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Venous Thromboembolism in Malignancy

Boston VA Healthcare System and Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA

ALTHOUGH A SMALL number of patients will have a spontaneous venous thromboembolic episode as the initial manifestation of an occult cancer,¹ approximately 20% of patients with symptomatic deep venous thrombosis have a known active malignancy. Although augmented blood coagulability resulting directly or indirectly from the underlying tumor is frequently considered to be important in the pathogenesis of many of these thrombotic events, other risk factors are frequently present. These include advanced age, recent surgery, immobilization, chemotherapy, hormonal therapy, and indwelling central venous catheters.

Thrombosis therefore frequently complicates the course of the cancer patient and has the potential to produce significant morbidity and even mortality. The objectives of therapy in venous thromboembolism are the prevention of death from pulmonary emboli and the reduction of morbidity from the acute event as well as sequelae such as recurrences and the post-phlebitic syndrome. Treatment with anticoagulants is clearly effective, but, even in a noncancer population, 5% to 7% of patients with deep venous thrombosis will develop recurrent venous thromboembolic complications during heparinization and the 3- to 6-month period of oral anticoagulant therapy; there is also a 2% to 3% incidence of major bleeding complications during this period.^2,3 This can make the decision to anticoagulate a cancer patient with a limited life expectancy difficult because of the need for close laboratory monitoring of warfarin’s anticoagulant effect and the possible concomitant administration of myelosuppressive chemotherapy.

For many years, experienced clinicians have recognized the existence of a relatively small subset of cancer patients with thrombosis and so-called warfarin resistance who develop recurrent venous thromboembolism despite an International Normalized Ratio (INR) of 2 to 3. It is, however, difficult to prospectively identify such patients. Although some recent studies indicate that an underlying cancer leads to an increased risk for recurrent thrombosis during anticoagulant therapy,^4,5 there are conflicting data regarding whether they are more susceptible to bleeding complications.^4-6 One of the studies that did not demonstrate an increased rate of major bleeding among cancer patients found that they required more frequent INR monitoring to remain within the therapeutic range.⁶ However, the studies were relatively small, leading to a lack of precision regarding the estimated bleeding rate in cancer patients versus noncancer patients.

The study by Hutten et al⁷ in this issue of the Journal of Clinical Oncology retrospectively analyzed the incidence of recurrent venous thromboembolism and major bleeding complications with respect to the presence of malignancy and the achieved INR during a 3-month period of oral anticoagulation. More than 1,300 patients from two major multicenter trials comparing intravenous unfractionated heparin with low-molecular-weight heparin as initial therapy for symptomatic venous thromboembolism were analyzed, and 20% were known to have a malignancy.^8,9 The origin of the cancers were primarily in the genitourinary and gastrointestinal tracts as well as the breast; no details were given regarding the staging of the patients. The overall incidence of recurrent venous thromboembolism and major bleeding in the patients with malignancy was significantly higher than in those without malignancy (27.1% v 13.3% and 9.0% v 2.1% per patient-year, respectively). Despite the relatively high complication rate associated with warfarin, it can be inferred that the drug retains antithrombotic efficacy in the cancer population, because the incidence of recurrence followed the expected inverse relationship with the INR (54.9 v 18.9 events per 100 patient-years in patients with an INR 2 and an INR of 2 to 3, respectively). The pattern for major bleeding in patients with malignancy was surprisingly opposite to what would be expected, as those with an INR 2 had the most events. Although this result was statistically significant, the overall number of major bleeds was quite small. On the basis of their analysis, the authors conclude that oral anticoagulant therapy in cancer patients could be improved by getting patients’ INRs into the therapeutic INR range a greater percentage of the time with more frequent monitoring. This is not a particularly attractive strategy for patients with malignancy who are often quite infirm and have poor venous access, unless INRs could be performed at home using a self-monitoring INR device; the latter, however, is quite costly. Although complications during the 5 to 10 days of initial heparinization were excluded from the analysis performed by Hutten et al,⁷ it should be noted that 10 of 17 major bleeds and three of 21 recurrent thromboses occurred in cancer patients during this period; this can be contrasted with the 3 months of warfarin therapy in which seven of 12 major bleeds and 14 of 35 recurrent thromboses occurred in cancer patients. Analysis of whether heparin or low-molecular-weight heparin therapy also pose a significantly greater risk to the cancer population, particularly with respect to major bleeding, is complicated by the fact that warfarin was also administered during this time period.

