Extended Treatment of VTE in Cancer Patients Dr. Ayman Samir M.D. Prof. of Vascular Surgery, Zagazig University

In a population-based study, cancer was associated with a 4 In a population-based study, cancer was associated with a 4.1 fold greater risk of thrombosis, whereas the use of chemotherapy increased the risk 6.5 fold. (1) Of all patients with VTE, patients with cancer account for 20%, with patients receiving chemotherapy accounting for as much as 13% of the total burden of VTE. (2) (1) Heit JA, Silverstein MD, Mohr DN, et al: Risk factors for deep vein thrombosis and pulmonary embolism: A population-based case-control study. Arch Intern Med 160:809-815, 2000 (2) Caine GJ, Stonelake PS, Lip GY, et al: The hypercoagulable state of malignancy: Pathogenesis and current debate. Neoplasia 4:465-473, 2002 Introduction

In a recent analysis of more than 66,000 patients with cancer hospitalized at 120 US academic medical centers, 5.4% developed VTE per hospitalization, increasing by 36% from 1995 to 2002 (P .0001 for trend). Khorana AA, Francis CW, Culakova E: Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 5:632-634, 2007 Introduction

Vascular toxicity particularly thromboembolism, is a specific toxicity of antiangiogenic drugs. Newer cancer regimens that include thalidomide, lenalidomide, or bevacizumab have reported very high rates of VTE. Shah MA, Ilson D, Kelsen DP: Thromboem- bolic events in gastric cancer: High incidence in patients receiving irinotecan- and bevacizumab- based therapy. J Clin Oncol 23:2574-2576, 2005 Introduction

Risk Factors for VTE in Cancer Patients Patient-related factors 1. Older age 2. Race (higher in African Americans; lower in Asian-Pacific Islanders) 3. Comorbid conditions (obesity, infection, renal disease, pulmonary disease, arterial thromboembolism). Prior history of VTE 4.Elevated pre-chemotherapy platelet count 5. Heritable prothrombotic mutations Risk Factors for VTE in Cancer Patients

Cancer-related factors 1 Cancer-related factors 1. Primary site of cancer (GI, brain, lung, gynecologic, renal, hematologic) 2. Initial 3-6 months after diagnosis 3. Current metastatic disease Risk Factors

Treatment-related factors 1. Recent major surgery 2 Treatment-related factors 1. Recent major surgery 2. Current hospitalization 3. Active chemotherapy 4. Active hormonal therapy 5. Current or recent antiangiogenic therapy (thalidomide, lenalidomide, bevacizumab ), Current erythropoiesis- stimulating agents 6. Presence of central venous catheters Risk Factors

According to ASCO Guidelines 2016: Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS?

According to ASCO Guidelines 2016: (1) Routine prophylaxis with an antithrombotic agent is not recommended. (2) Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. This recommendation is based on extrapolation from studies of postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose warfarin in breast cancer. (3) Research identifying better markers of ambulatory patients with cancer most likely to develop VTE is urgently needed. SHOULD AMBULATORY PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS DURING SYSTEMIC CHEMOTHERAPY?

SHOULD PATIENTS WITH CANCER UNDERGOING SURGERY RECEIVE PERIOPERATIVE VTE PROPHYLAXIS? According to ASCO Guidelines 2016: (1) All patients undergoing major surgical intervention for malignant disease should be considered for thromboprophylaxis. (2) Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting greater than 30 minutes should receive pharmacologic thromboprophylaxis with either low-dose UFH or LMWH unless contraindicated because of a high risk of bleeding or active bleeding.

(3) Mechanical methods may be added to pharmacologic methods, but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated because of active bleeding. (4) Prophylaxis should be continued for at least 7 to 10 days postoperatively. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major abdominal or pelvic surgery for cancer with high-risk features such as residual malignant disease after operation, obese patients, and those with a previous history of VTE.

Initial management of a first episode of cancer-associated VTE Choice of Anticoagulation: LMWH is the recommended anticoagulant for the initial therapy of VTE in most patients with cancer. (1,2) However, UFH can be used in those with severe renal impairment (creatinine clearance [CrCl] ,30 mL/min) given its shorter half-life, reversibility with protamine sulfate, and dependence on hepatic clearance. (1,2) Fondaparinux is a reasonable choice in patients with a history of HIT. (2) (1) Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update. J Clin Oncol. 2013;31(17): 2189-2204. (2) National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease version 2.2013. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/vte.pdf. Accessed July 9, 2013.

Long-term management of a first episode of cancer-associated VTE Although vitamin K antagonists (VKAs) have been the mainstay agents for long-term management and secondary prophylaxis of acute VTE in patients without cancer, their use is problematic in oncology patients. VKAs are less effective in patients with cancer, with rates of recurrent VTE three-fold higher than in patients without cancer despite maintenance of the international normalized ratio (INR) within the therapeutic range. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e419S-94S. Long-term management of a first episode of cancer-associated VTE

LMWH also offers other advantages including (a) no need for laboratory monitoring of its anticoagulant activity; (b) shorter half-life that facilitates temporary interruption for procedures or thrombocytopenia; (c) limited drug interactions; and (d) no food interactions or reliance on oral intake or gastrointestinal tract absorption. As a result, LMWH is recommended for both initial and long-term anticoagulation in cancer-associated thrombosis by major consensus guidelines National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease version 2.2013. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/vte.pdf. Accessed July 9, 2013.

