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Management of Venous Thromboembolism in Cancer Patients

Management of Venous Thromboembolism in Cancer Patients

When one considers the frequency with which practicing oncologists encounter situations and issues involving venous thrombosis in their patients, it is remarkable how little attention has been paid to this problem in the oncology literature or standard textbooks of oncologic theory and practice. Although the topic of hypercoagulability in cancer patients has been the subject of several excellent articles,[1,2] these reviews, while exhaustive with respect to pathophysiology, provide relatively little information of practical use to the oncologist.

Fortunately, Drs. Lee and Levine have reprised and expanded on their previously published review[3] in this issue of Oncology in order that this topic of extraordinary practical significance be made available in a journal read by many oncologists. Dr. Levine’s previous contributions to the subject of hypercoagulability in breast cancer patients[4] have stood alone in their practicality and simplicity of clinical trial design. Along with Dr. Lee, there is perhaps no individual better able to compile a useful summary of hypercoagulability and its management.

Algorithms for Deep-Venous Thrombosis and Pulmonary Embolism

Unfortunately, any attempt to create a practical guide to the management of thrombosis in cancer patients must be predicated on the assumption that cancer patients will respond or not respond to anticoagulant therapies in much the same way as patients with nononcologic disease. Although we may acknowledge that this assumption is incorrect, there are no adequate data to support a set of algorithms purely for the management of thrombosis in cancer patients. We must draw from the thrombosis literature in general, extrapolate to the cancer patient, and be content, for the moment, with this shortcoming.

Thus, Drs. Lee and Levine begin with a pair of simple algorithms to aid in the diagnosis of deep-venous thrombosis and pulmonary embolism. The algorithms are practical and in keeping with good medical practice. These algorithms, like all others, will be restricted by institutional biases and limitations. For example, a relative aversion to the pulmonary angiogram by virtue of its morbidity or unavailability leads, in some hospitals, to the use of the high-resolution chest computed tomography (CT) in patients with suspected pulmonary emboli in whom lung scintigraphy and lower-extremity duplex scanning have failed to yield a diagnosis.

These algorithms are followed by a cogent discussion of the treatment of acute thrombotic complications. This discussion reiterates standard clinical practice coupling unfractionated heparin and warfarin in the customary fashion. The degree to which we may, or should, incorporate the low-molecular-weight heparins into the treatment of venous thrombosis continues to evolve.

The article is highly laudatory of the low-molecular-weight heparins in this setting, as perhaps it should be, particularly when one considers that the performance of these newer heparins in randomized clinical trials has been equally effective in cancer and noncancer patients with acute thrombosis.[3] Readers must acknowledge, however, that the purported survival advantage in cancer patients receiving low-molecular-weight heparins, secondary to a putative antiangiogenesis effect, remains a research question; this as yet unconfirmed survival benefit should not be used as a justification for the use of these expensive compounds when a less expensive treatment, such as warfarin, might suffice.

Duration of Anticoagulant Therapy

The duration of anticoagulant therapy in cancer patients remains, perhaps, the most difficult issue of all. This vexing problem is discussed with the brevity necessitated by the existing lack of data. When one considers those clinical trials in which different durations of anticoagulant therapy have been compared in noncancer patients,[3] the recommendation of Drs. Lee and Levine to continue anticoagulant therapy “for as long as there is evidence of cancer and while the patient is receiving antineoplastic therapy” stands as a sound recommendation. It also obligates the practitioner to expend the necessary effort to ensure an appropriate therapeutic window of anticoagulation, thus avoiding unwarranted bleeding or treatment failure in the long-term user of warfarin.

The prohibitive costs of the low-molecular-weight heparins should discourage practitioners from their presumptive use in lieu of warfarin, until the results of ongoing clinical trials comparing the two agents have been compiled. An exception, of course, would be in cases where warfarin fails to provide adequate prophylaxis against recurrent thromboembolism.

