Cancer Cohort sample paper

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Critical Reviews in Oncology/Hematology 76 (2010) 196207

Cancer patients with cardiovascular disease have survival ratescomparable 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

a Department of Research, Eindhoven Cancer Registry, Eindhoven, The Netherlandsb Department of Public Health, Erasmus University Medical Centre, Rotterdam, The Netherlands

c Department of Geriatric Medicine, Tweesteden Hospital, Tilburg, The N etherlandsd Department of Cardiology, Tweesteden Hospital, Tilburg, The Netherlands

Accepted 26 November 2009

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

2. Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

2.1. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

2.2. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

3.1. Patient characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

3.2. The influence of cardiovascular disease on treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

3.3. The influence of cardiovascular disease on survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

4.1. Prevalence of cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2014.2. Cardiovascular diseases and stage of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

4.3. Cardiovascular disease and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

4.4. Cardiovascular disease and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

4.5. Strengths and limitations of the study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Abstract

Due to aging of the population the prevalence of both cardiovascular diseases (CVDs) and cancer is increasing. Elderly patients are oftenunder-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:[email protected](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
http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.critrevonc.2009.11.004mailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.critrevonc.2009.11.004http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.critrevonc.2009.11.004mailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.critrevonc.2009.11.004


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M.L.G. Janssen-Heijnen et al. / Critical Reviews in Oncology/Hematology 76 (2010) 19 6207 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 can-

cer 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 inci-

dence of cancer among those aged 65 or older is expected

to increase with 43% in men and 36% in women, so the pro-

portion of elderly people with both cancer and CVD will

increase [3]. Apart from affecting life expectancy, cardio-vascular disease can also complicate cancer treatment and

(dose of) treatment might be adjusted more often. Previ-

ous 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-smallcell lung cancer(NSCLC) haveshown that patients

with CVDwere less likelyto undergo surgery andthat mortal-

ity (especially due to CVD) was higher compared to patients

without cardiovascular diseases[24,25].

Elderly and especially those with comorbidity are under-

represented 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.

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. Complete-

ness of the registry is over 95% [27]. Trained registration

clerks actively collect data on patient characteristics, progno-

sis, topography, histology, stage and information about initial

treatment directly from hospital records. The hospital record

is considered to be the most complete source of informa-

tion on the patients past and current health status. Since

1993 the Eindhoven Cancer Registry collects serious comor-

bidity at the time of cancer diagnosis. A slightly modified

version of the Charlson comorbidity index is used for record-

ing comorbidity[1]. Cardiovascular disease includes valvulardisease, myocardial infarction, angina pectoris, congestive

heart failure, cardiomyopathy, arrhythmias, deep vein throm-

bosis, 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 guide-

lines 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 primarytumour. 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.

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

Table 1

Patient characteristics according to type of cancer and the presence of cardiovascular disease.

Tumour type and presence of CVD N(%) Median age (years) Male (%) Stagesa 1234 (%) COPD (%) DM (%) SES 1234 (%)

Breast

CVD 1494 (15) 74 3844126 11 24 38321812

No. CVD 8707 (85) 63 434395 5 9 2739295

ColonCVD 2175 (30) 75 61 17392618 15 21 3337228

No. CVD 5019 (70) 69 46 15382621 9 10 2836306

Rectum

CVD 1037 (25) 73 71 30302218 16 19 3336247

No. CVD 3079 (75) 67 56 28282420 9 9 2540314

NSCLC

CVD 3071 (34) 70 84 3466b 30 15 3539215

No. CVD 5939 (66) 67 77 3268b 26 8 3141253

SCLC

CVD 687 (33) 70 77 4060c 29 17 4139155

No. CVD 1383 (67) 65 65 4456c 22 8 3440224

Prostate

CVD 2736 (32) 72 6641119 14 12 2838286No. CVD 5799 (68) 69 7621318 11 8 2337364

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-squarep < 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 condi-

tions of which one consisted of CVD). Because of the high

prevalence of diabetes mellitus (DM) and chronic obstruc-

tive pulmonary disease (COPD) among cancer patients with

CVD we also focussed on the application of cancer ther-apies and survival among patients with both CVD and

DM/COPD. For all analyses the reference population con-

sisted of cancer patients with other comorbid conditions than

CVD, COPD or DM and cancer patients without comorbid

conditions.

