Critical Reviews in Oncology/Hematology 76 (2010) 196207

Cancer patients with cardiovascular disease have survival rates

comparable to cancer patients within the age-cohort of 10 years older
without cardiovascular morbidity
Maryska L.G. Janssen-Heijnen a,b, , Karolina Szerencsi a , Saskia A.M. van de Schans a ,
Huub A.A.M. Maas c , Jos W. Widdershoven d , Jan Willem W. Coebergh a,b
b

a Department of Research, Eindhoven Cancer Registry, Eindhoven, The Netherlands

Department of Public Health, Erasmus University Medical Centre, Rotterdam, The Netherlands
c Department of Geriatric Medicine, Tweesteden Hospital, Tilburg, The Netherlands
d Department of Cardiology, Tweesteden Hospital, Tilburg, The Netherlands

Accepted 26 November 2009

Contents
1.
2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Patient characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. The influence of cardiovascular disease on treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. The influence of cardiovascular disease on survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Prevalence of cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Cardiovascular diseases and stage of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Cardiovascular disease and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Cardiovascular disease and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Strengths and limitations of the study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract
Due to aging of the population the prevalence of both cardiovascular diseases (CVDs) and cancer is increasing. Elderly patients are often
under-represented in clinical trials, resulting in limited guidance about treatment and outcome. This study gives insight into the prevalence of
CVD among unselected patients with colon, rectum, lung, breast and prostate cancer and its effects on cancer treatment and outcome. Over
one fourth (N = 11,200) of all included cancer patients aged 50 or older (N = 41,126) also suffered from CVD, especially those with lung (34%)
or colon cancer (30%). These patients were often treated less aggressively, especially in case COPD or diabetes was also present. CVD had
an independent prognostic effect among patients with colon, rectum and prostate cancer. This prognostic effect could not be fully explained
by differences in treatment.
Corresponding author at: Department of Research, Eindhoven Cancer Registry, P.O. Box 231, 5600 AE Eindhoven, The Netherlands.
Tel.: +31 40 2971616; fax: +31 40 2971610.
E-mail address: research@ikz.nl (M.L.G. Janssen-Heijnen).

1040-8428/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2009.11.004

M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

197

Conclusions: Many cancer patients with severe CVD have a poorer prognosis. More research is needed for explaining the underlying factors
for the decreased survival. Such research should lead to treatment guidelines for these patients.
2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cancer; Cardiovascular diseases; Comorbidity; Prevelance; Prognosis; Treatment; Population-based

1. Introduction
Due to aging of the population, the mean age of cancer patients and the presence of comorbidity is increasing.
In cancer patients aged 65 or older about 60% had one or
more concomitant disease(s); 23% had cardiac diseases [1].
In 2000, in the Netherlands, cardiovascular disease (CVD)
was the number one cause of death, accounting for 33%
of the total mortality [2]. In the next 15 years the incidence of cancer among those aged 65 or older is expected
to increase with 43% in men and 36% in women, so the proportion of elderly people with both cancer and CVD will
increase [3]. Apart from affecting life expectancy, cardiovascular disease can also complicate cancer treatment and
(dose of) treatment might be adjusted more often. Previous population-based studies have shown that patients with
comorbidity among prostate [1,411], breast [1219], and
colorectal cancer [2023] were treated less aggressively and
had a worse survival. Previous studies among patients with
non-small cell lung cancer (NSCLC) have shown that patients
with CVD were less likely to undergo surgery and that mortality (especially due to CVD) was higher compared to patients
without cardiovascular diseases [24,25].
Elderly and especially those with comorbidity are underrepresented in clinical trials due to exclusion criteria [26],
resulting in limited guidance about treatment and outcome in
these patients. This study gives insight into the prevalence of
CVD among unselected cancer patients and investigates the
relationship of CVD with stage of cancer at diagnosis, the
effect on cancer treatment and survival.

ing comorbidity [1]. Cardiovascular disease includes valvular

disease, myocardial infarction, angina pectoris, congestive
heart failure, cardiomyopathy, arrhythmias, deep vein thrombosis, abdominal aorta aneurysm, claudicatio intermittens
and cerebrovascular disease. Patients diagnosed with cancer
of the colon, rectum, non-small cell lung cancer (NSCLC),
small cell lung cancer (SCLC), breast and prostate (most
common tumour types) between 1995 and 2006 and aged 50
years or older were included. Since preoperative radiotherapy
for rectal cancer was only recommended in treatment guidelines since 2002, these patients were included from 2002 to
2006. Patients were excluded if the diagnosis of cancer was
obtained at autopsy and when it did not concern a primary
tumour. Prevalence and general characteristics were based on
all stages of the tumours. The effect of CVD on treatment and
overall survival was analysed by stage.

2. Patients and methods

2.1. Patients
The Eindhoven Cancer Registry collects data on all
patients newly diagnosed with cancer in the southern part of
the Netherlands. This area comprises 2.3 million inhabitants,
10 general hospitals and 2 radiotherapy institutes. Completeness of the registry is over 95% [27]. Trained registration
clerks actively collect data on patient characteristics, prognosis, topography, histology, stage and information about initial
treatment directly from hospital records. The hospital record
is considered to be the most complete source of information on the patients past and current health status. Since
1993 the Eindhoven Cancer Registry collects serious comorbidity at the time of cancer diagnosis. A slightly modified
version of the Charlson comorbidity index is used for record-

Fig. 1. (a) Prevalence of cardiovascular disease in female patients, according

to tumour type and age, (b) prevalence of cardiovascular disease in male
patients, according to tumour type and age.

