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Thromboembolism in hospitalized cancer patients

Article in Journal of Clinical Oncology · February 2006

DOI: 10.1200/JCO.2005.03.8877 · Source: PubMed

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 VOLUME 24 䡠 NUMBER 3 䡠 JANUARY 20 2006

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Thromboembolism in Hospitalized Neutropenic

From the James P. Wilmot Cancer
Center and the Departments of Medi-
cine and Biostatistics and Computa-
tional Biology, University of Rochester,
Rochester, NY.
Submitted August 17, 2005; accepted
October 5, 2005.
Supported by the James P. Wilmot
Cancer Research Fellowship (A.A.K.)
and National Institutes of Health Grant
No. 2T32 ES007271 (E.C.).
Presented in part at the 40th Annual
Meeting of the American Society of
Clinical Oncology, New Orleans, LA,
June 5-8, 2004.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Address reprint requests to Alok A.
Khorana, MD, 601 Elmwood Ave, Box
704, Rochester, NY 14642; e-mail:
alok_khorana@URMC.rochester.edu.
© 2006 by American Society of Clinical
Oncology
0732-183X/06/2403-484/$20.00
DOI: 10.1200/JCO.2005.03.8877
Cancer Patients
Alok A. Khorana, Charles W. Francis, Eva Culakova, Richard I. Fisher, Nicole M. Kuderer, and Gary H. Lyman
A B S T R A C T
Purpose
Cancer is associated with thrombosis, but the frequency of thromboembolism in hospitalized
cancer patients receiving current chemotherapy regimens is not known. We investigated venous
and arterial thromboembolism and associated outcomes in hospitalized cancer patients actively
receiving therapy, as identified by neutropenia.
Methods
We conducted a retrospective cohort study using the discharge database of the University
HealthSystem Consortium. This included 66,106 adult neutropenic cancer patients with 88,074
hospitalizations between 1995 and 2002 at 115 medical centers in the United States.
Results
Thromboembolism was reported in 5,272 patients (8%), with 5.4% patients developing venous
thromboembolism and 1.5% developing arterial thromboembolism during the first hospitalization.
Patients with lymphoma and leukemia accounted for one third of venous and nearly one half of
arterial events. Clinical variables most frequently associated with thromboembolism were age
ⱖ 65 years; primary site of cancer, including lung, GI, gynecologic, and brain; and comorbidities,
including infection, pulmonary and renal disease, and obesity. In-hospital mortality was signifi-
cantly greater in patients with venous (odds ratio [OR] ⫽ 2.01; 95% CI, 1.83 to 2.22) or arterial
thromboembolism (OR ⫽ 5.04; 95% CI, 4.38 to 5.79). From 1995 to 2002, there was a 36%
increase in venous events and a 124% increase in arterial events (P ⬍ .0001 for trend).
Conclusion
Thromboembolism is frequent in hospitalized neutropenic cancer patients, including in perceived
low-risk subgroups such as patients with hematologic malignancies and nonmetastatic disease,
and seems to be increasing. Thromboembolism is associated with increased in-hospital mortality.
Increased efforts at thromboprophylaxis are warranted.

J Clin Oncol 24:484-490. © 2006 by American Society of Clinical Oncology

thromboembolism over a median follow-up time of

INTRODUCTION
An association between thrombosis and malig-
nancy has been reported since at least the 19th
century, and the risk of venous thromboembo-
lism is increased in cancer patients, especially in
those receiving chemotherapy.1-3 The estimated
annual incidence of thromboembolism in the can-
cer population is 0.5%,4 and thromboembolism is
the second leading cause of death in these patients.5
An analysis of Medicare claims data for hospital
discharges from 1988 to 1990 indicated that cancer
patients developed venous thromboembolism dur-
ing initial hospitalization significantly more fre-
quently than noncancer patients, although
incidence rates were only 0.6% and 0.57%, respec-
tively.6 More recently, 7.8% of cancer patients
treated at three medical centers developed venous
26 months.7
Varying rates may be observed because of the
heterogeneity of the hospitalized cancer popula-
tion, which includes patients with a new diagnosis
of cancer and patients admitted subsequently for
surgery, elective chemotherapy, complications of
therapy, or end-of-life care. The incidence of
thromboembolism among these subgroups may
vary, and the implications for prophylaxis and
therapy differ.8 Therefore, we chose to study can-
cer patients with neutropenia as reflecting a large
and more homogenous population of patients
receiving active therapy. We investigated the pro-
portion of patients with venous and arterial
thromboembolism in this population and charac-
terized its association with in-hospital mortality
and other variables.

