Introduction

Venous thromboembolism (VTE) is a highly prevalent and significant cause of both morbidity and mortality in patients with cancer.^1,2 It is currently estimated that the annual incidence of VTE in patients with cancer is 0.5% compared to 0.1% in the general population.³ Active cancer accounts for 20% of the overall incidence of VTE.^4,5 VTE occurrence in cancer patients results from a combination of cancer-induced hypercoagulability, endothelial and vessel wall damage, and venous stasis.⁶ Management of cancer-associated VTE remains a challenge given limited trial data for many oral anticoagulant medications.

Risk Factors for Cancer-Related VTE

Virchow's triad summarizes the multi-factorial risks associated with VTE development, including both acquired and inherited risk factors.⁷ Hypercoagulability is induced through pro-coagulant and inflammatory cytokines, while venous stasis can be caused by both immobility and venous external compression. Endothelial and vessel damage can occur through chemotherapy-induced interleukin and tumor necrosis factor release as well as indwelling catheters needed for medication administration. Risk for VTE and recurrent VTE is highest among patients with hematologic malignancies, lung cancer, gastrointestinal cancer (stomach/colon), pancreatic cancer, kidney cancer, and bone cancer, patients with myelodysplastic disorder, and in patients with distant metastases.^2,4,6 The risk of VTE is amplified in cancer patients with concomitant risk factors such as factor V Leiden mutation or prothrombin 20210A mutation.² Other risk factors include older age, platelet count ≥350 x 10^9/L, hemoglobin <100 g/L or use of red cell growth factors, leukocyte count ≥11 x 10^9/L, or BMI >35 kg/m^2.^4,6 Finally, chemotherapeutic agents, such as thalidomide/lenalidomide plus high dose dexamethasone, and exogenous hormonal therapies, such as tamoxifen/raloxifene, diethylstibestrol, hormone replacement therapy, and oral contraceptives, all increase VTE risk.⁶ Risk predictions models include the Ottawa score for recurrent cancer-associated VTE (Table 1) and the Khoranna score for chemotherapy-associated VTE (Table 2).^8,9

Table 1: Ottawa Score: Recurrent VTE Risk in Cancer-Associated Thrombosis⁸

Factor	Point
Female	1
Lung cancer	1
Breast cancer	-1
TNM stage I	-2
Previous VTE	1
Interpretation: Total Score Risk -3 to 0 Low 1 to 3 High

Table 2: Khorana Score: Predictor for Chemotherapy-Associated Thrombosis⁹

Patient Characteristic	Risk Score
Site of Primary Cancer Very High Risk  (Stomach, pancreas) High Risk (lung, lymphoma, gynecologic, bladder, testicular)	2 1
Prechemotherapy platelet count ≥350 x 109/L	1
Hgb <10 g/dL	1
Prechemotherapy leukocyte count ≥11 x 109/L	1
BMI ≥35 kg/m2	1
Interpretation: Total Score Risk of Symptomatic VTE 0 Low (0.8-3%) 1-2 Intermediate (1.8-8.4%) 3 or higher High (7.1-41%)

Treatment

VTE management in patients with cancer requires a complicated balance between high recurrence risk and concerns for significant hemorrhagic complications.^5,10 Additionally, patients with cancer frequently have comorbid conditions (e.g., renal failure, thrombocytopenia) or use of medications that interact with and limit the safe use of many anticoagulant medications. Finally, these patients require frequent interruptions in therapy for invasive procedures, have medication-induced dietary changes affecting vitamin K intake, and potential intolerance for oral administration due to GI adverse effects associated with chemotherapy.¹⁰

Current guideline-endorsed therapy options for cancer-associated thrombosis include low molecular weight heparin (LMWH), unfractionated heparin (UFH), warfarin, and fondaparinux.¹ These include the American College of Chest Physician (ACCP), the National Comprehensive Cancer Network (NCCN), and the American Society of Clinical Oncology (ASCO).^5,11,12 Based largely on the CLOT (Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism) and CATCH trials, all current guidelines recommend LMWH for at least 3-6 months in cancer-associated VTE, with the potential to treat indefinitely in patients with active malignancy and ongoing treatment.^10,13 UFH can be considered for patients with renal insufficiency, and fondaparinux can be considered for patients with heparin-induced thrombocytopenia (HIT).

The landmark CLOT trial demonstrated that LMWH was more effective that warfarin at reducing the risk of recurrent VTE in patients with DVT/PE and active cancer. Even more important was that LMWH had a similar bleeding risk profile to warfarin in this trial.¹⁰ However, it is important to note that time in therapeutic range (TTR) for the CLOT trial was 46%, far below the standards of most high-quality anticoagulation clinics. Warfarin may be an appropriate alternative for long-term use in patients where LMWH is contraindicated (e.g., with advanced renal dysfunction), not feasible, or a patient refuses due to high cost of the need for subcutaneous injections. However, robust data on anticoagulant therapy beyond the initial 6 months is quite limited.⁵

Direct-acting oral anticoagulants (DOAC; apixaban, dabigatran, edoxaban, and rivaroxaban) are currently not recommended for cancer-associated VTE treatment due to a lack of prospective data. However, ongoing trials will soon define the role that these easy-to-use, oral agents may have for this high-risk population (Table 3).⁶

