2822
Risk Factors for Chemotherapy-Associated
Venous Thromboembolism in a Prospective
Observational Study
Alok A. Khorana, M.D.1
Charles W. Francis, M.D.1
Eva Culakova, Ph.D.1,2
Gary H. Lyman, M.D., M.P.H.1,2
1
James P. Wilmot Cancer Center and the Depart-
ment of Medicine, University of Rochester, Roch-
ester, New York.
2
Department of Biostatistics and Computational
Biology, University of Rochester, Rochester, New
York.
Dr. Khorana is supported by the James P. Wilmot
Cancer Research Fellowship. The Awareness of
Neutropenia in Cancer (ANC) Study Group Registry
is funded by Amgen, Inc.
Address for reprints: Alok A. Khorana, M.D., 601
Elmwood Ave, Box 704, Rochester, NY 14642; Fax:
(585) 273-1042; E-mail: alok_khorana@URMC.
rochester.edu
© 2005 American Cancer Society
DOI 10.1002/cncr.21496
Published online 13 November 2005 in Wiley InterScience (www.interscience.wiley.com).
BACKGROUND. The incidence of venous thromboembolism (VTE) is increased in
cancer, but little information is available about risk factors in cancer patients on
chemotherapy.
METHODS. We analyzed data from a prospective, multicenter observational study
to determine the frequency and risk factors for VTE in ambulatory cancer patients
initiating a new chemotherapy regimen. The association of VTE with clinical
variables was characterized using univariate and multivariate analysis.
RESULTS. Among 3003 patients treated with at least one cycle of chemotherapy,
VTE occurred in 58 (1.93%) over a median follow-up of 2.4 months (0.8%/mo). The
incidence varied significantly by site of cancer (P ⫽ 0.01) with highest rates in
upper gastrointestinal (2.3%/mo) and lung cancer (1.2%/mo), and lymphoma
(1.1%/mo). An elevated prechemotherapy platelet count was significantly associ-
ated with an increased rate of VTE (P for trend ⫽ 0.005). The incidence of VTE was
3.98% (1.66%/mo) for patients with a prechemotherapy platelet count ⱖ 350,000,
compared with 1.25% (0.52%/mo) for patients with platelet counts of ⬍ 200,000 (P
for trend⫽0.0003). In multivariate analysis, a prechemotherapy platelet count of
ⱖ 350,000/mm3 (adjusted OR 2.81, 95% CI 1.63– 4.93, P ⫽ 0.0002), site of cancer,
hemoglobin ⬍ 10g/dL or use of erythropoietin, and use of white cell growth factors
in high-risk sites of cancer were significantly associated with VTE.
CONCLUSIONS. Symptomatic VTE is a frequent complication of chemotherapy. The
prechemotherapy platelet count is a unique risk factor and can help identify
high-risk patients for future trials of thromboprophylaxis. Cancer 2005;104:
2822–9. © 2005 American Cancer Society.
KEYWORDS: venous thromboembolism, cancer, chemotherapy.
T he association between thrombosis and malignancy has been
known for centuries, with the earliest reference dating to the
Indian surgeon Sushruta who lived in approximately 1000 BC.1 Ar-
mand Trousseau of France was the first to comprehensively describe
the eponymous syndrome in 1865 and to suggest that thrombosis in
malignancy was more than an epiphenomenon.1,2 It is now well
recognized that the risk of VTE is increased in cancer patients, espe-
cially in those receiving chemotherapy.3– 6 Newer anticancer thera-
pies, in particular antiangiogenic agents, are associated with very high
rates of VTE.7–9 The estimated annual incidence of VTE in the cancer
population is 0.5% (0.04%/mo), compared with 0.1% in the general
population.10 The diagnosis of VTE in cancer has important clinical
implications, as it is the second leading cause of death in cancer
patients.11–13 Indeed, evidence suggests that elements of the coagu-
lation cascade including tissue factor, thrombin, and fibrinogen can
 Risk Factors for Thrombosis with Chemotherapy/Khorana et al.
