Deep vein thrombosis in cancer: the scale of the problem and approaches to management

A. Falanga1,* and L. Zacharski2

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


    Abstract
 Top
 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
Patients with cancer have long been recognised to be at high risk of venous thromboembolism (VTE), although the condition remains under diagnosed and under treated in these patients. As a consequence, the morbidity and mortality due to deep venous thrombosis and pulmonary embolism remains unacceptably high in this group. Furthermore, the management of VTE in the presence of malignancy is complex, due both to the effects of the cancer itself and its treatments. Conventional long-term management of VTE involves the use of vitamin K antagonists (VKAs), such as warfarin, to reduce the risk of recurrence. However, this approach is associated with a range of practical difficulties including the need for regular laboratory monitoring, the potential for drug interactions, in addition to the risk of treatment resistance and bleeding in patients with cancer. Recent research indicates that the use of low molecular weight heparin (LMWH) therapy instead of VKAs may be beneficial in these patients. In particular, evidence from a large clinical trial of the LMWH dalteparin indicates that this agent offers an effective alternative to VKAs in the long-term management of VTE, that is free from the practical problems associated with the use of VKAs and without increasing the risk of bleeding.

Key words: cancer, dalteparin, deep venous thrombosis, low molecular weight heparin, venous thrombosis, warfarin


    Introduction
 Top
 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
An association between venous thromboembolism (VTE) and cancer has been recognised for over 100 years [1Go]. Nevertheless, VTE remains under diagnosed and under treated in patients with cancer [2Go], although VTE significantly affects the morbidity and mortality associated with cancer [3Go, 4Go]. The relationship between cancer and thrombosis is further supported by the observation that presentation with VTE may precede the development or diagnosis of cancer [5Go].

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 [6Go]. However, traditional approaches to anticoagulant therapy are often hampered by the presence of malignant disease and its treatment [6Go]. In addition, cancer patients are at increased risk of recurrent VTE and anticoagulant-associated bleeding [3Go]. 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).


    The epidemiology of VTE in patients with cancer
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 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
Thrombosis is a common complication in cancer patients [6Go]. VTE is found at autopsy in at least 50% of cancer patients [7Go, 8Go]. However, assessment of the true incidence of VTE in cancer patients is difficult because most of these patients receive chemotherapy or hormonal therapy, both of which can precipitate VTE [9Go]. In addition, many cancer patients have indwelling central venous lines, which can also initiate thrombotic events in relation to the catheter [10Go].

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.


    Risk factors for VTE in cancer
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 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
The presence of subclinical activation of the coagulation system is widely recognised in untreated cancer patients [11Go, 12Go]. This hypercoagulable state associated with malignant disease is thought to arise from direct activation of the clotting system by neoplastic cells, leading to the production of thrombin [12Go, 13Go]. In addition, neoplastic cells may activate the coagulation system indirectly by stimulating a procoagulant phenotype on host cells, including monocytes, platelets and endothelial cells (Figure 1) [12Go, 13Go]. Although alterations in biochemical markers of haemostatic abnormalities among patients presenting with cancer are common, these changes are not useful for predicting subsequent development of thrombosis [14Go]. However, the presence of hypercoagulability may predict the presence of advanced disease in cancer patients. Conversely, patients with advanced cancer may be at a higher risk of VTE than those with early stage disease [4Go].



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Figure 1. Mechanisms of haemostatic system activation by tumour cells.

 
Chemotherapy further increases the risk of VTE associated with cancer [9Go]. This phenomenon has been extensively investigated in patients receiving treatment for breast cancer. In a prospective trial of 205 women with stage II breast cancer who received 12 or 36 weeks of chemotherapy plus hormonal therapy, the overall thrombosis rate was 6.8% [15Go]. All thrombotic events were recorded during the periods in which chemotherapy was administered, and these findings clearly demonstrate that chemotherapy contributes to the heightened risk of thrombosis in patients with cancer.

Similar findings were reported in a review of 2673 patients with breast cancer in trials organised by the Eastern Cooperative Oncology Group [16Go]. 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 [17Go]. 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 [18Go].

