The incidence of venous thromboembolism in cervical cancer: a nationwide population-based study.

Abstract

Venous thromboembolism (VTE) is a life-threatening condition that occurs as a complication of cervical cancer. The aim of this study was to evaluate the incidence of VTE in cervical cancer patients during a 5-year follow-up.
The study analyzed data deposited between 2003 and 2008 in the National Health Insurance Research Database (NHIRD), provided by the National Health Research Institutes in Taiwan. Totally, 1013 cervical cancer patients after treatment and 2026 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the VTE risk.
The 5-year cumulative risk for VTE was significantly higher in the cervical cancer group than in the control group (3.3% vs 0.3%, p < 0.001). The hazard ratio for VTE was 10.14 times higher in the cervical cancer group than in the controls. The combined presence of more comorbidities was associated with a higher risk for VTE. Furthermore, cervical cancer patients without VTE had a significantly higher survival (75.3% vs 30.3%, p < 0.001).
The cumulative risk of VTE was significantly higher in cervical cancer patients, and these patients also had lower survival rates. Strategies to reduce these risks need to be examined.

Full text

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RESEARCH ARTICLEOpen Access
The incidence of venous thromboembolism in
cervical cancer: a nationwide population-based
study
Shiang-Jiun Tsai1†, Ying-Xu Ruan2, Ching-Chih Lee3,5, Moon-Sing Lee1,5, Wen-Yen Chiou1,5, Hon-Yi Lin1,5,
Feng-Chun Hsu1, Yu-Chieh Su4,5and Shih-Kai Hung1,5*
Abstract
Background: Venous thromboembolism (VTE) is a life-threatening condition that occurs as a complication of
cervical cancer. The aim of this study was to evaluate the incidence of VTE in cervical cancer patients during a 5-
year follow-up.
Methods: The study analyzed data deposited between 2003 and 2008 in the National Health Insurance Research
Database (NHIRD), provided by the National Health Research Institutes in Taiwan. Totally, 1013 cervical cancer
patients after treatment and 2026 appendectomy patients were eligible. The Kaplan-Meier method and the Cox
proportional hazards model were used to assess the VTE risk.
Results: The 5-year cumulative risk for VTE was significantly higher in the cervical cancer group than in the control
group (3.3% vs 0.3%, p<0.001). The hazard ratio for VTE was 10.14 times higher in the cervical cancer group than in
the controls. The combined presence of more comorbidities was associated with a higher risk for VTE. Furthermore,
cervical cancer patients without VTE had a significantly higher survival (75.3% vs 30.3%, p<0.001).
Conclusions: The cumulative risk of VTE was significantly higher in cervical cancer patients, and these patients also
had lower survival rates. Strategies to reduce these risks need to be examined.
Background
Cervical cancer remains the most important malignant
disease in women, with an age-adjusted incidence of
26.2 per one hundred thousand people in Taiwan.[1]
Venous thromboembolism (VTE) is a life-threatening
condition in cervical cancer. Its incidence can be strati-
fied by patient, tumor, or treatment. Reports of the VTE
incidence in cervical cancer vary, and range from 0% to
34%.[2] For cancer-related VTE, the incidence of VTE is
higher in the first few months after cancer is diagnosed,
and subsequently decreases with time.[3,4] A literature
review indicates that surgery, chemotherapy, or radio-
therapy can be risk factors for VTE.[5] Radiation-
induced vascular disease has been reported. Concurrent
chemotherapy and radiotherapy is the standard treat-
ment for patients with advanced cervical cancer, and it
increases survival.[6] Although the number of long-term
survivors has increased, data on the incidence of
radiotherapy- or chemotherapy-induced VTE remains
limited. Thus, the aim of this study was to evaluate the
incidence of VTE in cervical cancer patients during a 5-
year follow-up.
Materials and methods
The study analyzed 2003–2008 data from the National
Health Insurance Research Database (NHIRD), provided
by the National Research Institutes in Taiwan. The
NHIRD contains the medical benefit claims for 97% of
the population from a registry of board-certified physi-
cians and contracted medical facilities. The procedures
we followed were in accordance with the ethical stan-
dards of the committee on human experimentation of
our institution and with the Helsinki Declaration. This
study was approved by the Institutional Review Board at
* Correspondence: oncology158@yahoo.com.tw
†Equal contributors
1Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital,
Chiayi, Taiwan
5School of Medicine, Tzu Chi University, Hualien, Taiwan
Full list of author information is available at the end of the article
© 2012 Tsai et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Tsai et al. BMC Research Notes 2012, 5:316
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Buddhist Dalin Tzu Chi General Hospital and approved
number is B10001017.