enhance tumor growth, metastasis, and angiogene-
sis.14 –17 Cancer diagnosed at the same time as or
within 1 year of an episode of VTE is associated with
an advanced stage and a threefold lower survival at 1
year.18 We have recently shown that hospitalized can-
cer patients experience a greater in-hospital mortality
rate if they develop VTE (odds ratio 2.01, 95% CI 1.83–
2.22, P ⬍ 0.0001), even without metastatic disease.19 In
addition, the occurrence of VTE may have conse-
quences related to patient morbidity, interruption of
chemotherapy, and cost of hospitalization.20
Contemporary studies characterizing the inci-
dence of VTE in cancer patients are scarce, with most
available literature comprising either retrospective
studies or post-hoc analyses of clinical trials. A study
using Medicare claims data for hospital discharges
from 1988 –90 indicated that cancer patients devel-
oped VTE during hospitalization significantly more
frequently than noncancer patients, although inci-
dence rates were only 0.6% and 0.57%, respectively.21
A more recent study found that 7.8% of cancer pa-
tients treated at three medical centers developed VTE
over a median follow-up of 26 months.22 Incidence
rates of VTE during adjuvant therapy of breast cancer
vary widely from 2.1% to 13.6%.6,23 Major advances
have been made in the past several years in under-
standing risk factors for VTE in the general population,
and some can be extrapolated to cancer-associated
VTE.4 In cancer patients, additional risk factors may
include the stage and site of disease, use of chemo-
therapy, and the presence of a central venous cathe-
ter.24,25 These associations are based on retrospective
analyses. A prospective study of VTE in cancer pa-
tients receiving chemotherapy has not been con-
ducted, and there is limited information concerning
risk factors that specifically predispose to VTE in this
patient group.24 In the only clinical trial of VTE pro-
phylaxis during chemotherapy, patients with meta-
static breast cancer who received very-low-dose war-
farin demonstrated a reduced incidence of VTE
compared with placebo.26 Current guidelines do not
recommend VTE prophylaxis for ambulatory cancer
patients,24 because the majority of cancer patients do
not develop VTE, and because the use of anticoagu-
lants in cancer patients is associated with an increased
risk of bleeding complications.27 Indeed, evidence in-
dicates that medical oncologists rarely provide throm-
boprophylaxis to cancer patients.28 The ability to strat-
ify risk would allow appropriate use of VTE
prophylaxis only in patients at highest risk.
We, therefore, chose to determine the occurrence
and risk factors for symptomatic VTE using data from
an ongoing prospective observational study of cancer
patients initiating a new chemotherapy regimen. This
2823
study population was relatively homogenous, because
cancer patients with acute medical illnesses, hospital-
ization, or terminal conditions who are already at high
risk for development of VTE were not included. This
allowed us to study risk factors associated primarily
with the patient’s cancer and cancer-related therapy.
We further determined the effects of multiple clinical
and laboratory covariates on VTE incidence to identify
a population of ambulatory patients at high risk for
VTE.
MATERIALS AND METHODS
Study Design and Population
The study population comprised consecutively en-
rolled patients in the Awareness of Neutropenia in
Cancer (ANC) Study Group Registry, an observational
multicenter study designed to evaluate febrile neutro-
penia and other chemotherapy-related complications
in cancer patients who are beginning a new chemo-
therapy regimen. Patients were followed prospectively
for a maximum of four cycles. Patients enrolled be-
tween March 2002 and August 2004 who had com-
pleted at least one cycle of chemotherapy were in-
cluded in this analysis. Patients were enrolled at 115
sites within the United States, balanced for practice
volume and geographic location. The study was ap-
proved by a central institutional review board (IRB) as
well as the University of Rochester IRB, and patients
provided informed consent.
