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Thromboembolic Complications of Malignancy

Thromboembolic Complications of Malignancy

ABSTRACT: Thromboembolism affects many patients with solid tumors and clonal hematologic malignancies. Thromboprophylaxis with low-molecularweight heparin (LMWH) is indicated for surgery and other high-risk situations, but not routinely for central venous catheters or nonsurgical, ambulatory management. Thrombotic events require full anticoagulation for the duration of active disease and/or the prothrombotic stimulus. LMWHs are safe and more effective than both unfractionated heparin for initial therapy and warfarin for secondary prevention. Antiinflammatory and antiangiogenic properties might account for this advantage and for a survival benefit of chronic LMWH in subgroups of cancer patients. Ongoing studies are characterizing the cost-effectiveness and antitumor mechanisms of LMWHs, the potential utility of newer anticoagulants, and the ability of predictive models to identify high-risk candidates for thromboprophylaxis.

As we noted in the June issue of
ONCOLOGY, recent or active
cancer is a powerful prothrombotic
risk factor, greatly increasing
the possibility of venous thromboembolism
(VTE). Part 1 of this review
considered the mechanisms involved
in thromboembolic complications,
their clinical presentation, and the
many prothrombotic risks that have
been identified in patients with solid
tumors and clonal hematologic malignancies
and disorders. In part 2, we
will address prophylaxis and treatment
of VTE in this setting.

VTE Prophylaxis in
Patients With Malignancy
Primary Surgical Prophylaxis
The significant incidence of VTE in
patients undergoing surgical procedures
has led to the development of graded
recommendations for prophylaxis in
these populations based on assessment
of underlying risk.[1] Current recommendations
from the American College
of Chest Physicians (ACCP)
suggest that patients with malignancy
should receive prophylaxis according
to their high state of risk (Table 1).
However, the presence of malignancy
may influence the selection of specific
pharmacologic agents for VTE prophylaxis,
the dosing of these agents, and
the duration of therapy.

In patients undergoing general surgery,
unfractionated heparin (UFH)
and low-molecular-weight heparin
(LMWH) are equally effective in preventing
postoperative thrombosis, according
to a meta-analysis of trials
comparing both therapies, without regard
to dose or duration of therapy.[2]
Some of the trials evaluated in this
meta-analysis included patients with
malignancy, and these patients were
compared to patients without cancer
in a subanalysis. Bleeding and thrombosis
occurred more frequently in patients
undergoing cancer surgery vs
noncancer surgery, but UFH and
LMWH were equally effective and
safe in both populations.

Several trials provide additional details
regarding the appropriate dosing
and duration of thromboprophylaxis in
surgical patients with malignancy. In
patients undergoing surgery for gynecologic
malignancy, UFH at 5,000 U
given three times daily was more effective
than UFH at 5,000 U given twice
daily, without an increase in bleeding
complications.[3] In the Enoxacan
Study, 1,115 cancer patients undergoing
abdominal or pelvic surgery were
randomized to prophylaxis with enoxaparin
(Lovenox) at 40 mg daily vs
UFH at 5,000 U three times daily.[4]
No differences were found in the rate
of venographically evident VTE at
3 months (14.7% vs 18.2%), or in the
rate of total bleeding complications
(18.7% vs 17.1%). In patients with
malignancy undergoing general surgery
and randomized to dalteparin (Fragmin)
at 5,000 U vs 2,500 U daily, the
higher dose was more effective in preventing
deep venous thrombosis detected
by fibrinogen uptake (8.5% vs
14%; P < .001), without an increased
risk of bleeding (4.6% vs 3.6%; NS).[5]

Although VTE prophylaxis is typically
continued until hospital discharge,
the risk of VTE extends beyond the
hospital stay. Extended prophylaxis was
investigated in the Enoxacan II Study
of 322 patients undergoing surgery for
abdominal or pelvic cancer.[6] After
initial prophylaxis with enoxaparin,
40 mg daily for 6 to 10 days, patients
were randomized to continue placebo
or enoxaparin for an additional 3 weeks.
Extended prophylaxis was associated
with a 60% reduction in the incidence
of total VTE at 1 month (4.8% vs 12%;
P = .02) and at 3 months (5.5% vs
13.8%; P = .01) without a significant
increase in the risk of minor, major, or
total bleeding.

