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Abstract

General Considerations

Patients with cancer who develop an episode of thrombosis are at higher risk of subsequent recurrent thrombosis, with a reported frequency of 27.1 per 100 patient years for those with cancer compared to 9.0 per 100 patient years for those without cancer.¹ In the same study, the bleeding risk of patients with cancer receiving oral anticoagulation therapy was 13.3 per 100 patient years and 2.1 per 100 patient years for patients without cancer. A further study by Prandoni et al, followed a cohort of 842 patients, 181 of whom had cancer-associated thrombosis and demonstrated a 12-month cumulative incidence of recurrent venous thromboembolism (VTE) of 20.7% for patients with cancer compared to 6.8% for those without cancer² and more frequent bleeding in the patients with cancer (12.4% vs 4.9%; hazard ratio [HR] 2.2).

Initial Treatment of VTE in Cancer

Studies have not addressed the initial treatment of VTE in patients with cancer. However, many trials that compared unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for initial treatment of deep venous thrombosis (DVT) included patients with malignant disease. Meta-analyses of these studies indicate that UFH administered intravenously with routine monitoring of activated partial thromboplastin time or LMWH administered subcutaneously according to body weight without need for monitoring of the dose is equally effective and safe for initial treatment of DVT. Recommendations generated for patients without cancer are therefore extrapolated for use in patients with cancer with thrombosis.^3–6

Few data are available for the pentasaccharide fondaparinux. Post hoc analyses from 2 randomized trials of 237 patients with cancer with VTE which compared the safety, efficacy, and overall survival with fondaparinux versus LMWH, followed in both groups by vitamin K antagonist (VKA), showed a recurrence rate of 5.4% in patients with DVT in the enoxaparin group versus 12.7% in the fondaparinux group (absolute difference 7.3%, 95% confidence interval [CI] 0.1-14.5). Among the patients with pulmonary embolism (PE), a recurrence was observed in 8.9% in the fondaparinux group versus 17.2% in the UFH group (absolute difference 8.3% (95% CI 16.7-0.1).⁷ The analysis did not show any difference in terms of bleeding or overall survival between the groups.

The LMWH therapy for the initial treatment of DVT offers an opportunity for outpatient management of patients with cancer-associated thromboembolic disease.^8–12 Initial management of PE in patients with cancer has not been specifically addressed. However, the trials have evaluated both intravenous UFH and subcutaneous LMWH for treatment of PE.^11,13 A single study of 108 patients with PE, 22% of whom had cancer, evaluated the potential for outpatient use of the LMWH (dalteparin sodium).¹⁴ Recurrent thrombosis occurred in 5.6% of the 108 patients with a major bleeding rate of 1.9%. Thus, patients with cancer with PE may receive either UFH or LMWH for initial PE treatment unless they are hemodynamically unstable.

A recent systematic review identified 13 studies that compared LMWH to UFH and 2 that compared fondaparinux to UFH. Meta-analysis of 11 studies showed a statistically significant reduction in mortality at 3 months follow-up with LMWH compared to UFH (relative risk [RR] 0.71; 95% CI 0.52-0.98). A meta-analysis of 3 studies comparing LMWH to UFH showed no reduction in VTE recurrence (RR 0.78; 95% CI 0.29-2.08). There were no difference between heparin and fondaparinux for mortality (RR 1.27; 95% CI 0.88-1.84), recurrent VTE (RR 0.95; 95% CI 0.57-1.60), major bleeding (RR 0.79; 95% CI 0.39-1.63), or minor bleeding (RR 1.50; 95% CI 0.87-2.59). The authors concluded that LMWH is possibly superior to UFH for the initial treatment of VTE in patients with cancer and that further trials are needed to clarify this issue.¹⁵

Outpatient therapy with LMWH is preferred in patients with cancer with a potentially shortened duration of life where quality of life is an essential issue.

