Cancer-associated thrombosis: prevention and treatment.

Patients with cancer are at high risk to develop venous thromboembolism, and they are also more likely to develop complications from anticoagulant treatment. Because little research has focused on the oncology population to date, the optimal methods of prophylaxis and treatment remain uncertain in some clinical situations. Currently, low molecular weight heparin and warfarin are the most frequently used pharmacologic agents; however, they have their limitations. Other therapeutic options, such as inferior caval filters, are poorly studied and remain controversial. A summary of the most recent evidence on the prevention and treatment of venous thromboembolism in cancer patients is presented here.


INTRODUCTION
It is well established that cancer patients are at an increased risk of venous thromboembolism (VTE). In fact, the presence of malignancy increases the risk of VTE by a factor of 4 to 6, and large population-based studies show that the incidence of VTE is on the rise 1,2 . Overall, cancer patients constitute 15%-20% of the patients diagnosed with VTE, and depending on the type of tumour, extent of malignancy, type of cancer treatment, and presence of other risk factors, 1%-25% of patients with malignancy will develop thrombosis.
Furthermore, cancer-associated thrombosis is linked with poor prognosis, and it is the second leading cause of death in cancer patients 3 . In one study of a population registry, the 1-year survival of cancer patients diagnosed with VTE was one third that of cancer patients without VTE (12% vs. 36%) matched for sex, age, tumour type, and duration of the cancer 4 . In another population-based study, the in-hospital mortality for cancer patients who developed VTE while in hospital was double that for patients who did not develop the complication 5 .
This increase in mortality is partly attributable to fatal pulmonary embolism, but it also reflects the advanced stages of cancer and underlying aggressive tumour biology in these patients.
Cancer patients are also prone to adverse effects and failure of anticoagulant therapy. In comparison with patients without cancer, patients with cancer who are receiving warfarin experience 2 to 6 times more major bleeding episodes and 2 to 3 times more VTE recurrences 6,7 . Based on prospective studies, the annual risk of recurrent VTE is 21%-27% and the annual risk of major bleeding is 12%-13%.
Primary prevention is the most effective way to reduce the morbidity and mortality associated with cancer-associated thrombosis, but surveys and registries consistently report the failure of physicians to comply with established guidelines leading to underutilization of primary prophylaxis in oncology patients 8 . Given the impact that VTE has on this highrisk population, an increased focus on identifying optimal methods to prevent and treat VTE in patients with malignancy is needed. Current management strategies, and the evidence supporting them, are presented here.

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CURRENT ONCOLOGY-VOLUME 15, SUPPLEMENT 1 as compared with patients without malignancy 24,25 . Of the agents available for thromboprophylaxis, low molecular weight heparins (LMWHs) provide the most convenient, efficacious, and safe option (Table I) [10][11][12][13][14]26 . Compared with LMWHs, unfractionated heparin requires 3-times-daily injection and has a higher risk of heparin-induced thrombocytopenia. And although fondaparinux appears to be comparable to LMWH in efficacy and safety, limited data are available for it in the cancer setting, and a specific antidote for it is lacking.
A post hoc subgroup analysis of cancer patients in a randomized trial found a lower risk of VTE with fondaparinux than with dalteparin, but that finding requires confirmation in future studies 12 . However, as hospital stays have shortened, the duration of prophylaxis may be inadequate for some patients. Cancer patients are at particularly high risk, considering that many of them undergo extensive surgery and require prolonged periods of recovery. In a prospective cohort study in which 2373 cancer patients were followed for a minimum of 30 days after surgery, 40% of symptomatic VTE occurred more than 3 weeks postoperatively, and 46% of deaths were the result of fatal pulmonary embolism 27 . Clinical factors found to be associated with a higher risk of VTE were previous history of VTE [odds ratio (OR): 6.0], anaesthesia lasting 2 hours or longer (OR: 4.5), bed rest for 4 days or longer (OR: 4.4), an advanced stage of cancer (OR: 2.7), and age 60 years or older (OR: 2.6).
Randomized controlled trials have shown that continuing prophylaxis with a LMWH up to 30 days postoperatively can reduce the risk of VTE by 60% without increasing the risk of bleeding (Table I) 13,14 . Based on these and other supportive studies, it is reasonable to prescribe extended prophylaxis in patients with one or more risk factors for VTE.

Neurosurgery
Neurosurgical patients present a challenging prophylaxis problem because of the underlying concern of intracerebral hemorrhage combined with a high incidence of VTE. In fact, craniotomy for brain neoplasm carries a VTE risk of 60% in the postoperative period and 23% at 1 year 28 . This risk can be reduced by 40% with the use of LMWH prophylaxis starting 24 hours postoperatively (Table II) [15][16][17][18] . The risk of major bleeding, including intracranial hemorrhage, is less than 3%, but that risk is increased if LMWH prophylaxis is administered preoperatively 29 . However, given the devastating consequences of an intracranial hemorrhage, most neurosurgeons prefer to use mechanical compression devices in the early operative period and to start pharmacologic prophylaxis when patients are more stable.