Thus, once-daily LMWH and threetimes-
daily UFH appear to be equally
effective in preventing VTE in patients
with malignancy undergoing general
surgery. Similar findings have been
observed in patients undergoing surgery
for breast and gynecologic malignancies.[
7] Despite higher drug
acquisition cost, LMWH offers advantages
over UFH, including once-daily
dosing, which improves patient acceptance
and limits nursing time, and a
lower incidence of heparin-induced
thrombocytopenia. Decision analytic
models have estimated that LMWH is
cost-effective for prophylaxis in gynecologic
oncology surgery.[8] However,
similar analyses have not yet
compared once-daily LMWH vs threetimes-
daily UFH in other settings, nor
are there data regarding the cost implications
of extended prophylaxis.
Well-designed prospective trials are
needed to gather this information for
optimal, evidence-based practice.

Similar aggressive prophylactic anticoagulation
strategies are indicated for
the perioperative management of patients
with hematologic malignancies,
including polycythemia vera and essential
thrombocythemia. In patients with
polycythemia vera, the hematocrit
should be normalized before elective
surgery (ie, to < 45% in men and < 42%
in women) to minimize the risks of
thrombosis and bleeding. It is also recommended
that the platelet count be
normalized preoperatively in polycythemia
vera or essential thrombocythemia
patients with high-risk
features (ie, age > 60 years or prior
thromboembolic event). Although lowdose
aspirin (ie, 100 mg/d) minimizes
the nonsurgical risk of arterial and
venous thromboemboli in patients with
polycythemia vera,[9] the benefit of aspirin
in the perioperative setting is untested
and one must weigh the
theoretical benefit against the potential
risks of bleeding.

Primary Prophylaxis in
Hospitalized Medically Ill Patients

The role of thromboprophylaxis in
immobile or bedridden hospitalized and
medically ill patients is well established
(reviewed in [1]). A number of clinical
trials showed that either twice-daily or
three-times-daily dosing of UFH effectively
reduces the incidence of VTE in
this population. A meta-analysis of the
general surgical literature suggests that
three-times-daily UFH is more effective
for VTE prophylaxis than twicedaily
dosing[10]; however, no trials
comparing these regimens have been
conducted in acutely ill medical
patients.

More recent clinical trials have established
the effectiveness of enoxaparin,
40 mg daily, or dalteparin,
5,000 U daily, compared to placebo,
and of fondaparinux (Arixtra), 2.5 mg
daily. Two studies comparing UFH,
5,000 U three times daily, with enoxaparin,
40 mg daily, in acutely ill
patients, including those with malignancy,
found similar rates of VTE as
detected by either duplex ultrasonography
or venography. As risk status
increased, so did the overall effectiveness
of enoxaparin compared to
UFH, although this was not specifical-
ly evaluated in patients with malignancy.
A subanalysis of the Prophylaxis in
Medical Patients with Enoxaparin
(MEDENOX) trial comparing enoxaparin
to placebo in acutely ill medical
patients found that the most significant
risk factors for thrombosis in this population
were age > 75 years, history of
VTE, and malignancy.[11]

Although it is clear that thromboprophylaxis
is effective and safe in bedbound
medically ill patients, several
controversies have yet to be resolved
in patients with malignancy, including:
(1) the relative efficacy of three-timesdaily
UFH vs LMWH; (2) the role of
chemotherapy- or radiation-induced
thrombocytopenia in bleeding risk;
(3) the role of ambulatory status on VTE
risk; and (4) the appropriate duration
of therapy. Although enoxaparin has
been determined to be more cost-effective
for VTE prophylaxis in acutely ill
medical patients than twice-daily
UFH,[12] no pharmacoeconomic studies
have yet compared enoxaparin to
three-times-daily UFH, nor have patients
with malignancy been specifically
addressed.

Prophylaxis in Ambulatory Patients
Low-intensity oral anticoagulation
with warfarin was observed to prevent
VTE during chemotherapy in 311 patients
with stage IV breast cancer.[13]
Those patients were randomized to placebo
or to fixed-dose warfarin, 1 mg
daily for 6 weeks, followed by dosing
adjustments to maintain the international
normalized ratio (INR) between 1.3
and 1.9. During 6 months of therapy,
anticoagulation was associated with an
85% reduction in the relative risk of
VTE without a significant increase in
bleeding complications or a significant
increase in costs.[14]

By comparison, a more recent study
in patients with limited-stage small cell
lung cancer treated with chemotherapy
and radiation found that oral prophylactic
anticoagulation had no influence
on survival.[15] Similarly, the Fragmin
Advanced Malignancy Outcome
Study (FAMOUS) trial comparing
dalteparin, 5,000 U daily, to placebo
for a mean of 9 months in ambulatory
patients with a variety of different advanced
malignancies found no difference
in the rate of VTE or overall
survival between the two cohorts.[16]
Therefore, among patients with solid
tumors, thromboprophylaxis should be
reserved for those who are hospitalized
and acutely ill, those undergoing surgical
procedures, and those with other
individual high-risk features (Table 2).

