Soff 4/15/2017 Thrombosis In Cancer: Gerald A Soff MD

Topics To Cover 1. History of “First” Paraneoplastic Syndrome 2. Pathophysiology and Clinical Relevance 3. Screening For Occult Malignancy: in patient presenting with unprovoked thrombosis 4. Management 5. Incidental Thrombosis, Clinical Relevance 6. Coincidental Thrombocytopenia 7. Primary Thrombosis Prophylaxis 8. Role of New Direct Oral Anticoagulants

Soff 4/15/2017 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

Soff 4/15/2017 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.

2. Pathophysiology and Clinical Relevance Soff 4/15/2017 2. Pathophysiology and Clinical Relevance [1/Heit.ArchIntMed. Mar.2000/p813/Table 2] [2/Pruemer.AmJHealth-SystPharm.Nov.2005/ pS4/c1/line 19-23] [3/Donati.Haemostasis. 1994/p129/c1/line 15-17] 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. 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 Thrombosis in cancer a property of aggressive disease, not simply manifestation of “late stage.” [1/Heit.ArchIntMed. Jun.2002/p1247/Table] [2/Heit.ArchIntMed.Mar. 2000/p813/Table 2] [3/Pruemer.AmJHealth-SystPharm.Nov.2005/ pS4/c1/line 19-23] [4/Donati.Haemostasis. 1994/p129/c1/line 15-17] 5 _______________________________________________________________________________________ Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2002;162:1245-1248. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2000;160:809-815. Pruemer J. Prevalence, causes, and impact of cancer-associated thrombosis. Am J Health-Syst Pharm. 2005;62(suppl 5):S4-S6. Donati MB. Cancer and thrombosis. Haemostasis. 1994;24:128-131.

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 Respiratory failure Bleeding 2 (1.4) Aspiration pneumonitis Other 9 (6.4) Unknown Khorana AA et al. JTH 5: 632–634, 2007.

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.

Virchow’s Triad: Pathophysiology Of Thrombosis Altered blood vessel wall Altered blood flow/venous stasis Increase in blood coagulability Cancer

3. Endothelial cell damage. Soff 4/15/2017 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. Elevated platelet count increases thrombosis rates in cancer. Khorana AA & Connolly GC. JCO. 27:4839-4847, 2009. 3. Endothelial cell damage. Following endothelial cell damage, blood is exposed to a thrombogenic surface. Antiangiogenic agents target endothelial cells.

TF Expression In Pancreatic Neoplasia and Thrombosis Rates Low TF expression, VTE Rate: 4.5% High TF expression, VTE Rate: 26.3% 4-fold Risk Ratio, (P = 0.04). (Khorana AA. Clin. Canc. Res. 13, 2870-2875, 2007.)

TF Expression Predicts Poor Survival In Resected Pancreatic Cancer Patients. All cancer patients With Lymph node involvement Few deaths related to VTE. Poor prognosis associated with increased TF expression is largely independent of thrombosis. Nitori N. et al. Clin. Canc. Res. 11, 2531-2539, 2005

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, 2006 Hugel et al, Physiology 20: 22-27, 2005

Idiopathic Thrombosis Soff 4/15/2017 3. Screening For Occult Malignancy: in patient presenting with unprovoked thrombosis Likelihood of finding an occult malignancy is much greater after an unprovoked VTE than a secondary VTE. Study Idiopathic Thrombosis Secondary Thrombosis Odds Ratio Meta-Analysis of 7 Studies (1986-1998) 50/668 (7.5%) 19/1100 (1.7%) 4.3

Soff 4/15/2017 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.

4. Management of Thrombosis In Cancer Patients

Difficulty Using Warfarin For Anticoagulation in Cancer Patients Soff 4/15/2017 Difficulty Using Warfarin For Anticoagulation 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

The CLOT Study Patients with cancer and DVT &/or PE. Soff 4/15/2017 The 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

Soff 4/15/2017 Dalteparin Resulted in Approximately 50% Reduction in Thrombosis Recurrences Figure 1. Kaplan-Meier Estimates of the Probability of Symptomatic Recurrent Venous Thromboembolism among Patients with Cancer, According to Whether They Received Secondary Prophylaxis with Dalteparin or Oral Anticoagulant Therapy for Acute Venous Thromboembolism. An event was defined as an objectively verified, symptomatic episode of recurrent deep-vein thrombosis, pulmonary embolism, or both during the six-month study period. The hazard ratio for recurrent thromboembolism in the dalteparin group as compared with the oral-anticoagulant group was 0.48 (95 percent confidence interval, 0.30 to 0.77; P=0.002 by the log-rank test). Lee, A. et al. N Engl J Med 2003;349:146-153