Patients were required to have a histologically
confirmed diagnosis of cancer, with targeted enroll-
ment of specific tumor types (breast, lung, ovarian,
sarcoma, colon, and lymphomas), to be at the start of
a new chemotherapy regimen, be of age 18 years or
older, and capable of providing informed consent.
Patients were excluded if they were receiving concur-
rent cytotoxic, biologic, or immunologic therapy for
other conditions, or continuous single agent chemo-
therapy, if they had a diagnosis of acute leukemia or
myeloma, were pregnant or lactating, had an active
infection requiring treatment, were currently partici-
pating in a double-blind study, or had received stem
cell transplantation.
Data Collection
Data was collected prospectively for up to four cycles
of chemotherapy. This included baseline information
including current medications, recent surgery, comor-
bidities, a complete blood count, the planned chemo-
therapy regimen for the patient, including the individ-
ual drugs and doses being used, the dosing interval
within the cycle, dosing interval between cycles
(length of cycle), and the total number of cycles
planned. Data, including serial complete blood
2824 CANCER December 15, 2005 / Volume 104 / Number 12

counts, changes made to the planned chemotherapy TABLE 1

treatment, including dose reduction or discontinua- Characteristics of Study Population
tion for individual drugs within the regimen, as well as
Characteristic No. (%)
a change in the chemotherapy regimen itself, were
collected during visits at the beginning and nadir of All patients 3003 (100)
each new cycle and during unexpected midcycle visits. Age
VTE was diagnosed by the treating clinician on the ⬍ 65 yrs 1840 (61.5)
ⱖ 65 yrs 1152 (38.5)
basis of clinical suspicion by using usual diagnostic
Gender
procedures. The occurrence of a symptomatic VTE Female 2005 (67)
event after entering the study was reported in the Male 986 (33)
new-cycle visit forms, or in the midcycle visit forms, Stage
depending upon the timing of the event. 1 383 (13)
2 765 (25.9)
3 731 (24.8)
4 1075 (36.4)
Statistical Analysis.
ECOG performance status
The chi-square test was used to compare categorical 0-1 2717 (90.9)
variables, and the Cochran–Armitage test was used to 2-4 272 (9.1)
determine trend across multiple ordered categories. Site of cancer
The association of thromboembolism with clinical Breast 1074 (35.8)
Lung 574 (19.1)
variables was reported as a rate and evaluated in uni-
Colon 323 (10.8)
variate analysis using a chi-square test. Variables as- Upper gastrointestinal 89 (3)
sociated with an increased risk of VTE (P ⱕ 0.05) in Non-Hodgkin lymphoma 267 (8.9)
univariate analysis were included in a multivariate Hodgkin disease 49 (1.6)
logistic regression model. First-order interaction Others 627 (20.9)
Comorbidities
terms for the primary outcome of VTE were explored
Diabetes mellitus 356 (11.9)
and reported. Pulmonary disease 235 (7.9)
Myocardial infarction 102 (3.4)
Peripheral vascular disease 71 (2.4)
RESULTS Congestive heart failure 69 (2.3)
Patient Characteristics Cerebrovascular disease 51 (1.7)
The study population comprised 3003 patients en- Renal disease 33 (1.1)
Body surface area ⱖ 2 m2 803 (26.7)
rolled between March 2002 and August 2004. The av-
Baseline hematologic parameters
erage age was 60 years and over one-third were older Platelets ⱖ 350,000/mm3 653 (21.9)
than 65 years (Table 1). Breast cancer was the most Platelets 200-350,000/mm3 1,769 (59.3)
common diagnosis, followed by lung and colon can- Platelets ⬍ 200,000/mm3 559 (18.8)
cer. Non-Hodgkin lymphoma was the most common Hemoglobin ⬍ 10 g/dL 179 (6)
Use of growth factors during Cycle 1
hematologic malignancy. Women were predominant
White blood cell growth factors 1007 (33.5)
in the population because of the high enrollment of Red blood cell growth factors 791 (26.3)
breast cancer patients. Over one-third of patients had Type of regimen
metastatic disease at the time of study entry. Nearly Anthracycline-containing 1006 (33.5)
one-fourth of patients had one or more comorbidities. Platinum-containing 984 (32.8)
Taxane-containing 984 (32.7)
Other cancer treatment
Radiation 200 (7.1)
Thromboembolic Events
Hormonal therapy 212 (7.1)
A total of 58 patients (1.93%) developed VTE during a
median follow-up period of 2.4 months (0.8%/mo).
