Management of Venous Thromboembolism in Cancer Patients

Introduction

Cancer patients have a high risk of developing thromboembolic disease. Both venous and arterial thrombotic complications have been described in patients with a variety of malignancies.

Despite the well-established association between malignancy and thrombosis, the true incidence of thromoembolism in cancer patients is difficult to ascertain because of the paucity of data in most malignancies. The best information comes from trials of adjuvant therapy in patients with breast cancer.[1] In patients receiving tamoxifen(Drug information on tamoxifen) (Nolvadex), the incidence of thromboembolism is approximately 1%. In those undergoing chemotherapy, the risk of thrombosis varies from 2% to 18%, increasing with more advanced stages of disease.

In addition to the thrombogenic risk arising from intrinsic tumor procoagulant activity, extrinsic factors are also involved in the pathogenesis of thrombosis in cancer patients.[2-4] These include antineoplastic drugs, hormonal agents, surgery, immobilization, and indwelling central venous catheters. The interaction of these factors results in a heightened thrombophilic state and complicates the diagnosis and treatment of venous thromboembolism.

Establishing the Diagnosis

Deep-vein thrombosis and pulmonary embolism are the most common thrombotic conditions in patients with cancer.[2,3] Although cancer patients with venous thromboembolism often present with typical symptoms, such as limb swelling and pain or shortness of breath, the clinical presentation can be less specific than in patients without cancer. Therefore, the use of objective investigations is essential in confirming a diagnosis of deep-vein thrombosis or pulmonary embolism.

Deep-Vein Thrombosis

Contrast venography remains the reference standard for diagnosing deep-vein thrombosis. Increasingly, however, noninvasive testing is replacing venography in routine clinical practice because of the morbidity associated with venography and its limited availability.

Compression or duplex ultrasonography is a highly accurate, noninvasive method for diagnosing symptomatic proximal thrombosis in the legs, with a sensitivity of 95% and a specificity of 96%.[5-7] Based on the results of venous ultrasonography, in combination with either D-dimer testing or clinical assessment, patients with suspected deep-vein thrombosis can be managed safely.[8-10]

Although published studies evaluating the accuracy of noninvasive diagnostic methods have included patients with cancer, it is not known whether these diagnostic tests are as accurate in this subgroup of patients because the cancer and/or its treatments may reduce the diagnostic accuracy of noninvasive investigations.[11,12] For example, extrinsic venous compression by the tumor mass may cause both impedance plethysmography and venous ultrasonography to yield false-negative results.

Supporting these concepts, one study demonstrated that impedance plethysmography was less sensitive and specific in diagnosing deep-vein thrombosis in patients with cancer than in patients without the disease.[12] In addition, a recent analysis found that the specificity and negative predictive value of a D-dimer assay are significantly lower in cancer patients than in noncancer patients, resulting in a high number of false-negative results.[11]

A suggested algorithm for diagnosing deep-vein thrombosis in cancer patients is shown in Figure 1.

Pulmonary Embolism

Making a diagnosis of pulmonary embolism in patients with or without cancer remains difficult and often relies on clinical assessment plus a battery of investigations. These may include ventilation-perfusion lung scintigraphy, venous ultrasonography, and D-dimer testing.[13-16]

Spiral computed tomography (CT), recently shown to be specific and reliable for diagnosing pulmonary embolism in the central pulmonary vasculature, is not sufficiently sensitive for detecting emboli involving subsegmental arteries in more distal lung segments.[17,18] However, spiral CT may be superior to ventilation-perfusion lung scintigraphy in patients with cancer, as it detects other pulmonary abnormalities and can often differentiate pulmonary metastases from emboli.

To date, no published studies have specifically addressed the accuracy of noninvasive testing for the diagnosis of pulmonary embolism in patients with cancer. Figure 2 is a suggested algorithm for the diagnosis of pulmonary embolism in these patients.

Treatment

The treatment of cancer patients with venous thromboembolism can be difficult. The major concerns regarding treatment are anticoagulant-induced bleeding and recurrent thromboembolism. Other challenging issues include: (1) how to manage anticoagulant therapy around the time of invasive procedures; (2) whether to initiate anticoagulation in a patient with an extremely short life expectancy, or when to discontinue such therapy; (3) and when to use aggressive second-line antithrombotic treatments, such as insertion of an inferior vena caval filter or thrombolysis. Therefore, in addition to the usual treatment objectives of averting death from pulmonary embolism, reducing morbidity from the acute event, minimizing postphlebitic symptoms, and preventing thromboembolic pulmonary hypertension, anticoagulant treatment in cancer patients must be individualized based on the overall therapeutic and palliative goals of care.

