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Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Frequency, demographics and risk (according to tumour type or site)
of cancer-associated thrombosis among patients seen at outpatient
DVT clinics
Shankaranarayana Paneesha1; Aidan McManus2; Roopen Arya3; Nicholas Scriven4; Timothy Farren5; Tim Nokes6; Sue Bacon7;
Anthea Nieland8; Derek Cooper9; Harry Smith10; Denise O'Shaughnessy11; Peter Rose12; for the VERITY Investigators
1Consultant,
Department of Haematology, Heart of England NHS Foundation Trust, Birmingham, UK; 2Director, MMRx Consulting, Cheam, Surrey, UK; 3Consultant, Department
of Haematology, King's College Hospital, London, UK; 4Consultant, Medical Assessment Unit, The Calderdale Royal Hospital, Halifax, UK; 5Clinical Scientist, Department
of Haematology, Barts and The London School of Medicine and Dentistry, London, UK; 6Consultant, Department of Haematology, Derriford Hospital, Plymouth, UK; 7Thrombosis
Nurse Specialist, Scarborough Hospital, Scarborough, UK; 8 Thrombosis Nurse Specialist, Northampton General Hospital NHS Trust, Northampton, UK; 9Statistical Consultant,
London, UK; 10Harry Smith, Medical Advisor, Sanofi Aventis UK*; 11Special Advisor, Blood Policy Unit, Department of Health, London, UK; 12Consultant, Department
of Haematology, Warwick Hospital, Warwick, UK
Summary
Venous thromboembolism (VTE) is a clinically important complication
for both hospitalised and ambulatory cancer patients. In the current
study, the frequency, demographics and risk (according to tumour site)
of VTE were examined among patients seen at outpatient DVT (deepvein thrombosis) clinics. Of 10,015 VTE cases, 1,361 were diagnosed
with cancer, for an overall rate of cancer-associated VTE of 13.6% in this
outpatient population. Patients with cancer-associated VTE were significantly older than cancer-free VTE cases (66.4 ± 12.7 vs. 58.8 ± 18.5
years; p<0.0001). The frequency of cancer-associated VTE peaked earlier among females than males, occurring in the sixth (137/639, 21.4%
vs. 98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs.
197/1096, 18%; p=0.036). VTE was described most frequently in common cancers – breast, prostate, colorectal and lung (56.1% of cases).
The risk of VTE varied widely across 17 cancer types. Calculating odds
Correspondence to:
Dr. Peter Rose
Consultant Haematologist, Department of Haematology
Warwick Hospital, Warwick, CV34 5BW, UK
Tel.: +44 1926 495321, ext. 4209
E-mail: [email protected]
* Current position: Medical Manager, Pfizer, Walton-On-The-Hill, Surrey, UK.
Introduction
Venous thromboembolism (VTE) is a clinically relevant disease in
cancer patients (1), with recent studies suggesting it is becoming
more frequent (2). Large studies have shown that clinically apparent VTE is associated with worse mortality in cancer patients than
non-cancer patients. In hospitalised cancer patients undergoing
potentially curative surgery, fatal pulmonary embolism (PE) detected at autopsy was three-fold higher than in patients without
cancer undergoing surgery at the same sites (3). A Dutch cancer
registry that matched cancer patients with and without VTE
showed a 2.2-fold mortality increase in those with cancer-associated VTE (4). More recently, a study of ambulatory cancer patients
beginning chemotherapy showed that thromboembolism (includThrombosis and Haemostasis 103.2/2010
ratios (OR) to assess the effect size of cancer type on VTE risk, the highest odds were observed for patients with pancreatic cancer (OR 9.65,
95% confidence interval [CI] (5.51–16.91). Tumours of the head and
neck had higher odds than previously reported (OR 8.24, 95% CI
5.06–13.42). Reduced risk estimates were observed for skin cancers
(melanoma and non-melanoma: OR 0.89, 95% CI 0.42–1.87; OR 0.74,
95% CI, 0.32–1.69, respectively). We conclude that outpatients have a
similar rate of cancer-associated VTE as VTE patient populations previously reported, that cancer-associated VTE occurs in an older age
group and earlier in females and that outpatients exhibit distinct tumour site-specific risk from that described among hospitalised cancer
patients.
Keywords
Clinical studies, cancer, venous thrombosis
Financial support:
The VERITY registry is funded by sanofi-aventis.
