The close association between cancer and thrombosis has been recognized now for more than 150 years.1 Not only is it now known that patients with cancer are at substantially increased risk of developing venous thromboembolism, even prior to the diagnosis of cancer, but the association between coagulation factors and tumor growth and invasion and development of metastases has been unequivocally established.2
Reported rates of venous thromboembolism in patients with cancer have been increasing in recent decades, most likely reflecting improved diagnosis using sophisticated imaging techniques and more aggressive cancer diagnosis, staging, and therapeutic interventions. Indeed, patients with cancer are placed at increased risk of venous thromboembolism by several therapeutic interventions, including surgery, chemotherapy, hormonal therapy, and targeted therapeutic strategies, as well as by the frequent use of indwelling catheters and other invasive procedures.
The increased risk of venous thromboembolism, the multitude of risk factors, and the greater risk of venous thromboembolism recurrence and death among patients with cancer represent considerable real-world challenges for the practicing oncologist. ASCO originally developed guidelines for venous thromboembolism specifically in patients with cancer in 2007.3 Following an extensive systematic review of the literature since publication of the original guidelines, ASCO recently updated clinical practice guidelines on the treatment and prevention of venous thromboembolism in patients with cancer.4
Although several new studies in this area have added to our knowledge since the original guidelines were developed, many questions remain concerning the intimate relationship between venous thromboembolism and cancer. The updated guideline recommendations and the risks and consequences associated with venous thromboembolism in patients with cancer were discussed at a recent Education Session at the 2013 ASCO Annual Meeting and in the Education Book available online at the ASCO website.5
Hospitalized and Surgical Patients
The ASCO Venous Thromboembolism Guidelines address recommended measures for the treatment and prevention of venous thromboembolism in hospitalized medical and surgical patients with cancer, as well as in ambulatory patients receiving cancer therapy. Three recent randomized controlled trials of thromboprophylaxis in medically ill inpatients were identified,6-8 one of which evaluated extended prophylaxis.6
Despite limited cancer-specific data in these trials, the ASCO Guidelines continue to recommend that hospitalized patients with other major medical illnesses or reduced mobility without serious bleeding risk receive prophylactic anticoagulation. Although hospitalized patients with cancer without additional risk factors may also be considered for prophylactic anticoagulation, there are inadequate data supporting routine prophylaxis in patients admitted for minor procedures or infusions of chemotherapy.
The literature review identified three randomized controlled trials evaluating perioperative prophylaxis in patients undergoing major abdominal or pelvic surgery.9-11 The updated guidelines recommend perioperative prophylactic anticoagulation in patients undergoing major cancer surgery, ideally beginning preoperatively and continued for at least 7 to 10 days. Systematic reviews have been conducted of extended prophylaxis for up to 4 weeks.12-14 Based on the available evidence, extended postoperative prophylaxis for up to 4 weeks is recommended in high-risk patients undergoing major cancer surgery, and those with restricted mobility, obesity, or a history of venous thromboembolism.
Ambulatory Patients
Nine randomized controlled trials of low–molecular-weight heparin thromboprophylaxis compared to placebo or untreated controls in ambulatory patients with advanced cancer have been reported. A meta-analysis estimated a relative risk for symptomatic venous thromboembolism of 0.47 (95% confidence interval [CI] = 0.36–0.61, P < .001) but with an absolute reduction in venous thromboembolism risk of only 2.8% (95% CI = 1.8%–3.7%, P < .001).15
The most dramatic impact on the absolute risk of venous thromboembolism was observed in patients with advanced pancreatic cancer receiving specific chemotherapy.16-18 Nevertheless, due to the limitations in these trials and the small incremental benefit observed in most trials of ambulatory patients, the ASCO Guideline panel concluded that routine anticoagulation prophylaxis is not warranted. One notable exception to this recommendation relates to patients with multiple myeloma receiving thalidomide (Thalomid) or lenalidomide (Revlimid) along with chemotherapy and/or dexamethasone, where the risk of venous thromboembolism is sufficient to justify routine thromboprophylaxis.
Established and Incidental Venous Thromboembolism
In patients with cancer and established venous thromboembolism, the ASCO Guidelines recommend low–molecular-weight heparins for both the initial 5 to 10 days of anticoagulation as well as for secondary prevention of recurrence for at least 6 months. Extended anticoagulation to prevent venous thromboembolism recurrence is encouraged in high-risk patients with active malignancy continuing on chemotherapy.
Of importance, the risk of recurrence, bleeding, and mortality appears similar between patients with cancer who have symptomatic venous thromboembolism and those who have incidental or unsuspected venous thromboembolism.19 The ASCO Guideline panel recommends that incidental venous thromboembolism be treated the same as symptomatic venous thromboembolism, based on consensus.
Although a meta-analysis of randomized controlled trials has demonstrated a significant reduction in mortality with anticoagulation in patients with cancer without a clear indication for treatment or prevention, anticoagulation for cancer treatment is not currently recommended in the updated guidelines due to the limitations of the trials reported to date and concern over an increased risk for major bleeding complications.4,20
Risk Factors
Finally, risk factors for venous thromboembolism in patients with cancer include patient-, disease-, and treatment-related factors. Importantrisk factors include such comorbid conditions as infection, pulmonary or renal disease, and obesity. Elevations in leukocyte and platelet counts, reductions in hemoglobin, and use of the erythroid stimulating factors also increase the risk of venous thromboembolism in patients with cancer.
