Venous Thromboembolic Complications of Cancer

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are common and potentially serious clinical challenges. In the United States, the estimated incidences of DVT and PE are approximately 450,000 and 355,000 cases per year, respectively. The actual incidence is likely much higher than presently documented because of often vague complaints and symptoms. PE may be associated with increased mortality and contributes to approximately 240,000 deaths annually in the United States.

Armand Trousseau noted the association between thrombosis and cancer more than 125 years ago. The risk of venous thromboembolism (VTE) in cancer patients depends on the type and extent of the malignancy; the type of cancer treatment; the existence and nature of comorbidities; and changes in hemostasis of the blood, which have been noted in more than 90% of cancer patients. The prevalence of clinically noted venous thrombosis in cancer patients is 15%; patients undergoing surgery, hormonal therapy, and chemotherapy have the highest risk. Venous thrombosis is the second leading cause of death in cancer patients.

Etiology of VTE in Cancer Patients

The etiology of VTE in cancer patients may be attributed to several factors, including hypercoagulable states, surgical interventions, chemotherapy, indwelling central venous catheters, and prolonged immobilization.

The mechanisms by which tumors cause a hypercoagulable state are not completely understood, but they may be attributed to abnormalities of blood composition (increased plasma levels of clotting factors, cancer procoagulant A, tissue factor, and cytokines) and increased release of plasminogen activator. Postoperative VTE was more common in patients with malignant disease (36%) than in patients with benign disease (20%), according to recent analyses of several clinical trials in surgical patients.

Patients undergoing chemotherapy are at increased risk for venous thrombosis secondary to endothelial cell damage from drug toxicity. In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, the aromatase inhibitor anastrozole (Arimidex) was compared with tamoxifen for 5 years in 9,366 postmenopausal women with localized breast cancer. Forty-eight patients (1.6%) receiving anastrozole developed DVT events, compared with 74 patients (2.4%) in the tamoxifen arm (P = .02). Anastrozole was associated with significant reductions in DVT events and should be considered for initial treatment in this population.

Indwelling central venous catheters predispose patients to upper-extremity thrombosis and thrombosis of the axillary/subclavian vein. The catheters are also prone to occlusion. Increased venous stasis caused by immobility also promotes blood pooling into the intramuscular venous sinuses of the calf and may lead to thrombosis formation.

Tumor Type Associated With VTE

Several tumor types have been associated with higher rates of VTE, including those arising from the pancreas, lungs, and other mucin-secreting tumors. In general, tumor types associated with an increased incidence of thromboembolic events reflect the frequency of the tumors in the general population: In women, the most common tumors are breast, lung, gynecologic, and gastrointestinal (GI) tumors; in men, prostate, lung, and GI tumors are most common. However, hematologic malignancies (multiple myeloma, lymphoma, and leukemia) also have significant rates of VTE.

Treatment

Several classes of agents have been used for prevention and treatment of VTE. Nonpharmacologic approaches to prophylaxis may include intermittent pneumatic compression and elastic stockings. Commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include unfractionated heparin (UFH; standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low-molecular-weight heparins (LMWHs). Most hospitalized cancer patients are at moderate to high risk for VTE, and pharmacologic thromboprophylaxis is usually indicated. The preferred and recommended anticoagulants for treatment of VTE are LMWHs (with administration following the American Society of Clinical Oncology [ASCO] guidelines). UFH may be needed if the patient has a planned procedure or is on dialysis. If long-term LMWHs are not accessible, consider switching to warfarin after 5 days of LMWH therapy.

Initial treatment of DVT and PE includes inpatient LMWH and outpatient LMWH for low-risk patients with VTE.

The LMWH treatment and prophylaxis doses for VTE are variable. The most common LMWHs used in the United States are dalteparin, enoxaparin, and tinzaparin. If UFH is used, it is administered as a bolus of 5,000 U followed by a continuous drip, usually initiated at a dosage between 750 and 1,000 U/h. A baseline partial thromboplastin time (PTT) and prothrombin time (PT) are drawn before the initiation of treatment. PTT is then rechecked approximately 4 to 6 hours after treatment is begun, and the UFH is titrated to approximately 1.5 to 2 times PTT control levels in most patients.

