review Cancer and thrombosis: implications of published guidelines for clinical practice

review
Annals of Oncology 20: 1619–1630, 2009
doi:10.1093/annonc/mdp068
Published online 26 June 2009
Cancer and thrombosis: implications of published
guidelines for clinical practice
A. A. Khorana*
Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
introduction
Venous thromboembolism (VTE), which includes both deep
vein thrombosis (DVT) and pulmonary embolism (PE), is the
second leading cause of death in hospitalized and ambulatory
cancer patients [1–3]. Compared with patients who do not have
cancer, oncology patients are at substantially higher risk for
new and recurrent VTE [4–7]. The risk of VTE in cancer
patients is particularly increased for those who are undergoing
surgery (three- to fivefold) [2], those who are receiving
chemotherapy (6.5-fold) [6], those who carry certain genetic
mutations [8], and those with previous DVT [9]. The increased
risk of recurrent VTE in cancer patients is greatest in the
first few months after malignancy is diagnosed [8] and can
persist for many years after an initial episode of symptomatic
DVT [9].
VTE may itself be a sign of occult malignancy [10, 11]. In
a series of patients hospitalized for bilateral DVT, 25% were
known to have cancer at admission, and new cancer was
diagnosed in 26% of those without known cancer at admission
[10]. Of note, 62% of the known cancers and 70% of the new
*Correspondence to: Dr A. A. Khorana, James P. Wilmot Cancer Center, University of
Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 704,
Rochester, NY 14642, USA. Tel: +1-585-275-4797; Fax: +1-585-273-1042;
E-mail: [email protected]
cancers had already metastasized. The odds of cancer in this
series were nearly five times higher for patients with idiopathic
thrombosis than for those with secondary thrombosis [10].
VTE also adversely affects quality of life. In a study assessing
the effect of VTE on the Short Form-36 physical component
summary (PCS) and mental component summary scores, the
mean PCS scores among patients with VTE were lower than
those in the general population at baseline, 1 month, and 4
months [12]. In fact, the mean PCS scores were lower in these
patients at 1 month than in patients who have arthritis or
chronic lung disease.
Given that patients requiring treatment for DVT are often
hospitalized initially, the management of DVT also adds
considerably to healthcare resource use [13]. Early or late
complications of VTE can extend the hospital stay by 7–11
days, adding a mean $1784 (2002 USD) per day to
hospitalization costs [13]. Costs associated with bleeding
complications of DVT are particularly high: a mean hospital
stay of 18 days and hospital costs of $43 187 (2002 USD) [13].
Acknowledging the significant impact of VTE, the American
Society of Clinical Oncology (ASCO) [14], the American
College of Chest Physicians (ACCP) [15], and the National
Comprehensive Cancer Network (NCCN) [16] have all recently
issued clinical practice guidelines for the prevention and
treatment of cancer-associated thrombosis. Despite these
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
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Cancer is a frequent finding in patients with thrombosis, and thrombosis is much more prevalent in patients with
cancer, with important clinical consequences. Thrombosis is the second most common cause of death in cancer
patients. Venous thromboembolism (VTE) in cancer is also associated with a high rate of recurrence, bleeding,
a requirement for long-term anticoagulation, and worsened quality of life. Risk factors for cancer-associated VTE
include particular cancer types, chemotherapy (with or without antiangiogenic agents), the use of erythropoietinstimulating agents, the presence of central venous catheters, and surgery. Novel risk factors include platelet and
leukocyte counts and tissue factor. A risk model for identifying cancer patients at highest risk for VTE has recently been
developed. Anticoagulant therapy is safe and efficacious for prophylaxis and treatment of VTE in patients with cancer.
Available anticoagulants include warfarin, heparin, and low-molecular weight heparins (LMWHs). LMWHs represent
the preferred therapeutic option for VTE prophylaxis and treatment. Their use may be associated with improved
survival in cancer, although this issue requires further study. Despite the significant burden imposed by VTE and the
availability of effective anticoagulant therapies, many oncology patients do not receive appropriate VTE prophylaxis as
recommended by practice guidelines. Improved adherence to guidelines could substantially reduce morbidity,
decrease resource use, enhance quality of life, and improve survival in these patients.
Key words: anticoagulant, cancer, heparins, thromboembolism, thrombosis, warfarin
review
Received 12 August 2008; revised 2 February 2009; accepted 23 February 2009
review
guidelines, however, many oncology patients do not receive
appropriate VTE prophylaxis and treatment. In a recent
registry, for example, only 45% of 1735 patients with cancer
received thromboprophylaxis according to the ACCP
guidelines [17]. In a larger multinational survey of VTE
prophylaxis, only 59% and 40% of surgical and medical
patients, respectively, in 32 countries received ACCPrecommended therapies [18]. Finally, a recent survey of
providers found that oncologists consider thromboprophylaxis
routinely for <5% of their medical oncology patients [19].
These findings highlight the need for increased education about
the burden imposed by VTE and the optimal approach to
managing this condition.
This article reviews the association between thrombosis and
cancer, discusses novel prevention and treatment regimens,
and describes the impact of recently published guidelines on
clinical practice.
mechanisms and risk factors for
cancer-associated thrombosis
anticancer therapies
Many common antineoplastic treatment modalities carry an
increased risk of thrombotic events. Large population-based
studies involving groups of pooled cancer patients have
demonstrated a significantly increased risk in patients
undergoing chemotherapy. In a population-based study of
patients with a new diagnosis of VTE, there was a significantly
increased risk of VTE in those who were receiving
chemotherapy [odds ratio (OR) 6.5, confidence interval (CI)
2.11–20] [6]. In a large retrospective cohort of cancer patients,
patients receiving chemotherapy were at significantly higher
risk for VTE than were patients not receiving chemotherapy
(OR 2.3 and 2.0, respectively) [26].
1620 | Khorana
Studies in specific types of cancer and with specific
antineoplastic agents have also supported the role of
chemotherapy in predicting the risk of cancer-associated VTE.