484
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 Thromboembolism in Cancer Patients
METHODS
All discharge summaries of adult cancer patients with febrile neutropenia
admitted between 1995 and 2002 to one of 115 medical centers in the United
States were reviewed using the discharge database of the University HealthSys-
tem Consortium. Patients were identified using International Classification of
Diseases, 9th revision, clinical modification (ICD-9-CM) codes that contained
at least one diagnosis of malignant disease (ICD-9-CM 140 to 208) and the
diagnosis of agranulocytosis (ICD-9-CM 288). Patients with thromboembo-
lism were identified using codes for venous thrombosis (codes 451.0 to 451.9,
452, 453.0 to 453.9, and 557.0), pulmonary embolism (codes 415.1 to 415.9),
arterial embolism (codes 444.0 to 444.9), acute cerebrovascular disease (codes
433.0 to 434.9 and 436), and acute coronary arterial disease (codes 410.0 to
410.9 and 411.1 to 411.8). Patients with a history of venous thromboembolism
or of receiving anticoagulation were identified using codes V125.1, V125.2,
and V586.1. The major categories of cancer that were studied (and their codes)
included lung (162 and 163), breast (174), colon (153), rectum (154), stomach
(151), pancreas (157), other abdominal cancers (152, 155, 156, 158, and 159),
ovary (183), endometrium and cervix (179 to 182), head and neck (140 to
149), esophageal (150), Hodgkin’s disease (201), non-Hodgkin’s lymphoma
(200 and 202), brain (191 and 192), prostate (185), bladder (188), renal (189),
leukemia (204 to 208), testicular (186), myeloma (203), and sarcoma (170 and
171). Comorbidities and risk factors included documented infection (001 to
139.8, 480 to 486, and 9966.2), pulmonary disease (487 to 519.9), hypertension
(401), renal disease (580 to 593.9), diabetes mellitus (250 to 250.9), tobacco
abuse (305.1 to 305.12 and V1582), congestive heart failure (428 to 428.9),
hepatic disease (570 to 576.9), and obesity (278). These comorbidities and risk
factors referred to the period of hospitalization only. In-hospital mortality was
defined as death from any cause during the period of hospitalization.
Statistical Analysis
The association of thromboembolism with clinical variables was studied
using a univariate analysis and reported as odds ratios (ORs) with 95% CIs.
The association results were re-evaluated using a multivariate logistic regres-
sion model with venous thromboembolism as the response variable. The full
cohort of 66,106 patients was used in the multivariate model because data
regarding age, sex, and mortality were complete (except for data on 90 patients
regarding mortality). For missing data regarding race, an other/unknown
category was created. Clinically relevant factors, including age ⱖ 65 years, race,
sex, comorbidities, and sites of cancer known to be associated with thrombo-
embolism, were included in the model. To test homogeneity of ORs between
mortality and thromboembolism, we split the data set into 54 groups based on
zip code and year (P ⫽ .20 for venous thromboembolism and P ⫽ .10 for
arterial thromboembolism). The association between mortality and thrombo-
embolism was also tested in a multivariate analysis. The association of categor-
ical variables with outcomes were based on a ␹2 test while the Cochran-
Armitage test was used to determine trend. Statistical significance of
independent variables in multivariate analyses were based on the Wald ␹2 test.
Statistical analysis was conducted using SAS version 8.2 (SAS Institute, Cary, NC).
RESULTS
Patient Characteristics
A total of 88,074 hospitalizations with neutropenia occurred in
66,106 cancer patients between 1995 and 2002 in 115 medical centers,
including 14,727 patients (22.3%) with multiple hospitalizations. The
average age was 53 years, and 26.2% of patients were greater than 65
years old (Table 1). Nearly three fourths of the population (72.8%)
was white, with blacks representing 11.2% and Hispanics representing
4.6% of the population. Hematologic malignancies were common
and included leukemia (22.1%), non-Hodgkin’s lymphoma (19.6%),
myeloma (6.8%), and Hodgkin’s disease (3.1%). Solid tumors were
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Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
categorized into 17 types, and these represented one third of the
population. A small minority of patients (1.4%) had multiple cancers.
Thromboembolic Events
Thromboembolic events were reported in 5,272 patients
(7.98%), including 4,434 patients (6.71%) who developed thrombo-
embolism during the first hospitalization (Table 2). Of 14,727 patients
with multiple hospitalizations, 838 (5.69%) developed thromboem-
bolism during subsequent hospitalizations. For further analysis, we
considered events during the first hospitalization only. The most fre-
quent events were venous thrombosis (4.79%) and pulmonary embo-
lism (0.93%). Arterial events, including acute coronary disease
(0.8%), acute cerebrovascular disease (0.5%), and arterial embolism
(0.2%), occurred less frequently. A prior history of venous thrombo-
sis, pulmonary embolism, or chronic anticoagulation was more com-
mon in patients who developed venous thromboembolism than in
patients who did not (P ⬍ .0001), although this comprised only a
small percentage of patients (1.7%).
The proportion of patients with venous and arterial thromboem-
bolism increased by 36% and 124%, respectively, over the 8 years of
study (Fig 1; P ⬍ .0001 for trend for both). This increase occurred
despite a decrease in median length of hospital stay from 8 to 7 days
and a decline in the proportion of patients with lengths of stay greater
than 10 days from 46.1% to 42.5% (P ⬍ .0001). Notably, the propor-
tion of patients greater than 65 years old increased during the same
period from 23.2% to 28.1%, as did the proportion of obese patients,
which increased from 0.48% to 1.14% (P ⬍ .0001 for both).
Sites of cancer with the highest proportion of patients with ve-
nous thromboembolism were pancreas (12.1%), brain (9.5%), and
endometrial or cervical (9%; Table 3). Patients with non-Hodgkin’s
lymphoma (n ⫽ 650) and leukemia (n ⫽ 641) represented more than
one third of all patients with venous events, and lung (n ⫽ 326) and
breast (n ⫽ 204) cancers accounted for nearly one sixth of all patients
with venous events. Sites of cancer with the highest proportion of
patients with arterial thromboembolism were prostate (3.9%), lung
(2.8%), and bladder (2.8%; Table 3). Patients with non-Hodgkin’s
lymphoma (n ⫽ 173) and leukemia (n ⫽ 279) represented nearly half
of all patients with arterial events, with lung (n ⫽ 131) and breast
cancer (n ⫽ 36) accounting for a further one sixth of patients.
Variables significantly associated with venous thromboembo-
lism included age ⱖ 65 years; site of cancer, including pancreas, brain,
endometrial or cervical, and lung (P ⱕ .01 for each); and presence of
comorbidities, including infection, pulmonary disease, hypertension,
renal disease, congestive heart failure, hepatic disease, and obesity
(Table 1). Variables associated with arterial thromboembolism in-
cluded age ⱖ 65 years; male sex; black race; site of cancer, including
leukemia, colon, prostate, and lung (P ⱕ .01 for each); and presence of
comorbidities, including infection, pulmonary disease, hypertension,
renal disease, diabetes mellitus, congestive heart failure, and hepatic
disease. There was a significant association between the occurrence of
venous and arterial thromboembolism (OR ⫽ 1.73; 95% CI, 1.38 to
2.16). Among patients with age ⱖ 65 years, women were more likely to
develop venous thromboembolism (5.7% of men v 6.6% of women;
OR ⫽ 1.16; 95% CI, 1.02 to 1.31; P ⫽ .02), and the proportion was
highest among black women with age ⱖ 65 years (7.7% v 6.5%
for other women aged ⱖ 65 years; P ⫽ .13). Information regarding
presence or absence of metastatic disease was available for only a
subgroup of the population (n ⫽ 38,010). In this subgroup, venous
485
 Khorana et al