The primary site of cancer is particularly important, with highest rates of venous thromboembolism observed in patients with brain, pancreas, stomach, kidney, ovary, and lung cancers as well as hematologic malignancies including lymphoma and myeloma. The risk of venous thromboembolism is further increased in patients receiving systemic therapy, including chemotherapy, hormonal therapy, and certain targeted agents. Although the risk of arterial thrombotic events is increased with bevacizumab (Avastin), it remains unclear whether the risk of venous thromboembolism is increased after adjusting for duration on treatment.21
A risk score for cancer-associated venous thromboembolism based on five readily available clinical and laboratory parameters has been developed and validated in multiple studies (see Table).22-24 When the risk model was retrospectively evaluated in large randomized trials, the risk of venous thromboembolism among high-risk patients was significantly reduced in those randomized to thromboprophylaxis.25,26
The updated ASCO Guidelines recommend that patients with cancer be educated about the symptoms and signs of venous thromboembolism and that venous thromboembolism risk be assessed at the time of chemotherapy initiation and periodically thereafter. ■
Dr. Lyman is Professor of Medicine in the Division of Medical Oncology, Duke University School of Medicine and Duke Cancer Institute, Durham, North Carolina.
Disclosure: Dr Lyman is supported by grants from the National Cancer Institute (RC2CA148041-01) and the National Heart, Lung and Blood Institute (R01HL095109).
References
1. Rickles FR, Falanga A: Molecular basis for the relationship between thrombosis and cancer. Thromb Res 102:V215-V224, 2001.
2. Falanga A, Panova-Noeva M, Russo L: Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 22:49-60, 2009.
3. Lyman GH, Khorana AA, Falanga A, et al: American Society of Clinical Oncology guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 25:5490-5505, 2007.
4. 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 31:2189-204, 2013.
5. Lyman GH, Khorana AA, Falanga A: Thrombosis and cancer. Am Soc Clin Oncol Educ Book 2013:337-345, 2013.
6. Hull RD, Schellong SM, Tapson VF, et al: Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: A randomized trial. Ann Intern Med 153:8-18, 2010.
7. Schellong SM, Haas S, Greinacher A, et al: An open-label comparison of the efficacy and safety of certoparin versus unfractionated heparin for the prevention of thromboembolic complications in acutely ill medical patients: CERTAIN. Expert Opin Pharmacother 11:2953-2961, 2010.
8. Riess H, Haas S, Tebbe U, et al: A randomized, double-blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill, non-surgical patients: CERTIFY Study. J Thromb Haemost 8:1209-1215, 2010.
9. Sakon M, Kobayashi T, Shimazui T: Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study. Thromb Res 125:e65-e70, 2010.
10. Kakkar AK, Agnelli G, George D, et al: The ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients undergoing major abdominal surgery. Presented at the American Society of Hematology Annual Meeting, December 10-13, 2011.
11. Simonneau G, Laporte S, Mismetti P, et al: A randomized study comparing the efficacy and safety of nadroparin 2850 IU (0.3 mL) vs. enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer. J Thromb Haemost 4:1693-1700, 2006.
12. Akl EA, Terrenato I, Barba M, et al: Extended perioperative thromboprophylaxis in patients with cancer. A systematic review. Thromb Haemost 100:1176-1180, 2008.
13. Bottaro FJ, Elizondo MC, Doti C, et al: Efficacy of extended thrombo-prophylaxis in major abdominal surgery: What does the evidence show? A meta-analysis. Thromb Haemost 99:1104-1111, 2008.
14. Rasmussen MS, Jørgensen LN, Wille-Jørgensen P: Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev (1):CD004318, 2009.
15. Kuderer NM, Ortel TL, Khorana AA, et al: Low-molecular-weight heparin for venous thromboprophylaxis in ambulatory cancer patients: A systematic review meta-analysis of randomized controlled trials. Blood (ASH Annual Meeting Abstracts) 114:490, 2009.
16. Maraveyas A, Waters J, Roy R, et al: Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 48:1283-1292, 2012.
17. Riess H, Pelzer U, Hilbig A, et al: Rationale and design of PROSPECT-CONKO 004: A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy. BMC Cancer 8:361, 2008.
18. Riess H, Pelzer U, Opitz B, et al: A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy: Final results of the CONKO-004 trial. 2010 ASCO Annual Meeting. Abstract 4033. Presented June 4, 2010.
19. den Exter PL, Hooijer J, Dekkers OM, et al: Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: A comparison with symptomatic patients. J Clin Oncol 29:2405-2409, 2011.
20. Kuderer NM, Khorana AA, Lyman GH, et al: A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: Impact on survival and bleeding complications. Cancer 110:1149-1161, 2007.
21. Hurwitz HI, Saltz LB, Van Cutsem E, et al: Venous thromboembolic events with chemotherapy plus bevacizumab: A pooled analysis of patients in randomized phase II and III studies. J Clin Oncol 29:1757-1764, 2011.
22. Khorana AA, Kuderer NM, Culakova E, et al: Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111:4902-4907, 2008.
23. Ay C, Dunkler D, Marosi C, et al: Prediction of venous thromboembolism in cancer patients. Blood 116:5377-5382, 2010.
24. Khorana AA, O’Connell C, Agnelli G, et al: Incidental venous thromboembolism in oncology patients. J Thromb Haemost 10:2602-2604, 2012.
25. George DJ, Agnelli G, Fisher W, et al: Venous thromboembolism (VTE) prevention with semuloparin in cancer patients initiating chemotherapy: Benefit-risk assessment by VTE risk in SAVE-ONCO. American Society of Hematology Annual Meeting. Abstract 206. Presented December 12, 2011.
26. Verso M, Agnelli G, Barni S, et al: A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: The Protecht score. Intern Emerg Med 7:291-292, 2012.