Received: June 24, 2009
Accepted after major revision: October 26, 2009
Prepublished online: December 18, 2009
doi:10.1160/TH09-06-0397
Thromb Haemost 2010; 103: 338–343
ing arterial events) was a leading cause of death, accounting for up
to 9% of mortality (5).
The distinction between hospitalised cancer patients and those
patients receiving outpatient care is important when considering
thrombosis risk and prevention. The benefit of heparin-based
thromboprophylaxis has been proven in selected cancer surgery inpatients (6), but this is not the case for cancer outpatients with metastatic breast or lung cancer (7), or for those patients with intravenous
catheters (8), for whom clinical trials of low-molecular-weight heparin (LMWH) showed no benefit. These findings are reflected in current guidelines that do not recommend thromboprophylaxis in
cancer outpatients (9, 10). This suggests that high-risk populations
have not been accurately identified and that a greater understanding
is required of cancer-associated thrombosis in outpatients to ident-
Paneesha et al. Cancer-associated VTE in outpatient DVT clinics
ify appropriately high-risk subgroups of cancer patients. In the current study, we conducted an analysis to define the frequency, demographics and risk (according to tumour site) of cancer-associated
VTE among patients seen at outpatient DVT clinics.
Materials and methods
Patients
UK hospitals participating in the VEnous thromboembolism RegIsTY (VERITY) prospectively enroll patients attending DVT outpatient clinics. Details of the VERITY registry have been published
previously (11, 12). Data (demographic characteristics, medical
history, presenting symptoms, diagnosis, treatment practices including location of treatment and follow-up data) are collected by
trained hospital staff in a standardised electronic case report form
and submitted to the electronic database. Patient data are anonymised. Centers enroll patients presenting with suspected VTE and
are requested to complete the case report form irrespective of
whether the final diagnosis of VTE is positive. A variety of algorithms, mainly based on D-dimer measurement and pre-test probability, are used to exclude VTE. Confirmatory, objective testing is
undertaken according to local protocols, usually including ultrasonography or venography for suspected DVT and pulmonary angiography, lung scintigraphy or helical computed tomography
scan for suspected PE (12).
This analysis included patients who presented with suspected
VTE for whom the VTE diagnosis was recorded, together with the
presence or absence of a cancer diagnosis. Data were validated to
eliminate, as far as possible, data entry problems. Cancer is defined
in the database as current or having received treatment for cancer in
the last six months. On the cancer screen, 17 specific cancer types are
listed [bone/sarcoma, breast, central nervous system (CNS), colorectal, endocrine, gynecologic, head/neck, leukemia, lung, lymphoma,
melanoma, myeloma, non-melanoma, pancreas, prostate, urological, upper gastrointestinal (GI)] with other. No record is made of
metastatic disease, but patients with multiple cancer sites are recorded; no histological description, tumour grade or stage are recorded. We included patients who had a diagnosis of cancer after the
initial presentation for VTE in the analyses.
Statistical analysis
The Chi2 test was used to analyse the difference in categorical variables. The mean age at consultation was compared between groups
using the independent samples t-test and one-way analysis of variance (ANOVA); the Games-Howell post-hoc test was used for pairwise comparisons. Odds ratios (ORs) and corresponding 95%
confidence intervals (CIs) were calculated for individual cancer
types. Age- and sex-matched comparisons were made using a
matched dataset derived from the main dataset. A p-value <0.05
© Schattauer 2010
Figure 1: Patients included in study.
was considered statistically significant. All analyses were conducted using a commercial software package (SPSS version 16;
SPSS Inc., Chicago, IL, USA).
Results
Patients
Between February 2005 and March 2008, 49,044 patient entries
were made online in the VERITY registry by 43 hospitals in the UK.
VTE status (confirmed or excluded) and cancer status (malignancy or no malignancy) was known for 41,367 patient entries. Data
validation excluded 166 entries, for reasons of no hospital name
specified (n=86), female prostate cancer (n=11) and others
(n=69). In total, 41,201 patient entries from 39,618 individual patients were included in this analysis (씰Fig. 1).
VTE and cancer
VTE was diagnosed in 10,015 (25.3%) of the 39,618 patients in the
registry and cancer was diagnosed in 2,804 patients. Cancer type
was specified in 2,308 (82.3%) cancer cases; in 207 cases, cancer
type was recorded as “other” (i.e. not one of the 17 cancer types
listed) and in 298 cases, no record of cancer type was made. In 165
cases, more than one cancer site was reported. Among VTE cases,
13.6% (1,361/10,015) carried a diagnosis of cancer (씰Table 1).