Table 1. Characteristics of the Study Population and Association With Venous and Arterial Thromboembolism by Univariate Analysis
Venous Thromboembolism Arterial Thromboembolism
No. of % of % With Odds % With Odds
Characteristic Patients Total Event 95% CI Ratioⴱ 95% CI Event 95% CI Ratio 95% CI

All patients 66,106 100 5.37 5.20 to 5.54 1.47 1.38 to 1.56
Age, years
⬍ 65 48,750 73.75 5.08 4.89 to 5.28 1.14 to 1.33 0.97 0.89 to 1.06 2.64 to 3.40
ⱖ 65 17,356 26.25 6.18 5.82 to 6.54 1.23† 2.86 2.61 to 3.11 3.0†
Sex
Female 34,639 52.40 5.46 5.22 to 5.70 0.90 to 1.03 1.32 1.29 to 1.44 1.10 to 1.41
Male 31,467 47.60 5.27 5.02 to 5.52 0.96‡ 1.63 1.49 to 1.77 1.25‡
Race/ethnicity
White 48,161 72.85 5.35 5.15 to 5.55 0.99 0.92 to 1.07 1.44 1.33 to 1.55 0.94 0.81 to 1.08
Black 7,438 11.25 5.54 5.02 to 6.06 1.04 0.93 to 1.15 1.75 1.45 to 2.05 1.23 1.02 to 1.48
Hispanic 3,075 4.65 5.11 4.35 to 5.88 0.95 0.80 to 1.12 1.07 0.71 to 1.44 0.72 0.51 to 1.02
Other/unknown 7,432 11.24 5.42 4.91 to 5.94 1.01 0.91 to 1.13 1.52 1.24 to 1.80 1.04 0.86 to 1.27
Site of cancer
Leukemia 14,600 22.09 4.39 4.06 to 4.72 0.77 0.70 to 0.84 1.91 1.69 to 2.13 1.43 1.25 to 1.65
Non-Hodgkin’s lymphoma 12,977 19.63 5.01 4.63 to 5.38 0.91 0.84 to 1.00 1.33 1.14 to 1.53 0.89 0.75 to 1.05
Breast 5,187 7.85 3.93 3.42 to 4.50 0.70 0.61 to 0.81 0.69 0.47 to 0.92 0.45 0.32 to 0.63
Lung 4,655 7.04 7.00 6.27 to 7.74 1.36 1.21 to 1.53 2.81 2.34 to 3.29 2.09 1.74 to 2.52
Myeloma 4,527 6.85 5.79 5.11 to 6.47 1.09 0.96 to 1.24 0.93 0.65 to 1.21 0.61 0.45 to 0.84
Hodgkin’s disease 2,042 3.09 3.87 3.03 to 4.71 0.70 0.56 to 0.88 0.54 0.22 to 0.86 0.36 0.20 to 0.65
Ovary 1,955 2.96 6.50 5.40 to 7.39 1.23 1.03 to 1.48 1.38 0.86 to 1.90 0.94 0.64 to 1.38
Head and neck 1,606 2.43 2.74 1.94 to 3.54 0.49 0.36 to 0.66 1.81 1.15 to 2.46 1.24 0.86 to 1.80
Sarcoma 1,597 2.42 4.82 3.77 to 5.87 0.89 0.71 to 1.12 0.31 0.04 to 0.59 0.21 0.09 to 0.50
Endometrium/cervical 1,060 1.60 8.96 7.24 to 10.68 1.76 1.42 to 2.17 1.42 0.70 to 2.13 0.96 0.58 to 1.61
Colon 756 1.14 6.75 4.96 to 8.53 1.28 0.96 to 1.70 2.65 1.50 to 3.79 1.84 1.18 to 2.89
Other abdominal 720 1.09 7.64 5.70 to 9.58 1.47 1.11 to 1.93 1.39 0.53 to 2.24 0.95 0.51 to 1.77
Brain 716 1.08 9.50 7.35 to 11.64 1.87 1.45 to 2.40 0.70 0.09 to 1.31 0.47 0.19 to 1.13