In prospective studies of breast cancer patients, the risk of VTE
in patients receiving chemotherapy in addition to tamoxifen or
surgery was increased two- to sevenfold [27, 28]. A recent
meta-analysis of breast cancer patients revealed that use of
adjuvant hormonal therapy was associated with a 1.5- to
sevenfold increased risk of VTE [29].
More recently, antiangiogenic agents have been associated
with particularly high rates of thrombosis. Thalidomide and
lenalidomide do not significantly increase the risk of
thrombosis when used alone for the treatment of newly
diagnosed or refractory or relapsed multiple myeloma; reported
rates of VTE range from 2% to 4% [30, 31]. However, when
these agents are combined with steroids, melphalan,
doxorubicin, or other chemotherapeutic agents, much higher
rates of VTE have been reported, ranging from 8% to 27%
[32, 33]. Rates as high as 43% have been reported among adults
receiving thalidomide and chemotherapy for renal cell
carcinoma [34]. High rates of cancer-associated VTE have also
been reported in patients with colon and gastric cancers who
are receiving antiangiogenic agents [35237]. In a recent metaanalysis of clinical trials of bevacizumab in combination with
chemotherapy or interferon across a variety of cancers, the use
of bevacizumab was associated with a 33% relative increase
in the risk of VTE [38]. This finding contradicts that of an
earlier pooled analysis of clinical trials [39]. However, the later
meta-analysis included a larger study population, and its
findings were consistent with data from nonrandomized studies
of bevacizumab and with the known increased risk of VTE
associated with antiangiogenic inhibitors as a class. This
increased risk of VTE must be considered in the context of the
known increased risk of serious bleeding events with
bevacizumab. The risk–benefit ratio of prophylaxis for patients
receiving bevacizumab will have to be evaluated in
a prospective clinical study before changes in clinical practice
can be recommended [39].
The mechanisms behind the risk of thromboembolic events
with these treatment strategies are poorly understood. Many of
these therapies do induce vascular damage, either directly or
indirectly, thereby promoting local activation of the
coagulation process.
risk factors for cancer-associated thrombosis
Potential risk factors for VTE can be divided into patient-,
cancer-, and treatment-related characteristics [40]. Patientrelated factors include advanced age, female sex, black ethnicity,
comorbid conditions, and prothrombotic mutations. Tumorrelated factors relate to the site, stage, and duration of cancer.
Treatment-related factors include both pharmacologic agents
[e.g. chemotherapeutic agents, hormonal agents, antiangiogenic
agents, and erythropoiesis-stimulating agents (ESAs) and
mechanical causes, e.g. surgery and central venous catheters
(CVCs)]. Most recently, the predictive relationship between
cancer-related thrombosis and biomarkers has been
investigated, with pretreatment platelet and leukocyte counts
showing promise as predictors, in addition to TF expression,
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hemostasis, tissue factor, and angiogenesis
The hemostatic system is known to influence tumor
angiogenesis, which is critical to the growth of solid tumors
[20]. In particular, the expression of tissue factor (TF) by
tumor or stromal cells results in a generally procoagulant
tumor microenvironment [21]. TF expressed in this manner is
a procoagulant and can directly activate factor X; TF released
by monocytes or macrophages can induce activation of
factor VII [22].
TF also may stimulate angiogenesis both directly, by means
of signaling through cytoplasmic tails, and indirectly, through
generation of thrombin and interaction with protease-activated
receptors. In a recent retrospective analysis, TF was expressed
in both noninvasive and invasive pancreatic neoplasms, but
not in normal pancreatic cells [23]. TF expression in cancer
cells was correlated with expression of vascular endothelial
growth factor and increased microvessel density, which
suggested linkage with angiogenesis. More important, VTE was
significantly more frequent among patients with high levels
of TF expression in resected tumor specimens than among those
with low levels (26.3% versus 4.5%; P = 0.04) [23]. High levels of
TF expression have also been shown to predict poor prognosis in
patients with ovarian [24] and pancreatic cancers [25].
Annals of Oncology
review
Annals of Oncology
inflammatory status as measured by C-reactive protein, and
markers of platelet activation [40].
Recently, a predictive model was shown to discriminate
between outpatients with a low, intermediate, or high risk of
chemotherapy-associated thrombosis (Table 1) [41]. The final
model, which had a C-statistic of 0.7 for both the test
(n = 2701) and validation (n = 1365) cohorts, included five
variables: (i) high-risk cancer site (two points for very high-risk
sites and one point for high-risk sites); (ii) platelet count
‡350 000/mm3, (iii) hemoglobin concentration <10 g/dl, or use
of ESAs, or both; (iv) leukocyte count >11 000/mm3; and (v)
body mass index ‡35 kg/m2 (one point for each). In the
validation cohort, the incidence of VTE over a median 2.5
months of follow-up was 0.3% among patients with a score of
0, 2% among those with a score of 1 or 2, and 6.7% among
those with a score of 3 or higher [41]. Such a model might be
used to identify patients who are clinically at high risk for VTE.
The National Heart, Lung, and Blood Institute has recently
funded a prophylaxis study for cancer outpatients identified as
high risk on the basis of this predictive model.
general considerations: warfarin
For >50 years, warfarin anticoagulation has been a standard
treatment for prophylaxis and treatment of VTE. For treatment
of VTE, it has typically been given after initial therapy with
unfractionated heparin (UFH) or, more recently, a lowmolecular weight heparin (LMWH) [42].