For patients without accessibility to LMWHs, or if such therapy is contraindicated, warfarin is usually begun on day 1 or 2 of treatment; therapy is monitored to maintain an international normalized ratio (INR) between 2 and 3. (Patients with prosthetic valves require a higher INR if UFH is used.) It is standard practice to maintain UFH for 4 to 5 days while the warfarin is titrated to therapeutic levels. Most patients are maintained on warfarin for a minimum of 6 months, depending on underlying risk factors. Patient response to warfarin depends on numerous factors, such as age, diet, alcohol consumption, and liver and GI function, as well as concomitant medications. Patients with active cancer should continue anticoagulation therapy, preferably with LMWH, for as long as the cancer remains active. Patients with recurrent VTE are usually maintained on anticoagulants for the rest of their lives.

Recent studies have demonstrated the safety and efficacy of LMWH in the treatment and management of VTE. Several studies have demonstrated no appreciable differences in recurrent thromboembolism and increased risk of bleeding with UFH and LMWHs. Because LMWHs do not require a continuous drip and frequent serum testing, low-risk patients are now treated as outpatients. Both ASCO and the National Comprehensive Cancer Network (NCCN) recommend LMWHs as the preferable agents for treatment of VTE in cancer patients.

LMWH doses vary by product and are not equivalent. Enoxaparin is generally administered once or twice a day for treatment of VTE, whereas tinzaparin and dalteparin are indicated for once-daily dosing. The commonly administered dose for treatment of DVT with enoxaparin is 1 mg/kg SC every 12 hours. Tinzaparin is given via SC injection at a dose of 175 IU/kg body weight once daily, and the dalteparin dose is 200 IU/kg SC once daily for the first month, followed by 150 IU/kg SC daily thereafter. Therapy with LMWH is continued for a minimum of 5 days during the acute phase of treatment. Generally, laboratory monitoring is unnecessary, although for individuals with renal insufficiency or those who weigh less than 50 kg or who are obese, plasma anti–factor Xa concentrations may need to be monitored.

In an international study comparing the long-term treatment benefits of dalteparin with those of warfarin in cancer patients with VTE, dalteparin substantially reduced the rate of recurrent VTE, without an increase in bleeding. On the basis of this trial, cancer patients who require VTE treatment should continue dalteparin (or possibly another LMWH) during the chronic phase of treatment instead of switching to warfarin. Cost issues may require patients to continue taking warfarin. Because of limited data, the use of novel oral anticoagulants is not recommended for patients with malignancy and VTE.

Inpatient cancer patients should be assessed for VTE and given appropriate prophylaxis with pharmacologic agents. If these are contraindicated, then mechanical alternatives (graduated compression stockings, intermittent pneumatic compression) should be considered. Early ambulation as tolerated should be encouraged. Prophylaxis for VTE includes the following: UFH 5,000 units SC every 8 hours; dalteparin at 5,000 units SC daily; enoxaparin at 40 mg SC daily; and fondaparinux at 2.5 mg SC daily (for patients allergic to heparin products).

Difficulties in Anticoagulation

Often, therapeutic challenges arise in patients receiving anticoagulation therapy for VTE who require surgical interventions and, therefore, temporary discontinuation of their anticoagulation treatment.

Preoperative guidelines

The timing of discontinuation of anticoagulation depends on the type of treatment and the surgical intervention planned. For patients receiving continuous-drip heparin, the drip may be discontinued 4 to 6 hours before the procedure. A PTT should be drawn before the procedure to check for total reversal of the treatment. In cases in which only partial reversal is noted or an emergency arises, fresh frozen plasma may be administered for rapid reversal.