Gynecologic Surgery
Compared with the previous two groups, women undergoing gynecologic cancer surgery have a lower risk of VTE-about 2%. But that level of risk represents an increase by a factor of 5 over the risk in women having surgery for benign gynecologic problems 9 . As with abdominal and pelvic surgery, unfractionated heparin and LMWH are both equally effective and safe in preventing DVT in this setting (Table III) [19][20][21][22][23]30 . Mechanical devices have also been shown to be effective.

Other Surgeries
There is a paucity of research on the risk of VTE and on its prevention in other surgical settings. Based on limited data and extrapolation from other surgical groups, unfractionated heparin and LMWH both appear relatively safe and effective, but solid evidence is lacking.

Mechanical Prophylaxis in Surgical Settings
As shown in one meta-analysis 31 , compression stockings are effective in reducing the risk of VTE by two thirds in patients at moderate risk. Pneumatic compression devices are also effective, but they are cumbersome and interfere with mobilization. Also, they are more likely than pharmacologic prophylaxis to fail in high-risk groups 32 . Compression devices are therefore currently reserved for situations in which anticoagulation is contraindicated. These devices are most effective when applied intraoperatively or immediately after surgery (Table IV) [33][34][35] . Whether mechanical methods in combination with anticoagulants result in additional risk reduction is not clear.

Summary: Surgical Settings
Good evidence supports the routine use of postoperative thromboprophylaxis in patients undergoing surgery for cancer (Tables I to IV). That finding is endorsed by international and national consensus guidelines, including those from the American College of Chest Physicians (ACCP) 9 , the American Society of Clinical Oncology (ASCO) 36 , and the Italian Association of Medical Oncology (AIOM) 37 . Unfractionated heparin and LMWH are equally effective in preventing VTE and have a comparable risk for bleeding. Less experience and data are available for fondaparinux. Extended prophylaxis should be strongly considered in patients with additional risk factors for VTE. In those patients who have a contraindication for anticoagulation, mechanical methods are reasonable substitutes.

Ambulatory Patients
The risk of symptomatic VTE in the ambulatory outpatient setting is lower than that in the surgical setting,

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and little research had been done to investigate the role of anticoagulant prophylaxis. More recently, three separate randomized controlled trials have evaluated LMWH prophylaxis in patients with metastatic breast cancer, non-small-cell lung cancer, and grades III and IV malignant glioma (Table V) [38][39][40] . No significant difference in VTE or major bleeding was observed between the groups receiving LMWH and placebo. Consequently, routine prophylaxis is not recommended in ambulatory patients. Notably, the risk of VTE and major bleeding appear to vary considerably, depending on the type of tumour.
On the other hand, as many as 20%-30% of patients receiving thalidomide in combination with chemotherapy or high-dose corticosteroids for treatment of multiple myeloma will develop symptomatic VTE 41,42 . Although many studies have reported the use of warfarin, aspirin, or LMWH, insufficient reliable data are available to support the efficacy and safety of these agents. Whether lenalidomide is also associated with a high risk of VTE is uncertain. Patients receiving vascular endothelial growth factor inhibitors such as bevacizumab also have an increased risk of arterial and, possibly, venous thrombosis 43,44 , but because of an increased bleeding tendency already associated with this treatment, anticoagulation prophylaxis is not recommended.

Hospitalized Patients
No study has been conducted in cancer patients to determine the effects of VTE prophylaxis in the inpatient setting. Large randomized trials that included small numbers of cancer patients have shown that LMWH or fondaparinux can reduce the VTE risk by 50% or more, but whether such results can apply to all hospitalized cancer patients is questionable, because of the higher risks for VTE and major bleeding in those patients [45][46][47] .

Summary: Medical Settings
Based on limited data, routine prophylaxis in the outpatient setting is not recommended, but prophylaxis should be considered in patients receiving thalidomide-or lenalidomide-containing regimens. Anticoagulant prophylaxis for hospitalized patients is warranted based on studies in non-cancer patients, but the risk-benefit ratio is uncertain, given the lack of randomized trial evidence.

PROPHYLAXIS FOR CENTRAL VENOUS CATHETERS
Central venous catheters are frequently placed in cancer patients, and those devices represent an ongoing thrombogenic focus 48 . Many attempts have been made to reduce the incidence of thrombotic complications in this setting, but randomized placebo-con-

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CURRENT ONCOLOGY-VOLUME 15, SUPPLEMENT 1 trolled trials have failed to show a reduction in catheter-related thrombosis with thromboprophylaxis. In particular, low-dose warfarin 49 , adjusted-dose warfarin 50 , and prophylactic-dose LMWH 51,52 do not reduce the 4% risk of symptomatic catheter-related thrombosis (Table VI) [49][50][51][52] . For that reason and because of the possibility of increased risk of bleeding, the routine use of prophylaxis in this setting is not recommended 9 .