Deep venous thrombosis (DVT) developed in 47 pa-
tients, pulmonary embolism (PE) in 14, and concur- Platelet Counts and Risk of VTE
rent DVT and PE in 3 patients. One patient developed An elevated prechemotherapy platelet count was sig-
VTE before starting chemotherapy. The rate of VTE did nificantly associated with an increased rate of VTE
not differ significantly among chemotherapy cycles, (Fig. 2A, P for trend ⫽ 0.005). When the study popu-
occurring in 0.77% during Cycle 1, 0.74% during Cycle lation was divided by quartiles of prechemotherapy
2, and 0.7% during Cycle 3. The cumulative rate of VTE platelet counts, 3.6% of patients in the highest quartile
was 2.22% (95% CI, 1.65–2.79) during Cycles 1 through (⬎ 337,000/mm3) developed VTE, and this was signif-
3 (Fig. 1). icantly higher than the rate of 1.2% of patients who
 Risk Factors for Thrombosis with Chemotherapy/Khorana et al. 2825

FIGURE 1. Cumulative rate of VTE. The cumulative rate of symptomatic VTE

during the first three cycles of new chemotherapy regimen in the study
population of 3003 patients was 2.22% (95% CI, 1.65–2.79%). Error bars
represent standard errors.

developed VTE in the lowest quartile (⬍ 217,000/mm3,

P ⫽ 0.0001). We analyzed this data further using ap-
proximation of quartile platelet counts to numbers
that were more clinically relevant, and we observed a
similar trend. Six hundred fifty-three (21.9%) patients
had a platelet count of 350,000/mm3 or greater before
starting chemotherapy on study. The incidence of VTE
was 3.98% (1.66%/mo) for these patients, significantly
higher than the rate of 1.25% (0.52%/mo) for patients
with prechemotherapy platelet count of ⬍ 200,000/
mm3 (P for trend⫽0.0003). This incidence was also
significantly higher than the rate of 1.38% (0.58%/mo)
observed for the rest of the study population (P for
trend ⫽ 0.0001). The distribution of prechemotherapy
platelet counts in patients who subsequently devel-
oped VTE was significantly higher than those who did
not (Fig. 2B, t-test P ⫽ 0.002, Wilcoxon rank sum test
P ⫽ 0.0002). Indeed, of 167 patients with prechemo-
therapy platelet counts ⬍ 150,000/mm3, none devel-
oped VTE. The increased risk of VTE with higher plate-
let counts persisted while the patients were on FIGURE 2. Elevated platelet count and the risk of VTE during chemotherapy. (A)
chemotherapy. Patients who developed VTE had sig- The frequency of VTE is shown for the study population when divided by quartiles
nificantly elevated mean platelet counts before each of prechemotherapy platelet count (P for trend ⫽ 0.005). (B) The distribution of
cycle of chemotherapy when compared with patients prechemotherapy platelet counts in the study populations that subsequently did
who did not develop VTE (P ⫽ 0.001) (Fig. 2C). Nadir (straight line) or did not (dashed line) develop VTE (t-test P ⫽ 0.002, Wilcoxon rank
platelet counts were also higher in patients who de- sum test P ⫽ 0.0002). (C) Mean platelet counts before each cycle of chemotherapy
veloped VTE (212,000 ⫾ 15,333/mm3), compared with in patients who did (straight line) or did not (dashed line) develop VTE (P ⫽ 0.001).
