The link between cancer and thrombosis has been known for many years. Recently this connection has come to the forefront with increased recognition by healthcare providers and mandates by governing bodies. The results of a thromboembolic event can be catastrophic in a patient with cancer. Malignant neoplasms alone are associated with a 4-fold increased risk of a venous thromboembolic event (VTE), and cytotoxic or immunosuppressive chemo therapy in creases the malignant neoplasm–associated risk to more than 6-fold.1,2 VTE leads to a significant reduction in survival3-5 and is the second-leading cause of death in patients with cancer.6 Patients with cancer who have a VTE are also at increased risk of recurrence, bleeding complications, and morbidity.7
Patients with cancer have multiple factors that increase their risk of VTE. First, the cancer itself produces a hyper - coaguable state for these patients. Certain cancers appear to carry a higher risk than others (malignant brain tumors; adenocarcinoma of the lung, ovary, pancreas, colon, stomach, prostate, and kidney; and hematologic malignancies),8 but all cancers will increase the patient’s overall VTE risk.
The patient’s therapy also plays a major role in the risk of VTE. Many newer chemotherapeutic agents, such as bevacizumab, carry an increased risk of thromboembolism.9 VTE risk increases 2- to 5-fold when women with breast cancer are treated with tamoxifen.10,11 Aromatase inhibitors also increase this risk, but at about half the rate of tamoxifen.12 Thalidomide or lenalidomide increases throm boembolic risk, especially when used in combination with chemotherapy or highdose dexamethasone.13 All of these are additive to the other general risk factors that these patients may already be exposed to, such as decreased mobility, surgeries or procedures, age, indwelling catheters, and other comorbidities.
Due to the high risk faced by cancer patients, many guidelines have been developed to help assist in the prevention and treatment of thromboembolic events in these patients. The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and the American College of Chest Physicians (CHEST) have issued guidelines to help practitioners prevent and treat thrombosis in patients with cancer. These guidelines have much overlap in their recommendations, and rightfully so. I will attempt to give a brief summary of some of these guidelines specific to patients with cancer (Table).
For prevention of VTE, all 3 societies agree that pharmacologic prophylaxis should be initiated in hospitalized cancer patients in the absence of contraindications.14-16 Low-dose unfractionated heparin (LDUH), lowmolecular- weight heparin (LMWH), or fondaparinux should be utilized. Pharmacologic prophylaxis would be contraindicated in patients who are bleeding or have a high risk for major bleeding. In these patients, consider mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression. If the thrombotic risk persists once the bleeding risk has subsided, the use of pharmacologic prophylaxis should be reassessed and substituted for mechanical prophylaxis.
For prevention of VTE in the surgical patient with cancer, again all 3 societies agree. The guidelines recommend extended prophylaxis for surgical cancer patients for up to 4 weeks, particularly in high-risk abdominal or pelvic surgery.14,15,17 All 3 recommend LMWH. NCCN and ASCO also support unfractionated heparin as an alternative, and NCCN supports fondaparinux as well. Mechanical methods can be added to pharmacologic prophylaxis in patients at highest risk.
For patients in the ambulatory setting, the societies previously agreed that routine prophylactic anticoagulation was not recommended except in patients with multiple myeloma who were receiving thalidomide- or lenalidomidebased combination regimens and in whom the risk of VTE warranted prophylaxis.14,15 The latest additions to the CHEST guidelines have extended this recommendation. These guidelines suggest that outpatients with solid tumors who have additional risk factors for VTE but who have a low risk for bleeding use prophylactic doses of LMWH or LDUH over no prophylaxis.16 The additional risk factors include previous thrombosis, immobilization, hormonal therapy, angiogenesis in hibitors, and again thalidomide or lenalidomide therapy. This recommendation is based on moderate- quality evidence of reduction in mortality and high-quality evidence of reduction in VTE. These effects were larger than any plausible increase in bleeding risk.
For patients with cancer who have indwelling central venous catheters (CVCs), routine prophylactic anticoagulation is not recommended.14-16 Over the next few years, more evidence may become available on the efficacy and cost-effectiveness, and specific groups of patients with CVCs that may benefit from prophylaxis, taking into consideration VTE risk versus bleeding risk.