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Table 1
Patient characteristics according to type of cancer and the presence of cardiovascular disease.
Stagesa 1234 (%)

COPD (%)

DM (%)

SES 1234 (%)

3844126
434395

11
5

24
9

38321812
2739295

61
46

17392618
15382621

15
9

21
10

3337228
2836306

73
67

71
56

30302218
28282420

16
9

19
9

3336247
2540314

3071 (34)
5939 (66)

70
67

84
77

3466b
3268b

30
26

15
8

3539215
3141253

SCLC
CVD
No. CVD

687 (33)
1383 (67)

70
65

77
65

4060c
4456c

29
22

17
8

4139155
3440224

Prostate
CVD
No. CVD

2736 (32)
5799 (68)

72
69

14
11

12
8

2838286
2337364

Tumour type and presence of CVD

N (%)

Median age (years)

Breast
CVD
No. CVD

1494 (15)
8707 (85)

74
63

Colon
CVD
No. CVD

2175 (30)
5019 (70)

75
69

Rectum
CVD
No. CVD

1037 (25)
3079 (75)

NSCLC
CVD
No. CVD

Male (%)

6641119
7621318

SES = socioeconomic status: 1 = low, 2 = middle, 3 = high, 4 = living in an institution. All variables have a significant different distribution between the CVD
and no CVD group (Chi-square p < 0.10), except for the relationship with stage among rectum carcinoma (p = 0.13).
a Unknown stage excluded (ranging from 2% to 18% among the various cancer types).
b Loclaizednon-localized.
c Limitedextensive.

The study population consisted of all cancer patients

with CVD (also those with 2 or more comorbid conditions of which one consisted of CVD). Because of the high
prevalence of diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD) among cancer patients with
CVD we also focussed on the application of cancer therapies and survival among patients with both CVD and
DM/COPD. For all analyses the reference population consisted of cancer patients with other comorbid conditions than
CVD, COPD or DM and cancer patients without comorbid
conditions.
Pathological tumour stage was classified in four categories
based on the pathological/post-operative TNM classification.
That for lung cancer was classified in two categories: NSCLC
as localized (stages I and II) or non-localized (stages III and
IV); SCLC as limited or extensive disease. Clinical TNM
was used when pathological TNM was not available. Cancer
treatment was defined as surgery, surgery plus adjuvant therapy and combined chemoradiation therapy (the latter only
for SCLC). Surgery did not comprise diagnostic operations
and biopsies. Postal codes of residential area were used to
establish the socioeconomic status (SES) of diagnosed cancer patients. At the six-position level of postal code, data on
household income and economical value of the house are
available from fiscal data. Patients were categorized as: low,
medium and high socioeconomic status, and a separate category of patients who were institutionalized (i.e. an elderly or
nursing home). Follow-up of all patients was completed until
January 1st, 2008. In addition to passive follow-up from the
hospital records, this information was actively obtained from

the Municipal personal records database that registers vital

status.
2.2. Statistical analyses
The age-specific prevalence of CVD for each tumour type
was calculated separately for men and women. Differences
in treatment between patients with and without CVD were
tested with the chi-square test. Logistic regression analysis was used to evaluate the independent influence of CVD
on treatment of cancer. Age was included as a categorical variable because there was no linear relation between
treatment and age. For each tumour type and stage, models
were fitted with receiving therapy as dependent variable
and CVD, CVD + COPD, CVD + DM, age, gender and SES
as independent variables. The clinical TNM stage was used
when surgery was the dependent variable, because surgery
decisions are based on this tumour stage. An exception has
been made for patients with colorectal cancer because the
majority underwent surgery and cTNM is generally not determined. When interaction was found between CVD and other
dependent variables, the results were stratified per variable
outcome.
Survival time was defined as the time from diagnosis to
death or January 1st, 2008 for the patients who were still alive.
The crude survival was calculated and the independent prognostic effect of CVD was estimated by using Cox regression
models. The proportional hazard assumption of CVD was
evaluated by applying KaplanMeier curves. Univariate differences in survival were evaluated with the log rank test. The

M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

hazard rates for death (model A, unadjusted) were adjusted

for age, gender, SES, tumour size, nodal status and differentiation grade (model B). In model C treatment was included
to investigate whether the effect of CVD on prognosis could
be explained by differences in treatment. Hazard ratios with
95% confidence intervals were reported. The SAS computer
package (version 8.2) was used for all statistical analyses
(SAS Institute Inc., Cary, NC, USA, 1999).

199

In contrast, earlier stages at diagnosis were found in case of

NSCLC, colon and rectal cancer.
The prevalence of COPD was significantly higher among
patients with CVD and varied from 11% among patients with
breast cancer to 30% among patients with lung cancer. DM
also occurred significantly more often among patients with
CVD and varied from 12% among patients with prostate cancer to 24% among patients with breast cancer. Cancer patients
with CVD had a significantly lower SES than patients without
CVD.

3. Results
3.1. Patient characteristics
Fig. 1a and b shows that the prevalence of CVD was
higher among men and among patients with lung or colon
cancer, and increased with age in both men (up to 49% among
patients aged 75 or older with colon cancer) and women (up
to 40% among patients with lung cancer). Table 1 gives baseline characteristics of cancer patients with CVD and cancer
patients without CVD. Patients with CVD were older and
were significantly more often male. Patients with CVD had
more extensive disease in case of SCLC and breast cancer.