The risk of postoperative VTE is approximately twice as high in cancer patients as in patients without cancer undergoing comparable surgery [19Go, 20Go]. Immobilisation due to prolonged bed rest in debilitated cancer patients further increases the risk of VTE [21Go, 22Go].

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 [3Go]. 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 [3Go]. 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.


    The relationship between VTE and cancer
 Top
 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
In view of the well-recognised risk of VTE in established cancer, it has been suggested that idiopathic VTE may predict the presence of occult cancer. This could lead to the recommendation of screening for very early (i.e. treatable) cancer in patients presenting with idiopathic VTE. Large prospective studies yield an incidence of previously undiagnosed cancer of 4%–5% in patients presenting with VTE [23Go–25Go]. Other, smaller, studies have detected cancer in as many as 7%–12% of patients with idiopathic VTE, compared with only 2%–3% of patients with VTE associated with identifiable risk factors [5Go, 26Go, 27Go]. In two studies in which patients presenting with VTE underwent intensive investigation for cancer, the incidence of occult cancer was detected in up to 1 in 4 patients [27Go–29Go].

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 [30Go]. 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 [31Go]. 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 [3Go, 4Go]. 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 [4Go]. 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.


    Current management strategies for VTE in cancer patients
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 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
In general, the management of DVT and PE are similar, as the two conditions stem from the same pathological process. Standard thrombosis management involves the initial administration of weight-adjusted LMWH by subcutaneous injection (once daily with dalteparin or tinzaparin, twice daily with enoxaparin or nadroparin) or unfractionated heparin (UFH) by intravenous injection or infusion, for 5–7 days. If UFH is used, patients are generally required to remain in hospital for this period and the dose of UFH administered is adjusted to maintain an activated partial thromboplastin time of approximately 1.5–2.5 times the normal. Treatment with a vitamin K antagonist (VKA), i.e. warfarin or another coumarin, is usually commenced on day 1 during initial LMWH/UFH therapy, adjusted to achieve an international normalised ratio (INR) of 2–3, and continued for 3–6 months, in order to reduce the risk of recurrent VTE [32Go]. Current guidelines from the American College of Chest Physicians (ACCP) recommend the use of LMWH, specifically dalteparin or tinzaparin, for the long-term treatment of acute VTE, and that this should be continued for a minimum of 3–6 months (Grade 1A) [32Go].

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) [6Go, 32Go].


    Challenges of antithrombotic therapy in cancer patients
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 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
Patients with cancer and VTE, including those treated with VKAs, are more likely to have recurrent episodes of VTE than non-cancer patients [32Go]. The use of VKAs is associated with practical difficulties in all patients, due to the narrow therapeutic window of these agents and the need for regular laboratory monitoring (Table 1). However, this is particularly problematic in patients with cancer because of frequent changes in nutritional status, multiple drug interactions and alterations in liver metabolism, arising both from the disease itself and its treatment. In addition, there is a delay of several days between the initiation of treatment with a VKA and the appearance of a full anticoagulant effect because this depends on the clearance of clotting factors from the plasma. This adds to the inconvenience associated with interruptions in therapy that may be required in cancer patients due to chemotherapy-induced thrombocytopenia, or prior to surgery or other invasive procedures.


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Table 1. Problems with the use of VKAs in cancer patients

 
The principal problem with VKAs is the risk of bleeding, which is considerably greater in patients with cancer than it is in those without cancer [7Go]. The risk of bleeding appears to correlate with the extent of the disease; one study found that the risk of major bleeding was increased by a factor of 2–3 in patients with moderately extensive cancer, and by a factor of 5 in patients with extensive cancer [33Go]. It has been suggested that these findings may result from bleeding at the site of the cancer.

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 [34Go].

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 [6Go]. 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) [35Go]. Furthermore, patients with cancer are at increased risk of perioperative bleeding [36Go]. 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 [6Go]. The thromboprophylactic efficacy of the LMWH dalteparin has been compared with that of UFH in patients undergoing elective abdominal surgery (63% with malignant disease) [37Go]. The study showed that 5–8-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 [38Go] 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 [39Go]. Notably, the FAME study demonstrated that the reduction in VTE achieved with dalteparin was driven by a reduction in proximal DVT.