Table 3: Ongoing Clinical of DOAC in Cancer-related thrombosis

Ongoing Apixaban trials in cancer-associated VTE Apixaban for the Prevention of Venous Thromboembolism in Cancer Patients (AVERT): NCT02048865 Apixaban as Treatment of Venous Thrombosis in Patients With Cancer: The CAP Study (CAP): NCT02581176 Apixaban or Dalteparin in Reducing Blood Clots in Patients With Cancer Related Venous Thromboembolism: NCT02585713 Evaluation of the Use of Apixaban in Prevention of Thromboembolic Disease in Patients With Myeloma Trated With iMiDs (MYELAXAT): NCT02066454 A Pilot Study Investigating Apixaban and Dexamethasone InterAction in Multiple Myeloma (ADAM): NCT02749617

Ongoing Rivaroxaban trials in cancer-associated VTE Rivaroxaban Utilization for Treatment and Prevention of Thromboembolism in Cancer Patients: Experience at a Comprehensive Cancer Center: NCT02502396 Rivaroxaban in the Treatment of Venous Thromboembolism (VTE) in Cancer Patients: NCT02583191 Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban (CASTA-DIVA): NCT02746185 A Study to Evaluate the Efficacy and Safety of Rivaroxaban Venous Thromboembolism (VTE) Prophylaxis in Ambulatory Cancer Participants: NCT02555878 A Randomized Phase II Study to Compare the Safety and Efficacy of Dalteparin vs. Rivaroxaban for Cancer-associated Venous Thromboembolism (PRIORITY): NCT03139487 Study in Cancer Patients With Central Line Associated Clots in the Upper Extremity Treated With Rivaroxaban (Catheter 2): NCT01708850 A Non-interventional Study on Xarelto for Treatment of Venous Thromboembolism (VTE) and Prevention of Recurrent VTE in Patients With Active Cancer (COSIMO): NCT02742623

Other trials in cancer-associated VTE Direct Oral Anticoagulants (DOACs) Versus LMWH +/- Warfarin for VTE in Cancer (CANVAS): NCT02744092

Special Consideration

A concern when considering an oral anticoagulant within this population is the patient's ability to tolerate oral intake, as adverse effects of chemotherapy can include loss of appetite, emesis, and mucositis. Although warfarin is an oral agent and is subject to drug-drug interactions and chemotherapy-induced adverse effects, the availability of an INR laboratory test makes appropriate dose titration possible. However, maintaining patients within their therapeutic range may be challenging. Unlike warfarin, there is currently no mechanism for monitoring DOAC levels in the presence of drug-drug interactions or GI adverse effects resulting from chemotherapy. Finally, it is important to consider drug clearance when selecting appropriate anticoagulant medications. Patients with hepatic cancer or metastases may not do well on warfarin, whereas patients with renal cancer may not be well suited for LMWH therapy.

Conclusion

Patients with active cancer are at high risk for cancer-related thrombosis. Management of cancer-related VTE can be challenging due to limited therapeutic options with robust, prospective clinical trial data. The guidelines currently recommend LMWH for 3-6 months as first-line treatment for patients with cancer-associated VTE. Indefinite anticoagulation should be continued as long as the malignancy is felt to be "active" or chemotherapy is ongoing. Use of DOAC medications is currently not supported by guidelines, but ongoing studies will provide much needed evidence to guide clinical care.

References

1. Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood 2013;122:2310-7.
2. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715-22.
3. Elyamany G, Alzahrani AM, Bukhary E. Cancer-associated thrombosis: an overview. Clin Med Insights Oncol 2014;8:129-37.
4. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thromboysis 2016;41:3-14.
5. Francis CW, Kessler CM, Goldhaber SZ, et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015;13:1028-35.
6. Streiff MB, Bockenstedt PL, Cataland SR, et al. Venous thromboembolic disease. J Natl Compr Canc Netw 2013;11:1402-29.
7. Bick RL. Cancer-associated thrombosis. N Engl J Med 2003;349:109-11.
8. Louzada ML, Carrier M, Lazo-Langner A, et al. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Circulation 2012;126:448-54.
9. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902-7.
10. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
11. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2015;149:315-52.
12. Lyman GH, Bohlke K, Falanga A, American Society of Clinical oncology. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Oncol Pract 2015;11:e442-4.
13. Lee AY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015;314:677-86.

Keywords: Anticoagulants, Body Mass Index, Bone Neoplasms, Breast Neoplasms, Coagulants, Cytokines, Dalteparin, Dexamethasone, Gastrointestinal Neoplasms, Hematologic Neoplasms, Hemoglobins, Heparin, Heparin, Low-Molecular-Weight, Hormone Replacement Therapy, Injections, Subcutaneous, Interleukins, Kidney Neoplasms, Liver Neoplasms, Lung Neoplasms, Medical Oncology, Multiple Myeloma, Pancreatic Neoplasms, Platelet Count, Polysaccharides, Prothrombin, Pyrazoles, Pyridines, Pyridones, Raloxifene Hydrochloride, Risk Factors, Tamoxifen, Thalidomide, Thiazoles, Thrombocytopenia, Thrombosis, Thrombophilia, Tumor Necrosis Factors, Venous Thromboembolism, Venous Thrombosis, Vitamin K, Warfarin, Aneurysm

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