3.2. The inuence of cardiovascular disease on

treatment
Fig. 2 shows the influence of CVD, CVD + COPD and
CVD + DM in each age group. The proportion receiving
adjuvant chemotherapy (CT) among patients diagnosed with
colon cancer stage III seemed to be lower among patients with
combined CVD and COPD. Among patients with pT2 or pT3
rectal cancer the proportion receiving preoperative radiotherapy was clearly lower among patients with both CVD and
diabetes (Fig. 2B).

Fig. 2. Treatment of cancer according to age and comorbidity, (A) colon cancer stage III, (B) rectal cancer pT2pT3, (C) localized NSCLC, (D) SCLC limited
disease, (E) breast cancer, T1T2, (F) prostate cancer stages III.

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Fig. 2. (Continued).

The proportion undergoing surgery of patients with localized NSCLC was lower among patients with combined CVD
and COPD (Fig. 2C). Patients older than 65 with limited
SCLC received less combined radiotherapy (RT) and CT if
CVD was present (Fig. 2D), and these proportions were even
lower when COPD of diabetes were also present.
Among breast cancer patients undergoing lumpectomy the
proportion receiving adjuvant radiotherapy was significantly
lower for those with combined CVD + COPD or CVD + DM
(Fig. 2E).
The proportion of patients with stage I or II prostate cancer
undergoing surgery decreased when CVD was present (age
groups 5064 and 6574, Fig. 2F).
After adjustment for age, SES and gender almost all effects
of CVD on treatment disappeared except for the lower proportion undergoing surgery for prostate cancer (Table 2). When
considering the effect of additional comorbid conditions,
patients with CVD and diabetes had a lower chance of receiving preoperative RT in case of rectal cancer, and surgery in
case of prostate cancer. The combination of CVD and COPD
led to less surgery in patients with NSCLC or prostate cancer, and also to less chemoradiation in SCLC. Breast cancer

patients undergoing lumpectomy with both CVD and COPD

received adjuvant radiotherapy less often.
3.3. The inuence of cardiovascular disease on survival
Fig. 3 shows survival curves according to age and CVD.
Colon, rectum, breast and prostate cancer patients with CVD
aged 5064 had a prognosis that was comparable to the agecohort without CVD that was 10 years older. The presence
of additional COPD or diabetes led to a further increased
risk of dying (Table 3). After adjustment for other prognostic variables (age, SES, gender, tumour size, nodal status,
and differentiation grade) patients with CVD experienced
a 1.22.1 times higher risk of dying compared to patients
without CVD for most tumour types (Table 3). The effect of
CVD did not reach statistical significance at the 0.05 level for
patients with NSCLC, SCLC (except those aged 75 or older)
and for patients with breast cancer. Further adjustment for
treatment did not clearly change the odds ratios for dying.
Among patients with prostate cancer, colon cancer (stages
III) and limited SCLC the effect of CVD on survival was
different for the age groups and was therefore presented sep-

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201

Table 2
Odds Ratios (OR) for receiving treatment for patients with CVD, CVD + COPD and CVD + DM, according to tumour type and treatment.
Tumour and stage

Therapy

Comorbiditya

Unadjusted OR (95% CI)

Adjusted ORb (95% CI)

Colon cancer stages III

Surgery

CVD
CVD + COPD
CVD + DM

0.8 (0.41.7)
2.0 (0.314.8)
1.0 (0.33.3)

1.2 (0.62.4)
2.7 (0.420.5)
1.3 (0.44.5)

Colon cancer stage III

Adjuvant chemotherapy

CVD
CVD + COPD
CVD + DM

0.7 (0.50.8)
0.5 (0.30.8)
0.4 (0.30.7)

0.9 (0.71.2)
0.8 (0.41.4)
0.8 (0.51.5)

Rectal cancer stages III

Surgery

CVD
CVD + COPD
CVD + DM

0.6 (0.41.1)
0.5 (0.21.2)
1.5 (0.46.3)

1.0 (0.51.7)
0.8 (0.32.0)
2.5 (0.610.8)

Rectal cancer T2 + T3, M0, since 2002

Preoperative RT

CVD
CVD + COPD
CVD + DM

1.0 (0.71.4)
1.1 (0.52.6)
0.4 (0.20.7)

1.1 (0.71.6)
1.1 (0.52.6)
0.4 (0.20.7)

NSCLC localized disease

Surgery

CVD
CVD + COPD
CVD + DM

0.7 (0.60.9)
0.3 (0.20.4)
0.6 (0.40.9)

1.1 (0.81.4)
0.4 (0.30.6)
0.9 (0.51.4)

SCLC limited disease

CT + RT

CVD
CVD + COPD
CVD + DM

0.7 (0.51.1)
0.4 (0.20.6)
0.3 (0.10.8)

0.8 (0.51.3)
0.5 (0.20.9)
0.4 (0.21.0)

Breast cancer stages IIII, T1T2, undergone lumpectomy

Adjuvant radiotherapy

CVD
CVD + COPD
CVD + DM

0.4 (0.20.8)
0.1 (0.00.4)
0.3 (0.10.6)

0.5 (0.31.0)
0.1 (0.00.4)
0.4 (0.11.0)

Prostate cancer stages III

Surgery

CVD
CVD + COPD
CDV + DM

0.4 (0.30.5)
0.2 (0.10.4)
0.2 (0.10.4)

0.5 (0.40.6)
0.4 (0.20.7)
0.3 (0.20.6)

a
b

Reference group consisted of patients without CVD, COPD or DM.