    Improving VTE management in cancer
 Top
 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
In view of the difficulties associated with standard thromboprophylactic regimens in cancer patients, alternatives to long-term VKA therapy are being investigated. Secondary prophylaxis with a LMWH may offer an alternative to long-term treatment with VKAs (Table 2), although until recently no large randomised trials had been conducted in this patient population. The CLOT (Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy) trial is the first large-scale study to compare the safety and efficacy of LMWH and VKA therapy in the prevention of recurrent VTE in cancer patients. The trial showed that, in cancer patients with acute VTE, long-term treatment with the LMWH dalteparin was more effective in reducing the risk of recurrent VTE than treatment with a VKA, which increased the risk of bleeding [40Go]. Patients with cancer, in addition to symptomatic proximal DVT, PE or both, were randomised to receive initial treatment with the LMWH dalteparin (200 IU/kg body weight) once daily for 5–7 days, followed by a VKA (warfarin or acenocoumarol) for 6 months (target INR 2.5). The second, experimental, group of patients received dalteparin alone for 6 months (200 IU/kg once daily for 1 month, then a daily dose of approximately 150 IU/kg for 5 months). This new LMWH dosing regimen was designed to provide initial intensive anticoagulation, followed by a period of reduced-dose therapy, with the aim of reducing the long-term risk of anticoagulant-related bleeding. Over the 6-month study period, the probability of recurrent VTE was 17.4% in the VKA group, compared with 9% in the LMWH group. Importantly, the efficacy advantage of this new dalteparin regimen was not achieved at the expense of an increase in bleeding risk compared with VKA therapy: there was no significant difference in the incidence of major bleeding in the two groups (4% in the VKA group and 6% in the dalteparin group). This is likely to reflect the new dalteparin dosing regimen that was used in the CLOT study. This regimen was well tolerated by the patients in the study.


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Table 2. Advantages of LMWH over VKAs

 
Prior to the CLOT study, there was no clear evidence to suggest that LMWH therapy was more effective or had a superior safety profile compared with VKAs in the prevention of recurrent VTE in patients with cancer [41Go]. Several small trials that included both cancer and non-cancer patients, failed to demonstrate a substantial advantage of LMWH therapy over VKAs in the secondary prevention of VTE [42Go–44Go]. In a more recent randomised trial of 146 patients with VTE and cancer, 3-month treatment with the LMWH enoxaparin was compared with warfarin and a combined outcome of haemorrhage plus recurrent VTE was evaluated [45Go]. Of the 71 evaluable patients assigned to receive warfarin, 15 (21.1%) had a major haemorrhage or recurrent VTE, compared with seven (10.5%) of the 67 patients allocated to enoxaparin (P=0.09). In the CLOT study, the LMWH dalteparin, demonstrated superior safety and efficacy compared with VKAs in this patient population [40Go].

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 [46Go]. 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 5–6 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 [47Go, 48Go] and a lower total mortality rate [49Go].


    Conclusions
 Top
 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
Patients with cancer present a number of unique challenges in the treatment of initial thrombotic events and subsequent thromboprophylaxis. Furthermore, cancer-associated hypercoagulability increases the risk of complications associated with surgery and other invasive procedures. Conventional long-term management with VKAs is particularly difficult in patients with cancer, because of the need for regular monitoring of the anticoagulant effect, suboptimal efficacy, and the high risk of bleeding, in addition to the potential for drug interactions. A new, evidence-based approach to the long-term management of VTE, in particular the use of the LMWH dalteparin, offers several advantages for cancer patients. These include practical advantages such as a predictable anticoagulant effect, thus avoiding the need for regular monitoring, in addition to superior efficacy to VKAs without an increased risk of bleeding.

Received for publication November 9, 2004. Revision received January 28, 2005. Accepted for publication February 1, 2005.


    References
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 Abstract
 Introduction
 The epidemiology of VTE...
 Risk factors for VTE...
 The relationship between VTE...
 Current management strategies...
 Challenges of antithrombotic...
 Improving VTE management in...
 Conclusions
 References
 
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