The study included two cohorts. The principal diagno-
sis in the first cohort was cervical cancer, identified by
the International Classification of Disease, Ninth Revi-
sion, Clinical Modification (ICD-9-CM) code 180. The
different treatment modalities included surgery alone
(S), radiotherapy alone (RT), surgery plus radiotherapy
(SRT), surgery plus chemotherapy and radiotherapy
(SCRT), surgery plus chemotherapy (SCT), chemother-
apy and radiotherapy (CCRT), and chemotherapy alone
(CT). Participants in the second cohort, who served as a
control group, underwent appendectomy (ICD-OP code
47). Appendectomy patients were selected as a control
group because of their similarity to the general popula-
tion.[7,8]
Data on each patient were collected starting from the
first hospitalization or outpatient visit in 2003. Totally,
1013 cervical cancer patients after treatment and 2026
appendectomy patients were eligible. Because of signifi-
cant differences in mean age and comorbidities be-
tween the 2 groups, the control cohort criteria were
further refined by randomly selecting 1013 matched fe-
male appendectomy patients at 1: 2 ratio based on age
and comorbidities.
The primary dependent variable was venous thrombo-
embolism (VTE; ICD-9-CM codes 415.11,415.19,451.11,
451.19,451.81,453.40,453.41,453.42,4538–4539). In both
Table 1 Demographic characteristics and comorbidities of the cervical cancer and control groups
Variable Cervical cancer group (N=1,013)No. (%)Control group(N=2,026)No. (%)
p
Age, year
<0.001
≦44366 (36.1)641 (31.6)
45–54325 (32.1)556 (27.4)
55–64155 (15.3)351 (17.3)
65–74 130 (12.8)325 (16.0)
≧7537 (3.7)153 (7.6)
Hypertension
<0.001
Yes256 (25.3) 395 (19.5)
No 757 (74.7)1631 (80.5)
Diabetes0.22
Yes130 (12.8) 229 (11.3)
No883 (87.2) 1797 (88.7)
Coronary heart disease
<0.001
Yes92 (9.1)90 (4.4)
No921 (90.9)1936 (95.6)
Hyperlipidemia
<0.001
Yes 36 (3.6)30 (1.5)
No977 (96.4)1996 (98.5)
Geographic region0.008
Northern 444 (43.8)942 (46.5)
Central 289 (28.5)496 (24.5)
Southern262 (25.9)518 (25.6)
Eastern18 (1.8)70 (3.5)
Urbanization level 0.06
Urban268 (26.5) 618 (30.5)
Suburban 464 (45.8) 870 (42.9)
Rural 281 (27.7)538 (26.6)
EC0.01
EC 1, 2 384 (37.0)836 (41.3)
EC 3 442 (43.6)897 (44.3)
EC 4 187 (18.5)293 (14.5)
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groups, subjects who suffered aVTE and diagnosed before
the index date were excluded from the data analysis.
Patients were also excluded if distant metastases were
diagnosed at initial.
Deaths recorded in the database were marked to cal-
culate the vascular event-free survival, with cases cen-
sored if the patients died from non-vascular causes
during follow–up. The independent variables were age,
comorbidities, geographic region, urbanization level, and
socioeconomic status. Comorbidities included hyperten-
sion, diabetes, coronary heart disease, and hyperlipid-
emia. There were four geographic regions (Northern,
Central, Southern, and Eastern) and three urbanization
levels (urban, suburban, and rural). This study also used
enrollee category (EC) as a proxy measure for the socio-
economic status. All patients were categorized as EC1
(the highest socioeconomic status), EC2, EC3, or EC4
(the lowest socioeconomic status). These variables were
associated with vascular disease.[9-11]
Statistical analysis
The statistical software packages SAS (version 9.2; SAS
Institute, Inc., Cary, NC, USA) and SPSS (version 17;
SPSS Inc., Chicago, IL, USA) were used for data analysis.