Adjustment has been made for age, socioeconomic status, and gender.

arately. Among patients with stage I or II colon cancer over

65 years old, the risk of dying for those with CVD compared
to those without CVD was over 1.5 times higher. Among
patients with SCLC the risk of dying for those with CVD
compared to those without CVD was only higher among
those aged 75 or older (HR = 2.0). Finally, among patients
with prostate cancer, the increased mortality risks for CVD
were most marked among younger patients (Table 3). For
many tumour types, the HR for dying was higher for patients
with CVD in combination with either COPD or DM, and was
especially high for stage I or II colon cancer patients with both
CVD and COPD (HR up to 4.4) and for stage I or II prostate
cancer (HR up to 6.1, Table 3).

4. Discussion
Over one fourth of all cancer patients aged 50 or older also
suffered from cardiovascular diseases, especially those aged
75 or older and those with lung or colon cancer. Although
patients with NSCLC, colon or rectal cancer were diagnosed
in an earlier stage when CVD was present, the opposite was
seen among patients with SCLC or breast cancer. Patients
with CVD were often treated less aggressively, especially
elderly and in case COPD or diabetes was present in combination with CVD. CVD had an independent effect on survival,
which could hardly be explained by differences in treatment.

In breast, colon, rectal and prostate cancer survival curves of

patients with CVD aged 5064 were comparable to those of
patients without CVD but within an age-cohort of 10 years
older. The effect on survival was less clear among patients
with lung cancer.
4.1. Prevalence of cardiovascular diseases
Due to new treatment modalities CVD has become
a chronic disease and patients have a considerable life
expectancy. This means that these (elderly) patients are at
risk for cancer and therefore the prevalence of patients with
both cancer and CVD has increased. The prevalence of CVD
among cancer patients was higher than that among general patients aged 55 or older admitted to Dutch hospitals
[28]. The high prevalence of CVD in patients with lung or
colon cancer can be explained by similarity in risk factors
[24,2931]. Ross et al. have reviewed the concept of similarities in the pathways of CVD and cancer [32]. Oxidative
stress has a central role in the initiation of atherosclerosis and
cancer. The generation of oxidative stress has been associated
with hyperlipidemia, hypertension and smoking. Hyperlipidemia is associated with colon cancer and CVD, whereas
smoking is associated with lung cancer and CVD. Furthermore, male gender and increasing age are also risk factors
for developing CVD [33], which is reflected by the results
of the present study. As previous studies showed, the lowest

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M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

prevalence of CVD was found in breast and prostate cancer

patients [34,35].
4.2. Cardiovascular diseases and stage of cancer
Patients with breast cancer and SCLC were more often
diagnosed with advanced disease stage in the presence of
CVD, whereas NSCLC and colorectal cancer patients were
more often diagnosed with localized disease. Cancer might be
detected earlier because patients with CVD are under surveillance which might lead to earlier diagnosis of cancer. Also,
cancer patients diagnosed with a resectable tumour undergo
preoperative examinations, especially when it concerns high
risk surgery. This might lead to diagnosis of previously
unknown CVD. Diagnostic bleeding as in hemoptoe or
rectal blood loss may occur earlier in patients with CVD
while they often use drugs that affect their hemostatic system. This could explain the higher prevalence of CVD in
early stage NSCLC and colorectal cancer patients. In contrast, cancer might also be detected later because complaints
of cancer are assigned to CVD. We can only postulate why
breast cancer is more frequently diagnosed with advanced

stage in patients with CVD. A lesser adherence to breast

cancer screening program in patients with CVD and their
relatively lower socioeconomic status may play a role. Three
population-based American studies have shown conflicting
results with respect to the influence of comorbidity on stage of
cancer. Fleming et al. [36] showed that breast cancer patients
with CVD had 13% lower odds of being diagnosed with
advanced breast cancer, while Yancik et al. [17] concluded
that comorbidity did not have any influence on disease stage
in breast cancer patients. Gonzalez et al. [37] showed that
comorbidity (measured with Charlson comorbidity index) in
breast, colorectal and prostate cancer patients was associated
with a more advanced stage at the time of diagnosis.
4.3. Cardiovascular disease and treatment
No association was found between cancer treatment
and CVD after adjusting for confounding factors, except
for patients with prostate cancer and SCLC. In patients
with prostate cancer alternative treatment plans are widely
available with results comparable to surgery. Therefore the
threshold to avoid surgery is relatively low. Chemoradiation

Fig. 3. Crude survival according to the presence of cardiovascular disease and age. (A) Colon cancer stages III. (B) Colon cancer stage III. (C) Rectal cancer
stages III. (D) Localized NSCLC. (E) Limited SCLC. (F) Breast cancer stages IIII. (G) Prostate cancer stages III.

M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

203

Fig. 3. (Continued).

in case of limited SCLC gives a high rate of treatment-related

complications and, while its benefits are clear but relatively
small, any comorbidity and high age are commonly used as
contraindications to chemoradiotherapy. CVD in combination with other comorbidity (diabetes or COPD), however,
also showed a significant association with adjusted treatment in patients with rectal cancer, SCLC, NSCLC and breast
cancer.
Complications after surgery can be expected in colorectal cancer patients with comorbidity, especially in those with
deep vein thrombosis and COPD [38]. In the present study

this did not result in refraining from surgery in colorectal

cancer patients with CVD. This can probably be explained
by the fact that surgery is often inevitable for preventing
life-threatening complications of colorectal cancer, also in
patients with CVD.
In this study also no relation was found between colon
cancer patients with CVD and the receipt of adjuvant
chemotherapy. Previous studies have shown that patients with
comorbidity received chemotherapy significantly less often
[2022]. However, the specific effect of CVD was not investigated in these studies.