There were 1,164 DVT, 22 cases of DVT and PE, 116 cases of PE and
59 cases designated as VTE.
The diagnosis of cancer was more frequent in VTE cases than in
VTE-negative patients: 13.6% vs. 4.9% (1,443/29,603), OR 3.07
Thrombosis and Haemostasis 103.2/2010
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Paneesha et al. Cancer-associated VTE in outpatient DVT clinics
Table 1: Cancer and VTE status for patients included in the study.
Cancer
No VTE
No
Yes
28,160
1443
VTE
Total
Total
29,603
8654
1361
10,015
36,814
2804
39,618
Table 2: Age, cancer and VTE.
Valid
Missing
Mean, years
All
VTE
All
Non-cancer Cancer
39,609
10,008
8647
9
60.38
7
59.88
7
58.85
1361
0
66.43
Median, years
63.00
62.00
61.00
68.00
Standard deviation,
years
18.23
18.05
18.54
12.70
Range, years
4–102
4–102
4–102
were significantly older (66.43 ± 12.7 vs. 58.85 ± 18.5 years;
p<0.0001).
There were marked differences in age distribution; cancer-associated VTE was less prevalent in the first five decades of life, but
markedly more prevalent in the seventh and eighth decades (씰Fig.
2). Among VTE patients, the proportion of those with cancer increased with increasing age, with gender-specific differences
(씰Fig. 3). The peak incidence of cancer-associated VTE occurred
earlier among females than males, in the sixth (137/639, 21.4% vs.
98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs.
197/1096, 18%; p=0.036), and was more frequent in males than females in the eighth (198/934, 21.2% vs. 183/1054, 17.4%; p=0.035)
and ninth decades (65/350, 18.6% vs. 82/708, 11.6%; p=0.001).
Cancer was uncommon in VTE patients younger than 31 years
(19/745; 2.6%).
22–96
(95% CI 2.84–3.31; p<0.001). VTE was more frequent in patients
with cancer (48.5%, 1,361/2,804) than those without cancer
(23.5%, 8654/36814; p<0.001).
Cancer sites in VTE patients
Four common cancers (breast, prostate, colorectal and lung) accounted for 56.1% (724/1290) of the VTE cases (for whom cancer
site was specified). Certain tumour sites were more common in
VTE cases than non-VTE cases, including CNS, pancreas, upper GI
and head/neck (씰Fig. 4).
Effect size of cancer type on VTE risk
Age and cancer-associated thrombosis
Age data are presented in 씰Table 2. Comparing non-cancer
VTE cases with cancer-associated VTE cases, patients with cancer
The ORs and adjusted ORs for the association of specific cancers
with VTE are presented in 씰Table 3. The ORs of the four most
common cancers ranged from 1.94 (95% CI 1.57 – 2.39) for prostate cancer to 4.01 (95% CI 3.26–5.32) for lung cancer. The highest
Figure 2: Age distribution in all VTE cases
and cases with cancer-associated VTE.
Thrombosis and Haemostasis 103.2/2010
© Schattauer 2010
Paneesha et al. Cancer-associated VTE in outpatient DVT clinics
served for skin cancers (melanoma and non-melanoma: OR 0.89,
95% CI 0.42–1.87; OR 0.74, 95% CI, 0.32–1.69, respectively). The
OR for VTE in patients with more than one cancer site was 3.46
(95% CI 2.67–4.48).
Discussion
Figure 3: Percentage of VTE patients with cancer within each age
decade by gender.
ORs for VTE [both adjusted (9.65, 95% CI 5.51–16.91) and unadjusted (16.75, 95% CI 5.22–53.71)] were found in patients with
pancreatic cancer. Tumours of the head and neck had high odds
(OR 8.24, 95% CI 5.06–13.42). Reduced risk estimates were ob-
This analysis of more than 10,000 patients with VTE in an outpatient treatment setting found that one in seven had a diagnosis of
cancer. This is similar to the overall prevalence of cancer-associated thrombosis reported in the literature, which is described as
approximately 15% (1). This is despite the selected population of
cancer patients treated in an outpatient setting. Indeed, a recent
prospective clinical trial confirmed that cancer was the most common reason cited for in-hospital treatment of VTE (13). In our
study, cancer was three times more common in VTE cases than in
non-VTE cases, which is low in comparison with previous findings
(14, 15) but reflects the selected nature of the registry population,
in which patients with suspected VTE who subsequently had that
diagnosis excluded would be expected to have an over-representation of thrombosis-related risk factors such as cancer.
