US Pharm. 2008;33(7)(Oncology suppl):23-26.

ABSTRACT: Cancer, chemotherapy, and surgery are conditions that increase the risk of the development of venous thromboembolism (VTE), a common and potentially life-threatening condition. The estimated incidence of VTE in cancer patients is 1 in 200. Unfractionated heparin, low-molecular-weight heparin (LMWH), and oral vitamin K antagonists are therapies used to treat VTE. Based on findings of three key trials, LMWH therapy is recommended by several prominent organizations for the management or prevention of VTE in patients with cancer.

Venous thromboembolism (VTE) is a common condition that can manifest in many ways. It is often observed clinically as either deep venous thrombosis (DVT) of the lower extremities or pulmonary embolism (PE), which can be life-threatening. It is difficult to determine the incidence of VTE since more than 50% of patients present with clinically silent pathology.1 It has been suggested that VTE occurs at a rate of 7.1 per 10,000 persons per year among community residents and 17 per 100,000 persons per year in the general population.2,3 VTE may occur more frequently in men, with a slightly higher prevalence in African American males.2 The incidence of VTE increases with age and almost doubles with each decade of life beyond 50 years.1,2 Pathologic factors associated with increased risk of VTE include circulatory stasis, increased blood coagulability, and vessel-wall injury, commonly known as Virchow's triangle or triad.1 The classic model of blood coagulation involves a cascade of precursor protein (zymogen) activation reactions (FIGURE 1).4 At each stage, a zymogen is converted to an active protease (denoted in FIGURE 1 by a lowercase "a") by cleavage of one or more peptide bonds in the precursor molecule. The end result of this cascade is the formation of an insoluble fibrin clot, or thrombus.4

The risk of developing VTE increases in the presence of cancer, chemotherapy, and surgery.2 Malignancy and chemotherapy augment the risk of VTE by greater than fourfold and 6.5-fold, respectively, for an estimated yearly incidence of 1 per 200 patients with cancer.3 Cancer cells interact with monocytes and macrophages releasing tumor necrosis factor, interleukin 1, and interleukin 6, resulting in endothelial damage and creating a thrombogenic surface. The interaction between tumor cells and macrophages also activates platelets, factor XII- and factor X–generating thrombin, and ultimately, the potential for thrombosis.5 Tumor type, stage or severity of disease, and concomitant and adjunctive treatments all affect the risk of VTE in patients with cancer.3

A recent study of patients with lung cancer suggests that venous thrombosis may be more prevalent in patients with adenocarcinoma (ACA) than in those with squamous cell carcinoma. 6 The interaction of carcinoma mucins with leukocyte L-selectin and platelet P-selectin without thrombin generation is a reasonable molecular explanation for the increased rate of venous thrombosis in patients with ACA. 6 Adenocarcinoma develops in cells lining glandular internal organs such as the lungs, breast, colon, prostate, stomach, pancreas, and cervix. 7 Cancers more highly associated with VTE are those of the brain, pancreas, ovary, and breast.3

Treatments for VTE include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and oral vitamin K antagonists (VKAs) like warfarin. UFH and LMWH are indicated for acute treatment of DVT; UFH, LMWH, and oral VKAs are indicated for chronic treatment. Oral VKAs are initiated with UFH or LMWH and continued until two international normalized ratios (INRs) 24 or more hours apart are within appropriate range.3

The literature suggests that LMWH may be superior to oral VKAs with respect to risk of recurrent VTE, bleeding, and mortality.3 UFH and LMWH potentiate antithrombin and block P-selectin and L-selectin, decreasing platelet aggregation.6 Both agents potentiate the activity of antithrombin III, which inhibits activated coagulation factors X and II.8 UFH, unlike LMWH, requires frequent monitoring due to its unpredictable dose response and narrow therapeutic window.3 Several prominent organizations support the use of subcutaneous (SC) LMWH for three to six months, among them the American College of Chest Physicians, the American Society of Health-System Pharmacists, and the National Comprehensive Cancer Network.3 See TABLE 1 for specific recommendations.3,8-10

Alternatives to standard oral VKA therapy are under investigation for several reasons, namely the drug–drug and drug–disease interactions and monitoring requirements associated with warfarin.3 Most cancer treatments and adjunctive therapies are complex, involving not only chemotherapy but also antiemetics, growth factors, antibiotics, steroids, and pain medications. Cancer-related gastrointestinal (GI) problems, malnutrition, and liver impairment may complicate anticoagulation of patients with warfarin. In addition, chemotherapy-induced thrombocytopenia and the need for invasive procedures may result in subtherapeutic INRs, which may be perpetuated by warfarin's exceptionally long half-life. The difficulty of maintaining a therapeutic INR (and perhaps the inability to do so) may result in recurrence of VTE as well as potential bleeding complications. Also, the frequent, close monitoring requirements for warfarin may further erode quality of life in patients with cancer.

Several landmark trials have been conducted that are the foundation for the aforementioned recommendations, including CLOT, FAMOUS, and ONCENOX.

CLOT Study
CLOT (Low Molecular Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) was the first large-scale study comparing an oral anticoagulant with extended LMWH treatment in cancer patients with VTE. CLOT was a multicenter, international, open-label, clinical trial evaluating 676 patients with cancer and symptomatic proximal DVT, PE, or both. Patients were randomized to receive an oral anticoagulant or SC dalteparin (Fragmin). The first group (n = 338) received SC dalteparin 200 IU/kg qd for five to seven days (maximum 18,000 IU), followed by oral anticoagulant therapy (warfarin or acenocoumarol; target INR 2.5, range 2.0–3.0) for six months. The second group (n = 338) received dalteparin alone for six months (200 IU/kg qd for one month, then approximately 150 IU/kg qd for five months). Ninety percent of patients had solid tumors and 67% had metastatic disease. Endpoints of the study included incidence of symptomatic, recurrent DVT, PE, or both during the six-month study period (primary) and events of major bleeding, any bleeding, and death at six to 12 months (secondary).