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M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

Table 3
Hazard ratios (HR) for overall mortality for CVD, CVD + COPD, CVD + DM according to tumour type and stage.
Tumour and stage

Comorbiditya

Colon III

CVD
5064d
6574
75+
CVD + COPD
5064d
6574
75+
CVD + DM
5064d
6574
75+

Model A HR (95% CI)

Model B adjusted HR (95% CI)

1.1 (0.71.9)
1.9 (1.52.3)
1.6 (1.41.9)

1.1 (0.61.8)
1.8 (1.42.2)
1.5 (1.31.8)

6.7 (3.313.7)
3.2 (2.24.6)
2.0 (1.42.7)

4.4 (2.09.7)
3.0 (2.14.3)
1.8 (1.42.5)

3.3 (1.66.7)
2.0 (1.42.9)
1.8 (1.42.3)

2.9 (1.46.0)
1.9 (1.32.8)
1.7 (1.42.2)

Model Cb adjusted HR (95% CI)

c

Colon III

CVD
CVD + COPD
CVD + DM

1.5 (1.31.7)
1.7 (1.22.3)
1.6 (1.22.1)

1.3 (1.21.6)
1.4 (1.01.9)
1.3 (1.01.8)

1.3 (1.21.6)
1.3 (1.01.8)
1.3 (1.01.7)

Rectum III

CVD
CVD + COPD
CVD + DM

1.7 (1.42.0)
2.7 (2.03.7)
2.1 (1.62.9)

1.3 (1.11.6)
1.9 (1.42.7)
1.5 (1.12.0)

Rectum T2T3, M0, since 2002

CVD
CVD + COPD
CVD + DM

1.7 (1.22.3)
3.8 (2.26.6)
2.2 (1.33.8)

1.3 (0.91.9)
2.5 (1.44.4)
1.6 (0.92.7)

1.3 (0.91.9)
2.5 (1.44.4)
1.5 (0.82.5)

NSCLC local

CVD
CVD + COPD
CVD + DM

1.3 (1.11.4)
1.5 (1.31.8)
1.6 (1.32.0)

1.1 (1.01.2)
1.3 (1.11.5)
1.4 (1.11.7)

1.1 (1.01.2)
1.1 (0.91.3)
1.3 (1.11.7)

SCLC limited

CVD
5064d
6574
75+
CVD + COPD
5064d
6574
75+
CVD + DM
5064d
6574
75

1.1 (0.71.5)
0.9 (0.71.3)
2.1 (1.23.6)

1.0 (0.71.5)
0.9 (0.71.3)
2.0 (1.23.5)

1.1 (0.71.6)
0.8 (0.61.2)
2.6 (1.44.8)

1.4 (0.72.7)
1.3 (0.82.0)
1.7 (0.93.1)

1.2 (0.62.4)
1.3 (0.82.0)
1.5 (0.82.8)

1.2 (0.62.4)
1.0 (0.61.6)
1.8 (1.03.3)

1.2 (0.52.8)
2.9 (1.75.1)
1.6 (0.73.7)

1.1 (0.52.5)
2.8 (1.65.1)
1.4 (0.53.4)

1.0 (0.42.4)
2.4 (1.44.4)
1.4 (0.53.8)

1.4 (0.92.1)
3.7 (1.211.7)
2.4 (1.44.3)

1.1 (0.71.7)
2.8 (0.98.8)
1.7 (0.93.0)

1.1 (0.71.6)
2.7 (0.98.7)
1.5 (0.88.7)

2.1 (1.43.1)
1.4 (1.21.7)
1.2 (1.11.4)

2.0 (1.43.0)
1.4 (1.11.6)
1.2 (1.01.4)

2.0 (1.42.9)
1.3 (1.11.6)
1.2 (1.01.4)

6.5 (3.212.8)
2.2 (1.73.1)
2.4 (1.93.0)

6.1 (3.112.2)
2.0 (1.52.8)
2.4 (1.93.0)

5.6 (2.811.2)
2.0 (1.52.7)
2.4 (1.93.0)

3.3 (1.29.0)
2.4 (1.73.1)
1.4 (1.01.9)

3.2 (1.28.8)
2.2 (1.63.1)
1.3 (0.91.8)

2.9 (1.18.0)
2.2 (1.63.0)
1.3 (0.91.8)

Breast IIII, T1T2, undergone lumpectomy

CVD
CVD + COPD
CVD + DM

Prostate III

CVD
5064d
6574
75+
CVD + COPD
5064d
6574
75+
CVD + DM
5064d
6574
75+

c
c

In model A the unadjusted hazard ratios for CVD, CVD + COPD, CVD + DM are presented, in model B adjustment has been made for age, gender, socioeconomic
status, differentiation grade, tumour size, nodal status. In model C additional adjustment has been made for treatment. When interaction was present with age
the hazard ratios are shown according to age group.
a Reference group consisted of patients without CVD, COPD or DM.
b Adjustment has been made for the following treatment according to tumour type: colon III: adjuvant CT (yes/no); NSCLC local: surgery, RT and no therapy;
SCLC limited: CT, CT + RT and no therapy; breast cancer patients undergoing lumpectomy: adjuvant RT (yes/no); prostate: surgery, RT, HT, no therapy.
c No adjustment for treatment has been made, because majority (>95%) of the patients underwent surgery.
d Interaction with age was present.