We found that cancer-associated VTE was most prevalent in the
seventh and eighth decades of life, with peaks occurring significantly earlier in females than males reflecting, we suspect, the ear-
Figure 4: Distribution of VTE by cancer site.
© Schattauer 2010
Thrombosis and Haemostasis 103.2/2010
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Paneesha et al. Cancer-associated VTE in outpatient DVT clinics
Table 3: Odds ratios and adjusted odds ratios for VTE for specific
cancer types or tumour sites.
Cancer type
OR
95% CI
Adjusted OR
95% CI
Pancreas
9.65
5.51–16.91
16.75
5.22–53.71
Head/neck
8.24
5.06–13.42
7.54
3.60–15.78
CNS
7.19
2.98–17.34
5.34
1.56–18.33
Upper GI
6.41
3.99–10.31
4.02
2.19–7.38
Endocrine
4.93
1.79–13.57
10.01
1.28–78.20
Lung
4.17
3.26–5.32
3.87
2.73–5.49
Colorectal
4.01
3.23–4.97
4.04
2.94–5.55
Multiple sites
3.46
2.67–4.48
3.05
2.14–4.35
Myeloma
3.33
2.07–5.37
3.01
1.52–5.95
Bone/sarcoma
3.30
2.09–5.22
1.90
1.11–3.27
Gynaecologic
3.05
2.38–3.91
3.74
2.56–5.47
Urology
2.78
2.06–3.73
2.72
1.80–4.12
Breast
2.52
2.11–3.01
2.94
2.27–3.82
Prostate
1.94
1.57–2.39
1.48
1.14–1.92
Lymphoma
1.92
1.32–2.78
2.00
1.19–3.39
Leukemia
1.84
1.09–3.10
1.77
0.90–3.50
Non-melanoma
0.89
0.42–1.87
1.00
0.40–2.52
Melanoma
0.74
0.32–1.69
0.78
0.29–2.09
Other
3.44
2.62–4.53
3.79
2.51–5.71
Unspecified
1.55
1.21–1.97
2.03
1.44–2.86
VTE , venous thromboembolism; OR, odds ratio; CI, confidence interval; CNS,
central nervous system; GI, gastrointestinal.
lier peak seen in breast cancer than prostate cancer in the general
population. As far as we are aware, this is the first analysis of
cancer-associated VTE by age and gender in the setting of outpatient care. Cancer patients with VTE were significantly older
than non-cancer patients and our findings are almost identical to
the MASTER Registry, which described an 8.1-year difference in
mean ages (16). On the basis of these findings, we suggest that age
and sex should be included as potential predictive variables when
developing patient-specific risk assessment models for VTE prevention in cancer outpatients.
The most common cancer types found in VTE outpatients were
breast, prostate, lung and colorectal, mirroring previous findings
and reflecting the high prevalence of these cancers in the general
population (17). Among patients with cancer, our analysis showed
that those with pancreatic, head and neck, CNS and upper GI
cancers had the highest incidence of VTE. Our outpatient findings
are largely consistent with previous reports, which describe high
risk associated with pancreatic, brain and gastric cancer (18), but
differ for head and neck cancers. Head and neck cancers have been
shown to be at the lowest risk of thrombosis, both in hospitalised
patients with a discharge diagnosis of VTE in the Medicare Provider Analysis and Review Record database (19) and in outpatients
enrolled in the Awareness of Neutropenia in Chemotherapy Study
Group Registry (20). In the former, head and neck patients had a
Thrombosis and Haemostasis 103.2/2010
relative risk of 0.29, and in the latter, a stage-adjusted OR of 1.0 was
reported. In our analysis, head and neck cancers had the second
highest OR of 8.24, which is very similar to the risk experienced by
patients with pancreatic cancer. This extreme difference in risk of
VTE we found for head/neck cancer outpatients is hard to explain,
but it is conceivable that inpatients have a markedly different risk
profile for VTE. However, for the comparison with the Chemotherapy Study Group Registry that enrolled outpatients, we feel
that our finding is more likely to be accurate given the large
number of cases with cancer-associated VTE (n=1,361) and head/
neck associated VTE (n=61) reported here and the small numbers
of VTE cases reported overall in the Chemotherapy Study Group
Registry (n=60). Again, we suggest that these findings should contribute to study design for the development of risk assessment
models for cancer outpatient VTE prevention.
