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 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. Levines
previous contributions to the subject of hypercoagulability in breast
cancer patients 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. 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,
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
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. Unfortunately, the
factors that mandate the use of filters are
controversial, 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.
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. 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.
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 scenariosthe firstinvites 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
idiopathicnot postoperativein 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.
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.
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.
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
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.