Although efficacious, warfarin has several important
limitations to its use. The first is that its dosing can be difficult,
particularly because of its slow onset (the anticoagulant effect
Table 1. Predictive model for calculating risk of chemotherapyassociated thrombosisa
Patient characteristics
Site of cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic,
genitourinary excluding prostate)
Low risk (breast, colorectal, head and
neck)
Prechemotherapy platelet count
‡350 000/mm3
Hemoglobin level <10 g/dl or use of red
cell growth factors
Prechemotherapy leukocyte count
>11 000/mm3
BMI ‡35 kg/m2
a
Odds ratio
(95% CI)
VTE risk
score
4.3 (1.2–15.6)
1.5 (0.9–2.7)
2
1
1.0 (reference)
1
1.8 (1.1–3.2)
1
2.4 (1.3–4.2)
1
2.2 (1.2–4)
1
2.5 (1.3–4.7)
1
Shown are multivariate analysis-identified variables independently
associated with the risk of VTE and corresponding risk scores calculated on
the basis of the risk model [41].
CI, confidence interval; VTE, venous thromboembolism; BMI, body mass
index.
Volume 20 | No. 10 | October 2009
general considerations: UFH
UFH has been used for >40 years in the prevention and
treatment of VTE. The heparin species contain
a pentasaccharide sequence, which binds to antithrombin and
enhances heparin’s ability to inhibit both thrombin and factor
Xa. UFH can be given either s.c. or i.v., and its effects can be
reversed with protamine sulfate. A potential complication
associated with UFH administration is the development of
heparin-induced thrombocytopenia [52].
Subcutaneous low-dose UFH is commonly used for
thromboprophylaxis in medical and surgical cancer patients.
A meta-analysis of 29 trials of surgical patients who received
UFH, 919 of whom had cancer, showed a significant reduction
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prevention and treatment of VTE in
cancer patients
may not reach its peak until after 72–96 h) and slow clearance
from the body (duration of action, 2–5 days) [43]. Warfarin use
also can be a burden to patients. The most recent guidelines for
management of VTE from the NCCN recommend dosing of
long-term warfarin therapy to achieve a target international
normalized ratio (INR) of 2.0–3.0 [16]. Thus, patients must
undergo frequent blood sampling in an attempt to maintain
adequate, but not excessive, dosing.
Achievement of the target INR with oral warfarin may be
more difficult in cancer patients than in those without cancer
[44], especially in view of the anorexia and emesis common
in patients with cancer [45, 46]. Cancer patients require
frequent interruption of anticoagulation for procedures, which
further compounds the difficulty of warfarin dose management.
In one large randomized trial, the INR was within the target
range in the warfarin group only 46% of the time [47]. Even
when the INR is within the target range, however, VTE can
still occur [4]. Cancer is often suspected as a contributing cause
in such cases of ‘warfarin failure’ [48].
Furthermore, interactions between chemotherapeutic agents,
particularly 5-fluorouracil (5-FU)-based regimens and
warfarin, can add to the difficulty associated with maintaining
a therapeutic INR. A study assessing changes in the INR and
bleeding in cancer patients given minidose warfarin during
treatment with 5-FU-based regimens found a high incidence of
INR abnormalities and bleeding [49]. Another study in
patients with advanced cancer found a significant
pharmacokinetic interaction between capecitabine and
warfarin, resulting in exaggerated anticoagulant activity [50].
With warfarin treatment, as with all anticoagulant
treatments, there is an increased risk of bleeding, which may
be particularly pronounced in patients with cancer [4, 51]. In
a retrospective analysis of patients enrolled in two randomized
trials of UFH versus LMWH followed by warfarin treatment,
the risk of major bleeding was six times higher in patients with
cancer [51]. Moreover, the increased risk among cancer
patients did not appear to relate to the INR. Indeed, bleeding
complications occurred most often among patients in the
lowest INR category (INR £ 2.0) [51].
Finally, the anticoagulant effects of warfarin may be
influenced by interactions with nutrients and herbal
preparations as well [43]. Together, these factors can make the
use of warfarin therapy particularly challenging for clinicians
and patients in the oncologic setting.
review
in the incidence of VTE, from 30.6% in the group not receiving
prophylaxis to 13.3% in the UFH group [53]. Another metaanalysis of heparin studies in medical patients showed 56%
and 58% risk reductions in the incidence of DVT and clinical
PE, respectively, in the heparin group versus the control
group (P < 0.001) [54].
prophylaxis of VTE in hospitalized patients
with cancer
In randomized trials of VTE prophylaxis in various populations
of patients with cancer, the rates of VTE and DVT generally
have been significantly lower with LMWHs than with UFH or
placebo, without a significant increase in major bleeding (Table 2)
[56–63]. In these trials, the benefit of the LMWHs appeared to
be related to both the dose and the duration of treatment
[59, 60]. Three studies have assessed the benefits of LMWHs
in medical patients, although patients with malignancies
constituted only a minority of those enrolled [61, 63, 64]. Each
study reported a significant reduction in VTE with LMWH
compared with placebo; however, only one provided efficacy
data for the cancer subset. The reduction in the incidence of
VTE in this substudy was not statistically significant [7, 62].
The low bleeding rates observed with LMWH prophylaxis in
the three major medical trials strongly argue for pharmacologic
prophylaxis in hospitalized patients with cancer [61, 63, 64].
Unfortunately, none of these studies has published bleeding
rates specifically for the cancer subgroups of their populations.
Both the ASCO and NCCN guidelines support the use of
pharmacologic VTE prophylaxis in hospitalized cancer patients
unless one or more contraindications to prophylactic
anticoagulation are present. According to the ASCO guidelines,
relative contraindications to anticoagulation include active,
uncontrollable bleeding; active cerebrovascular hemorrhage;
1622 | Khorana
dissecting or cerebral aneurysm; bacterial endocarditis;
pericarditis, active peptic or other gastrointestinal ulceration;
severe, uncontrolled, or malignant hypertension; severe head
trauma; pregnancy (for warfarin); heparin-induced
thrombocytopenia; and epidural catheter placement [14].