Prandoni et al¹⁰ also recently examined the incidence of recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in cancer patients followed-up for up to 1 year. Within a cohort of 842 Italian patients from a single center with confirmed symptomatic deep vein thrombosis, cancer was known to be present in 191; the relative risks of recurrent thrombosis and major bleeding were 3.6-fold and 2.1-fold higher, respectively, in patients with cancer than in those without; both were statistically significant. The frequency of adverse events was also analyzed with respect to cancer severity, and patients with higher-stage disease and the poorest estimated survival had a significantly higher likelihood of recurrent thrombosis or bleeding. These complications could not be explained by subtherapeutic anticoagulation or overanticoagulation, leading these authors to conclude that more intensive INR monitoring was unlikely to significantly improve outcomes.

What is the optimal way to manage the cancer patient with an initial episode of venous thromboembolism? Unless the risks of anticoagulants are deemed prohibitive, initial treatment consists of therapeutic doses of unfractionated heparin or low-molecular-weight heparin for at least 5 days. Low-molecular-weight heparin has the advantage that it is administered subcutaneously, does not require laboratory monitoring, and some medication regimens require only one daily dose, thereby facilitating therapy in the home environment. As clinical experience indicates that heparin is often effective in treating recurrent thrombosis in cancer patients on seemingly adequate doses of warfarin, it has been thought that long-term heparin therapy may provide more effective secondary prophylaxis than warfarin in this population. A multicenter international randomized clinical trial is currently being conducted to evaluate whether long-term low-molecular-weight heparin is superior to oral anticoagulant therapy in cancer patients with venous thromboembolism. With regard to the duration of anticoagulation, it is generally recommended to continue anticoagulation as long as there is evidence of active cancer or the patient continues on anticancer therapy. Vena caval filters should be reserved for patients with bleeding and those who are at very high risk for this complication were anticoagulants to be administered or for patients who fail to respond to adequate doses of heparin or low-molecular-weight heparin.

Using treatment paradigms developed for the noncancer population, we now have solid data that cancer patients with venous thromboembolism are more likely to develop recurrent thrombotic events and major bleeding. Although the management of thrombosis in such patients remains difficult, the ongoing trials specifically designed for this population with low-molecular-weight heparin and the clinical development of other new anticoagulants with specificity for individual coagulation enzymes (eg, inhibitors of the factor VIIa-tissue factor pathway, factor Xa, and thrombin inhibitors) will hopefully provide more effective and safer treatment options than those that are currently widely used.

REFERENCES

1. Prandoni P, Lensing AWA, Buller HR, et al: Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Eng J Med 327: 1128-1133, 1992[Abstract]

2. Ginsberg JS: Management of venous thromboembolism. N Engl J Med 335: 1816-1828, 1996[Free Full Text]

3. Lensing AWA, Prandoni P, Prins MH, et al: Deep-vein thrombosis. Lancet 353: 479-485, 1999[Medline]

4. Gitter MJ, Jaeger TM, Petterson TM, et al: Bleeding and thromboembolism during anticoagulant therapy: A population-based study in Rochester, Minnesota. Mayo Clinic Proc 70: 725-733, 1995[Medline]

5. Prandoni P, Lensing AWA, Cogo A, et al: The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 125: 1-7, 1996[Abstract/Free Full Text]

6. Bona RD, Sivjee KY, Hickey AD, et al: The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 74: 1055-1058, 1995[Medline]

7. Hutten BA, Prins MH, Gent M, et al: The incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: A retrospective analysis. J Clin Oncol 19: 3078-3083, 2000

8. Koopman MM, Prandoni P, Piovella F, et al: Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared to subcutaneous low-molecular-weight heparin administered at home. N Eng J Med 334: 682-687, 1996[Abstract/Free Full Text]

9. The Columbus Investigators: Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Eng J Med 337: 657-662, 1997[Abstract/Free Full Text]

10. Prandoni P, Lensing AWA, Piccioli A, et al: Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Haemostasis 30:58, 2000 (suppl 1) (abstr)

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