Guidelines According to ASCO Guidelines 2016: (1) LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the cancer patient with established VTE. (2) LMWH given for at least 6 months is also the preferred approach for long- term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2 to 3 are acceptable for long-term therapy when LMWH is not available. (3) For patients with CNS malignancies, anticoagulation is recommended for established VTE as described for other patients with cancer. Careful monitoring is necessary to limit the risk of hemorrhagic complications. (4) For elderly patients, anticoagulation is recommended for established VTE as described for other patients with cancer. Careful monitoring and dose adjustment is necessary to avoid excessive anticoagulation and further increase in the risk of bleeding.

According to CHEST Guidelines 2016: In patients with DVT of the leg or PE and cancer (“cancer- associated thrombosis”), as long-term (first 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2C), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C).

studies regarding the optimal duration of anticoagulant therapy are lacking in oncology patients. Given that the risk for recurrent thrombosis in patients with active cancer is high even while they are receiving anticoagulation, it is generally recommended that extended anticoagulation be considered in this population. Duration of anticoagulation and anticoagulant options for extended therapy

Guidelines According to ASCO Guidelines 2016: After 6 months, indefinite anticoagulant therapy should be considered for selected patients with active cancer, such as those with metastatic disease and those receiving chemotherapy. This recommendation is based on Panel consensus in the absence of clinical trials data. Guidelines

Guidelines According to CHEST Guidelines 2016: In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), or (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B).

Use of Thrombolysis in Cancer-Associated VTE As most trials of thrombolytic therapy exclude patients with cancer because of a perceived higher risk of bleeding, evidence for thrombolysis in patients with malignancy is limited to small single-center, retrospective series. Although comparable results between cancer and non-cancer patient groups were observed, these studies provide a low level of evidence because of insufficient statistical power and patient selection bias. Vedantham S, Goldhaber SZ, Kahn SR, et al. Rationale and design of the ATTRACT Study: a multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J. 2013;165(4):523-530.e3.

Inferior vena cava (IVC) filters Rates of recurrent VTE up to 32% have been reported in patients with cancer treated with IVC filters, and fatal PE after filter insertion has been well documented. (1) Given the high rates of complications and the absence of data to support their efficacy, IVC filters should be restricted to patients with acute VTE and contraindications to anticoagulation. (2) (1) Elting LS, Escalante CP, Cooksley C, et al. Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med. 2004;164(15):1653-1661. (2) Durack JC, Westphalen AC, Kekulawela S, et al. Perforation of the IVC: rule rather than exception after longer indwelling times for the Gu ̈nther Tulip and Celect retrievable filters. Cardiovasc Intervent Radiol. 2012;35(2):299-308. Inferior vena cava (IVC) filters

Guidelines According to ASCO Guidelines 2016: The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long- term therapy with LMWH. Guidelines

Treatment of recurrent VTE during anticoagulant therapy Once recurrent VTE is confirmed, it is essential that HIT be excluded in patients who were first exposed to LMWH or UFH within the past 10- 14 days. Compliance should also be reviewed. For patients who experienced warfarin failure while the INR values had been therapeutic, transition to LMWH is recommended given its greater efficacy vs warfarin. Recurrent VTE events during LMWH therapy can be treated with a dose escalation of LMWH. Luk C, Wells PS, Anderson D, Kovacs MJ. Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy. Am J Med. 2001;111(4):270-273. Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost. 2009;7(5):760-765.

Treatment of cancer-associated thrombosis in patients with a high risk of bleeding Bleeding is frequently associated with anticoagulant use in patients with cancer. In a prospective study including 181 oncology patients receiving VKA for the treatment of DVT, the 1-year cumulative incidence of major bleeding was 12.4%, with one third of the bleeding events occurring during the initial phase of anticoagulation. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):3484- 3488.

Acute DVT Platelet < 50*106/L Platelet < 20*106/L Hold Anticoagulation Platelet 20-50*106/L Half-Dose LMWH Transfuse to maintain Full dose LMWH Platelet >50*106/L

Subacute/Chronic VTE Platelet > 50*106/L Full-Dose LMWH Platelet 20-50*106/L Half-Dose LMWH Platelet < 20*106/L Hold Anticoagulation

Treatment of catheter-related thrombosis To date, published data and clinical experience suggest that catheter-related thrombosis is associated with a low risk for thrombosis recurrence and post-thrombotic syndrome. Therefore, conservative treatment is recommended. A sensible approach is to remove the catheter only if (1) central venous access is no longer required; (2) the device is nonfunctional or defective; or (3) line-related sepsis is suspected or documented Elman EE, Kahn SR. The post-thrombotic syndrome after upper extremity deep venous thrombosis in adults: a systematic review. Thromb Res. 2006;117(6):609-614.

Treatment of catheter-related thrombosis Unless contraindicated, therapeutic anticoagulation should be given using either LMWH alone or LMWH followed by warfarin therapy. A short period of anticoagulation (3-5 days of LMWH) may even salvage some thrombosed catheters and obviate the need to remove and replace the line. Anticoagulation is recommended for a minimum of 3 months and while the catheter remains in place. Agnes Y. Y. Lee and Erica A. Peterson. Treatment of cancer-associated thrombosis, Blood 2013;122(14):2310- 2317) Treatment of catheter-related thrombosis

SHOULD PATIENTS WITH CANCER RECEIVE ANTICOAGULANTS IN THE ABSENCE OF ESTABLISHED VTE TO IMPROVE SURVIVAL? According to ASCO Guidelines 2016: (1) Anticoagulants are not recommended to improve survival in patients with cancer without VTE. (2) Patients with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies.

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