According to the NCCN guidelines, relative contraindications
include recent central nervous system bleeds; intracranial or
spinal lesions at high risk for bleeding; active bleeding (more
than two units transfused in 24 h); chronic, clinically significant
measurable bleeding (>48 h); thrombocytopenia (<50 000/
mm3); severe platelet dysfunction; recent operation at high risk
for bleeding; underlying coagulopathy [clotting factor
abnormalities or lengthening of prothrombin time or activated
partial thromboplastin time); spinal anesthesia or lumbar
puncture; and high risk for falls [16].
Although both the ASCO and NCCN recommend VTE
prophylaxis for cancer patients throughout the duration of
hospitalization, cancer patients are known to remain at risk for
VTE after hospital discharge. The NCCN guidelines
acknowledge that the risk of VTE is sufficiently high in some
medical and surgical oncology patients to warrant extended
VTE prophylaxis in the outpatient setting [16]. Based on data
from two large studies of prolonged prophylaxis in the surgical
setting, the ASCO guidelines recommend that prophylaxis for
up to 4 weeks be considered in patients undergoing major
abdominal or pelvic surgery for cancer who have risk factors for
VTE (e.g. a residual tumor after operation, obesity, or a history
of VTE) [57, 60].
prophylaxis of VTE in ambulatory patients
with cancer
Subgroups of ambulatory cancer patients may have rates of
VTE as high as those in hospitalized medical or surgical
patients. Indeed, owing to shifts in the care of cancer patients
from the hospital setting to the ambulatory setting, a high
percentage of VTE events currently occur in the outpatient
setting. Prophylaxis may therefore be beneficial in such groups.
In the earliest randomized study of VTE prophylaxis in
ambulatory cancer patients, low-dose warfarin or placebo was
administered to 311 women receiving therapy for metastatic
breast cancer [65]. There were seven events in the placebo
group, but only one in the warfarin group [relative risk
reduction (RRR) 85%; P = 0.03]. Unfortunately, subsequent
trials have failed to confirm the benefit of prophylaxis in the
ambulatory setting. The TOPIC-1 and TOPIC-2 studies
evaluated LMWH prophylaxis in patients with metastatic breast
cancer (n = 353) and patients with stage III or IV non-small-cell
lung carcinoma (n = 547), respectively [66]. Patients were
randomly assigned to receive either certoparin (3000 U daily)
or placebo for 6 months, and all underwent screening
ultrasonography every 4 weeks. Over the 6 months of
treatment, the rates of major bleeding complications in breast
cancer patients were 1.7% in the LMWH arm and 0% in the
placebo arm. The rates of major bleeding complications in lung
cancer patients were 3.7% in the LMWH arm and 2.2% in the
placebo arm. LMWH showed a nonsignificant trend toward
effectiveness, with a VTE rate of 4.5% among lung cancer
patients, compared with 8.3% for placebo (P = 0.07). Similar
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general considerations: LMWHs
LMWHs were developed to overcome some of the limitations
of UFH—namely, the variable anticoagulant effects, the low
bioavailability, the need for frequent monitoring, the longer
time of onset, and the variable pharmacokinetics [55]. Because
warfarin has known limitations as well (described previously),
especially for patients with cancer, the role of LMWHs in longterm anticoagulant treatment also has been investigated.
Compared with UFH, LMWHs have more predictable
pharmacokinetics and greater bioavailability. Thus, a weightadjusted dose of a LMWH can be given by s.c. injection once or
twice daily without laboratory monitoring in most patients
[55]. These agents have been shown to be safe and efficacious in
numerous clinical situations and are recommended by the
ACCP for thromboprophylaxis in moderate- and high-risk
surgical patients [15], for postdischarge prophylaxis in highrisk surgical patients (including those who have undergone
cancer surgery) [15], for initial short-term treatment of DVT in
general patient populations [55], and for the first 3–6 months
of long-term anticoagulation in patients with DVT and cancer
[55]. The drawbacks of LMWHs include the need for daily
injection, with the attending risk of local injury, and the higher
direct costs, although overall costs are lower with LMWHs than
with UFH because LMWHs can be administered at home [55].
Annals of Oncology
Study
n
Follow-up
Population
Interventions
VTE
Major bleeding
Surgical patients
Bergqvist et al. [56]
2070
30 days
Dalteparin 5000 IU q.d.,
dalteparin 2500 IU q.d.
8.5%a, 14.9%; P < 0.001
4.6%b, 3.6%; P = NS
ENOXACAN [57]
631
3 months
Elective abdominal
surgery for cancer
(66.4% of patients
had surgery as result
of a malignant
disorder)
Elective cancer surgery
14.7%, 18.2%
McLeod et al. [58]
475
10 days
Bergqvist et al.
(ENOXACAN II) [59]
332
31 days,
3 months
Enoxaparin 40 mg q.d.,
UFH t.i.d.
Enoxaparin 40 mg q.d.,
heparin 5000 U t.i.d.
Enoxaparin 40 mg q.d. ·
6–10 days, then enoxaparin
40 mg q.d. or placebo ·
19–21 days
Dalteparin 5000 IU q.d. ·
1 week, dalteparin
5000 IU q.d. · 4 weeks
Partial or total bowel
resection
Planned surgery for
abdominal or pelvic
cancer
198a
4 weeks
Major abdominal
surgery for cancer
849 [131 cancer
patients (15.4%)]
6–14 days
Immobilized medical
inpatients
MEDENOX 2003 [62]
118a
6–14 days
Immobilized medical
inpatients
PREVENT 2004 [63]
3706 [190 cancer
patients (5.1%)]
21 days
Immobilized medical
inpatients
Rasmussen et al.