Inter-cohort differences in the frequency of variables
were evaluated using the chi-square test. Cox regression
model analysis was used to calculate the effects of VTE
events on the case and control groups after adjusting for
confounders. The risk factors included age, comorbid-
ities, geographic region, urbanization level, and socioe-
conomic status. The vascular event-free survival was
calculated using the Kaplan-Meier method. P<0.05 was
defined as statistically significant.
Results
The distribution of demographic characteristics and
comorbidities for the two cohorts is shown in Table 1.
Compared to the control group (after matching), the
case group had a high prevalence of hypertension, cor-
onary heart disease, hyperlipidemia, and diabetes. There
were 321, 162, 246, 69, 43, 36, and 624 patients in the
RT, SRT, CCRT, SCRT, SCT, CT, and S groups, respect-
ively. The 5-year cumulative risk of VTE in the RT, SRT,
CCRT, SCRT, SCT, CT, and S groups was 3.0%, 3.8%,
3.0%, 3.0%, 6.5%, 11.0%, and 2.1%, respectively. If we
excluded chemotherapy alone, there were no significant
differences in the prevalence of vascular events between
different treatment modalities. In addition, the 6 months,
1 year and 5 year cumulative risk of VTE in all case
groups were 0.5%, 1.4% and 2.9%, respectively.
At the end of follow-up in 2008, a total of 39 patients
had VTE, including 33 in the cervical cancer group and
6 in the control group. The median interval between
treatment and the VTE event was 21.4 months. The
average range for follow-up duration was 66.5 months.
The 5-year cumulative risk of VTE was significantly
higher for the cervical cancer group than for the con-
trols (3.3% vs 0.3%, p<0.001; Figure 1). Figure 2 shows
survival in cervical cancer patients by comparing the
vascular event of VTE. Cervical cancer patients without
VTE had significantly higher survival (75.3% vs 30.3%,
p<0.001; Figure 2).
Unadjusted and adjusted hazard ratios for the associ-
ation of VTE with cervical cancer after treatment and
appendectomy are shown in Table 2. After adjustments
for age and comorbidities, the hazard ratio for VTE dur-
ing the 5-year follow-up was 10.14 times higher than
among controls.
Five risk factors (age older than 55 years, hypertension,
diabetes, coronary artery disease, and hyperlipidemia)
were used to stratify the cervical cancer cohort into 2
groups: a low-risk group (n=276; no risk factors), and
high-risk group (n=737; ≥1 risk factor). The 5-year cu-
mulative risks of VTE in the stratified groups were 2.2%
and 3.4%, respectively (Table 3).
Discussion
Cervical cancer is an important health problem. Although
its incidence is decreasing, it remains the most important
cause of cancer death in women from Taiwan. VTE is a
life-threatening condition in cervical cancer. It is import-
ant to record the incidence of VTE and design preventive
strategies. For all cervical cancer patients, the 5-year cu-
mulative risk of VTE was 3.3%. Our study reveals that cer-
vical cancer patients have a higher cumulative risk of VTE
as compared to the general population.
The incidence of VTE in cervical cancer can be strati-
fied into patient, tumor, or treatment-related. However,
Figure 1 Figure reveals the cumulative risk of VTE in patients
with cervical cancer and control patients.
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it is difficult to separate these three categories. Few
reports described the risk factors for patients with
cervical-cancer-related VTE, which include age[12],
comorbidities[13], immobilization[14], or inherited traits
[15]. However, these reports were not recorded specific-
ally in patients with cervical cancer.[2] For cancer-
related VTE, Chew et al. reported the incidence of VTE
from cancer diagnosis data. The VTE rate of uterus at
one year was 1.6%.[16] Furthermore, the stage of the dis-
ease is defined by tumor extension and the extent to
which it influences venous compression and stasis. Im-
portantly, clinical findings reported an increased VTE
risk in the advanced stages.[17] This means that the inci-
dence of VTE correlates with the biological aggressive-
ness of the tumor.[18] Our study had similar reports,
and cervical cancer patients without VTE experienced
significantly higher survival rates.
Compared with the general population, cancer patients
are often observed to have lower socioeconomic status.
[19] This has subsequently been associated with a higher
prevalence of comorbidities, such as diabetes mellitus,
hypertension, or hyperlipidemia. These factors exacer-
bate vascular disease. In our study, five risk factors were
used to stratify the cancer patients into low- and high-
risk groups. The 5-year VTE incidence was lower in the
low-risk group, 2.2%, than in the high-risk groups, 3.4%.
