly contribute to tumor growth & progression.
Expression of Tissue Factor By Fibrosarcoma Cells in Mice • Palumbo, J et al. Blood 2007 110: 133-141
Effects of Coagulation System on Primary and Metastatic Tumor Growth• Serine proteases degrade local extracellular matrix, facilitating invasion and angiogenesis.• Locally, cancers produce a fibrin network which protects against immune surveillance and provides the scaffolding for invasion and angiogenesis.• Thrombin and other enzymes activate “Protease-Activated Receptors” (PARs) which regulate cancer, platelets, and endothelial cells.
Systemic Effects of Tissue Factor?• Why do patients experience thrombosis at sites distant from the underlying cancer?• If Tissue Factor is cell-surface associated, how does it influence cancer growth at distant sites?
Tissue Factor Circulates in Cell- Derived Microparticles.Boulanger et al. Hypertension, Hugel et al, Physiology 20: 22-27, 20052006
Predictive Model for Chemotherapy- Associated VTE Patient characteristic Risk Score Site of cancer Very high risk (stomach, pancreas) 2 High risk (lung, lymphoma, gynecologic, bladder, testicular) 1 Prechemotherapy platelet count 350 x 109/L or more 1 Hemoglobin level less than 10 g/dL or use of red cell growth factors 1 Prechemotherapy leukocyte count more than 11 x 109/L 1 BMI 35 kg/m2 or more 1Khorana AA et al. Blood. 111:4902-4907, 2008.Khorana AA & Connolly GC. JCO. 27:4839-4847, 2009
Rates of VTE according to scores from the riskmodel in the derivation and validation cohorts Khorana, A. A. et al. Blood 2008;111:4902-4907
Difficulty Using Warfarin ForAnticoagulation in Cancer Patients• Unpredictable levels of anticoagulation – Drug interactions – Malnutrition/anorexia – Vomiting – Liver dysfunction.• Need for interruption of therapy – Invasive procedures – Chemotherapy-induced thrombocytopenia• Higher thrombosis recurrence rate with warfarin in cancer patients. – Prandoni et al Blood 100:3484-3488, 2002
CLOT Study• Patients with cancer and DVT &/or PE.• LMWH, (Dalteparin) compared with warfarin (vitamin K antagonist).• All got LMWH (Dalteparin 200 IU/kg, SQ, daily for 5-7 days, then randomized to: – 6 months of Warfarin (INR target 2.5) or – 6 months of LMWH: • 200 IU/kg, SQ, daily for 1 month, then 150 IU/kg for 5 months.• Lee et al. NEJM 349:146-53, 2003
Dalteparin Resulted in Approximately 50% Reduction in Thrombosis RecurrencesLee, A. et al. N Engl J Med 2003;349:146-153
CLOT Study: Death From All Causes• While VTE complications were reduced by effective anticoagulation withLMWH this was not associated with improved survival.• No evidence of an anti-tumor effect.• Lee, A. Y.Y. et al. N Engl J Med 2003;349:146-153
Enoxaparin vs Warfarin inTreatment of Thrombosis In Cancer • Enoxaparin 1.5 mg/kg qd in acute phase, then randomization to continued Enoxaparin or Warfarin – Meyer G et al. Arch Int Med. 162: 1729-1735, 2002
Is There A Benefit of Anticoagulation In Cancer Survival Beyond Treatment of Thrombosis? • 1. Several studies have shown that some anticoagulants, particularly LMWH, may prolong survival in cancer patients, specifically in “good” prognosis patients (i.e. those with no identifiable metastases). – May be synergistic with chemotherapy. • 2. Other studies have failed to show any benefit to overall survival. • 3. No human study has shown objective benefit of anticoagulation on tumor burden, (but no study designed to test this). • 4. Most studies suffer from heterogeneity of cancer types and stages. • 5. Anticoagulants are not currently recommended to improve survival in patients with cancer without VTE.
Characterization of Recurrent VTE In CancerGoal is to identify subgroup of VTE in cancer who have high or low recurrence rates, to better stratify needs for anticoagulation.1,392 patients, treated for VTE with daily Dalteparin 200, 2008-2009 at MSKCC. – Weber C et al. ASH Abstract 2010.
Incidence of Recurrent VTE Variable Recurrent 6 month incidence P value VTE of recurrent VTE (frequency) (95% CI) All patients 34 2.3% (1.7%-3.3%) Sex Female 23 3.0% (2.0%-4.6%) 0.08 Male 11 1.6% (0.8%-2.9%) Age Continuous 0.04Diagnosis Lung 10 5.6% (3.1%-10.3%) 0.03 Breast 4 2.7% (0.8%-8.3%) Ovarian 2 1.9% (0.5%-7.8%) Soft tissue 0 0 Lymphoma 0 0 Other 18 2.1% (1.3%-3.3%) Weber C et al. ASH Abstract 2010.
Age of Patients and VTE Recurrence Rates (%)7.06.05.04.03.02.01.00.0 <55 yr 55-64 yr 65-73 yr 74+ yr Weber C et al. ASH Abstract 2010.
Recurrent VTE The risk of death was 3-fold higher among patients with recurrent thrombosis. This result is maintained when sex, age, and diagnosis are included in a multivariate analysis. Age, tumor type, and gender may require different treatment strategies. Weber C et al. ASH Abstract 2010.