(FAME) [60]
Medical patients
ARTEMIS 2006 [61]
Fondaparinux 2.5 mg
q.d. · 14 days,
placebo · 6–14 days
Enoxaparin 40 mg
q.d. · 6–14 days,
placebo · 6–14 days
Dalteparin 5000 IU q.d. ·
14 days, placebo · 14 days
Mortality
13.9%, 16.9%;
P = 0.052
E/E 4.8%, E/P 12%,
P = 0.02; E/E 5.5%,
E/P 13.8%, P = 0.01
NR
NR
E/E 0.8%, E/P 0.4%,
P > 0.99; E/E 1.2%,
E/P 0.4%, P = 0.62
E/E 0%, E/P 0%;
E/E 1.8%, E/P 3.6%
19.6%b, 8.8%; P = 0.03
NR
NR
5.6%, 10.5%;
P = 0.029
0.2%, 0.2%
3.3%, 6%
9.7%, 19.5%;
P = 0.4
NR
NR
2.77%, 4.96%;
P = 0.0015
0.49%, 0.16%
2.35%, 2.32% (day 21)
Annals of Oncology
Volume 20 | No. 10 | October 2009
Table 2. Studies of venous thromboembolism prophylaxis in patients with cancer
a
Rates shown are for deep vein thrombosis.
Rates shown are for any bleeding.
E/E, enoxaparin followed by enoxaparin; E/P, enoxaparin followed by placebo; q.d., each day; t.i.d., three times daily; NR, not reported; NS, not significant; UFH, unfractionated heparin; VTE, venous
thromboembolism.
b
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1624 | Khorana
Recurrent VTE or death possibly related to pulmonary embolism.
Subgroup analysis of the overall trial population.
c
Composite of major bleeding or recurrent VTE.
d
Six patients died of bleeding complications.
e
Except in Spain and The Netherlands, where acenocoumarol was used.
b.i.d., twice daily; DVT, deep vein thrombosis; HD, high dose; LD, low dose; NR, not reported; PE, pulmonary embolism; q.d., each day; T, tinzaparin; UFH, unfractionated heparin; VTE, venous
thromboembolism; W, warfarin.
122
Deitcher et al.
(ONCENOX) [75]
b
T 6%, W 10%; T 7%,
W 16%; P = 0.04
LD 6.9%; HD 6.3%;
W 10%
200
Hull et al. (LITE) [74]
3 months,
12 months
3 months
Symptomatic acute DVT
and/or PE
Symptomatic acute proximal
vein thrombosis
Symptomatic VTE
6 months
672
a
LD 6.5%; HD 11.1%;
W 2.9%
T 20%, W 19%;
T 47%, W 47%
LD 22.6%; HD 41.7%;
W 32.4%
T 7%, W 7%
41%, 39%; P = 0.53
15.8%, 8.0%; P = 0.002
Dalteparin q.d. · 5–7 days + warfarine ·
6 months, dalteparin q.d. · 6 months
Tinzaparin; UFH + warfarin · 6 days,
then warfarin
Enoxaparin · 5 days, then; LD
enoxaparin; HD enoxaparin;
warfarin
6%, 4%; P = 0.27
NR
11.3%, 22.7%; P = 0.07
1.3%, 1.7%, 2.1%
7%, 16%d; P = 0.09
6.4%, 12.2%, 6.7%
10.5%c, 21.1%c; P = 0.09
Enoxaparin b.i.d., enoxaparin q.d., UFH
Enoxaparin, warfarin
3 months
3 months
141b
146
Symptomatic DVT
PE or DVT
1.2%, 1.3%
Mortality
Major bleeding
VTE
7.2%a, 4.1%a
Agents
Nadroparin b.i.d., nadroparin q.d.
Proximal DVT
Population
3 months
Charbonnier et al.
(FRAXODI) [71]
Merli et al. [72]
Meyer et al.
(CANTANOX) [73]
Lee et al. (CLOT) [47]
Follow-up
–
n
Study
Table 3. Studies of venous thromboembolism treatment in patients with cancer
treatment of VTE in patients with cancer
Several studies have addressed treatment of VTE in patients
with cancer (Table 3) [47, 71–75]. To date, the CLOT
(Comparison of Low-Molecular-Weight Heparin Versus Oral
Anticoagulant Therapy for the Prevention of Recurrent Venous
Thromboembolism in Patients with Cancer) study, which
compared dalteparin with vitamin K antagonist (VKA) therapy,
is the largest randomized trial of VTE treatment in patients
with cancer (n = 672) [47]. This study reported a 52% RRR in
the incidence of recurrent VTE in favor of dalteparin: during
the 6-month study period, 27 of 336 patients in the dalteparin
group had recurrent VTE versus 53 of 336 patients in the VKA
group (P = 0.002) (Table 3) [47]. No significant differences in
the rates of major bleeding or any bleeding were observed
between the two groups. Dalteparin is currently the only
LMWH approved by the United States Food and Drug
Administration for extended treatment of symptomatic VTE to
reduce the recurrence of VTE in patients with cancer.
Three additional studies assessed the use of LMWH for
extended VTE treatment in patients with cancer. The
CANTHANOX (Secondary Prevention Trial of Venous
Thrombosis with Enoxaparin) study compared 3 months of
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trials in patients with glioma also have not shown
thromboprophylaxis to be beneficial [67].
Results from the PROTECHT study, a large Italian study of
prophylaxis in the ambulatory setting, were recently presented
[68]. The study randomly assigned >1100 cancer patients
undergoing chemotherapy to receive either nadroparin (3800
IU s.c. once daily) or placebo. Prophylaxis began at the
initiation of chemotherapy and lasted throughout
chemotherapy treatment or up to 4 months. At the 12-month
follow-up, fewer thromboembolic events had occurred in the
nadroparin arm than in the placebo arm (2.0% versus 3.9%).
Furthermore, patients with lung or pancreatic cancer were
more likely to experience thromboembolic events than were
patients with breast, gastrointestinal, ovarian, or head and neck
cancers, which suggested that these patient groups may benefit
from LMWH prophylaxis. Given the conflicting data from
clinical trials and the known risk of bleeding in the cancer
population, prophylaxis is not currently recommended even for
high-risk ambulatory cancer patients, although these
recommendations may change as new data emerge.