Esophagus 699 1.06 6.72 4.87 to 8.58 1.27 0.95 to 1.72 2.00 0.96 to 3.04 1.38 0.81 to 2.35
Rectum 645 0.98 6.98 5.13 to 9.22 1.33 0.98 to 1.80 1.86 0.82 to 2.90 1.28 0.72 to 2.27
Stomach 580 0.88 7.41 5.28 to 9.55 1.42 1.04 to 1.94 1.72 0.66 to 2.78 1.18 0.63 to 2.21
Testicular 491 0.74 6.52 4.33 to 8.70 1.23 0.86 to 1.76 0.81 0.02 to 1.61 0.55 0.21 to 1.47
Prostate 439 0.66 7.29 4.86 to 9.72 1.39 0.97 to 2.00 3.87 2.07 to 5.68 2.74 1.68 to 4.46
Pancreas 438 0.66 12.10 9.05 to 15.15 2.45 1.84 to 3.27 1.60 0.42 to 2.77 1.09 0.52 to 2.31
Bladder 288 0.44 6.60 3.73 to 9.46 1.25 0.78 to 1.99 2.78 0.88 to 4.68 1.93 0.95 to 3.90
Renal 212 0.32 7.55 3.99 to 11.10 1.44 0.87 to 2.40 0.47 0.00 to 1.39 0.32 0.05 to 2.27
Multiple cancers 906 1.37 4.97 3.55 to 6.38 0.92 0.68 to 1.24 2.43 1.43 to 3.43 1.69 1.10 to 2.59
Other cancers 9,010 13.63 5.98 5.49 to 6.47 1.14 1.04 to 1.26 1.02 0.81 to 1.23 0.66 0.53 to 0.82
Comorbidities
Infection 28,904 43.72 6.32 6.04 to 6.60 1.39 1.30 to 1.49 1.85 1.69 to 2.00 1.59 1.40 to 1.80
Pulmonary disease 13,100 19.82 8.05 7.59 to 8.52 1.77 1.65 to 1.91 3.18 2.88 to 3.48 3.11 2.73 to 3.53
Hypertension 12,463 18.85 5.89 5.48 to 6.30 1.13 1.04 to 1.23 2.27 2.01 to 2.53 1.79 1.56 to 2.06
Renal disease 7,549 11.42 7.91 7.30 to 8.52 1.62 1.48 to 1.77 3.30 2.90 to 3.70 2.74 2.36 to 3.17
Diabetes mellitus 5,122 7.75 5.62 4.99 to 6.25 1.05 0.93 to 1.19 3.05 2.58 to 3.52 2.32 1.95 to 2.76
Congestive heart failure 2,722 4.12 7.02 6.06 to 8.04 1.35 1.16 to 1.57 7.35 6.37 to 8.33 6.45 5.49 to 7.57
Hepatic disease 2,090 3.16 7.37 6.25 to 8.49 1.42 1.20 to 1.68 2.11 1.49 to 2.72 1.47 1.08 to 1.99
Obesity 518 0.78 8.11 5.76 to 10.46 1.56 1.14 to 2.15 1.74 0.61 to 2.86 1.19 0.61 to 2.31
Past history
Venous thromboembolism 878 1.33 3.87 2.60 to 5.15 0.71 0.50 to 1.00 1.25 0.52 to 1.99 0.85 0.47 to 1.55
Chronic anticoagulation 397 0.6 15.87 12.41 to 19.46 3.37 2.57 to 4.42 1.76 0.71 to 3.6 1.2 0.57 to 2.56
ⴱ
An odds ratios of ⬎ 1.0 for age signifies a greater likelihood of thromboembolism in neutropenic cancer patients age ⱖ 65 years, and, for sex, signifies a greater
likelihood of thromboembolism in male patients. For sites of cancer, an odds ratio of ⬎ 1.0 signifies a greater likelihood of thromboembolism relative to other
neutropenic cancer patients.
†For age ⱖ 65 years.
‡For male sex.