Pathological tumour stage was classifiedin four categories

based on the pathological/post-operative TNM classification.

That for lung cancer was classified in twocategories: 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 ther-

apy and combined chemoradiation therapy (the latter onlyfor SCLC). Surgery did not comprise diagnostic operations

and biopsies. Postal codes of residential area were used to

establish the socioeconomic status (SES) of diagnosed can-

cer 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 cate-

gory 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 typewas calculated separately for men and women. Differences

in treatment between patients with and without CVD were

tested with the chi-square test. Logistic regression analy-

sis was used to evaluate the independent influence of CVD

on treatment of cancer. Age was included as a categori-

cal 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 underwentsurgery andcTNM is generally not deter-

mined. 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 forthe patients whowere still alive.

The crude survival was calculated and the independent prog-

nostic effect of CVD was estimated by using Cox regression

models. The proportional hazard assumption of CVD was

evaluated by applying KaplanMeier curves. Univariate dif-

ferences in survival were evaluated with the log rank test. The


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

for age, gender, SES, tumour size, nodal status and differen-

tiation 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).

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 base-

line characteristics of cancer patients with CVD and cancerpatients 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.

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 can-certo 24%among patients with breastcancer. Cancerpatients

with CVDhad a significantlylower SESthan patients without

CVD.

3.2. The influence 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 cancerstageIII seemedto be loweramongpatientswith

combined CVD and COPD. Among patients with pT2 or pT3rectal cancer the proportion receiving preoperative radiother-

apy 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 local-

ized 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.

Amongbreast cancer patients undergoing lumpectomythe

proportion receiving adjuvant radiotherapy was significantly

lower for those with combined CVD + COPD or CVD + DM

(Fig. 2E).

Theproportion of patients with stage I or II prostate cancerundergoing surgery decreased when CVD was present (age

groups 5064 and 6574,Fig. 2F).

After adjustment forage, SESand genderalmost alleffects

of CVDon treatmentdisappearedexcept forthe lowerpropor-

tion 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 receiv-

ing 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 can-

cer, 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 influence of cardiovascular disease on survival

Fig. 3shows 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 age-

cohort 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 prognos-

tic 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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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 0.8 (0.41.7) 1.2 (0.62.4)

CVD+ COPD 2.0 (0.314.8) 2.7 (0.420.5)

CVD + DM 1.0 (0.33.3) 1.3 (0.44.5)

Colon cancer stage III Adjuvant chemotherapy CVD 0.7 (0.50.8) 0.9 (0.71.2)CVD + C OPD 0.5 (0.30.8) 0.8 (0.41.4)

CVD + DM 0.4 (0.30.7) 0.8 (0.51.5)

Rectal cancer stages III Surgery CVD 0.6 (0.41.1) 1.0 (0.51.7)

CVD + C OPD 0.5 (0.21.2) 0.8 (0.32.0)

CVD + D M 1.5 (0.46.3) 2.5 (0.610.8)

Rectal cancer T2 + T3, M0, since 2002 Preoperative RT CVD 1.0 (0.71.4) 1.1 (0.71.6)

CVD + C OPD 1.1 (0.52.6) 1.1 (0.52.6)

CVD + DM 0.4 (0.20.7) 0.4 (0.20.7)

NSCLC localized disease Surgery CVD 0.7 (0.60.9) 1.1 (0.81.4)

CVD + C OPD 0.3 (0.20.4) 0.4 (0.30.6)

CVD + DM 0.6 (0.40.9) 0.9 (0.51.4)

SCLC limited disease CT + RT CVD 0.7 (0.51.1) 0.8 (0.51.3)

CVD + C OPD 0.4 (0.20.6) 0.5 (0.20.9)CVD + DM 0.3 (0.10.8) 0.4 (0.21.0)

Breast cancer stages IIII, T1T2, undergone lumpectomy Adjuvant radiotherapy CVD 0.4 (0.20.8) 0.5 (0.31.0)

CVD + C OPD 0.1 (0.00.4) 0.1 (0.00.4)

CVD + DM 0.3 (0.10.6) 0.4 (0.11.0)

Prostate cancer stages III Surgery CVD 0.4 (0.30.5) 0.5 (0.40.6)

CVD + C OPD 0.2 (0.10.4) 0.4 (0.20.7)

