1 Department of Hematology-Oncology, Ospedali Riuniti, Bergamo, Italy; 2 VA Medical Center, 215 North Main Street, White River Junction, Vermont 05009, USA
* Correspondence to: A. Falanga, Department of Hematology-Oncology, Ospedali Riuniti di Bergamo, Largo Barozzi 1, 24128 Bergamo, Italy. Tel: +39-035-269-492; Fax: +39-035-266-659; Email: annafalanga{at}yahoo.com
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Abstract |
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Key words: cancer, dalteparin, deep venous thrombosis, low molecular weight heparin, venous thrombosis, warfarin
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Introduction |
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Patients with VTE are generally managed with anticoagulant therapy with the aim of treating the acute event and preventing death due to pulmonary embolism (PE), in addition to minimising the risk of post phlebitic symptoms and recurrent VTE [6]. However, traditional approaches to anticoagulant therapy are often hampered by the presence of malignant disease and its treatment [6
]. In addition, cancer patients are at increased risk of recurrent VTE and anticoagulant-associated bleeding [3
]. Thus, the management of VTE may be complex in patients with cancer, and VTE can further compromise quality of life.
In this article we review the clinical significance of VTE in patients with cancer and the strategies for management of VTE in these patients, including the potential role of low molecular weight heparins (LMWHs).
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The epidemiology of VTE in patients with cancer |
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It is not certain whether particular types of cancer are associated with an increased risk of cancer or whether the distribution of cancer types in patients with thrombosis simply reflects the prevalence of individual cancers in the general population. Nevertheless, given the presence of a range of risk factors for VTE in patients with cancer, it may be prudent to anticipate that all cancer patients are at a higher risk of VTE than the general population.
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Risk factors for VTE in cancer |
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Similar findings were reported in a review of 2673 patients with breast cancer in trials organised by the Eastern Cooperative Oncology Group [16]. Venous and arterial thromboses were significantly more common among women receiving chemotherapy plus hormonal therapy than in controls (5.4% versus 1.6%, P=0.0002). The addition of tamoxifen to chemotherapy regimens increased the incidence of VTE from 0.8% to 2.8% (P=0.03) in premenopausal women, and from 2.3% to 8.0% in postmenopausal women (P=0.03). Another study has shown that the addition of chemotherapy to tamoxifen therapy also increases the risk of arterial and venous thromboembolic events in patients with breast cancer [17
]. Thromboembolic events were observed in 13.6% of women receiving combination therapy, compared with 2.6% of those randomised to tamoxifen therapy alone (P <0.0001). Importantly, thromboembolic complications resulted in more days in hospital and more deaths than any other complication of therapy, including infection, in this study. In fact, it was suggested that these events outweighed any benefits of the chemotherapy. Thus, the clinical impact of VTE should not be underestimated. A high incidence of VTE (11% at 1 year) has also been reported recently in other cancer types following chemotherapy [18
].
The risk of postoperative VTE is approximately twice as high in cancer patients as in patients without cancer undergoing comparable surgery [19, 20
]. Immobilisation due to prolonged bed rest in debilitated cancer patients further increases the risk of VTE [21
, 22
].
Cancer patients who survive an initial thrombotic event are also at heightened risk of recurrent VTE. A cohort study of 355 patients with symptomatic deep vein thrombosis (DVT) estimated that the presence of cancer was associated with a hazard ratio of 1.72 for the risk of recurrent VTE, compared with patients without cancer [3]. Furthermore, the risk of death after VTE was shown to be greater in the presence of cancer (hazard ratio 8.1) compared with non-cancer patients and is consistent with the view that VTE in patients with cancer is a predictor of poor survival.
The heightened risk of recurrent VTE among patients with cancer persists for many years after the initial event. A prospective cohort study of patients presenting with symptomatic DVT revealed a cumulative incidence of recurrent VTE of 17.5% after 2 years, 24.6% after 5 years and 30.3% after 8 years [3]. The presence of cancer increased the risk of recurrent VTE by a factor of 1.72. Furthermore, the cumulative incidence of the post-thrombotic syndrome was 22.8% after 2 years, 28% after 5 years and 29.1% after 8 years. These findings challenge the conventional short-term approach to antithrombotic therapy and indicate that extended thromboprophylaxis may be necessary in patients with cancer.
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The relationship between VTE and cancer |
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In view of these findings, it has been suggested that an underlying cancer should always be considered in patients presenting with VTE, especially if there is no identifiable risk factor. A careful medical history and thorough physical examination, plus standard laboratory tests and a chest radiograph have been suggested as routine screening for underlying cancer in patients with idiopathic VTE [30]. A prospective study of extensive screening in patients with idiopathic DVT was completed recently, although the study was not sufficiently powered to demonstrate an effect of extensive screening on cancer survival [31
]. The value of extensive screening for cancer in patients with idiopathic DVT remains unclear and further trials are needed.