Initial Anticoagulant Therapy

The current standard initial treatment of patients with venous thrombosis consists of either intravenous unfractionated heparin(Drug information on heparin) or subcutaneous low-molecular-weight heparin. Large clinical trials conducted during the past decade have demonstrated that low-molecular-weight heparins are as safe and effective as unfractionated heparin in both inpatient and outpatient settings.[19-24] An oral anticoagulant is administered within 24 hours of the start of unfractionated or low-molecular-weight heparin and is continued for long-term secondary prophylaxis. Currently, the same treatment regimens are used for patients with and without cancer.

Unfractionated Heparin—The standard, 5,000-unit intravenous loading dose for unfractionated heparin should be followed by a continuous infusion of at least 30,000 U/24 h. Subsequent doses should be adjusted based on a validated nomogram to reach and maintain a therapeutic activated partial thromboplastin time (APTT) of approximately 1.5 to 2.0 times the control value. This therapeutic range should correspond to a heparin level of 0.2 to 0.4 U/mL by protamine sulfate(Drug information on protamine sulfate) titration, or 0.4 to 0.7 U/mL by anti–factor Xa assay.[25]

The therapeutic range differs depending on the APTT reagent and automated coagulation machine used, and a fixed ratio of 1.5 times control may not be therapeutic for insensitive reagents.[26] Therefore, each laboratory should perform standardizing procedures for its specific reagent and equipment. In patients who require large doses of heparin (> 40,000 U/24 h), the anti–factor Xa heparin level should be monitored instead of the APTT because of a dissociation between the APTT and heparin concentration in these heparin-resistant patients.[27]

In patients with uncomplicated acute thrombosis, the heparin infusion should be continued for a minimum of 5 days, and it should not be stopped until the oral anticoagulant has reached therapeutic levels for 2 consecutive days, as indicated by the international normalized ratio (INR) of 2.0 to 3.0. For patients presenting with extensive disease, eg, phlegmasia cerulea dolens or life-threatening pulmonary embolism, a longer, 7- to 10-day course of heparin is indicated.[28]

The major advantage of a heparin infusion is that rapid reversal of the anticoagulant effect can be achieved by stopping the infusion and by administering protamine sulfate, if necessary. This is clearly desirable in a patient who has a high risk of bleeding, and yet urgently requires anticoagulant therapy.

The disadvantages of a heparin infusion include the need for intravenous administration and frequent laboratory monitoring, the lack of standardized assays, the potential development of heparin resistance, and the uncommon but potentially fatal complication of heparin-induced thrombocytopenia with thrombosis.[25-27,29] In addition, the need for hospitalization and laboratory monitoring required make this a costly treatment.

Low-Molecular-Weight Heparins, which have an average molecular weight of 5,000 d, are fractionated products of standard heparin (average molecular weight of 15,000 d). Low-molecular-weight heparins, which include enoxaparin(Drug information on enoxaparin) sodium (Lovenox), dalteparin (Fragmin), and ardeparin(Drug information on ardeparin) (Normiflo), are produced by enzymatic or chemical depolymerization and have similar biochemical properties.[30]

Low-molecular-weight heparins have many experimental and clinical advantages over unfractionated heparin. Because low-molecular-weight heparins bind less to plasma proteins, macrophages, platelets, and endothelium than unfractionated heparin, they have longer plasma half-lives, better bioavailability, and more predictable pharmacokinetics.[30] These properties translate clinically into once- or twice-daily subcutaneous, weight-based dosing that does not require laboratory monitoring; hence, outpatient administration of these products is a feasible, safe option.[25] This option is particularly attractive for cancer patients, in whom quality of life is an important issue.

Although this class of drugs is more expensive than unfractionated heparin, the elimination of hospitalization and laboratory monitoring has made this initial therapy option more cost-effective.[31,32] It is important to emphasize that different low-molecular-weight heparins may vary in their clinical effects, and that efficacy and safety profiles cannot be completely extrapolated from one preparation to another.

Other potential advantages of low-molecular-weight heparins over unfractionated heparin suggested by meta-analyses of clinical trials and by animal experiments include a lower risk of bleeding,[33-35] osteoporosis,[36-38] and heparin-induced thrombocytopenia.[25,29]

Possible Antineoplastic Effect—More interestingly, both low-molecular-weight heparins and unfractionated heparin may have an antineoplastic effect and, thus, may offer a survival advantage to cancer patients with thrombosis.[33,34,39] The mechanism for this effect is unclear, but experimental studies suggest that heparin and its low-molecular-weight fractions may inhibit angiogenesis.[40,41] Ongoing randomized trials are exploring this possibility.

Bleeding Risk—The risk of clinically important bleeding during the initial period of anticoagulation with heparin or low-molecular-weight heparins is likely less than 5%.[42] The exact risk depends on the total dose of unfractionated or low-molecular-weight heparin, the age of the patient, underlying bleeding tendencies (eg, peptic ulcer disease), and whether the patient is receiving concomitant antiplatelet therapy.[25,42] However, studies of heparin-associated bleeding have included many noncancer patients. Hence, the true rate of bleeding in cancer patients receiving unfractionated or low-molecular-weight heparin is unclear.