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Management of Venous Thromboembolism in Cancer Patients

Management of Venous Thromboembolism in Cancer Patients

ABSTRACT: Venous thromboembolism is a common complication in patients with cancer. The management of deep-vein thrombosis and pulmonary embolism can be a considerable challenge in these patients. Diagnosing venous thrombosis requires objective testing, and noninvasive investigations may be less accurate in patients who have cancer than in those who do not. Treatment of acute venous thrombosis at home with low-molecular-weight heparin is an attractive option in patients with malignant disease, in whom quality of life is especially important. Comorbid conditions, warfarin resistance, difficult venous access, and a potentially high bleeding risk are some of the factors that often complicate the prolonged course of anticoagulant therapy needed in this group. In addition, the use of central venous catheters is increasing, but the optimal treatment of catheter-related thrombosis remains controversial. This article reviews the current diagnostic and treatment approaches to venous thromboembolism in patients with cancer and provides several clinical scenarios to illustrate and discuss some common management problems. [ONCOLOGY 14(3):409-417, 2000]

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 (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 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 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 sodium (Lovenox), dalteparin
(Fragmin), and 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.

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