Prophylactic therapy for patients
with polycythemia vera include phlebotomy
to maintain the hematocrit in
the normal range (ie, < 45% for men
and < 42% for women)[17] and daily
low-dose aspirin (81 to 100 mg) for
those who are not at increased risk of
bleeding (Table 2).[9] Cytoreductive
therapy should be given to normalize
the platelet count in patients with polycythemia
vera or essential thrombocythemia
who also have high-risk
features, including prior thromboembolism
or age > 60 years; and considerations
given for patients with comorbid
cardiovascular risks (eg, smoking, diabetes,
atherosclerotic disease).[17,18]

Hydroxyurea is the cytoreductive
agent of choice for patients with myeloproliferative
disorders, based on
the limited available information from
randomized clinical trials.[18,19]
Anagrelide is inferior to hydroxyurea
for patients with essential thrombocythemia,[
19] but it is a reasonable
second-line option. Interferon alfa
should be used in women of childbearing
potential to avoid the teratogenic
effects of the other agents.
Primary prophylaxis with therapeutic
warfarin has been recommended for
patients with paroxysmal nocturnal
hemoglobinuria (PNH) who have a
high level of circulating PNH granulocytes[
20]; however, this intervention
must be weighed against the risks of
bleeding, especially in patients with severe
hemolysis and thrombocytopenia.

Prophylaxis for Indwelling
Central Venous Catheters

Clinical trials evaluating anticoagulation
for prevention of central
venous catheter (CVC) thrombosis
have produced conflicting results (reviewed
in [21,22]). Oral anticoagulation
with "minidose" warfarin, at 1
mg daily, reduced CVC clot formation
by roughly fourfold (9.5% compared
to 37.5% for no treatment) in
84 patients with cancer. By contrast,
a more recent study found no benefit
among 100 cancer patients treated
with warfarin, 1 mg daily, compared
to placebo. The potential hemorrhag
ic risk of prophylaxis must also be
considered. Roughly one-third of patients
receiving minidose warfarin
with continuous-infusion 5-FU
reached an INR > 1.5, and 23% of
those anticoagulated patients suffered
a bleeding complication.[23]

Similar discrepant outcomes have
been observed with LMWH prophylaxis.
Dalteparin has been found to
be both effective and ineffective in
preventing clot formation associated
with CVCs.[22] Because of these
conflicting results, neither fixed, lowdose
warfarin nor LMWH are currently
recommended for routine
prevention of CVC thrombosis in patients
with malignancy.[1] However,
prophylaxis with adjusted-dose warfarin
or LMWH should be considered
on a case-by-case basis for patients
who are felt to be at a high risk of
line-associated thrombosis (Table 2).

Treatment of Venous
Thromboembolism
Initial Treatment
Current evidence-based guidelines
for the initial treatment of VTE recommend
that patients receive concurrent
warfarin and either UFH or LMWH
for a minimum of 5 days and until the
INR is stable and ≥ 2 (Table 3).[24]
Meta-analyses of a number of clinical
trials comparing UFH and LMWH in
the initial treatment of VTE concluded
that these agents are equally safe
and effective, with similar rates of
recurrent VTE and major bleeding.
However, LMWHs are associated
with a 24% to 29% reduction in the
risk of mortality compared to UFH.

In patients with cancer, this mortality
benefit may be magnified. In the subgroup
of 279 patients with cancer
included in one meta-analysis, mortality
was 25.9% among patients treated
with UFH and 16.7% in patients treated
with LMWH.[25] In addition, the combined
results of two early trials comparing
UFH and LMWH in the initial
treatment of VTE found a mortality rate
of 31% among 67 cancer patients treated
with UFH, compared to 11% in 62
cancer patients treated with LMWH
(P < .005).[26] Although UFH and
LMWH have not been compared in a
head-to-head trial in patients with cancer,
these subgroup analyses of comparative
trials strongly support the
contention that LMWH provides a mortality
benefit over UFH for the initial
treatment of VTE in cancer patients.