Treatment of VTE
Traditional therapy for acute VTE has consisted of initial therapy with unfractionated heparin or LMWH, followed by long-term warfarin therapy. Unfortunately, many cancer patients tolerate warfarin poorly, especially when receiving chemotherapy, with its ensuing gastrointestinal and hematologic side effects. Also, despite maintenance of therapeutic levels of warfarin, one third of patients experience recurrent VTE or treatment-related bleeding 6,7 . However, LMWH is clearly superior to warfarin with respect to convenience and efficacy. Given as a once-daily subcutaneous injection, LMWH does not require routine laboratory monitoring, has few drug interactions, and does not rely on gastrointestinal absorption. In the CLOT study, 676 cancer patients with acute DVT or pulmonary embolism were randomized to a 6-month course of traditional therapy with dalteparin followed by warfarin, or to dalteparin alone 53 . To reduce the risk of bleeding in the dalteparin-only group, the dalteparin dose was reduced by 20%-25% after the first month of therapy. After 6 months of treatment, the long-term dalteparin group experienced a 52% reduction in symptomatic recurrent VTE (17% vs. 9%, p = 0.002) as compared with the group continuing on warfarin. In other words, 1 episode of recurrent VTE was prevented for every 13 patients treated. Furthermore, the groups showed no significant difference in bleeding (4% vs. 6% respectively) and no difference in overall mortality.
Based on those results and on supportive findings from other trials (Table VII) [53][54][55][56] , the 2004 ACCP guidelines 57 , the ASCO VTE guidelines 36 , and AIOM 37 recommend the use of LMWH alone for treatment of VTE in most patients with cancer. Currently, only dalteparin has received regulatory approval for longterm treatment of symptomatic VTE in patients with cancer.

Recurrent VTE
As mentioned earlier, recurrence of VTE is more common in the setting of warfarin therapy than of LMWH therapy. Unfortunately, the optimal treatment for such patients has yet to be determined. Inferior caval filters have frequently been used in cases of warfarin failure, but evidence from a large randomized trial primarily in patients without cancer showed that, although the risk of short-term pulmonary embolism is reduced by about three quarters, patients receiving a filter are about twice as likely to develop recurrent VTE. Also, no difference in overall survival was seen 58 . Furthermore, because of the increased risk of recurrent VTE, cancer patients may be at higher risk for development of postphlebitic syndrome. Based on the foregoing findings, using caval filters as treatment for recurrent VTE cannot be recommended. Rather, changing a warfarin regimen to

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CURRENT ONCOLOGY-VOLUME 15, SUPPLEMENT 1 LMWH, or increasing the dose of LMWH would be appropriate.

Duration of Therapy
The optimum duration of anticoagulation in patients with cancer has not been investigated. Extrapolating from populations without cancer, most patients should receive a minimum of 3-6 months of therapy. However, given that cancer represents an ongoing risk factor in this population, the general recommendation is to continue anticoagulation for long as evidence of active malignancy continues. It is of foremost importance that patient care be tailored to suit the individual, with due consideration for quality of life and life expectancy.

Summary of Secondary Prevention
First-line treatment of VTE in patients with cancer is LMWH for a minimum of 3-6 months. This approach is endorsed by the ACCP, ASCO, AIOM, and the National Comprehensive Cancer Network. The optimum duration is not known, but treatment is usually continued for as long as evidence of malignancy continues.

FUTURE DIRECTIONS
The LMWHs have simplified and improved the prevention and treatment of VTE in patients with cancer. Much work must still be done to help identify highrisk patients who would benefit from primary thromboprophylaxis for extended periods after cancer surgery, during medical hospitalization, for prevention of catheter-related thrombosis, and for prevention of VTE associated with highly thrombogenic agents (thalidomide, for example). Also, optimal management in patients with established VTE should be investigated, especially with regard to duration of therapy and the potential role, if any, of invasive strategies such as filter insertion. Lastly, education of physicians to improve the appropriate utilization of prophylaxis in various settings will go a long way toward reducing morbidity and mortality in this vulnerable population.

SUMMARY
Recommendations for managing risk of thrombotic events: • Cancer patients undergoing surgery require VTE prophylaxis, and this prophylaxis can safely be extended in high-risk patients after discharge. • Medical inpatients with cancer should receive VTE prophylaxis unless absolute contraindicationsactive bleeding, for instance-are present. • Prophylaxis for central venous catheters is not recommended.
• Prophylaxis in ambulatory patients is not recommended, except in those who are receiving thalidomide-or lenalidomide-based combination chemotherapy. • Venous thromboembolism is best treated with LMWH for a minimum of 3-6 months, and treatment can be continued for as long as active cancer is present. • Inferior caval filters prevent pulmonary embolism in the short term, but they carry a long-term risk of increased VTE and should therefore be avoided when anticoagulation can be administered.