For treatment of VTE in cancer patients, therapy is driven by the findings of the CLOT trial.18 This trial was conducted over a 6-month period. It compared the efficacy of LMWH (dalteparin) to oral anticoagulation in the prevention of recurrent thrombosis in patients with cancer. The trial showed no significant difference in bleeding risk or 6-month mortality but did show a statistically significant difference in recurrent thromboembolism at 6 months favoring the LMWH group.
When treating cancer patients who have a pulmonary embolism (PE) or deep vein thrombosis (DVT), LMWH is the preferred agent. These patients should be treated indefinitely as long as they have active cancer or risk factors persist.14,15,19 Well-managed vitamin K antagonists, such as warfarin, may be an acceptable alternative when LMWH is not advisable. This may be true in patients who cannot afford LMWH, patients who are opposed to daily injections, or those who have renal insufficiency.
As for the dose of LMWH, in the CLOT trial dalteparin was given at 200 IU/kg once daily for the first month then 150 IU/kg once daily for the remaining 5 months.18 Enoxaparin carries an indication for inpatient treatment of DVT with or without PE at a dose of 1 mg/kg every 12 hours or 1.5 mg/kg every 24 hours. For outpatient DVT without PE, the indicated dose is 1 mg/kg every 12 hours.20 Both indications are in conjuction with the initiation/administration of warfarin. The quality of evidence comparing once-daily versus twice-daily LMWH is low because of impression and inconsistency in studies comparing the 2 types of administration. A metaanalysis of studies showed similar rates of mortality, recurrent DVT, and major bleeding.21 Keep in mind, these studies were not for long-term treatment with LMWH. LMWH was administered for a period of 5 to 10 days in conjunction with a vitamin K antagonist. The study by Merli and colleagues, published in Annals of Internal Medicine in 2001, suggested that outcomes may be inferior with once-daily versus twice-daily regimens.22 In the subset of patients with malignancy, the study showed a 12.2% rate of recurrence with the once-daily dose and only a 6.4% rate of recurrence with the twice-daily group; however, statistical significance was not achieved. This study also did not include long-term use of LMWH.
These studies did lead to the latest CHEST recommendation for patients with acute DVT of the leg treated with LMWH. They suggest once-daily over twice-daily administration, but this recommendation applies only if the approved once-daily regimen uses the same total daily dose as the twice-daily regimen.19 This would be true for dalteparin using 200 IU/kg once daily but not for enoxaparin that uses 1.5 mg/kg once daily (twice-daily dose is 1 mg/ kg every 12 hours). This recommendation could then be interpreted as indicating that the preferred treatments are dalteparin 200 IU/kg every 24 hours or enoxaparin 1 mg/kg every 12 hours. The recommendation carries a 2C grade from CHEST, which is a weak recommendation with low- or very low-quality evidence. In patients with cancer, again based on the CLOT trial that did study long-term LMWH therapy, clinicians should utilize LMWH dosing where the full total daily dose is utilized. Dalteparin is the only LMWH to carry a treatment indication for patients with cancer at 200 IU/kg daily for the first month, then 150 IU/kg daily. If we carry this to a class indication, enoxaparin should be dosed at 1 mg/kg every 12 hours initially for treatment of VTE in patients with cancer. Also, one must remember that LMWH is eliminated renally, so dose adjustments may be necessary based on the patient’s renal function.
For the treatment of catheter-related thrombosis, it is suggested that the catheter not be removed if it is still functioning. The treatment for this thrombosis is based on whether the catheter is or is not removed. If the catheter is removed, the patient should be treated for 3 months after the catheter is removed. If the catheter is not removed, the patient should be treated with anticoagulation therapy as long as the catheter remains in place.15,19
Two new oral anticoagulants have recently joined the market, and more are in the pipeline. These will most likely be approved in the next few years, as will additional indications for the oral anticoagulants already available. Two agents that have recently been approved are dabigatran (Pradaxa) and rivaroxaban (Xarelto). Dabigatran is a direct thrombin inhibitor, and rivaroxaban is a selective inhibitor of factor Xa. Currently both are approved for nonvalvular atrial fibrillation, and rivaroxaban is also approved for DVT prophylaxis post knee and hip replacement.23,24 Neither is currently approved for the treatment of VTE. The goal for any of the new anticoagulants is to develop an agent that is oral, requires minimal monitoring, has a predictable and rapid effect, has a large therapeutic index, and has minimal drug interactions.