The safety and efficacy of inferior vena cava filters for the management of cancer-associated thrombosis have not been evaluated. In general, unless anticoagulant therapy is contraindicated due to active bleeding, vena cava filters are not recommended in patients with cancer. Early benefits are outweighed by longer term risks of recurrent thrombosis in patients with malignant disease.¹⁶

Long-Term Anticoagulation for Secondary Prevention of VTE

As indicated above, patients with malignancy compared to those without malignancy have a 4-fold greater risk of recurrent thrombosis and a 3-fold greater risk of anticoagulant-associated bleeding.¹⁷ A study involving 676 patients with cancer-associated VTE was sufficiently powered to define long-term treatment outcomes.¹⁸ All patients received 5 to 7 days of treatment with the LMWH dalteparin sodium in a dose of 200 IU/kg followed by either LMWH in the full treatment dose for the remainder of the month then 75% to 80% of the full treatment dose for the remaining 5 months, or by VKA treatment with a target international normalized ratio of 2 to 3 for 6 months. The trial demonstrated 52% reduction in the frequency of recurrent VTE over 6 months in favor of dalteparin sodium (8.0% with dalteparin vs 15.8% with VKA), with no significant increase in the risk of bleeding complications. These findings are supported by data from 2 randomized open-label trials.^19,20 In the prospective multicenter LITE trial,¹⁹ 200 patients with cancer and acute symptomatic proximal vein thrombosis were randomized to usual care (intravenous heparin followed by long-term warfarin sodium) or the LMWH tinzaparin. At 12 months, the rate of recurrent VTE was 15% in the usual-care group versus 7% in the tinzaparin group (P = .044).¹⁹ The superiority of long-term treatment with LMWH over VKA for secondary prevention of VTE in patients with cancer has been confirmed in several meta-analyses.^16,21,22 One such analysis that involved 6 randomized controlled trials (RCTs) comparing LMWH with VKA showed reduction in risk of VTE with LMWH (hazard ratio [HR] 0.47; 95% CI 0.32-0.71) without an increased risk of bleeding (RR 0.91; 95% CI 0.64-1.31) or thrombocytopenia (RR 1.02; 95% CI 0.60-1.74) but did not demonstrate a survival benefit (HR 0.96; 95% CI 0.81-1.14).²¹

Potential Survival Benefit of LMWH

As indicated above, data from several prospective randomized clinical trials suggest that patients with cancer receiving LMWH over a prolonged period have improved survival.^17,23–29 These data are of considerable interest because LMWH therapy when compared to placebo was not associated with adverse safety (no increase in bleeding) and thus may present a potential novel adjuvant anticancer therapy.

The potential role of LMWH to prolong survival appears dependent upon the tumor stage. Two randomized trials in patients with advanced malignancy did not demonstrate any survival benefit with LMWH therapy versus placebo.^30,31 In one of these studies, Kaplan-Meier survival estimates in patients alive 17 months after randomization³⁰ showed improved survival with LMWH versus placebo (78% vs 55% at 2 years and 60% vs 36% at 3 years, respectively, P = .03), but these patients were not defined a priori.³⁰ In a further randomized study in 302 patients with advanced solid malignancy without VTE,³² a 6-week course of nadroparin versus placebo was associated with a lower risk of death at 12 months (median survival 8.0 vs 6.6 months; HR 0.75, 95% CI 0.59-0.96), which remained significant after adjustment for confounders. An a priori analysis in patients with a life expectancy of 6 months or more at enrollment demonstrated a greater benefit of LMWH treatment (15.4 vs 9.4 month survival; HR 0.64, 95% CI 0.45-0.90), which was reduced in patients with a shorter life expectancy (HR 0.88, 95% CI 0.62-1.25). A recent systematic review of 5 randomized clinical trials involving heparin treatment (UFH or LMWH) demonstrated a survival benefit with heparin treatment (HR 0.77; 95% CI 0.65-0.91) without any increased risk of bleeding (RR 1.78; 95% CI 0.73-4.38). The benefit was most notable in the subgroup with limited small-cell lung cancer (HR 0.56; 95% CI 0.38-0.83) and was not significant for patients with extensive small-cell lung cancer (HR 0.80; 95% CI 0.60-1.06) or advanced cancer (HR 0.84; 95% CI 0.68-1.03). These data suggest that LMWH may offer a survival benefit, which is greater in patients with less advanced disease and better prognosis. These preliminary data need to be confirmed in further prospective clinical trials with appropriate design and power to assess cancer outcome before any recommendations can be made.

Recommendations

The initial and long-term treatment of DVT and PE in patients with cancer is LMWH administered for 3 to 6 months (level of evidence: high). If the health care economics of a system do not allow for use of long-term LMWH, it is acceptable to treat initially with UFH or LMWH followed by long-term VKA therapy (level of evidence: high).

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Treatment for Patients With Cancer

Abstract

General Considerations

Initial Treatment of VTE in Cancer

Long-Term Anticoagulation for Secondary Prevention of VTE

Potential Survival Benefit of LMWH

Recommendations

References