During the six-month period, the incidence of recurrent VTE in patients treated with dalteparin alone was 8% versus approximately 16% in the oral anticoagulant group (hazard ratio [HR] 0.48; P =.002). Out of 53 thrombotic events, 20 occurred in the oral anticoagulant group when INR was below 2.0. Patients were above therapeutic range 24%, below therapeutic range 30%, and at therapeutic range 46% of the treatment time. The Kaplan–Meier estimate of risk of recurrent VTE at six months was 9% in the dalteparin group versus 17% in the oral anticoagulant group.11

There were no significant differences between the dalteparin and oral anticoagulant arms, respectively, in rates of major bleeding (6% vs 4%; P =.27), any bleeding (14% vs 19%; P =.09), or overall mortality (39% vs 41%; P =.53) at six months. In each group, cancer progression was the cause of mortality 90% of the time. The researchers concluded that the risk of recurrent DVT was significantly lower with dalteparin compared with oral anticoagulant in VTE patients with cancer. Some of the study's limitations were the open-label design, wide variations in INRs in the oral anticoagulant group, and possible bias in VTE symptom detection.11

A post hoc analysis of the CLOT study results was performed in 602 of the patients with solid tumors to determine whether a treatment-related difference in mortality existed between patients with metastatic (n = 452) and nonmetastatic (n = 150) disease at randomization. During 12-month follow-up, 70% of patients with metastatic disease had died, with no difference in mortality between the two treatment groups (HR 1.1; P =.46). In patients with nonmetastatic disease, however, 12-month cumulative mortality was 20% for those in the dalteparin group versus 35% in the oral anticoagulant group (HR 0.50; P =.03). The results of the post hoc analysis are consistent with the theory that LMWHs may exert clinically relevant antineoplastic effects in nonmetastatic cancer.12

FAMOUS (Fragmin Advanced Malignancy Outcome Study) was a randomized, double-blind, placebo-controlled, multicenter trial investigating the efficacy and safety of chronic LMWH administration in cancer patients without a known history of thrombosis. The primary endpoint of the study was mortality after one year of therapy. Secondary endpoints were rates of symptomatic, objectively confirmed VTE and bleeding complications. Inclusion criteria were age range 18 to 80 years and histologically confirmed advanced stage III or IV cancer of the breast, lung, GI tract, pancreas, liver, genitourinary tract, ovary, or uterus with an expected survival of at least three months. Patients were excluded if they had an active bleeding disorder, known hypersensitivity to heparin, or a platelet count less than 50,000/µL. Patients received either 5,000 IU dalteparin qd or 0.9% normal saline qd.13

Survival estimates for the dalteparin and placebo groups at one year were 46% (95% CI, 39%–53%) and 41% (95% CI, 34%–49%), respectively (P =.19). Possible explanations for the lack of statistical difference in survival between groups are that the study was underpowered and that most patients had a relatively short life span from baseline. In addition, these patients had highly advanced disease with aggressive pathology. Though not a primary endpoint of this study, it is worth noting that the survival rate at two years was 27% (95% CI, 20%–34%) in the dalteparin group versus 18% (95% CI, 11%–25%) in the placebo group and the rate at three years was 21% (95% CI, 14%–28%) versus 12% (95% CI, 5%–19%). 13

The study did successfully establish low rates of symptomatic VTE and bleeding. Dalteparin was given without routine monitoring of anti-Xa activity or platelet levels, suggesting that dalteparin therapy at this dose is safe in this patient population. Thus, this trial demonstrated the feasibility and safety of long-term dalteparin administration in patients with advanced cancer. A post hoc analysis suggested that dalteparin also might modify a tumor's angiogenic response and physiologic behavior through gene upregulation; this possibility requires further investigation.13

ONCENOX study was a randomized, open-label, multicenter trial that assessed the effectiveness and safety of enoxaparin for prevention of recurrent DVT in cancer patients and examined patient compliance. All patients initially received enoxaparin 1.0 mg/kg twice daily for five days and then received one of the following regimens: enoxaparin 1.0 mg/kg qd (group 1), enoxaparin 1.5 mg/kg qd (group 2), or oral VKA therapy (group 3). The incidence of recurrent VTE was 7.1% in group 1, 3.2% in group 2, and 10.3% in group 3. No differences in major or minor bleeding rates were detected. Compliance rates were 97.6%, 94.1%, and 92.8% in groups 1, 2, and 3, respectively.14

Additional Considerations
The management of cancer and thrombosis and the prevention of thrombosis in cancer patients are complex processes that require due diligence in treatment considerations in order to minimize treatment complications, preserve quality of life, and reduce mortality risk. As with all treatment plans, efficacy, convenience, compliance, and satisfaction must be considered. The type and location of the cancer, comorbidities, concomitant therapies, and prognosis also must be considered.

Key organizations and associations, as previously discussed, support the use of LMWH therapy in patients with cancer. LMWH therapy offers patients efficacy without the intensive monitoring and dietary restrictions required with oral VKA therapy. The risks and dangers associated with multiple drug–drug and drug–disease interactions that often result in suboptimal anticoagulation with oral VKA therapy are minimized significantly with LMWH. Compared with UFH, less anticoagulant monitoring and shorter hospital stays are considerable benefits of LMWH therapy.3

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