thromboembolism was more frequent in patients with metastatic In-Hospital Mortality

disease (OR ⫽ 1.23; 95% CI, 1.13 to 1.34), whereas arterial thrombo- The in-hospital mortality for the entire population was 8.3% over
embolism was not (OR ⫽ 0.59; 95% CI, 0.51 to 0.69). the 8 years of study. Patients with venous thromboembolism had

486 JOURNAL OF CLINICAL ONCOLOGY

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Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
 Thromboembolism in Cancer Patients

Table 2. Thromboembolic Complications Observed in the Study Population

During First Hospitalization During Later Hospitalizations During All Hospitalizations
(n ⫽ 66,106) (n ⫽ 14,727) (N ⫽ 66,106)
Outcome No. % 95% CI No. % 95% CI No. % 95% CI

Any thromboembolism 4,434 6.71 6.52 to 6.9 838 5.69 5.32 to 6.06 5,272 7.98 7.77 to 8.18
Venous thromboembolism 3,550 5.37 5.2 to 5.54 705 4.79 4.44 to 5.13 4,255 6.44 6.25 to 6.62
Venous thrombosis 3,167 4.79 4.63 to 4.95 661 4.49 4.15 to 4.82 3,828 5.79 5.61 to 5.97
Pulmonary embolism 616 0.93 0.86 to 1.01 95 0.65 0.52 to 0.77 711 1.08 1 to 1.15
Arterial thromboembolism 970 1.47 1.38 to 1.56 165 1.12 0.95 to 1.29 1,135 1.72 1.62 to 1.82
Acute arterial embolism 141 0.21 0.18 to 0.25 30 0.20 0.13 to 0.28 171 0.26 0.22 to 0.3
Acute cerebrovascular disease 353 0.53 0.48 to 0.59 69 0.47 0.36 to 0.58 422 0.64 0.58 to 0.7
Acute coronary artery disease 506 0.77 0.7 to 0.83 71 0.48 0.37 to 0.59 577 0.87 0.8 to 0.94