Patients receiving warfarin may be advised to discontinue their medication several days before the planned procedure, coordinated with bridging with a LMWH. Appropriate timing of the bridging should be planned and detailed with the patient and the healthcare team. An example of a bridging schedule may be discontinuation of warfarin 5 days before the procedure. On days 3 through 1 before the procedure, the treatment dose of LMWH should be administered (with the dose dependent upon the particular LMWH used). The last dose of LMWH is given on the day before the procedure before 8 a.m. (consider administering half of the LMWH dose), and all anticoagulants are held on the day of surgery. Platelet counts, creatinine levels, and glomerular filtration rate should be reviewed at the time of bridging. For patients unable to access LMWH, warfarin may need to be discontinued 3 to 5 days before the planned procedure, with a check of PT/INR before the procedure. If partial reversal is noted or an emergency arises, vitamin K and/or fresh frozen plasma may be administered for acute reversal.

Postoperative guidelines

Timing of postoperative therapy depends on the type of procedure undertaken and its associated risk of bleeding. Direct communication between the surgeon and the physician managing the anticoagulation treatment is necessary. When the surgeon believes that the risk of bleeding is at an acceptable level, anticoagulation should be restarted. It may be prudent to use UFH or LMWH before the initiation of warfarin, especially if a substantial risk of bleeding remains.

High-risk patients

For high-risk patients (with prosthetic valves, recurrent VTE), it may be reasonable to switch from warfarin to either UFH or LMWH, with appropriate discontinuation before the procedure. Both UFH and LMWH have shorter reversal times than does warfarin, although the effects of LMWHs are not fully reversible. Another option is to continue warfarin until shortly before the procedure, reversing treatment with vitamin K and/or fresh frozen plasma. The risk-benefit ratio should be considered when reviewing options for the individual patient.

Surgery has long been known to be a risk factor for VTE. The nature of surgery in part determines the relative risk: Patients undergoing orthopedic surgery are at a particularly high risk. The risk is modified by the presence of other factors, such as underlying malignancy, age, obesity, and history of previous thromboembolism. Meta-analyses of clinical trials have shown there is a high overall risk of DVT during general surgery, based on rates observed in control subjects; there is a confirmed incidence of DVT of 25% noted by the fibrinogen uptake test. The risk is even higher (29%) in surgical patients with malignancy. Risk is also increased when multiple risk factors are present (eg, age > 65 years, obesity, bed rest > 5 days). A comparison of commonly used prophylaxis in 160 clinical trials indicates that overall, low-dose UFH and LMWH are the most effective agents in reducing the incidence of DVT after general surgery. A higher dosage of the prophylactic agent may be needed for adequate prevention in patients with malignant disease. Patients having major cancer surgery should begin VTE prophylaxis prior to surgery and should continue for a minimum of 7 to 10 days following the procedure. Patients having surgical procedures that are associated with high risk of VTE should be considered for extended VTE prophylaxis for as long as 4 weeks following the procedure.

Treatment alternatives for recurrence

There are several treatment options for patients with recurrent VTE. Patients who develop recurrence of thrombosis while receiving therapeutic doses of anticoagulation may need to be given higher doses of the anticoagulant or be switched to another anticoagulant. Inferior vena cava filter placement may be considered. The filter will not prevent new clots from forming, but it does provide a physical barrier to prevent propagation of clots to the pulmonary bed. Alternatively, an inferior vena cava filter can be placed to avoid the need for long-term anticoagulant therapy if there are contraindications to anticoagulation. Alternatively, another LMWH may be used before placement of an inferior vena cava filter, because there may be other complications related to filter placement (ie, postphlebitis syndrome, clotting of the filter) and filter placement should be considered as a final option. The decision to place a permanent or temporary inferior vena cava filter should be made by the healthcare team at the time of filter placement, and if a temporary filter is placed, a tentative plan for removal should also be made and delegated to a provider at the time of filter placement.

Depending on patient prognosis and tumor factors, other comorbidities, and propensity for bleeding, continued therapy with an anticoagulant may be considered in addition to filter placement.