patients without VTE (159,000 ⫾ 1466/mm3, P
⫽ 0.001). with upper gastrointestinal cancers (including gastric,
pancreatic, and hepatobiliary) (2.3%/mo), lung cancer
Other Risk Factors for VTE (1.2%/mo), and lymphoma (1.1%/mo) (Table 2). Pa-
The primary site of cancer also affected the risk of VTE tients with a baseline hemoglobin ⬍ 10g/dL or who
(P ⫽ 0.01), with the highest rates observed in patients were receiving red-cell or white-cell growth factors
2826 CANCER December 15, 2005 / Volume 104 / Number 12

during their first cycle of chemotherapy were also at TABLE 2

increased risk of VTE. Patients with Eastern Coopera- Univariate Analysis of Clinical Variables Associated
with Venous Thromboembolism
tive Oncology Group (ECOG) performance status of 2
or greater had a trend toward an increased frequency Rate of venous
of VTE, but this was not statistically significant (P thromboembolism
⫽ 0.21). The stage of cancer and particular types of Characteristic (%) P value
chemotherapy regimens were also not significantly
All patients 58 (1.93)
associated with VTE (P ⬎ 0.05).
Age
Age ⬍ 65 yrs 37 (2.01) 0.72
Multivariate Analysis Age ⱖ 65 yrs 21 (1.82)
We combined cancer categories into upper gastroin- Gender
testinal, lung, lymphoma, and other in developing a Female 40 (2.00) 0.75
Male 18 (1.83)
multivariate model for the risk of developing throm-
Stage 0.24
boembolism. In separate models, site of cancer was Stage 1 3 (0.78)
included as a categorical variable as well as an ordinal Stage 2 17 (2.22)
variable, with similar odds ratios estimated. In a mul- Stage 3 18 (2.46)
tivariate logistic regression analysis, we found a strong Stage 4 19 (1.77)
ECOG performance status
association between hemoglobin ⬍ 10g/dL and use of
0–1 50 (1.84) 0.21
red-cell growth factors (P ⬍ 0.0001), and we developed 2–4 8 (2.94)
a combined variable for this. In the final multivariate Site of cancer 0.0012
model, variables found to be significantly and inde- Breast 16 (1.49)
pendently associated with development of symptom- Colon 3 (0.93)
Lung 16 (2.79)
atic VTE included primary site of cancer (upper gas-
Upper gastrointestinal 5 (5.62)
trointestinal or lung), a prechemotherapy platelet Hodgkin disease 4 (8.16)
count ⱖ 350,000/mm3, hemoglobin ⬍ 10g/dL or use of Non-Hodgkin lymphoma 4 (1.50)
erythropoietin, and use of white-cell growth factors Other 10 (1.59)
(Table 3). We found a significant first-order interac- Comorbidities
Congestive heart failure 1 (1.45) 0.76
tion between site of cancer and use of white-cell
Myocardial infarction 2 (1.96) 0.99
growth factors (P ⫽ 0.02). Patients with sites of cancer Peripheral vascular disease 0 (0.00) 0.23
associated with higher risk of VTE (upper gastrointes- Cerebrovascular disease 3 (5.88) 0.04
tinal, lung, or lymphoma) had a significantly increased Moderate or severe renal disease 2 (6.06) 0.08
risk of VTE associated with white-cell growth factor Chronic pulmonary disease 4 (1.70) 0.78
History of surgery 20 (2.09) 0.68
use (VTE rate of 5.9% vs. 1.52% without growth factor
Diabetes 6 (1.69) 0.71
use, P ⫽ 0.0001; odds ratio 4.0, [95% CI, 1.8 – 8.7]). In BSA ⱖ 2 16 (1.99) 0.9
contrast, patients with other sites of cancer did not BSA ⬍ 2 42 (1.92)
appear to have an increased risk of VTE with the use of Prechemotherapy hematologic parameters
white-cell growth factors (VTE rate of 1.31% vs. 1.42% Platelet count ⱖ 350,000/mm3 26 (3.98) ⬍ 0.0001
Platelet count ⬍ 350,000/mm3 32 (1.37)
without growth factor use, P ⫽ 0.84).