One exception to this policy is the high-risk ambulatory
group comprising patients with multiple myeloma who are
receiving thalidomide- or lenalidomide-based combination
therapy. The current consensus, based on nonrandomized
studies, is that all newly diagnosed patients treated with
thalidomide- or lenalidomide-containing regimens should
receive thromboprophylaxis [14, 16]. Fixed low-dose warfarin
(1–2 mg) has been modestly effective at decreasing VTE rates in
patients receiving thalidomide with dexamethasone but has
been ineffective in patients receiving thalidomide with
chemotherapy [33, 69]. The use of prophylactic LMWH has
been shown to eliminate the excess VTE risk resulting from
adding thalidomide to doxorubicin-containing chemotherapy
regimens [33, 70]. Unfortunately, phase III studies have not
been carried out in this setting.
NR
Annals of Oncology
review
Annals of Oncology
long-term central venous catheters and
VTE in cancer patients
Rates of DVT among patients with a CVC in place have ranged
from 11.7% to 66% [77, 78]. These are higher than the rates
reported for mechanical or septic complications of CVCs [77].
The risk of thromboembolic complications appears to peak
within 4– 8 weeks after CVC placement [77, 78].
In cancer patients, CVCs can be associated with upper limb
DVT [79]. Thrombosis tends to develop ipsilaterally to the
catheter [77] and may be more prevalent in subclavian veins
than in innominate veins or venae cavae [78]. It is noteworthy
that most cancer patients with CVC-related thrombosis are not
symptomatic [77, 78].
CVC-related DVT can result in significant morbidity and
mortality. In a study of 86 consecutive patients with CVCrelated DVT, 15% of the patients were considered to have PE
[80]. Moreover, two of these patients died despite receiving
adequate heparin therapy.
No definite value has been established for prophylaxis of
CVC-related thrombosis in cancer patients. Although some
Volume 20 | No. 10 | October 2009
studies and meta-analyses have reported a benefit [81, 82],
more recent studies have not [83–85]. It may be that the sample
sizes of these studies were too small to permit detection of
significant differences between treatment groups [85].
ASCO, NCCN, and ESMO guidelines and
impact on clinical practice
Recent guidelines from the ASCO [14], the NCCN [16], and
the European Society for Medical Oncology (ESMO) [86]
recommend consideration of the use of anticoagulants in the
following groups:
All hospitalized adults (medical or surgical) who have known
or suspected cancer, for prophylaxis against VTE [14, 16].
The ESMO guidelines, however, restrict this recommendation
of prophylactic anticoagulation to hospitalized cancer
patients confined to bed. The ASCO guidelines also call for
the prophylactic use of anticoagulants in outpatients
receiving thalidomide or lenalidomide with chemotherapy or
dexamethasone [14, 86].
Cancer patients undergoing major cancer surgery. The ESMO
guidelines recommend prophylaxis with LMWH or UFH
[86].
Patients with cancer and established VTE, to prevent
recurrence of thromboembolic events [14, 16, 86].
In general, unless there is a contraindication, hospitalized
patients with cancer should be considered candidates for VTE
prophylaxis with anticoagulants (Table 4) [14, 16]. Routine
prophylaxis during outpatient chemotherapy is not indicated in
most cases [14, 86]. Mechanical techniques for
thromboprophylaxis (e.g. graduated compression stockings,
intermittent pneumatic calf compression, and mechanical foot
pumps) should be the sole method of prophylaxis only when
the patient has a contraindication to pharmacologic
anticoagulation [14].
For cancer patients with established VTE, initial therapy
should consist of either LMWH given for 5– 10 days [14, 16] or
UFH [86]. LMWH should also be used for long-term therapy
(‡6 months) to prevent recurrent VTE. A VKA may be used if
LMWHs are not available, with the dosage adjusted to achieve
an INR of 2.0–3.0. Indefinite anticoagulant prophylaxis should
be considered for high-risk patients, such as those with
metastatic disease and those receiving chemotherapy [14, 86].
The ESMO guidelines also recommend both VKAs and
LMWHs for treatment of VTE in patients with cancer, giving
the two regimens an equal-strength recommendation [86].
A vena cava filter is indicated only for patients with
contraindications to anticoagulants or patients with recurrent
VTE despite adequate long-term therapy with LMWH [14].
It is worth noting that even though guidelines
recommending anticoagulant prophylaxis and treatment have
been in place for years, only about half of the candidate patients
receive appropriate anticoagulation [17, 18]. Further,
oncologists consider routine thromboprophylaxis for only
a minority of their patients (<5% in one survey) [19].
Publication of guidelines for thromboprophylaxis, by itself,
may not be sufficient to change routine clinical practice;
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warfarin therapy with 3 months of enoxaparin therapy in
patients with malignancy and proximal DVT or PE [73].
Because of slow recruitment, the study was terminated
prematurely after 147 patients have been randomly assigned to
therapy. At 3 months, seven patients in the enoxaparin group
had recurrent VTE or major bleeding (the combined primary
end point) versus 15 patients in the warfarin group (P = 0.09).
Most of the primary outcomes were due to major bleeding (five
patients in the enoxaparin group versus 12 in the warfarin
group). In the warfarin group, six of the patients died of major
bleeding, and at the 6-month follow-up, 31% of patients in the
enoxaparin group had died, compared with 38.7% of patients
in the warfarin group (P = 0.25). These findings suggest that
warfarin may be associated with a higher risk of bleeding than
LMWH is when used as long-term VTE treatment in patients
with cancer [73].
The three-arm ONCENOX (Secondary Prevention Trial of
Venous Thrombosis with Enoxaparin) study included 101
patients with cancer and VTE. Because of the small number of
patients enrolled, no differences between the enoxaparin and
warfarin groups were observed with regard to the incidence of
recurrent VTE, major bleeding, or death [75].
The LITE (Long-Term Innohep Treatment Evaluation) study
found tinzaparin to be more efficacious than warfarin in 200
patients with cancer [74]. Tinzaparin treatment reduced the
rate of recurrent VTE by 50%; however, the difference was
not statistically significant at the end of the 3-month treatment
period. There were no differences in bleeding rates between the
two groups.