CLOT Study: Death From All Causes Soff 4/15/2017 CLOT Study: Death From All Causes Figure 2. Kaplan-Meier Estimates of the Probability of Death from All Causes among Patients with Cancer, According to Whether They Received Secondary Prophylaxis with Dalteparin or Oral Anticoagulant Therapy for Acute Venous Thromboembolism. There was no significant difference between the groups (P=0.53 by the log-rank test). While VTE complications were reduced by effective anticoagulation with LMWH 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

5. Incidental Thrombosis/ Pulmonary Embolism Clinical relevance? Risks of recurrence, need for anticoagulation? Retrospective cohort study (2004-2010) Incidental Pulmonary Embolism (n=51) Symptomatic Pulmonary Embolism (n=144) Observed for 1 year Den Exter P L et al. JCO 29:2405-2409, 2011.

Cumulative Recurrent VTE Cumulative risk of recurrent venous thromboembolism for patients with cancer with incidental versus symptomatic pulmonary embolism (PE; P = .77). den Exter P L et al. JCO 2011;29:2405-2409

Cumulative Overall Survival Kaplan-Meier cumulative survival curve until overall death for patients with cancer with incidental versus symptomatic pulmonary embolism (PE; P = .70). den Exter P L et al. JCO 2011;29:2405-2409

VTE Recurrence (12 Months), By Initial PE Anatomy Deng et al, ASH Abstract, 2012 (From MSKCC)

Monthly Death Rate After Cancer Associated PE Deng et al, ASH Abstract, 2012 (From MSKCC)

6. Coincidental Thrombocytopenia In general population, when thrombocytopenia develops in patient on heparin or LMWH: Stop heparin Send test for Heparin-Dependent Antiplatelet Antibody Initiate alternative anticoagulant until diagnosis confirmed or ruled out. However, in cancer patients on chemotherapy, thrombocytopenia is the norm. Likelihood of HITT a function of timing of chemotherapy nadir, and duration of heparin therapy. (Peak time for HITT is 5-15 days after initial exposure to heparin).

Suggested Dose Reduction of Therapeutic Anticoagulation For VTE In Setting Of Thrombocytopenia: MKCC Guidelines. Platelet Count (Not bleeding, and not-dependent on platelet transfusions) Enoxaparin >50,000/ul Full-dose (1 mg/kg, q 12 hours), but with close monitoring 25,000-50,000/ul Reduced-Dose Enoxaparin (30-40 mg SQ bid) < 25,000/ul Hold anticoagulation

7. Primary Thrombosis Prophylaxis Is there a role for thrombosis prophylaxis in outpatient, ambulatory cancer patients prior to development of a thrombosis. The hope has been that anticoagulation may exert a direct antitumor effect as well as prophylaxis against thrombosis. No clinical study has shown a direct anticancer effect.

7. Primary Thrombosis Prophylaxis (II) While increased thrombosis rates are clear, the absolute rate reduction with primary anticoagulation is not great enough to justify the cost and inconvenience. It is rare that cancer patients with thrombosis die from the event or develop significant morbidity. Therefore, one would need to justify a high number to treat with prophylactic anticoagulation, to avoid each patient with symptomatic thrombosis or death.

clinically relevant bleeding Soff 4/15/2017 SAVE-ONCO Semuloparin N=1,608 placebo N= 1,604 Hazard Ratio Thrombosis 20 (1.2%) 55 (3.4%) 0.36 (95% CI: 0.21–0.60) p<0.0001 Major Bleeding 19 (1.2%) 18 (1.1%) 1.05 (95%CI 0.55 to 1.99) clinically relevant bleeding 2.8% 2.0% HR=1.40 (95%CI 0.89–2.21). 59% risk reduction in PE rate (odds ratio 0.41, 95%CI 0.19–0.85).

8. Role of New Direct Oral Anticoagulants: Should we use the new oral anticoagulants for VTE treatment in cancer? Dabigatran (Pradaxa): Direct Thrombin Inhibitor Rivaroxaban (Xarelto): FXa inhibitor Apixaban: FXa inhibitor All 3 approved for non-valvular atrial fibrillation, Only rivaroxaban approved for DVT/PE treatment.

New Oral Anticoagulants 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.

New Oral Anticoagulants (II) LMWH > warfarin NOAC ~ warfarin, Therefore cannot conclude NOAC ~LMWH

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)? Will the new oral anticoagulants be proven to be equivalent to LMWH?

Soff 4/15/2017 "That's all Folks!"