The development of VTE in patients with established cancer is associated with a poor prognosis. The findings of two prospective studies indicate that cancer patients have a four- to eight-fold higher risk of death after an acute thrombotic event than patients without cancer [3, 4
]. Although cancer patients would be expected to have a lower survival rate than those without cancer, the occurrence of VTE in cancer patients further reduces patient survival rates. In another study, 44% of cancer patients presenting with VTE were found to have metastatic cancer at presentation, compared with 35% of age-matched controls with comparable cancers but no VTE [4
]. Furthermore, 1-year survival was only 12% in the group with cancer and VTE compared with 36% in the control group. It has been suggested that cancer associated with VTE tends to be more advanced and have a poorer prognosis than cancer without VTE.
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Current management strategies for VTE in cancer patients |
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Because of the high risk of VTE in cancer patients, the role of primary thromboprophylaxis is being evaluated in prospective, randomised trials. At present, the current ACCP guidelines recommend that primary prevention is considered for patients with cancer in the presence of additional risk factors for thrombosis: chemotherapy, or surgery, during periods of immobilisation, and in the presence of central venous catheters (grade 1A) [6, 32
].
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Challenges of antithrombotic therapy in cancer patients |
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VKAs are known to interact with a wide range of drugs, and the use of concomitant therapies may produce an increased anticoagulant effect. For example, the anticoagulant action of warfarin is augmented by many drugs including several non-steroidal anti-inflammatory drugs, antibacterial agents, antipeptic agents such as cimetidine and omeprazole, and anticancer therapies including ifosfamide and tamoxifen [34].
Surgery is also more hazardous for patients with cancer than in non-cancer patients. Surgery for malignant disease is associated with an approximately two-fold higher risk of VTE than similar surgery in patients without cancer [6]. One study that evaluated the risk of postoperative PE found that the presence of cancer markedly increased the risk of developing PE after surgery among patients with cancer compared with those without cancer (odds ratio 6.7) [35
]. Furthermore, patients with cancer are at increased risk of perioperative bleeding [36
]. This adds to the difficulties of ensuring adequate thromboprophylaxis in these patients.
However, in view of the high risk of VTE in surgical patients with cancer, recent guidelines published by the ACCP recommend the use of primary prophylactic treatment with UFH or LMWH [6]. The thromboprophylactic efficacy of the LMWH dalteparin has been compared with that of UFH in patients undergoing elective abdominal surgery (63% with malignant disease) [37
]. The study showed that 58-day treatment with dalteparin reduced the incidence of DVT in all patients (from 9.2% to 5.0%, P=0.02) with a similar, although non-significant, reduction in the subgroup of patients with cancer (from 11.2% to 6.4%; P=0.06). Importantly, there was no difference in bleeding rate for each treatment in the cancer subgroup (3.2% for dalteparin and 2.8% for UFH; P=0.28). Results from the ENOXACAN II study [38
] and the recently completed Fragmin After Major Abdominal Surgery (FAME) study indicate that extending thromboprophylactic therapy with enoxaparin 40 mg once daily or dalteparin 5000 IU once daily to 4 weeks duration provides additional benefit in patients undergoing surgery for abdominal malignancy [39
]. Notably, the FAME study demonstrated that the reduction in VTE achieved with dalteparin was driven by a reduction in proximal DVT.
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Improving VTE management in cancer |
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LMWHs have several practical advantages over VKAs. First, LMWHs exhibit predictable bioavailablity after subcutaneous administration and dose-independent renal clearance and, as a consequence, therapy does not require monitoring of coagulation tests. These agents can, therefore, be used in geographical areas without access to laboratories capable of determining INR values, and in patients in whom repeated blood sampling is difficult or inconvenient. Second, LMWHs have a rapid onset and offset of action, which offers greater flexibility than is possible with VKAs when treatment needs to be interrupted; for example, before invasive procedures. Furthermore, the predictable anticoagulant response achieved with LMWHs means that the initiation of treatment with a LMWH does not require patients to be hospitalised [46]. Not only is this more convenient for the patient but economic analyses suggest that outpatient treatment with LMWHs could reduce the duration of inpatient stay by an average of 56 days per patient, and could significantly affect the total cost of medical care for these patients.
LMWHs are readily bioavailable after subcutaneous administration and their long half-lives permit a twice-daily treatment regimen; some LMWHs require only once-daily administration. In contrast, UFH generally requires continuous intravenous infusion during treatment initiation. An additional advantage over UFH is that the dose of LMWHs can be calculated on the basis of body weight, and laboratory-based tests and subsequent dosage adjustment are not necessary. Furthermore, LMWHs are at least as effective as UFH for the treatment of acute DVT and are associated with less bleeding compared with UFH [47, 48
] and a lower total mortality rate [49
].
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Conclusions |
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Received for publication November 9, 2004. Revision received January 28, 2005. Accepted for publication February 1, 2005.
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