When enoxaparin is selected as the
LMWH for initial treatment of VTE,
the typical strategy is 1 mg/kg of total
body weight every 12 hours. This
schedule was compared to 1.5 mg/kg
daily and to UFH in 900 patients with
acute VTE.[27] The incidence of recurrent
VTE at 3 months was similar
for both once- and twice-daily enoxaparin
in all patients (4.4% vs 2.9%),
but in the subgroup of 96 patients
with malignancy, once-daily dosing was
inferior (12.2% vs 6.4%). In comparison,
once-daily dosing of tinzaparin
(Innohep) at 175 U/kg and dalteparin
at 200 U/kg are effective as initial treatments
of VTE in patients with malignancy.[
28,29] In patients with
thrombocytopenia (eg, due to myelosuppressive
chemotherapy or hematopoietic
failure), the platelet count must
be monitored and transfusions given to
maintain the count at ≥ 50,000/μL. In
addition, patients on UFH or LMWH
should be monitored for development
of heparin-induced thrombocytopenia.

For CVC-associated events, fibrin
sheath occlusion is usually cleared by
instillation of a fibrinolytic agent, such
as urokinase (Abbokinase) or tissuetype
plasminogen activator (tPA). This
procedure can be safely carried out in
thrombocytopenic patients. Nonocclusive
subclavian clots and proximal
CVC-associated deep venous thromboses
are usually managed with therapeutic
anticoagulation (either UFH
or LMWH) without removal of the
catheter.[30] Prospective monitoring
with duplex ultrasound must be performed
to ensure resolution of the clot.
Extension of proximal thromboses on
therapeutic anticoagulation or more
extensive/occlusive central deep
venous thromboses (eg, with superior
vena cava syndrome) require catheter
removal followed by full
anticoagulation
and, in some cases, thrombolysis.
Full anticoagulation, with LMWH
or warfarin, should be continued for
at least 3 to 6 months, and subsequent
prophylactic anticoagulation should
be given for long-term indwelling
catheters or if a new CVC is placed.

Acute thromboembolic events in
patients with myeloma, leukemias,
polycythemia vera, essential thrombocythemia,
or PNH are managed initially
with therapeutic LMWH or UFH,
similar to events in patients with solid
tumors. Thrombocytopenic patients
should be closely monitored and transfused
with platelets as indicated. Additional
considerations include the
possible need for urgent white cell reduction
(ie, by leukapheresis) in patients
with acute myeloid leukemia and
leukostasis (usually with circulating
blast counts greater than 50,000 to
100,000/μL), urgent red cell reduction
(ie, by erythrocytapheresis) in patients
with polycythemia vera and uncontrolled
erythrocytosis, and urgent
platelet reduction (ie, by plateletpheresis)
in patients with polycythemia
vera or essential thrombocythemia and
uncontrolled thrombocytosis.

Systemically administered thrombolysis
should be considered for selected
patients with massive ileofemoral
deep venous thrombosis who are at
risk for limb gangrene (eg, with phlegmasia
alba dolens) and patients with
pulmonary embolism who are hemodynamically
unstable.[24] Local administration
of thrombolytic agents is not
recommended. Vena caval interruption,
most commonly accomplished by
placement of a wire filter, is indicated
for patients with acute deep venous
thrombosis and/or pulmonary embolism
with absolute contraindications to
anticoagulation or with bleeding or recurrent
pulmonary embolism while on
appropriate anticoagulant therapy. Permanent
and removable wire filters can
be placed in either the inferior or superior
vena cava using fluoroscopic or
ultrasound guidance. These devices reduce
the rate of recurrent pulmonary
embolism, but they are associated with
an increased 2-year risk of recurrent
deep venous thrombosis. Therefore,
full anticoagulation should be resumed
as soon as possible in patients with
chronic filters.[24]

Ongoing Treatment
Following the initial treatment of
VTE in general medical and surgical
patients, an oral vitamin K antagonist
is typically continued for at least
3 months in order to prevent recurrence.[
24] However, oral anticoagulation
is less successful in patients
with cancer. An inception cohort study
evaluated the long-term outcomes of
842 consecutive patients with VTE,
181 of whom had known cancer.[31]
All patients were treated initially with
either UFH or LMWH and subsequently
switched to oral anticoagulant
therapy dosed to maintain the INR
between 2 and 3 for 3 to 6 months
(notably, 56% of patients with malignancy
continued oral anticoagulation
for longer than 6 months). The 12-
month cumulative incidence of recurrent
VTE was 20.7% in the cancer
patients, compared to only 6.8% in
patients without malignancy (hazard
ratio [HR]: 3.2; 95% confidence interval
[CI]: 1.9-5.4). Major bleeding
occurred in 12.4% of patients with
malignancy, compared to only 4.9%
of patients without malignancy (HR:
2.2; 95% CI: 1.2-4.1).

