Commentary (Crowther/Kelton): Thromboembolic Complications of Malignancy

Advances in cancer treatment over the past 50 years have cured or prolonged the life expectancy of many patients with cancer. These advances have accelerated over the past 2 decades. Increasingly, physicians who manage patients with cancer are turning their attention to the management of the complications of malignancy, since these complications are often avoidable, can shorten life spans, and can reduce quality of life. Consequently, it is appropriate for the journal ONCOLOGY to publish a thoughtful and detailed review of the thrombotic complications of malignancy. In their article, Linenberger and Wittkowsky review the thromboembolic complications seen in patients with malignancy including its pathogenesis, relative risks, and therapeutic options.[ 1,2] This review also summarizes uncommon complications (arterial thromboembolism in certain hematologic malignancies) and the relatively common thromboembolic complications of distinctly uncommon disorders such as paroxysmal nocturnal hemoglobinuria. For physicians who manage patients with venous thromboembolism (VTE), several recurring questions arise in the context of known or suspected malignancy. Value of Screening for Cancer in Patients With Idiopathic VTE
If a patient presenting with acute VTE lacks an obvious thrombembolic risk factor (such as recent surgery), the patient is typically investigated for an inherited or acquired predisposition to thrombosis. These risk factors are known as hypercoagulable or thrombophilic disorders. The value of identifying a risk factor for VTE relates to a number of factors, including (1) the relative risk of finding that abnormality, (2) the clinical usefulness of identifying a risk factor (inherited or acquired) that can be treated or prevented from recurring, (3) the natural history of the risk factor for that patient (and the implications for family members who may have that risk factor), and (4) the implications of finding an underlying risk factor that would cause illness for the patient in the future. It is our experience that a risk analy- sis (cynics might term it "paramutual medicine") can be helpful when deciding whether patients should be screened for malignancy. However, risk analysis is not a concept well understood by patients. An example of this situation is highlighted by the dilemma for screening for occult malignancies in patients who present with an idiopathic VTE. In a patient presenting with idiopathic VTE, most physicians would consider performing serologic tests to look for a thrombophilic disorder. Depending upon the ethnicity of the patient, appropriate testing might include the factor V Leiden mutation, the prothombin gene 20210A mutation, and levels of antithrombin, protein C, and protein S.[3] Most patients would also be screened for antiphospholipid antibodies (IgG anticardiolipin antibody and lupus anticoagulant).[4] But decisions about screening for occult malignancies in patients without another obvious precipitant for their malignancy are more difficult and often debated. The literature is only partially helpful. About 1 in 10 patients presenting with idiopathic VTE will have an underlying malignancy identified within 1 to 2 years.[5] But the actual risk varies according to the individual's age and coincident medical conditions; older patients or those with an extensive smoking history, for example, are more likely to have an occult malignancy than a younger patient. It is sometimes suggested that investigations should be restricted to detecting treatable lesions such as colorectal, breast, and prostate cancer. There is currently no evidence that early detection of malignancy, based on screening at the time of presentation with idiopathic VTE, reduces morbidity or mortality from cancer, although such screening detects disease earlier in its course.[5] Reducing morbidity or mortality, however, is not the only aim of screening. Not screening for malignancy may be unacceptable to many patients and their families. If underlying malignancy is identified some time after the initial presentation of VTE (usually within 1 to 2 years), patients and families are often angry and will wonder why an initial investigation was not performed. Few patients can understand that detection of the cancer a few months or years earlier would not have changed their prognosis. Consequently, it is always prudent for the physician to discuss with patients who have idiopathic VTE the fact that they may harbor an occult malignancy. If the patient and physician decide screening is indicated, investigations should search for gastrointestinal, breast, pancreatic, and prostate malignancies. Duration of Anticoagulant Therapy in Patients With Malignancy
Recurrent VTE is associated with a high risk of morbidity (such as acute pulmonary embolism and the postthrombotic syndrome) and a substantive risk of mortality. Therefore, anticoagulation should be continued until the risk factor is identified and dealt with. That said, there is inadequate evidence to guide the duration of anticoagulation in patients with malignancy. In general, we continue patients on anticoagulants indefinitely if they harbor active malignancy; patients who have undergone curative therapy should likely be maintained on anticoagulants for a minimum of 3 to 6 months after they are considered to be disease-free. Selection of Anticoagulation and Managing Anticoagulant Failures
Acute VTE is traditionally managed with a rapidly acting parenteral anticoagulant initiated in concert with an oral vitamin K antagonist. In North America, most patients are initially treated with weight-adjusted, low- molecular-weight heparin (LMWH) on an outpatient basis, and the patient is subsequently switched to warfarin. Oral anticoagulant therapy (international normalized ratio [INR] 2-3) will fail in about one in six patients with active malignancy.[6] Warfarin therapy also can be problematic in patients with malignancy because of impaired anticoagulant control as a result of hepatic (and gastrointestinal) dysfunction and chemotherapy. The use of warfarin as an ongoing therapy for VTE complicating malignancy has recently been challenged by the work of Lee and colleagues.[6] This paper, discussed in the review by Linenberger and Wittkowsky, demonstrates that extended-duration LMWH was superior to warfarin for the secondary prevention of VTE in patients with malignancy, producing a relative risk reduction for recurrence of about 50%. Based on these observations, many clinicians are now treating patients who have a known, active malignancy with long-term LMWH. Nevertheless, concerns remain about this approach. For example, LMWH is more expensive than warfarin and there is no evidence to allow an informed decision about whether the patient should be switched to oral anticoagulants after an extended course of LMWH. Given the cost and inconvenience of daily LMWH, many clinicians choose to switch patients to warfarin at the end of a 6-month course. In summary, the optimal management of thrombotic complications in patients with malignancy is becoming more clear as studies are reported. Appropriate investigations in patients presenting with idiopathic VTE, extended-duration therapy, and longterm LMWH may reduce the morbidity (and perhaps mortality) associated with cancer.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Linenberger ML, Wittkowsky AK: Thromboembolic complications of malignancy. Part 1: Risks. Oncology 19:853-861, 2005.
2. Linenberger ML, Wittkowsky AK: Thromboembolic complications of malignancy. Part 2. Management. Oncology 19:000-000, 2005.
3. Crowther MA, Kelton JG: Congenital thrombophilic states associated with venous thrombosis: A qualitative overview and proposed classification system. Ann Intern Med 138:128-134, 2003.
4. Crowther MA, Wisloff F: Evidence based treatment for the antiphospholipid antibody syndrome II. Optimal anticoagulant therapy for thrombosis. Thromb Res 115:3-8, 2005.
5. Piccioli A, Lensing AW, Prins MH, et al: Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial [see comment]. J Thromb Haemost 2:884-889, 2004.
6. Lee AY, Levine MN, Baker RI, et al: Lowmolecular- weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146-153, 2003.