M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

Our study showed that rectal cancer patients with CVD and
diabetes were less likely to receive preoperative radiotherapy. A previous study from the Eindhoven Cancer Registry
already found that unselected patients with two or more
comorbid conditions (especially the combination of diabetes
and hypertension) received preoperative radiotherapy significantly less often [21].
In our study no influence was found of CVD on the proportion of patients with localized NSCLC undergoing surgery.
For considering cardiac risk in non-cardiac surgery not only
the presence of pre-existing cardiovascular disease needs to
be identified. Also severity of the disease, stability, prior treatment, functional capacity, age, other comorbid conditions
and type of surgery needs to be evaluated [39]. This information (except for age, presence of comorbidity and type of
surgery) is not registered by the cancer registry. Previous studies, however, have found that NSCLC patients with COPD
underwent surgery less often compared to patients without
COPD [25,40]. The lower proportion of patients with NSCLC
and both CVD + COPD undergoing surgery in this study was
therefore not surprising.
A significant relation was found in our study between
CVD in combination with COPD or DM and the decreased
receipt of combined chemoradiation among patients with
SCLC. This is in conformity with the results of JanssenHeijnen et al. [41]. Ludbrook et al. [42] showed that SCLC
patients with a Charlson comorbidity score of at least 2 had
a lower chance of combined treatment compared to patients
with a score between 0 and 1. Radiotherapy in addition to
chemotherapy does not only improve survival (cancer mortality is reduced with 14%, although no reduction was observed
in patients above 70 years) and local tumour control, but
can also lead to a small increase in treatment-related death
[4346].
In elderly breast cancer patients undergoing lumpectomy
a physician has to outweigh the benefits of adjuvant RT in the
perspective of life expectancy, costs of radiation and adverse
effects [47]. Patients with both CVD + COPD might not live
long enough to benefit from RT and are therefore likely to be
omitted from RT as it was also found in our study.
The decision to perform surgery in prostate cancer patients
is, among other considerations, related to life expectancy. The
presence of CVD shortens life expectancy [48] and patients
with CVD are expected to have a higher risk of dying from
CVD than from prostate cancer. This is comparable to other
studies, where older patients and those with comorbidity were
omitted from surgery [46].
4.4. Cardiovascular disease and survival
The impact of comorbidity (in this case CVD) on overall survival is most marked in types of cancer which have a
good prognosis [34]. In the present study a worse survival
was seen among patients with CVD for localized NSCLC,
prostate and colorectal cancer patients. This is in line with
the results of previous studies [11,15,19,23,49]. In contrast,

205

most patients with a more lethal tumour type die from cancer
before they become at risk of dying from CVD. A previous American study on causes of death among breast cancer
patients has shown that the probability of death from breast
cancer generally declined with age at diagnosis, especially
for those with localized disease [50]. In agreement with the
American study, we found an effect of CVD on risk of mortality among breast cancer patients. After adjustment for age,
gender, socioeconomic status, differentiation grade, tumour
size and nodal status, this effect did not reach significancy at
the 0.05 level.
The observation that patients with CVD have survival rates
comparable to older age groups without CVD might be an
argument to include these patients into another therapeutic
plan if treatment guidelines have age-specific recommendations (i.e. breast cancer). Of course, this statement needs to
be evaluated in prospective studies.
A negative influence of cardiovascular disease on survival of cancer might be due to several mechanisms: the
increased risk of death due to cardiovascular disease, more
contraindications for anti-cancer treatment and a higher rate
of treatment-related complications such as cardiovascular
events. Unfortunately, causes of death, treatment of the
comorbid condition and complications are not routinely registered in the cancer registry. Therefore, excess mortality due
to cardiovascular disease and death due to complications of
treatment could not be investigated. However, by adjusting
our survival analyses for treatment, we could conclude that
the increased risk of dying for patients with CVD could hardly
be explained by less aggressive treatment. This means that
other factors play an important role.
4.5. Strengths and limitations of the study
Most previous studies have investigated the influence of
comorbidity (measured as a comorbidity count or a comorbidity score/index) instead of focussing on the specific effect
of CVD or combinations of diseases as was done in this
study. Another strength of this study was the reliable source
of information: medical records, and a standardized method
for extracting data from the medical records by trained registrars [27]. A third strength was the inclusion of unselected
patients.
A limitation of this study was that information about the
severity of the comorbid condition was lacking. Therefore,
we could not differentiate between less severe and more
severe conditions. However, the cancer registry only registers severe comorbid conditions with a possible effect on
prognosis. Also we were only able to register treatment
modalities; minor adjustments in treatment regimens were
not registered (i.e. adjustments in cardiovascular treatment,
chemotherapeutic regimens or surgical procedures). With
regard to receiving adjuvant chemotherapy we did not have
information on completion or early termination of the treatment, dose, time between administration and the kind of
chemotherapy.

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M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

Furthermore, no information was available on social support, preference of patient, transportation availability and
time spent by the physician, whereas these factors also play a
role in deciding whether or not to undergo a certain treatment
[12].

5. Conclusion
This study has shown that the presence of CVD (especially in combination with COPD or diabetes) in cancer
patients influences treatment and treatment outcome. Therefore, cancer patients with severe CVD need to be discussed
in multidisciplinary meetings in the presence of a cardiologist. The underlying factors for the decreased survival
in these patients should be systematically addressed, such
as motive for non-adherence to guidelines, complications
of treatment, recurrence or progression and cause of
death.