greater mortality than patients without such a diagnosis (OR ⫽ 2.01;
95% CI, 1.83 to 2.22; P ⬍ .0001), and a similar trend was observed in
the subgroup of patients with information regarding metastatic dis-
ease (Fig 2A). In-hospital mortality was greater in patients with venous
thromboembolism and either nonmetastatic disease (OR ⫽ 1.62; 95%
CI, 1.37 to 1.91; P ⬍ .0001) or metastatic disease (OR ⫽ 2.06; 95% CI,
1.74 to 2.44; P ⬍ .0001). Similarly, in-hospital mortality was greater in
patients with arterial thromboembolism (OR ⫽ 5.05; 95% CI, 4.38 to
5.79) and either nonmetastatic disease (OR ⫽ 3.6; 95% CI, 2.96
to 4.37; P ⬍ .0001) or metastatic disease (OR ⫽ 3.87; 95% CI, 2.93 to
5.13; P ⬍ .0001; Fig 2B).
Multivariate Analysis
The following clinical variables were found to be significantly
associated with venous thromboembolism using a multivariate
logistic regression analysis: age ⱖ 65 years; site of cancer, including
brain, lung, stomach, pancreas, other abdominal, ovary, endome-
trium, and cervix; arterial thromboembolism; and presence of
comorbidities, including infection, pulmonary and renal disease,
and obesity. Their association with venous thromboembolism is
described in Table 4. A similar multivariate analysis for mortality
identified venous (OR ⫽ 1.5; 95% CI, 1.3 to 1.6) and arterial throm-
boembolism (OR ⫽ 2.7; 95% CI, 2.3 to 3.2) as significantly associ-
ated with increased in-hospital mortality. Other variables of
Fig 1. Increase in the proportion of patients with venous and arterial thrombo-
embolism over time. Results are presented as annual proportions between 1995
and 2002. Significant trends for increase in occurrence were observed for both
venous and arterial thromboembolism (P ⬍ .0001 for trend).
significance in this model were year of hospitalization (with mor-
tality declining over the duration of study), age ⱖ 65 years, race,
site of cancer, and comorbidities.
DISCUSSION
We studied the occurrence of thromboembolism in hospitalized
cancer patients receiving chemotherapy, as identified by the pres-
ence of neutropenia. The analysis shows that venous and arterial
thromboembolic events are frequent complications of hospitaliza-
tion in this population and that they both contribute to increased
in-hospital mortality. The proportion of patients with thrombo-
embolism is high across all subgroups studied including patients
with hematologic malignancies and with nonmetastatic disease,
who are commonly perceived to be at lower risk for thromboem-
bolism. Older age, particular sites of cancer, infection, and other
comorbidities are associated with a higher risk of thromboembolic
events. Of particular concern is the increasing frequency of venous
and arterial thromboembolism.
The proportion of patients with venous thromboembolism re-
ported in our study is greater than the proportion observed in a
prospective study of acutely ill medical patients, which found an inci-
dence of 0.7% symptomatic venous thrombosis and 1% pulmonary
embolism in the placebo arm.9 The proportion is also much higher
than the 0.6% incidence observed in Medicare claims data from 1988
to 1990.6 The incidence of arterial thromboembolism in hospitalized
cancer patients has not been previously reported. Several factors may
have contributed to the high proportion of thromboembolism ob-
served. The study population comprised only patients receiving
chemotherapy because a discharge diagnosis of neutropenia was
required. Nearly 44% of patients experienced an infectious com-
plication during hospitalization. Both chemotherapy and infection
are risk factors for thrombosis.3,10-12 Hematopoietic growth fac-
tors, which are commonly used in hospitalized patients with febrile
neutropenia, may be thrombogenic, although a recent meta-
analysis was inconclusive.13 The true risk of thromboembolism
may have increased since the last report; indeed, we observed a
significant increase in its occurrence over the study duration. There
may be an increased awareness of the diagnosis of thromboembo-
lism, leading to increased testing.14 Risk factors, such as patient age
and obesity, increased over the same period, although length of hos-
pitalization declined. Newer, more thrombogenic cancer treatment

