VTE in Cancer Patients: New Guidelines Define Role of Anticoagulants

	Blood clots and their complications are a major cause of death in cancer patients, and affect up to 20% of persons with cancer at some point in their treatment. Major risk factors for developing a blood clot include age, primary site of cancer, hospitalization, history of venous thromboembolism (VTE), and active therapy such as chemotherapy, antiangiogenic drugs, and hormonal therapy.

	The most common malignancies associated with thrombosis are those of the breast, colon, and lung, reflecting the prevalence of these malignancies in the general population. When adjusted for disease prevalence, the cancers most strongly associated with thrombotic complications are those of the pancreas, ovary, and brain. Idiopathic thrombosis can be the first manifestation of an occult malignancy.

	The American Society of Clinical Oncology (ASCO) has released new clinical guidelines on the use of anticoagulants for the prevention and treatment of VTE in persons with cancer.

 The new guidelines were developed by an international panel of researchers, and are based on published clinical studies. Key recommendations in the new guidelines include:

	• All hospitalized patients with cancer should receive preventive anticoagulation.

	• All patients with cancer who develop a blood clot should be treated with an anticoagulant for at least 6 months, and possibly longer in those who continue treatment for active cancer.

	• Physicians should evaluate all patients with cancer receiving major surgery, for administering anticoagulation, beginning before the operation or as soon afterward as possible.

	• Regular use of an anticoagulant for patients with cancer who are not hospitalized and receiving chemotherapy is not recommended, except for patients with multiple myeloma receiving thalidomide or lenalidomide with chemotherapy or dexamethasone.

	• Low—molecular weight heparin (LMWH) is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the cancer patient with established VTE.

	• LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted international normalized ratio of 2 to 3 are acceptable for long-term therapy when LMWH is not available.

	• 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.

	A key clinical trial on which the new ASCO guidelines were based is the CLOT (Randomized Comparison of LMWH versus Oral Anticoagulant Therapy for the Prevention of Recurrent VTE in Patients with Cancer) study.

 This was a landmark randomized trial that evaluated the impact of a LMWH—dalteparin (Fragmin)&mdash;on survival in cancer patients with VTE. In the CLOT study, 676 cancer patients with acute symptomatic proximal DVT and/or pulmonary embolism were randomized to receive treatment with either dalteparin plus oral anticoagulant therapy or dalteparin alone. During the 6-month study period, 27 of 336 patients in the dalteparin group (8.0%) had recurrent VTE, compared with 53 of 336 patients in the oral-anticoagulant group (15.8%; 

= 0.002). The probability of recurrent VTE at 6 months was 9% in the dalteparin group versus 17% in the oral-anticoagulant group. No significant difference between dalteparin-treated patients and those who received oral-anticoagulant therapy was detected in the rate of major bleeding (6% and 4%, respectively) or any bleeding (14% and 19%, respectively). The investigators concluded that in patients with cancer and acute VTE, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.

	According to Gary H. Lyman, MD, co-chair of the guideline panel and Director, Health Services and Outcomes Research Program—Oncology at Duke University Medical Center in Durham, NC, “The primary treatment for blood clots in cancer patients is an anticoagulant, a drug that helps to break up the blood clot. Anticoagulants may raise a patient’s risk of bleeding, and treatment often requires a short hospital stay, but, in virtually every case, the benefits of treatment with anticoagulants outweigh the risks.”

	Dr. Lyman also noted that the frequency of diagnosed blood clots in cancer patients has been rising yearly, but several studies cited in the new guidelines suggest that anticoagulants are underused, particularly in hospitalized cancer patients. “More research is also urgently needed to identify better markers of who is most likely to develop VTE among ambulatory cancer patients. People with cancer should be encouraged to ask their oncologist about their risk of VTE and to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies.”

	The new guidelines emphasize using anticoagulants preventively in populations that are at risk, including hospitalized cancer patients. The guidelines also suggest that cancer patients who develop a blood clot should be treated with an anticoagulant for at least 6 months afterward. Conversely, the guidelines recommend that patients who are not hospitalized should not be routinely treated with an anticoagulant, unless they are receiving certain types of therapies that may increase risk.

	Dr. Lyman added, “We have long known that there is an association between cancer and risk for VTE, and we can speculate what some of the reasons for this link might be. Tumor cells may release proteins that encourage clotting, and these patients are often bedridden and immobile, which also puts them at increased risk. Treatments, especially newer ones such as the antiangiogenesis agents which work by cutting offa tumor’s blood supply, may also increase the risk of VTE.

	Dr. Lyman also said that patients should be aware of their risk and should ask their doctor about how to minimize it. “The message to patients is to add VTE to the list of things to ask their doctor about.”

	The new guidelines are consistent with previous guidelines issued by the National Comprehensive Cancer Network (NCCN)

 and the American College of Chest Physicians (ACCP).

 The NCCN guidelines focus on risk factors, prophylactic measures, and anticoagulation treatment. The ACCP guidelines advocate VTE prophylaxis prior to surgery in cancer patients.

	The new guidelines and accompanying patient guide were published in the December 1, 2007 issue of 

. An online version is available at the ASCO website (www.asco .org) and at ASCO’s People Living With Cancer website (www.plwc.org) ahead of print.

	1. Lyman GH, Khorana AK, Falanga A, et al: American Society of Clinical Oncology guideline: Recommendations for

	    venous thromboembolism prophylaxis and treatment in patients with cancer. 

	2. 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. 

	3. Wagman LD, Baird MF, Bennett CL, et al: Venous thromboembolic disease. Clinical practice guidelines in oncology.

	4. Geerts WH, Pineo GF, Heit JA, et al: Prevention of venous thromboembolism: The Seventh ACCP Conference on

	    Antithrombotic and Thrombolytic Therapy. 

Articles

Blood clots and their complications are a major cause of death in cancer patients, and affect up to 20% of persons with cancer at some point in their treatment.

John Zoidis, MD

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VTE in Cancer Patients: New Guidelines Define Role of Anticoagulants