Conict of interest
None

Acknowledgements
The authors thank the registration team of the Eindhoven
Cancer Registry for their dedicated data collection. This work
was carried out with grants from the Dutch Cancer Society
(KWF).

References
[1] Janssen-Heijnen ML, Houterman S, Lemmens VE, Louwman MW,
Maas HA, Coebergh JW. Prognostic impact of increasing age and comorbidity in cancer patients: a population-based approach. Crit Rev
Oncol Hematol 2005;55:23140.
[2] Signaleringscommissie Kanker. Kanker in Nederland: Trends, Prognoses en Implicaties Voor Zorgvraag. Amsterdam: KWF Kankerbestrijding; 2004.
[3] Driver JA, Djousse L, Logroscino G, Gaziano JM, Kurth T. Incidence of
cardiovascular disease and cancer in advanced age: prospective cohort
study. BMJ 2008;337:a2467.
[4] Fowler Jr JE, Terrell FL, Renfroe DL. Co-morbidities and survival of
men with localized prostate cancer treated with surgery or radiation
therapy. J Urol 1996;156:17148.
[5] Hall WH, Jani AB, Ryu JK, Narayan S, Vijayakumar S. The impact
of age and comorbidity on survival outcomes and treatment patterns in
prostate cancer. Prostate Cancer Prostatic Dis 2005;8:2230.
[6] Marr PL, Elkin EP, Arredondo SA, Broering JM, DuChane J, Carroll
PR. Comorbidity and primary treatment for localized prostate cancer:
data from CaPSURE. J Urol 2006;175:132631.
[7] Otto SJ, Schroder FH, de Koning HJ. Risk of cardiovascular mortality
in prostate cancer patients in the Rotterdam randomized screening trial.
J Clin Oncol 2006;24:41849.
[8] Satariano WA, Ragland KE, Van Den Eeden SK. Cause of death in men
diagnosed with prostate carcinoma. Cancer 1998;83:11808.

[9] Schwartz KL, Alibhai SM, Tomlinson G, Naglie G, Krahn MD. Continued undertreatment of older men with localized prostate cancer.
Urology 2003;62:8605.
[10] Hall HI, Satariano WA, Thompson T, Ragland KE, Van Den Eeden
SK, Selvin S. Initial treatment for prostate carcinoma in relation to
comorbidity and symptoms. Cancer 2002;95:230815.
[11] Houterman S, Janssen-Heijnen ML, Hendrikx AJ, van den Berg HA,
Coebergh JW. Impact of comorbidity on treatment and prognosis of
prostate cancer patients: a population-based study. Crit Rev Oncol
Hematol 2006;58:607.
[12] Bouchardy C, Rapiti E, Blagojevic S, Vlastos AT, Vlastos G. Older
female cancer patients: importance, causes, and consequences of undertreatment. J Clin Oncol 2007;25:185869.
[13] Cronin-Fenton DP, Norgaard M, Jacobsen J, et al. Comorbidity and
survival of Danish breast cancer patients from 1995 to 2005. Br J Cancer
2005:2007.
[14] Giordano SH, Hortobagyi GN, Kau SW, Theriault RL, Bondy ML.
Breast cancer treatment guidelines in older women. J Clin Oncol
2005;23:78391.
[15] Houterman S, Janssen-Heijnen ML, Verheij CD, et al. Comorbidity has negligible impact on treatment and complications but
influences survival in breast cancer patients. Br J Cancer 2004;90:
23327.
[16] Hurria A, Naeim A, Elkin E, et al. Adjuvant treatment recommendations
in older women with breast cancer: a survey of oncologists. Crit Rev
Oncol Hematol 2007;61:25560.
[17] Yancik R, Wesley MN, Ries LA, Havlik RJ, Edwards BK, Yates JW.
Effect of age and comorbidity in postmenopausal breast cancer patients
aged 55 years and older. JAMA 2001;285:88592.
[18] Ballard-Barbash R, Potosky AL, Harlan LC, Nayfield SG, Kessler LG.
Factors associated with surgical and radiation therapy for early stage
breast cancer in older women. J Natl Cancer Inst 1996;88:71626.
[19] Nagel G, Wedding U, Rohrig B, Katenkamp D. The impact of comorbidity on the survival of postmenopausal women with breast cancer. J
Cancer Res Clin Oncol 2004;130:66470.
[20] Gross CP, McAvay GJ, Guo Z, Tinetti ME. The impact of chronic
illnesses on the use and effectiveness of adjuvant chemotherapy for
colon cancer. Cancer 2007;109:24109.
[21] Lemmens VE, Janssen-Heijnen ML, Verheij CD, Houterman S,
Repelaer van Driel OJ, Coebergh JW. Co-morbidity leads to altered
treatment and worse survival of elderly patients with colorectal cancer.
Br J Surg 2005;92:61523.
[22] Lemmens VE, van Halteren AH, Janssen-Heijnen ML, Vreugdenhil G,
Repelaer van Driel OJ, Coebergh JW. Adjuvant treatment for elderly
patients with stage III colon cancer in the southern Netherlands is
affected by socioeconomic status, gender, and comorbidity. Ann Oncol
2005;16:76772.
[23] Rieker RJ, Hammer E, Eisele R, Schmid E, Hogel J. The impact
of comorbidity on the overall survival and the cause of death in
patients after colorectal cancer resection. Langenbecks Arch Surg
2002;387:726.
[24] Ambrogi V, Pompeo E, Elia S, Pistolese GR, Mineo TC. The impact
of cardiovascular comorbidity on the outcome of surgery for stage I
and II non-small-cell lung cancer. Eur J Cardiothorac Surg 2003;23:
8117.
[25] Dy SM, Sharkey P, Herbert R, Haddad K, Wu AW. Comorbid illnesses
and health care utilization among medicare beneficiaries with lung
cancer. Crit Rev Oncol Hematol 2006;59:21825.
[26] Townsley CA, Selby R, Siu LL. Systematic review of barriers to the
recruitment of older patients with cancer onto clinical trials. J Clin
Oncol 2005;23:311224.
[27] Schouten LJ, Hoppener P, van den Brandt PA, Knottnerus JA, Jager JJ.
Completeness of cancer registration in Limburg, The Netherlands. Int
J Epidemiol 1993;22:36976.
[28] Schram MT, Frijters D, van de Lisdonk EH, et al. Setting and registry
characteristics affect the prevalence and nature of multimorbidity in the
elderly. J Clin Epidemiol 2008:28.