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 Khorana et al

Table 3. Site of Malignancy and Proportion of Patients With Thromboembolism

Acute
Total Venous Venous Pulmonary Total Arterial Acute Coronary Cerebrovascular Arterial
Thromboembolism Thrombosis Embolism Thromboembolism Disease Disease Embolism
No. With % With No. of % With No. of % With No. of % With No. of % With No. of % With No. of % With
Site of Cancer Events Event Patients Event Patients Event Patients Event Patients Event Patients Event Patients Event
All sites 3,550 5.37 3,167 4.79 616 0.93 970 1.47 506 0.77 353 0.54 141 0.21
Pancreas 53 12.10 52 11.87 6 1.37 7 1.60 1 0.23 4 0.91 2 0.46
Brain 68 9.50 58 8.10 16 2.23 5 0.70 4 0.56 1 0.14 1 0.14
Endometrial/cervical 95 8.96 87 8.21 12 1.13 15 1.42 4 0.38 8 0.75 3 0.28
Other abdominal cancers 55 7.64 50 6.94 8 1.11 10 1.39 1 0.14 5 0.69 4 0.56
Renal 16 7.55 15 7.08 3 1.42 1 0.47 1 0.47 0 0.00 0 0.00
Stomach 43 7.41 36 6.21 10 1.72 10 1.72 3 0.52 6 1.03 1 0.17
Prostate 32 7.29 27 6.15 11 2.51 17 3.87 10 2.28 5 1.14 2 0.46
Lung 326 7.00 259 5.56 97 2.08 131 2.81 66 1.42 50 1.07 20 0.43
Rectum 45 6.98 43 6.67 8 1.24 12 1.86 6 0.93 1 0.16 5 0.78
Colon 51 6.75 44 5.82 14 1.85 20 2.65 10 1.32 7 0.93 3 0.40
Esophagus 47 6.72 42 6.01 7 1.00 14 2.00 6 0.86 7 1.00 1 0.14
Bladder 19 6.60 19 6.60 1 0.35 8 2.78 5 1.74 3 1.04 0 0.00
Testicular 32 6.52 31 6.31 2 0.41 4 0.81 1 0.20 0 0.00 3 0.61
Ovary 127 6.50 109 5.58 27 1.38 27 1.38 13 0.66 11 0.56 5 0.26
Myeloma 262 5.79 240 5.30 31 0.68 42 0.93 25 0.55 16 0.35 2 0.04
Non-Hodgkin’s lymphoma 650 5.01 578 4.45 116 0.89 173 1.33 98 0.76 61 0.47 24 0.18
Sarcoma 77 4.82 69 4.32 10 0.63 5 0.31 1 0.06 2 0.13 2 0.13
Leukemia 641 4.39 593 4.06 74 0.51 279 1.91 145 0.99 108 0.74 32 0.22
Breast 204 3.93 177 3.41 44 0.85 36 0.69 20 0.39 8 0.15 9 0.17
Hodgkin’s disease 79 3.87 72 3.53 13 0.64 11 0.54 7 0.34 3 0.15 1 0.05
Head and neck 44 2.74 41 2.55 5 0.31 29 1.81 16 1.00 10 0.62 3 0.19
Multiple cancers 45 4.97 42 4.64 3 0.33 22 2.43 13 1.43 3 0.33 7 0.77
Other cancers 539 5.98 483 5.36 98 1.09 92 1.02 50 0.55 34 0.38 11 0.12

regimens, increasing use of implanted venous access devices, and
an increased awareness of thrombosis as a complication of hospi-
talization may also have contributed.15-17 Although the discharge
codes we used to identify venous thrombosis included superficial
thrombophlebitis, the number of patients with this diagnosis alone
was small (n ⫽ 198, 0.2%).
The significance of cancer site suggests that intrinsic factors
unique to these particular tumors contribute to hypercoagulabil-
ity. The high risk of venous thromboembolism in patients with
pancreas, brain, and gynecologic cancers is consistent with prior
observations.7,18-20 The association of arterial thromboembolism
with prostate, lung, and colon cancers and leukemia is a novel
finding and deserves further investigation.
The occurrence of thromboembolism has several clinical conse-
quences related to patient morbidity, interruption of chemotherapy,
and cost of hospitalization.21 In our analysis, thromboembolism was
also associated with increased in-hospital mortality. Arterial throm-
boembolism and pulmonary embolism can be life threatening and
could have contributed to the observed increase in mortality. How-
ever, venous thrombosis without embolism is not a life-threatening
condition. Experimental models suggest that activation of the coagu-
lation cascade confers a growth advantage on the tumor. In particular,
tissue factor, thrombin, and fibrin(ogen) can enhance tumor growth,
metastasis, and angiogenesis.22-25 The presence of venous thrombosis
could signify an aggressive tumor biology and, therefore, a worse
short-term prognosis. Cancer diagnosed at the same time as or within
1 year of an episode of venous thromboembolism has previously been
shown to be associated with an advanced stage and a three-fold lower
survival at 1 year.26
Our study had several limitations. It was retrospective and based
on discharge codes. However, accuracy of coding for pulmonary em-
bolism and deep venous thrombosis has been previously shown to be
92% and 84%, respectively.27 Neither the time to thromboembolic
event nor the time from thromboembolism to mortality were avail-
able. The study included only inpatients and may have underesti-
mated the true proportion because venous thromboembolism is often
diagnosed and managed on an outpatient basis. Although neutrope-
nia is usually a manifestation of chemotherapy administration, it can
also occur without the use of chemotherapy, particularly in patients
with myeloproliferative disorders. In this study, however, the propor-
tion of patients with thromboembolism was not substantially altered
when patients with myeloproliferative disorders were excluded (data
not shown). We could not validate the diagnosis of neutropenia in our
study population, although it has been previously shown to be specific
in similar administrative datasets.28,29 Thromboprophylaxis can alter
the incidence of venous thromboembolism, but its use in our study
population was not known.30 According to a recent survey, however,
less than 5% of medical oncology patients are routinely administered
thromboprophylaxis.31 Venous thromboembolism occurred in 5.4%
of patients, and therefore, logistic regression analysis may be ham-
pered by the rare disease assumption. Information regarding stage of
disease, use of implanted intravascular access devices, type and timing
of chemotherapy regimens, and outside-hospital mortality was not
available. Documentation regarding other known risk factors for