Compared with warfarin, LMWHs generally reduce the
overall risk of recurrent VTE when used for the extended
treatment of VTE [55, 73–75], a finding confirmed by a recently
published Cochrane systematic review [76]. Furthermore,
LMWHs do not increase major bleeding rates and appear to be
as safe as VKAs. These findings, like those seen in the
prevention trials, appear to be related to the dose and the
duration of therapy.
review
Annals of Oncology
Table 4. Recommended anticoagulant regimens for venous thromboembolism prophylaxis and treatment in patients with cancer
Management phase
Dosage
Considerations
a
Prophylaxis
UFH
Dalteparin
Enoxaparin
Fondaparinux
Tinzaparin
Treatment: initialc
UFH
Dalteparin
5000 U s.c. every 8 h
5000 U s.c. daily
40 mg s.c. daily
2.5 mg s.c. dailyb
4500 U s.c. or 75 U/kg s.c. daily
80 U/kg i.v. bolus, then 18 U/kg/h i.v.d
100 U/kg s.c. every 12 h; 200 U/kg s.c. dailye
Enoxaparin
1 mg/kg s.c. every 12 h; 1.5 mg/kg s.c. dailye
Fondaparinux
<50 kg: 2.5–5 mg s.c. daily; 50–100 kg:
5–7.5 mg s.c. daily; >100 kg: 7.5–10 mg s.c. daily
175 U/kg s.c. daily
Tinzaparin
Treatment: long termf
Dalteparin
Warfarin
Significant renal clearance; avoid in
<35 ml/min or adjust dose based
Significant renal clearance; avoid in
<35 ml/min or adjust dose based
Significant renal clearance; avoid in
<35 ml/min or adjust dose based
patients with
on antifactor
patients with
on antifactor
patients with
on antifactor
creatinine clearance
Xa levels
creatinine clearance
Xa levels
creatinine clearance
Xa levels
200 U/kg s.c. daily · 1 month, then 150 U/kg s.c. daily
5–10 mg p.o. dailyg
additional interventions may be necessary [87]. In a study by
Kucher et al. [88], the implementation of a hospital-wide
computer alert program that warned physicians about patients
at risk for DVT increased the use of prophylaxis and
significantly reduced the rates of DVT and PE among the
hospitalized population. In another study, the use of a formal
continuing medical education program for prevention of VTE
did lead to some improvement in adherence, although
prophylaxis remained underused in the participating hospitals
[89]. This same study found that a formal quality assurance
program provided no additional benefit. Clearly, other
educational interventions are required to improve adherence to
thromboprophylaxis guidelines and thereby improve outcomes.
effects of VTE and cancer on survival
relation between cancer and survival after VTE
Thrombosis has long been known as the second leading cause
of death in cancer patients [90]. VTE is second only to infection
as a cause of death among hospitalized cancer patients,
contributing to as many as 18% of deaths in this population
[1]. One of every seven deaths among hospitalized cancer
patients is related to PE [19]. In one analysis, Medicare patients
who had concurrent VTE and malignancy had a 94%
probability of dying within 6 months, a probability that was
1626 | Khorana
three times higher than that of patients with VTE and no
malignancy [91].
Patients with concurrent VTE and cancer are also at higher
risk for other adverse outcomes. For example, the probability of
readmission for VTE within 6 months was almost four times
higher among Medicare patients with cancer than among
Medicare patients without malignancy [91]. DVT has also been
linked with negative quality-of-life measures in an inpatient
population, of whom 12.5% had active cancer as a risk factor
for VTE [12].
impact of antithrombotic therapy on survival after
VTE in patients with cancer
Some have speculated that thromboprophylaxis might improve
survival in patients with VTE and cancer. In fact, an early metaanalysis of 13 randomized trials of VTE treatment (in both
cancer and noncancer populations) found that the relative risk
of mortality was reduced by 25% with the use of LMWH as
compared with the use of UFH [92].
To date, four randomized trials have had sufficient statistical
power to detect a significant difference in 1-year survival
between cancer patients who received an LMWH and those
who received placebo or standard treatment (Table 5) [93–96].
Two of these studies showed a significantly longer median
survival time among patients treated with LMWH [94, 95]. In
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Adapted from NCCN [16] and Lyman 2007 [14].
a
Duration: until ambulatory or until hospital discharge.
b
Not approved by the U.S. Food and Drug Administration for this indication.
c
For 5–7 days minimum and until the INR is in the therapeutic range for two consecutive days if changing to warfarin.
d
Adjust to achieve PTT of 2–2.9 times control value.
e
Optimal dosing unclear in patients >120 kg.
f
Duration: minimum 3–6 months for DVT and 6–12 months for PE. LMWH monotherapy is preferred for treatment of proximal DVT or PE and prevention
of recurrent VTE in patients with advanced or metastatic cancer.
g
Adjust dose to achieve INR of 2.0–3.0.
DVT, deep vein thrombosis; INR, international normalized ratio; i.v., intravenously; LMWH, low-molecular weight heparin; PE, pulmonary embolism; p.o.,
per os (by mouth); PTT, partial thromboplastin time; s.c., subcutaneously; UFH, unfractionated heparin; VTE, venous thromboembolism.
review
141
Sideras et al. [96]
Design changed from randomized, double-blind, placebo-controlled trial to open-label versus standard care after 52 patients had been enrolled; grade 3–5 bleeding events and grade 3–4 thrombotic
complications assessed.
D, dalteparin; P, placebo; VTE, venous thromboembolism.