M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 196207

[29] Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and
cardiovascular disease: an update. J Am Coll Cardiol 2004;43:17317.
[30] Kushi L, Giovannucci E. Dietary fat and cancer. Am J Med
2002;113(Suppl. 9B):63S70S.
[31] Larsson SC, Rutegard J, Bergkvist L, Wolk A. Physical activity, obesity,
and risk of colon and rectal cancer in a cohort of Swedish men. Eur J
Cancer 2006;42:25907.
[32] Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS.
Atherosclerosis and cancer: common molecular pathways of disease
development and progression. Ann N Y Acad Sci 2001;947:27192,
discussion 92-3.
[33] Fokkema MR, Muskiet FA, van Doormaal JJ. Lifestyle intervention
for the prevention of cardiovascular disease. Ned Tijdschr Geneeskd
2005;149:260712.
[34] Read WL, Tierney RM, Page NC, et al. Differential prognostic impact
of comorbidity. J Clin Oncol 2004;22:3099103.
[35] Vulto AJ, Lemmens VE, Louwman MW, et al. The influence of age and
comorbidity on receiving radiotherapy as part of primary treatment for
cancer in South Netherlands, 1995 to 2002. Cancer 2006;106:273442.
[36] Fleming ST, Pursley HG, Newman B, Pavlov D, Chen K. Comorbidity
as a predictor of stage of illness for patients with breast cancer. Med
Care 2005;43:13240.
[37] Gonzalez EC, Ferrante JM, Van Durme DJ, Pal N, Roetzheim RG.
Comorbid illness and the early detection of cancer. South Med J
2001;94:91320.
[38] Lemmens VE, Janssen-Heijnen ML, Houterman S, et al. Which comorbid conditions predict complications after surgery for colorectal cancer?
World J Surg 2007;31:1929.
[39] Mangano DT. Perioperative cardiac morbidity. Anesthesiology
1990;72:15384.
[40] van de Schans SA, Janssen-Heijnen ML, Biesma B, et al. COPD in
cancer patients: higher prevalence in the elderly, a different treatment
strategy in case of primary tumours above the diaphragm, and a worse
overall survival in the elderly patient. Eur J Cancer 2007;43:2194202.
[41] Janssen-Heijnen ML, Lemmens VE, van den Borne BE, Biesma B, Oei
SB, Coebergh JW. Negligible influence of comorbidity on prognosis
of patients with small cell lung cancer: a population-based study in the
Netherlands. Crit Rev Oncol Hematol 2007;62:1728.
[42] Ludbrook JJ, Truong PT, MacNeil MV, et al. Do age and comorbidity
impact treatment allocation and outcomes in limited stage small-cell

[43]

[44]
[45]

[46]

[47]

[48]

[49]

[50]

207

lung cancer? A community-based population analysis. Int J Radiat

Oncol Biol Phys 2003;55:132130.
Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of
thoracic radiotherapy for small-cell lung cancer. N Engl J Med
1992;327:161824.
Gridelli C, Langer C, Maione P, Rossi A, Schild SE. Lung cancer in
the elderly. J Clin Oncol 2007;25:1898907.
Socinski MA, Bogart JA. Limited-stage small-cell lung cancer:
the current status of combined-modality therapy. J Clin Oncol
2007;25:413745.
Warde P, Payne D. Does thoracic irradiation improve survival and local
control in limited-stage small-cell carcinoma of the lung? A metaanalysis. J Clin Oncol 1992;10:8905.
Smith BD, Gross CP, Smith GL, Galusha DH, Bekelman JE, Haffty BG.
Effectiveness of radiation therapy for older women with early breast
cancer. J Natl Cancer Inst 2006;98:68190.
Peeters A, Mamun AA, Willekens F, Bonneux L. A cardiovascular life
history. A life course analysis of the original Framingham Heart Study
cohort. Eur Heart J 2002;23:45866.
Froehner M, Koch R, Litz R, Oehlschlaeger S, Wirth MP. Which conditions contributing to the Charlson score predict survival after radical
prostatectomy? J Urol 2004;171:6979.
Schairer C, Mink PJ, Carroll L, Devesa SS. Probabilities of death from
breast cancer and other causes among female breast cancer patients. J
Natl Cancer Inst 2004;96:131121.

Biography
Maryska Janssen-Heijnen is working as a senior epidemiologist at the Eindhoven Cancer Registry. She focuses on
prognostic factors for cancer patients, with a special interest in elderly patients with comorbidity. Since 2000 she is
coordinating large population-based projects in which the
prevalence of comorbidity in cancer patients is studied, as
well as the influence of increasing age and comorbidity on
treatment, complications of treatment and prognosis.