CDV + DM 0.2 (0.10.4) 0.3 (0.20.6)

a Reference group consisted of patients without CVD, COPD or DM.b 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. Amongpatients 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 forstageI or II colon cancerpatientswith 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 combi-

nationwith CVD. CVDhad 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 yearsolder. 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 gen-

eral 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 simi-

larities in the pathways of CVD and cancer[32]. Oxidative

stress has a central role in the initiation of atherosclerosis and

cancer. The generationof oxidative stress has been associated

with hyperlipidemia, hypertension and smoking. Hyperlipi-

demia is associated with colon cancer and CVD, whereas

smoking is associated with lung cancer and CVD. Further-

more, 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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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 ofCVD, whereas NSCLC and colorectal cancer patients were

more often diagnosedwith localizeddisease.Cancer might be

detected earlier because patients with CVD are under surveil-

lance 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 sys-

tem. This could explain the higher prevalence of CVD in

early stage NSCLC and colorectal cancer patients. In con-trast, 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 theinfluenceof comorbidity on stage of

cancer. Fleming et al.[36]showed that breast cancer patients

with CVD had 13% lower odds of being diagnosed withadvanced 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 patientswith 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.


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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 combina-

tion with other comorbidity (diabetes or COPD), however,

also showed a significant association with adjusted treat-

ment in patients with rectal cancer, SCLC, NSCLC and breast

cancer.

Complications after surgery can be expected in colorec-

tal 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 inves-

tigated in these studies.


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Table 3

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

Tumour and stage Comorbiditya Model A HR (95% CI) Model B adjusted HR (95% CI) Model Cb adjusted HR (95% CI)

Colon III CVD c

5064d 1.1 (0.71.9) 1.1 (0.61.8)

6574 1.9 (1.52.3) 1.8 (1.42.2)

75+ 1.6 (1.41.9) 1.5 (1.31.8)

CVD+ COPD c

5064d 6.7 (3.313.7) 4.4 (2.09.7)

6574 3.2 (2.24.6) 3.0 (2.14.3)

75+ 2.0 (1.42.7) 1.8 (1.42.5)

CVD+DM c

5064d 3.3 (1.66.7) 2.9 (1.46.0)

6574 2.0 (1.42.9) 1.9 (1.32.8)

75+ 1.8 (1.42.3) 1.7 (1.42.2)

Colon III CVD 1.5 (1.31.7) 1.3 (1.21.6) 1.3 (1.21.6)

CVD + COPD 1.7 (1.22.3) 1.4 (1.01.9) 1.3 (1.01.8)

CVD + DM 1.6 (1.22.1) 1.3 (1.01.8) 1.3 (1.01.7)

Rectum III CVD 1.7 (1.42.0) 1.3 (1.11.6) c

CVD+ COPD 2 .7 (2.03.7) 1.9 (1.42.7) c

CVD + DM 2.1 (1.62.9) 1.5 (1.12.0) c

Rectum T2T3, M0, since 2002 CVD 1.7 (1.22.3) 1.3 (0.91.9) 1.3 (0.91.9)

CVD + COPD 3.8 (2.26.6) 2.5 (1.44.4) 2.5 (1.44.4)

CVD + DM 2.2 (1.33.8) 1.6 (0.92.7) 1.5 (0.82.5)

NSCLC local CVD 1.3 (1.11.4) 1.1 (1.01.2) 1.1 (1.01.2)

CVD + COPD 1.5 (1.31.8) 1.3 (1.11.5) 1.1 (0.91.3)

CVD + DM 1.6 (1.32.0) 1.4 (1.11.7) 1.3 (1.11.7)

SCLC limited CVD

5064d 1.1 (0.71.5) 1.0 (0.71.5) 1.1 (0.71.6)

6574 0.9 (0.71.3) 0.9 (0.71.3) 0.8 (0.61.2)

75+ 2.1 (1.23.6) 2.0 (1.23.5) 2.6 (1.44.8)

CVD+ COPD

5064d 1.4 (0.72.7) 1.2 (0.62.4) 1.2 (0.62.4)

6574 1.3 (0.82.0) 1.3 (0.82.0) 1.0 (0.61.6)

75+ 1.7 (0.93.1) 1.5 (0.82.8) 1.8 (1.03.3)CVD+DM

5064d 1.2 (0.52.8) 1.1 (0.52.5) 1.0 (0.42.4)