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 Thromboembolism in Cancer Patients

Table 4. Predictors of Venous Thromboembolism by Multivariate Logistic

Regression Analysis
Characteristic Odds Ratioⴱ 95% CI P

Age ⱖ 65 years 1.12 1.03 to 1.21 .0051

Site of Cancer
Lung 1.29 1.14 to 1.46 ⬍ .0001
Stomach 1.60 1.17 to 2.19 .0035
Pancreas 2.80 2.09 to 3.76 ⬍ .0001
Other abdominal 1.53 1.16 to 2.03 .0031
Ovary 1.35 1.12 to 1.63 .0016
Endometrium/cervical 1.98 1.59 to 2.46 ⬍ .0001
Brain 2.23 1.73 to 2.87 ⬍ .0001
Arterial thromboembolism 1.36 1.09 to 1.71 .0079
Comorbidities
Pulmonary disease 1.57 1.45 to 1.70 ⬍ .0001
Renal disease 1.41 1.30 to 1.54 ⬍ .0001
Infection 1.28 1.20 to 1.38 ⬍ .0001
Obesity 1.52 1.10 to 2.09 .0110
ⴱ
The odds ratios are adjusted for sex, race, hypertension, diabetes mellitus,
congestive heart failure, and hepatic disease, none of which were significant.

thromboembolism was also missing (eg, information on use of post-

Fig 2. Thromboembolism and inpatient mortality. Presence of (A) venous and
(B) arterial thromboembolism was significantly associated with increased mor-
tality in patients with metastatic or nonmetastatic disease (P ⬍ .0001). Informa-
tion regarding metastatic disease was available for only a subgroup of the
population (n ⫽ 38,010). Information regarding mortality was not available for 90
patients. Error bars represent 95% CIs.
menopausal hormonal replacement therapy was available for ⬍ 0.1%
of the study population).
Despite these limitations, it is clear from our analysis that the risk
of both venous and arterial thromboembolism is high and increasing
in hospitalized neutropenic cancer patients, and the occurrence of
thromboembolism portends a poor short-term prognosis. Thrombo-
prophylaxis with warfarin and low molecular weight heparins has
been shown to be effective in cancer outpatients and hospitalized
acutely ill medical patients, respectively.9,30 These compounds may
have other beneficial effects in cancer patients.32,33 Prospective studies
are necessary to characterize the risks and benefits of thromboprophy-
laxis in this patient population.

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■ ■ ■

Acknowledgment
We thank David Oakes, PhD, for critical comments and Susan Sullivan and Barbara Hartzog for editorial assistance.

Authors’ Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Alok A. Khorana, Charles W. Francis, Gary H. Lyman

Administrative support: Gary H. Lyman
Collection and assembly of data: Eva Culakova, Gary H. Lyman
Data analysis and interpretation: Alok A. Khorana, Charles W. Francis, Eva Culakova, Richard I. Fisher, Nicole M. Kuderer, Gary H. Lyman
Manuscript writing: Alok A. Khorana, Charles W. Francis, Eva Culakova, Richard I. Fisher, Nicole M. Kuderer, Gary H. Lyman
Final approval of manuscript: Alok A. Khorana, Charles W. Francis, Eva Culakova, Richard I. Fisher, Nicole M. Kuderer, Gary H. Lyman

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