Other Anticoagulant Measures

Drs. Lee and Levine exercise appropriate restraint in their discussion of inferior vena cava filters. I believe that it is important that they dampen enthusiasm for the overzealous use of such filters, except under circumstances in which the use of anticoagulants is absolutely contraindicated.[5] Unfortunately, the factors that “mandate” the use of filters are controversial,[2] particularly in the patient with cerebral metastases or primary glioma.

In one of the five case presentations that conclude this review, Drs. Lee and Levine advocate the avoidance of anticoagulation only in patients whose central nervous system metastases are already hemorrhagic or likely to become so (ie, patients with melanoma). Although this approach is consistent with general practice in our institution, a more thorough discussion of this phenomenon and supporting data would have been welcome. However, the lack of such a discussion is the only shortcoming in this otherwise outstanding article.

Catheter-Related Thrombosis

No subject within the confines of a discussion of thrombosis in cancer patients lends itself less well to a practical review than the issue of catheter-related thrombosis.[6] This article provides an excellent discussion of the problems confronting both patients with a central venous catheter and the physicians responsible for their care. Again, Drs. Lee and Levine provide a practical solution for patients with a suspected upper extremity thrombus, emphasizing the diagnostic standard of venography, while allowing for the alternate use of compressive ultrasonography in patients in whom venography is contra-indicated.

The troublesome issue of thromboprophylaxis in patients with central venous catheters who are asymptomatic will remain unresolved. Insofar as only two randomized trials have been conducted in this patient population, the weight of evidence supports the use of low-dose warfarin.[6]

Clinical Scenarios

The article concludes with a series of five clinical scenarios that illustrate many of the routine issues with which we are confronted on a regular basis. These include thromboprophylaxis in tamoxifen (Nolvadex) recipients, warfarin resistance in patients with gastrointestinal adenocarcinomas, anticoagulation management in individuals undergoing a minor invasive procedure (eg, thoracentesis), anticoagulation in patients with cerebral metastases, and the discontinuation of anticoagulants in the terminally ill.

Only one of these scenarios—the first—invites debate. In this case, a patient with a history of deep venous thrombosis as a complication of a previous operation is contemplating adjuvant tamoxifen therapy. Although it seems reasonable to prescribe tamoxifen therapy without regard to thrombosis risk in such a patient, the authors suggest that thromboprophylaxis might have been reasonable had her deep-venous thrombosis been truly “idiopathic”—not postoperative—in origin.

First, one wonders how cumbersome thromboprophylaxis might be for a 5-year duration of tamoxifen therapy in such a patient, whose real risk of tamoxifen-induced thrombosis is difficult to quantify. Second, one questions what would constitute adequate thromboprophylaxis in such a patient, as the role of low-dose warfarin in this setting has not been defined.[7]

Conclusions

Drs. Lee and Levine deserve our thanks for providing an outstanding, practical review of a difficult, important topic. A follow-up article after the completion and maturity of the ongoing trials of low-molecular-weight heparins as long-term thromboprophylaxis would be most welcome.

References

1. Goad KE, Gralnick HR: Coagulation disorders in cancer: Hematologic complications of cancer. Hematol Oncol Clin North Am 10(2):457-484, 1996.

2. Green KB, Silverstein RL: Hypercoagulability in cancer: Hematologic complications of cancer. Hematol Oncol Clin North Am. 10(2):499-528, 1996.

3. Levine MN, Lee AYY: Treatment of venous thromboembolism in cancer patients. Semin Thromb Hemost 25:245-249, 1999.

4. Levine M, Hirsh J, Gent M, et al: Double-blind, randomized trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 343:886-889, 1994.

5. Decousus H, Leizorovicz A, Parent F, et al: A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 338:409-415, 1998.

6. Bona RD: Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Hemost 25:147-155, 1999.

7. Kakkar AK, Williamson RC: Prevention of venous thromboembolism in cancer patients. Semin Thromb Hemost 25:239-243, 1999.

 
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