Dabigatran is a twice-daily medication, whereas rivaroxaban is given once daily. Both are eliminated by the kidneys, so are contraindicated in patients with renal impairment. They do have a rapid onset and a larger therapeutic index. There are no regular monitoring recommendations with these agents.
Although these medications seem to make anticoagulation therapy simpler, there are a few things to consider in patients with cancer. There is currently no reversal agent available to completely reverse the anticoagulation effect of these agents. This plays a major role in anticoagulation therapy in patients with cancer who are already at a higher risk of bleeding. With the rapid onset and rapid clearance of these agents, a short half-life syndrome can result. If compliance is an issue, patients on these medications can return to baseline after missing only 1 or 2 doses, which can rapidly increase their risk of a thromboembolic event.
An interesting phase 2 trial by Levine and colleagues that was recently published in the Journal of Thrombosis and Haemostasis initiated patients receiving chemotherapy on apixaban for 12 weeks.25 Apixaban is a factor Xa inhibitor that is not yet approved by the FDA. These were patients without a prior history of VTE. The outcomes were to determine major or clinically relevant nonmajor bleeding, VTE, and adverse events related to the drug. The trial did show a low bleeding risk for these patients and a decrease in VTE. The study protocol did potentially select for patients with a lower bleeding risk by not including patients with a prolonged bleeding time or patients receiving moderate to high doses of aspirin or other antiplatelet agents, and caution should be used when extrapolating these results to a less selective population. This does introduce what may be on the horizon for anticoagulation and cancer and the use of the newer agents. Further studies will need to be completed to support these findings.
In cancer patients in whom bleeding risk is already elevated, a clear picture of the real-life bleeding risk associated with these agents is still not available. Lack of monitoring may actually be a negative in these patients. With the other agents, we have a standard laboratory value that can measure the extent of the patient’s anticoagulation. There is no standard laboratory value to measure the newer agents. Certain anticoagulation markers may be elevated with therapy, but there is no direct correlation to the actual level of anticoagulation. With cancer patients receiving chemotherapy and having frequent procedures or surgeries, we cannot assess their true bleeding risk. In patients with cancer, these medications should be used with extreme caution until more postmarketing data are available and analyzed.
- 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. 2000;160:809-815.
- Blom JW, Doggen CJ, Osanto S, et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293:715-722.
- Alcalay A, Wun T, Khatri V, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol. 2006;24:1112-1118.
- Chew HK, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458-464.
- Sørensen HT, Mellemkjaer L, Olsen JH, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000;343: 1846-1850.
- Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632-634.
- 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;100:3484-3488.
- Falanga A, Donati MB. Pathogenesis of thrombosis in patients with malignancy. Int J Hematol. 2001;73:137- 144.
- Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277-2285.
- Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation. 2003;107(23 suppl 1):I17-I21.
- Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005; 97:1652-1662.
- Thürlimann B, Keshaviah A, Coates AS, et al. Breast International Group (BIG)1-98. Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353:2747-2757.
- El Accaoui RN, Shamseddeen WA, Taher AT. Thalidomide and thrombosis. A meta-analysis. Thromb Haemost. 2007;97:1031-1036.
- 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. 2007;25:5490-5505.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease. Version 1.2009. http://www.oncologycast.net/guidelinecasts/NCCN_Guidelines.pdf. Accessed April 26, 2012.
- Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e195S-e226S.
- Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e227S-e277S.
- 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;349:146-153.
- 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(suppl 2):e419S-e494S.
- Lovenox [package insert]. Bridgewater, NJ: sanofiaventis US LLC; 2011.
- Couturaud F, Julian JA, Kearon C. Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis. Thromb Haemost. 2001;86:980-984.
- Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134:191-202.
- Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim; 2012.
- Xarelto [package insert]. Leverkusen, Germany: Bayer HealthCare; 2011.
- Levine MN, Gu C, Liebman HA, et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10:807-814.