Other studies of cancer patients
whose vitamin K antagonist therapy
was managed in dedicated anticoagulation
clinics have found similar significantly
high rates of recurrent
thrombosis and major bleeding compared
to patients without cancer, as
well as high rates of warfarin-related
emergency room visits and hospital
admissions.[32]

Several clinical trials have compared
oral anticoagulation to LMWH
for the long-term management of VTE
in patients with malignancy. In a small
open-label study, 138 cancer patients
with VTE were randomized to receive
enoxaparin, 1.5 mg/kg once daily, or
enoxaparin followed by warfarin
dosed to an INR of 2 to 3.[33] After
3 months of therapy, patients who received
enoxaparin for the full treatment
course had a trend toward fewer
major bleeding events (7.5% vs
16.9%; P = .09) and a lower mortality
rate (11.3% vs 22.7%; P = .07) compared
to patients who received warfarin.
Unfortunately, this trial was
underpowered to reveal statistically
significant differences in these outcomes.
In addition, the number of
symptomatic, objectively confirmed
recurrent thromboembolic events (2 vs
3 events, respectively) were too infrequent
to see a difference between the
two treatment groups. Nonetheless, it
suggested a benefit of LMWH over
warfarin in the long-term treatment of
VTE in patients with malignancy.

The Comparison of Low-molecular-
weight heparin vs Oral anticoagulant
Therapy (CLOT) study provides
the most substantive evidence of the
benefits of LMWH over warfarin for
the continued management of VTE in
patients with cancer.[29] In this trial,
672 patients with malignancy and new
onset VTE were randomized to dalteparin,
200 U/kg once daily for a month,
followed by 150 U/kg once daily for
5 months, or to dalteparin, 200 U/kg
once daily for 5 to 7 days, with concurrent
acenocoumarol or warfarin, dosed
to an INR of 2 to 3, and continuation of
the coumarin derivative alone for a total
of 6 months. Symptomatic, recurrent
VTE occurred in 9% of patients
treated with long-term dalteparin compared
to 17% treated with an oral anticoagulant
(P = .002). This study did
not find a difference in major bleeding
(6% vs 4%) nor in 6-month mortality
(39% vs 41%) for the two treatment
groups, respectively. However, a post
hoc analysis revealed a significant difference
in 12-month mortality among
patients with nonmetastatic disease
treated with dalteparin vs coumarin
(20% vs 36%; HR: 0.50; 95% CI: 0.27-
0.95; P = .03).[34]

These studies indicate that LMWHs
are superior to warfarin in protecting
against recurrent events and improving
survival after cancer-associated thrombosis.
As a possible explanation, there
is growing evidence that at least some
LMWHs have anti-inflammatory and
antiangiogenic properties that are not
provided by warfarin or UFH.[35] On
a practical level, LMWHs are easier to
manage because dosing is based on
weight, laboratory monitoring is not
required, and the short half-life facilitates
adjustments during thrombocytopenic
periods. LMWHs can also be
safely interrupted for invasive procedures
or surgery without the need for
complicated "bridging" protocols.
Based on recent evidence, the current
ACCP guidelines recommend that patients
with cancer-associated thrombosis
receive therapeutic LMWH for 3 to
6 months (Table 3).[24]

It remains to be seen how quickly
clinical practice patterns will change
toward uniform use of long-term
LMWHs for secondary prevention of
VTE. The cost of LMWHs may be a
deterrent for health-care plans that limit
coverage and reimbursement for drug
expenses. In addition, it is unknown
whether LMWHs are superior to warfarin
for long-term treatment of CVCassociated
thrombosis or for secondary
prevention in patients with hematologic
malignancies, such as myeloma, lymphomas,
essential thrombocythemia,
polycythemia vera, or PNH. A recent
international survey of nearly 4,000
physicians who treat cancer patients
found that LMWH was the most common
choice for the initial treatment of
VTE, but oral anticoagulation was favored
as long-term treatment in the setting
of malignancy.[36]

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