Hemoglobin ⬍ 10g/dL 10 (5.59) 0.0003
Hemoglobin ⱖ10g/dL 48 (1.71)
DISCUSSION Use of growth factors during Cycle 1
Cancer patients are known to be at increased risk for White cell growth factors 28 (2.78) 0.02
VTE, but the general cancer population is heteroge- Red cell growth factors 25 (3.16) 0.003
Type of regimen
neous and comprises newly diagnosed patients, those
Anthracycline-containing 25 (2.49) 0.12
receiving active therapy, hospitalized patients, and Taxane-containing 17 (1.73) 0.57
those receiving end-of-life care. We chose to study the Platinum-containing 21 (2.13) 0.57
incidence of symptomatic VTE and its associated risk Other cancer treatment
factors in ambulatory cancer patients who were be- Hormonal therapy 5 (2.36) 0.64
Radiation 4 (2.00) 0.99
ginning a new chemotherapy regimen in a prospective
observational study. Unlike hospitalized patients, BS: body surface area.
thromboprophylaxis is not considered standard of
care for this subgroup of cancer patients. We found
the frequency of VTE to be greater in our study pop-
ulation than previously estimated for the general can-
cer population. An elevated prechemotherapy platelet

TABLE 3
Predictors of Venous Thromboembolism by Multivariate Logistic
Regression Analysis
Odds ratio (95%
Patient characteristic CI)
Site of cancera
Upper gastrointestinal 3.88b (1.43–10.05)
Lung 1.86b (0.99–3.49)
Lymphoma 1.50b (0.67–3.38)
Prechemotherapy platelet count
ⱖ 350,000/mm3 2.81 (1.63–4.93)
Use of white cell growth factorsa 2.09 (1.21–3.61)
Hemoglobin ⬍ 10 g/dL or use of
red cell growth factors 1.83 (1.07–3.14)
a
There was a significant interaction identified between cancer site and use of white cell growth factors
(␤-coefficient ⫽ 0.62, P ⫽ 0.018). For purpose of simplicity, this interaction was not considered in the
above model.
b
Odds ratio in comparison to other cancers.
count was significantly and independently associated
with increased risk of VTE. Certain cancer sites, par-
ticularly upper gastrointestinal, lung, and lymphoma,
contributed disproportionately to the burden of VTE
in this population.
The incidence of VTE observed in our study is
higher than previously estimated for the general can-
cer population.10 It is difficult to directly compare the
results from our study with previously published re-
ports, however, because we chose a population of
ambulatory patients on active treatment, but with a
varied distribution of age, type and stage of cancer,
and chemotherapy regimens. A study of risk factors
associated with this population eliminates the heter-
ogeneity observed in population-based or hospital-
based studies of VTE in cancer, because patients that
are immediately postoperative, suffering from debili-
tating comorbid illnesses, bedridden, or terminal
would not be considered eligible for initiation of a new
outpatient chemotherapy regimen. In a prospective
study of metastatic breast cancer patients on chemo-
therapy, the rate of VTE observed in patients not on
thromboprophylaxis was 4.4% over 188 days (0.7%/
mo).26 This is similar to the rate of 1.49% over 2.4
months (0.62%/mo) observed in breast cancer pa-
tients in our study. In a retrospective study of cancer
patients on chemotherapy, the annual incidence of
symptomatic VTE was 10.9% (0.9%/mo), which is also
similar to the 0.8%/month rate reported for our entire
study population.29
We found a strong association between elevated
platelet counts and risk of VTE during chemotherapy.