Ovarian cancer was previously identified as conferring high risk
for VTE (21), but our specified cancer list used a more generalised
term (gynecologic cancer), which does not allow us to distinguish
between different cancer types in this grouping and may explain
the relatively low OR found in our analysis. We found reduced risk
estimates for skin cancers (melanoma and non-melanoma: OR
0.89, 95% CI 0.42–1.87; OR 0.74, 95% CI, 0.32–1.69, respectively).
These findings are in keeping with the annual incidence rates of
first time VTE in California residents in Olmsted County, with the
lowest cumulative VTE incidence reported for melanoma (21).
Our data are not sufficiently detailed to provide further insight
into the role of metastatic disease or cancer stage and grade in VTE
risk. Nonetheless, an OR of 3.46 for patients with more than one
cancer site recorded is in keeping with the elevated risk of VTE
known to be associated with metastatic disease (2). Furthermore,
our data were not sufficiently detailed to allow us to determine the
impact of tumour- or stage-specific chemotherapy regimens, central venous catheter placement or the timing of surgery on VTE
risk and we did not review the prophylaxis history. To address these
limitations of the registry, we have initiated further data collection
with a revised CRF for cancer patients to include metastatic disease
fields and treatment history with the hope of offering more precise, tumour-specific VTE risk profiles.
The ORs in this study were calculated by comparing the incidence
of cancer in the VTE sample with the incidence in the non-VTE
sample. A more appropriate denominator is the population-based
incidence of each cancer type, but such data on ambulant, non-VTE
cases are not available. Thus, our denominator is a selected group
and has the limitation of potentially introducing a referral bias. We
would expect the ORs we calculated for VTE to be an underestimation compared to the general population. In an attempt to adjust
for this, we calculated ORs in an age- and sex-matched cohort. The
adjusted ORs were broadly similar, but were markedly increased for
pancreatic cancer and in particular for endocrine tumours, with reduced ORs for upper GI and CNS tumours. This indicates that pancreatic and endocrine tumours are markedly more thrombogenic
when age- and sex-matched cohorts are compared.
Registry data should not be considered as robust as clinical trial
data, and in VERITY there is no requirement to enroll consecutive
cases or to complete all data fields. This introduces the possibility of
© Schattauer 2010
Paneesha et al. Cancer-associated VTE in outpatient DVT clinics
What is known about this topic?
●
●
●
Venous thromboembolism (VTE) is a clinically relevant disease in
cancer patients.
In patients with cancer-associated thrombosis, there are few data
describing the relationships among age, sex and cancer type.
There is interest in defining outpatient-specific VTE risk.
What does this paper add?
●
●
●
Patients attending outpatient DVT clinics have a similar rate of
cancer-associated VTE as VTE patient populations previously reported.
Cancer-associated VTE has distinct age- and sex-specific differences from the overall outpatient VTE group.
We confirm previous reports of marked differences in tumour-specific VTE risk, and our data show that outpatients exhibit distinct
tumour site-specific risk from that described among hospitalised
cancer patients, in particular for patients with head/neck cancers
who are at higher risk than previously reported.
patient selection bias, with the least complicated patients with fewer
fields to complete potentially favored for entry into the database.
Data validation was performed to eliminate obvious data entry
problems but although the coding of the primary endpoint (diagnosis of VTE) was not subject to further validation, for example, by
confirming the diagnosis in the patient’s notes, we believe these diagnoses are robust and will have been confirmed locally by imaging.
Our data are distinct from other population-based studies in which
the diagnosis of VTE is based on disease coding and which could be
considered less reliable. A limitation of this study is the lack of a precise definition of what constitutes an outpatient. The cancer patients
enrolled had contact with the outpatient clinic and were recorded in
the registry, but they may have been largely hospitalised during their
care and only briefly used the outpatient service.
Identification of ambulatory cancer patients most at risk of
VTE has the potential to improve patient outcome by reducing
death and morbidity through effective prophylaxis provision. The
framework to do this accurately must include tumour-specific parameters, patient-specific factors and account for risk factor interactions. Interpretation of our findings in this context is limited by
our lack of data on the timing and type of therapeutic intervention
in these cancer patients. Nonetheless, our findings, particularly the
estimation of tumour-specific risk, will contribute to the design of
studies to identify patient groups that require VTE prevention.
Acknowledgements
The VERITY Steering Committee thanks the investigators for collecting the data. Editorial assistance was provided by Dr. Lucy Hyatt.
© Schattauer 2010
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