Patients with more comorbidities had a higher risk of
VTE. Therefore, interventions aimed at VTE prevention
are extremely important. Complete surveys of modifiable
risk factors and intensive lifestyle modification are
recommended in patients with multiple comorbidities.
In addition, some studies reported that low-molecular-
weight heparin (LMWH) for thromboprophylaxis shows
benefits for patient survival.[20] Further studies are
recommended to determine the role in primary preven-
tion of VTE.
Several limitations of this study should be mentioned.
First, during data collection, the recording of VTE events
in the NHIRD may have been inadvertently missed. In a
multivariate analysis, the increased incidence of VTE was
unrelated to the addition of platinum-based chemotherapy
to radiotherapy. The relatively small size of the census
populations and the relatively short follow-up period
probably hindered the analysis. Second, the NHIRD is
used primarily for administrative purposes and does not
provide information on clinical characteristics, including
staging, VTE severity, and biochemical data. Conse-
quently, these pieces of data were not available for analysis
in this study. Third, the NHIRD database does not have
information on tobacco use, dietary habits, and body mass
index, which may be additional risk factors for VTE.
Forth, the vascular events in cervical cancer are low (only
33 events from 2003–2008), we preferred to use whole
cervical cancer population to match control group. Al-
though appendicitis is subject to Berkson’s bias, there are
evidences that appendectomy patients could be selected as
a control group because of their similarity to the general
population.[7,8,21] Appendectomy patients are an accept-
able comparator. Take together, given the magnitude and
statistical significance of the effects observed in this study,
these limitations are unlikely to alter our conclusion.
Conclusion
In this cohort study, the cumulative risk of VTE was sig-
nificantly higher in cervical cancer patients than in the
general population. Cervical cancer patients with VTE
Figure 2 The survival of cervical cancer patients with VTE
compared with survival in patients without VTE.
Table 2 Crude and adjusted hazard ratios for different vascular events in the 5-year follow-up period
Events(%)UnadjustedHR (95%CI)
p
AdjustedHR (95%CI)
p
VTEControl group (N=2026) 6 (0.3)11
Cervix cancer group (N=1013)33 (3.3) 10.87 (4.54–25.99)
<0.00110.14 (4.19–24.54)
<0.001
Adjusted for age, hypertension, diabetes, coronary heart disease, hyperlipidemia, geographic region, urbanization level, and enrollee category.
VTE indicates venous thromboembolism.
Table 3 The annual VTE cumulative risk in different
stratified groups
N of Risk FactorsVTEevents,N (%)5-yearVTErisk (%)
0 (N=276) 7 (2.5) 2.2
1 (N=737)26 (3.5) 3.4
Risk factors included age older than 55 years, hypertension, diabetes, coronary
artery, disease, and hyperlipidemia.
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had significantly lower survival rates. Strategies to re-
duce these risks need to be examined.
Acknowledgment
This study utilizes data from the National Health Insurance Research
Database provided by the Bureau of National Health Insurance, Department
of Health, and managed by National Health Research Institutes (registry
number 99029). The interpretation and conclusions contained herein are not
those of the Bureau of National Health Insurance, Department of Health, or
National Health Research Institutes.
Author details
1Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital,
Chiayi, Taiwan.2Department of Chinese Medicine, Buddhist Dalin Tzu Chi
General Hospital, Chiayi, Taiwan.3Department of Otolaryngology,
Hematology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan.
4Department of Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi,
Taiwan.5School of Medicine, Tzu Chi University, Hualien, Taiwan.
Conflict of interest
The authors declare no conflicts of interest.
Authors’ contributions
TSJ, RYX and HSK developed the ideas for these studies, performed much of
the work, and drafted the manuscript. TSJ, CWY and HSK revised the
manuscript. LCC, LMS, SYC, CWY and LHY designed the study, managed and
interpreted the data. TSJ and HFC performed the statistical analysis. All
authors read and approved the final manuscript.
Received: 14 November 2011 Accepted: 21 June 2012
Published: 21 June 2012
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doi:10.1186/1756-0500-5-316
Cite this article as: Tsai et al.: The incidence of venous
thromboembolism in cervical cancer: a nationwide population-based
study. BMC Research Notes 2012 5:316.
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