Thrombocytosis in patients with essential thrombocy-
themia is associated with thrombotic events, but it has
Risk Factors for Thrombosis with Chemotherapy/Khorana et al. 2827
not been studied as a risk factor for VTE in large
epidemiologic or prospective studies in the general
population.4,30,31 A recent retrospective study of med-
ical inpatients identified an admission platelet count
P value of ⬎ 350,000/mm3 as predictive for VTE during hos-
pitalization.32 The risk of VTE associated with an ele-
0.03 vated platelet count in this study was similar in mag-
0.0076
nitude to that reported in our analysis (adjusted OR
0.05
0.32 3.1, 95% CI, 1.4 –7).32 The association of platelet count
with thrombosis may simply reflect an inflammatory
0.0002 state induced by a more advanced tumor. However, in
0.008 our analysis, this association was independent of stage
of cancer. It is possible, therefore, that platelets may
0.03
play a greater role in the pathogenesis of cancer-asso-
ciated VTE than previously known. Thrombocytosis is
often observed in cancer patients,33 and interactions
between platelet P-selectin and circulating carcinoma
mucins have been described as a possible explanation
for Trousseau syndrome.34 The poor prognosis de-
scribed in association with thrombocytosis in various
solid tumors35–38 may, at least in part, be explained by
an increased rate of VTE and its attendant complica-
tions, as shown in our study. Further studies investi-
gating the contribution of platelets to VTE in cancer
are warranted.
The other risk factors for VTE observed in our
study are consistent with prior reports. The signifi-
cance of cancer site suggests that intrinsic factors
unique to particular tumors contribute to the throm-
bophilic state. The high risk of VTE observed in pa-
tients with gastrointestinal or lung cancer is well
known.21,22,39,40 The association of lymphoma with
VTE is increasingly being recognized.41– 43 The pres-
ence of anemia or the use of red-cell growth factors
was associated with an elevated risk of VTE, and this is
consistent with earlier reports as well.44 Hematopoi-
etic growth factors may be thrombogenic, although a
recent metaanalysis was inconclusive.45,46 In our
study, white-cell growth factors were associated with
VTE only in patients with cancers that had already
predisposed to VTE (upper gastrointestinal, lung, and
lymphoma). White-cell growth factors are often pre-
scribed in the setting of infection, a known risk factor
for VTE,30,47,48 and this may have contributed to the
increased frequency observed. However, we found no
association between documented infection during
chemotherapy and the subsequent occurrence of VTE
in our study population.
Our analysis had some limitations. The ANC Study
Group Registry was designed to assess febrile neutro-
penia and related complications, as its primary end-
point, and not occurrence of VTE. However, data was
prospectively collected, and the sample size was ade-
quate for an analysis of this nature. We identified
2828 CANCER December 15, 2005 / Volume 104 / Number 12
patients with symptomatic VTE, which is the most
clinically significant endpoint. It is likely that there
were additional patients with subclinical disease,
thereby underestimating the true rate. The diagnosis
of VTE also was not standardized but depended on
usual clinical practice. Our analysis could not include
biologic variables such as expression of tissue factor
by tumor cells, or plasma levels of various hemostatic
factors that may be relevant to the pathogenesis of
VTE in this setting. Certain cancers known to be
strongly associated with VTE, such as brain tumors,
were underrepresented in the population.
In summary, this prospective observational study
describes the frequency of symptomatic VTE in cancer
patients initiating chemotherapy and suggests that pa-
tients with upper gastrointestinal or lung cancers, el-
evated prechemotherapy platelet count, anemia, and
on growth factor treatment are at greatest risk for
developing VTE during chemotherapy. Future direc-
tions include development of a clinical predictive
model based on this analysis, and subsequent valida-
tion in a cohort of approximately 1500 patients that
will be accrued in a second phase of this ongoing
prospective observational study. Once validated, such
a predictive model can help identify a subgroup of
ambulatory patients at higher risk for developing VTE.
Currently, thromboprophylaxis is not recommended
for ambulatory cancer patients, despite a randomized
trial showing its effectiveness in breast cancer pa-
tients.24,26 Future clinical trials could evaluate the ef-
fectiveness and feasibility of thromboprophylaxis in
high-risk subgroups of cancer patients.
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