Incidental Pulmonary Embolism Clinical relevance? Risks of recurrence, need for anticoagulation? Retrospective cohort study (2004-2010) Incidental PE (n=51) Symptomatic PE (n=144) Observed for 1 year Den Exter P L et al. JCO 29:2405-2409, 2011.
Incidental vs. Symptomatic VTE Incidental and symptomatic patients did not differ with respect to mean age, sex, cancer type and stage, and risk factors for VTE. As a result from evolving treatment guidelines, approximately half of the patients in both groups received long-term treatment with vitamin K antagonists in stead of currently recommended low- molecular-weight heparin. – Den Exter P L et al. JCO 29:2405-2409, 2011.
Cumulative Recurrent VTEden Exter P L et al. JCO 2011;29:2405-2409
Cumulative Overall Survivalden Exter P L et al. JCO 2011;29:2405-2409
Overall Survival Recurrent Thrombosis- Free SurvivalFont C, et al. Annals of Oncology 22: 2101–2106, 2011
Thrombosis Prophylaxis In Hospitalized Medical Patients Placebo Treatment Group Group Events Relative Trial Agent Events (%) (%) Risk P EnoxaparinMEDENOX 40 mg qd 14.9 5.5 0.37 <0.001MEDENOX Enoxaparin (Cancer 40 mg qdSubgroup) 19.5 9.7 0.5 DalteparinPREVENT 5000 Un pd 4.96 2.77 0.55 0.0015 FondaparinuxARTEMIS 2.5 mg qd 10.5 5.6 0.47 0.029 Lyman G, et al. J Clin Oncol 2007. 25:5490-5505.
Extended Thromboprophylaxis In Surgical Oncology Patients Thrombosis “Short” “Extended” P Prophylaxis Prophylaxis (7-10 days) (4-5 weeks) DVT (%) 15 6.5 <0.005 Proximal DVT (%) 5 1 <0.01 Symptomatic DVT (%) 1 0.3 0.27 Pooled data from 4 studies of surgical patients with Low Molecular Weight Heparin. Data on mortality not significant. Kakkar AK. JCO 27:4881-4884, 2009
Rates of VTE in Recent Primary Prophylaxis Studies (Ambulatory) Solid PancreasPancreas Tumor Ca CaAgnelli et al, 2009; Palumbo et al, 2009; Riess et al, 2009;Maraveyas et al, 2009.
Recent Studies Of Extended Prophylaxis In High Risk Medical Patients Study Primary Major Efficacy Bleeding (%) Endpoint (%) EXCLAIM Placebo (after open- 4.0 0.3 (2010)4 label enoxaparin run- in) Extended enoxaparin 2.5 0.8 MAGELLA Enoxaparin/placebo 5.7 0.4 N Extended rivaroxaban 4.4 1.11. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen etal, 2006; 4. Hull et al, 2010 45
SAVE-ONCO Semuloparin placebo Hazard Ratio N=1,608 N= 1,604Thrombosis 20 (1.2%) 55 (3.4%) 0.36 p<0.0001 (95% CI: 0.21–0.60) Major 19 (1.2%) 18 (1.1%) 1.05 Bleeding (95%CI 0.55 to 1.99) clinically 2.8% 2.0% HR=1.40 relevant (95%CI 0.89–2.21). bleeding59% risk reduction in PE rate (odds ratio 0.41,95%CI 0.19–0.85).
The Question Everyone Is Asking!Should we use the new oral anticoagulants for VTE treatment in cancer?Dabigatran (Pradaxa): Direct Thrombin InhibitorRivaroxaban (Xarelto): FXa inhibitorApixaban: FXa inhibitor
Use In Cancer Patients• Studies of the new agents did not have adequate cancer population for subgroup analysis.• VTE treatment studies used warfarin as the control arm, but warfarin has already been shown to be unsafe and ineffective for DVT treatment in cancer patients. – Warfarin is not the standard of care in cancer.• No reversal agent,• No established assay to monitor dose/effect• Specific studies will need to be conducted in cancer patients, with LMWH control.
Questions To Answer• Does anticoagulation reduce primary or metastatic tumor growth?• Is there a survival benefit from anticoagulation, separate from thrombosis prophylaxis?• Is there a role for anti-platelet agents?• In cancer setting, what is optimal anticoagulation therapy for indications besides venous thrombosis? (i.e. mechanical valves, atrial fibrillation)?• Interaction of Thrombophilia in Patient and Tumor Progression?
Effect of Malignancy on the Risk of Venous Thrombosis Depending on the Duration Between Diagnosis of Cancer and Venous Thrombosis Duration Between Malignancy Adjusted Odds Ratio and Venous Thrombosis (95% CI) No Malignancy 1.00 All Malignancies 4.3 (3.3-5.6) Time after index date (diagnosis) 0 to <3 mo 53.5 (8.6-334.3) >3 mo to <1 y 14.3 (5.8-35.2) >1 to <3 y 3.6 (2.0-6.5) >3 to <5 y 3.0 (1.5-5.7) >5 to <10 y 2.6 (1.4-4.7) >10 to <15 y 2.3 (0.9-5.8) >15 y 1.1 (0.6-2.2)Redrawn from Blom JW, et al. JAMA 2005;293(6):715-722.