6%a; 7%
Dalteparin 5000 U; placebo/
standard carea
602
Lee et al. 2005 (CLOT
post hoc analysis) [97]
12 months
Advanced breast, prostate,
lung, colorectal cancer
1%; 2%
Metastasized or locally
advanced solid tumors
Solid tumors and acute VTE
302
Klerk et al. [95]
1 year
0%; 2.5%
Small-cell lung cancer
1 year
84
Altinbas et al. [94]
a
3%a; 7%
Probability of death—patients
without metastatic disease: 20%
(dalteparin) versus 36%
(warfarin), P = 0.03; patients
w/metastatic disease: 72%
versus 69%, P = 0.46
Median time of survival—D:
10.5 (7.6–12.2) months; P:
7.3 (4.8–12.2) months; P = 0.46
39%; 27%
3%; 1%
51.3%; 29.5%
0%; 0%
Survival
Major bleeding
0.5%; 0%
VTE
2.4%; 3.3%
Agents
Dalteparin 5000 IU daily ·
1 year; placebo · 1 year
Chemotherapy, dalteparin
5000 U daily; chemotherapy alone
Nadroparin (weight based)
l placebo
Dalteparin · 1 week + warfarin or
acenocoumarol for 6 months;
dalteparin · 6 months
Advanced malignancy
Population
Follow-up
Kakkar et al. [93]
1 year
n
385
Study
Volume 20 | No. 10 | October 2009
one of them, this difference persisted after adjustments were
made for life expectancy, performance status, type and
histology of cancer, and concomitant treatment [95].
Moreover, evidence suggests that thromboprophylaxis offers
particular benefit to patients with less aggressive or less
advanced malignancy. In a post hoc subgroup analysis of
patients with a better prognosis in one of the studies, survival
was significantly better with dalteparin than with placebo
(P = 0.03): 2-year survival estimates of 78% and 55%,
respectively, and 3-year estimates of 60% and 36% [93]. In
a prespecified analysis by life expectancy in another of these
trials, the hazard ratios with nadroparin versus placebo were
0.61 (95% CI 0.42–0.89) for patients expected to live for
6 months or longer and 0.82 (95% CI 0.51–1.29) for those
expected to live for <6 months [95]. In a retrospective analysis
of data from the CLOT study, patients without metastases had
a significantly lower 1-year mortality rate with dalteparin than
with oral anticoagulation (Kaplan–Meier estimates: 20% and
34.7%, respectively; P = 0.03), and this advantage persisted after
adjustment for differences in baseline risk factors [97]. In
contrast, among patients with known metastatic disease, the
estimates for 1-year mortality with dalteparin did not differ
significantly from those with oral anticoagulation (72% and
69%, respectively; P = 0.46). Again, these studies cannot
evaluate a direct antitumor effect of anticoagulation,
particularly LMWHs, although preclinical studies have
suggested such an effect [97].
A recent meta-analysis also showed that anticoagulants,
particularly LMWH, significantly improved overall survival in
cancer patients without VTE but also increased the risk of
bleeding complications. Fatal bleeding events were extremely
rare, however, and LMWHs appeared to have a more favorable
bleeding profile than VKAs did [98]. Nonetheless, a recent
Cochrane review showed that with respect to long-term
treatment of VTE in patients with cancer, LMWH treatment
reduced VTE as compared with VKA treatment but did not
reduce mortality [76]. This finding may be due to the study’s
lack of sufficient statistical power to detect a reduction in allcause mortality, even though the results might indicate a trend in
that direction. Additional well-designed randomized clinical
trials are necessary to address the impact of LMWH on survival
in cancer patients.
The mechanism by which LMWH might provide a survival
benefit, beyond the prevention of VTE, is not known. The
observation that LMWH exhibited a clearer advantage in the
second survival study [94] than in the first [93] might be
explained by the fact that small-cell lung cancer is known to
express a thrombin-generating pathway with local fibrin
formation [94]. Of note, a recent in vitro study suggests that
LMWHs may exert their antitumor effects through inhibition
of cell growth and proliferation [99]. This study showed that
that dalteparin inhibited pulmonary adenocarcinoma cell
viability in a dose- and time-dependent manner, caused G1
phase cell cycle arrest, and induced apoptosis. Another recent in
vitro study supports the role of LMWHs in inhibiting the
proangiogenic effect exerted by tumor cells [100]. This study
demonstrated that both dalteparin and enoxaparin inhibited
the tumor-promoted angiogenic potential of human
microvascular endothelial cells to a significantly greater degree
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Table 5. Survival trials of low-molecular weight heparin in patients with cancer
46%; 41%; P = 0.19
Annals of Oncology
review
than UFH did. These results are consistent with those of another
study, which showed that the 6-kDa LMWH fraction inhibited
the proliferation of human umbilical vein endothelial cells
significantly more than either UFH or 3-kDa LMWH did. No
inhibition of proliferation was observed with heparin
tetrasaccharide, octasaccharide, or pentasaccharide
(fondaparinux) [101]. Because the 6-kDa fraction, which exerted
maximum endothelial inhibitory effects, is similar to LMWHs
currently in clinical use, which range from 4 to 5.5 kDa, its
antiproliferative effect on endothelial cells may be relevant to the
biology of malignancy and may explain the therapeutic effect of
LMWHs on survival in cancer patients. Further clinical research
is needed to clarify the possible survival benefits of LMWH in
patients with various types of tumors and to examine whether
extending LMWH therapy beyond the duration of
chemotherapy might offer incremental benefit.
summary
conflict of interest
AAK receives consultant and speakers fees from Eisai Inc.,
Sanofi-aventis, Genentech, and Roche.
acknowledgements
Financial and editorial support for this research was provided
by Eisai Inc. Jelena Arnold, PhD, AlphaMedica, Inc. assisted in
the preparation of this manuscript.
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VTE is the second most common cause of death in patients
with cancer [1, 90]. Risk factors for cancer-associated VTE
include chemotherapy, the use of antiangiogenic agents or
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option for VTE prophylaxis and treatment in most cases.
The use of LMWHs may also be associated with improved
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as recommended by clinical practice guidelines [14, 16].
Improved adherence to such guidelines could substantially
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