Joel S. Bennett, MD
2010-03-01
Professor of Medicine, Division of Hematology-Oncology, University of Pennsylvania School of Medicine
(Editor’s Note: The original question was submitted to Dr. Bennett through Consult a Colleague. He expanded his answer for print.)
Clinical Problem
I have been treating a 54-year-old woman with a resected breast cancer with adjuvant
docetaxel, cyclophosphamide, and trastuzumab. She developed a central line thrombosis
during treatment and was treated with warfarin for three months, after which the central
line was removed. I plan to discontinue the warfarin in the next several weeks, assuming
it is safe to do so while she is receiving trastuzumab. Should the patient undergo a workup
for thrombophilia despite a negative family history, and should warfarin be restarted
if she needs another central line to complete a one-year course of trastuzumab?
My Response
This is a common but complex situation. This patient has several predispositions to
venous thrombosis, including breast cancer, chemotherapy, and an indwelling venous
catheter. The thrombosis she experienced could have resulted from the cumulative effect
of these factors, but I suspect the presence of the indwelling catheter was the major
precipitating cause.
As you know, cancers — in particular malignancies of the brain, adenocarcinomas of
the lung and gastrointestinal tract, and hematologic malignancies - are associated
with a sixfold to sevenfold increase in the risk for venous thromboembolism (VTE).1,2
Although this risk is greatest in the months following diagnosis and declines with time,
the risk remains higher than in individuals without cancer even two years after diagnosis.
Moreover, the risk for patients with metastatic disease is increased further compared
to patients without. Although the risk for VTE in the first six months after a diagnosis of
breast cancer is twofold to fourfold less than for patients with the malignancies noted
above, the cumulative incidence of VTE for patients with breast cancer approaches that
of the others, because patients with breast cancer live substantially longer. This raises
the question whether prophylactic anticoagulation in a patient with breast cancer would
be beneficial. This issue was addressed in the most recent American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines.3 After reviewing the available
data, the authors of the guidelines concluded that the evidence does not support routine
thromboprophylaxis for the primary prevention of VTE in ambulatory patients such as
this one.
Chemotherapy administration and hormonal manipulation are also associated with
an increased risk of VTE. Therefore, it is surprising that there is a paucity of studies
addressing the efficacy of thromboprophylaxis in ambulatory cancer patients who are receiving
chemotherapy or hormonal therapy. One widely cited study from 1994 reported
that giving low-dose warfarin (INRs of 1.3-1.9) in patients with stage IV breast cancer receiving
chemotherapy resulted in a significant reduction in VTE.4 However, these results
were not replicated in subsequent studies,5 and thromboprophylaxis is not currently recommended
for patients with cancer receiving chemotherapy or hormonal therapy.3 With
specific regard to trastuzumab, after reviewing the prescribing information and searching
the literature, I could not find evidence that VTE is a common adverse event related to
the use of this drug.
As I mentioned earlier, I think the central venous catheter itself, as a foreign body
in the circulation, was the proximate cause of the thrombosis in your patient. So, it
would seem logical to ask whether prophylactic anticoagulation could prevent this
from happening again. There have been a number of studies addressing this question.
However, a recently reported meta-analysis of eight randomized controlled trials of
thromboprophylaxis in patients with cancer and central venous catheters concluded
that thromboprophylaxis had no significant effect on the risk of catheter-related thrombosis.6 Similarly, in the WARP study of warfarin thromboprophylaxis in cancer patients
with central venous catheters,7 it was found that neither fixed-dose warfarin at 1 mg per
day nor dose-adjusted warfarin to maintain an INR of 1.5 to 2.0 reduced the incidence of
catheter-related thromboses. Thus, the available evidence does not support the use of
prophylactic anticoagulation should the central line be re-inserted.
Although your patient has several recognized predispositions to thrombosis, the currently
available evidence does not support the use of thromboprophylaxis for her clinical
situation. Further, on the basis of this conclusion, as well her age and history, I don’t see
the utility of a thrombophilia work-up.
- Blom JW, Doggen CJ, Osanto S, et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293:715-22.
- Blom JW, Vanderschoot JP, Oostindiёr MJ, et al. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb
Haemost. 2006;4:529-35.
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
(8th Edition). Chest. 2008;133:381S-453S.
- Levine M, Hirsh J, Arnold A, et al. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet.
1994;343:886-89.
- Khorana AA. Cancer and thrombosis: implications of published guidelines for clinical practice. Ann Oncol. 2009;20:1619-30.
- Chaukiyal P, Nautiyal A, Radhakrishnan S, et al. Thromboprophylaxis in cancer patients with central venous catheters. A systematic review and meta-analysis.
Thromb Haemost. 2008;99:38-43.
- Young AM, Billingham LJ, Begum G, et al. Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial.
Lancet. 2009;373:567-74.
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