6574 2.9 (1.75.1) 2.8 (1.65.1) 2.4 (1.44.4)

75 1.6 (0.73.7) 1.4 (0.53.4) 1.4 (0.53.8)

Breast IIII, T1T2, undergone lumpectomy CVD 1.4 (0.92.1) 1.1 (0.71.7) 1.1 (0.71.6)

CVD + COPD 3.7 (1.211.7) 2.8 (0.98.8) 2.7 (0.98.7)

CVD + DM 2.4 (1.44.3) 1.7 (0.93.0) 1.5 (0.88.7)

Prostate III CVD

5064d 2.1 (1.43.1) 2.0 (1.43.0) 2.0 (1.42.9)

6574 1.4 (1.21.7) 1.4 (1.11.6) 1.3 (1.11.6)

75+ 1.2 (1.11.4) 1.2 (1.01.4) 1.2 (1.01.4)

CVD+ COPD

5064d 6.5 (3.212.8) 6.1 (3.112.2) 5.6 (2.811.2)

6574 2.2 (1.73.1) 2.0 (1.52.8) 2.0 (1.52.7)75+ 2.4 (1.93.0) 2.4 (1.93.0) 2.4 (1.93.0)

CVD+DM

5064d 3.3 (1.29.0) 3.2 (1.28.8) 2.9 (1.18.0)

6574 2.4 (1.73.1) 2.2 (1.63.1) 2.2 (1.63.0)

75+ 1.4 (1.01.9) 1.3 (0.91.8) 1.3 (0.91.8)

Inmodel A theunadjustedhazardratios forCVD,CVD+ COPD,CVD + DMare presented, inmodel B adjustment hasbeenmade forage,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 hasbeen made forthe following treatmentaccording to tumour type: colon III: adjuvantCT (yes/no);NSCLClocal: surgery, RT andno 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.


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Ourstudyshowed that rectalcancer patients with CVDand

diabetes were less likely to receive preoperative radiother-

apy. 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 signif-

icantly less often[21].In our study no influencewas found of CVD on the propor-

tion 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.Alsoseverityof the disease, stability, prior treat-

ment, functional capacity, age, other comorbid conditions

and type of surgery needs to be evaluated[39].This infor-

mation (except for age, presence of comorbidity and type of

surgery) is not registered by the cancer registry. Previous stud-

ies, however, have found that NSCLC patients with COPD

underwent surgery less often compared to patients without

COPD [25,40]. Thelower proportion of patients with NSCLC

and both CVD + COPD undergoing surgery in this study wastherefore 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 Janssen-

Heijnen 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 mortal-

ity is reduced with 14%, although no reduction was observed

in patients above 70 years) and local tumour control, butcan 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.

Thedecisionto performsurgeryin prostate cancerpatients

is, among otherconsiderations, 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 andthosewith comorbidity were

omitted from surgery[46].

4.4. Cardiovascular disease and survival

The impact of comorbidity (in this case CVD) on over-

all 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,

most patients with a more lethal tumour type die from cancer

before they become at risk of dying from CVD. A previ-

ous 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 mor-tality 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 withCVD have survivalrates

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 recommenda-

tions (i.e. breast cancer). Of course, this statement needs to

be evaluated in prospective studies.

A negative influence of cardiovascular disease on sur-

vival of cancer might be due to several mechanisms: the

increased risk of death due to cardiovascular disease, morecontraindications 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 reg-

istered 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

theincreased risk of dying forpatientswith 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 comor-

bidity 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 reg-

istrars[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 regis-

ters 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 treat-

ment, dose, time between administration and the kind of

chemotherapy.


11/12


Furthermore, no information was available on social sup-

port, 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 (espe-

cially in combination with COPD or diabetes) in cancer

patients influences treatment and treatment outcome. There-

fore, cancer patients with severe CVD need to be discussed

in multidisciplinary meetings in the presence of a cardi-

ologist. 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.

Conflict of interest

None

Acknowledgements

The authors thank the registration team of the Eindhoven

CancerRegistry for their dedicateddata collection. This work

was carried out with grants from the Dutch Cancer Society

(KWF).

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Biography

Maryska Janssen-Heijnenis working as a senior epidemi-

ologist at the Eindhoven Cancer Registry. She focuses on

prognostic factors for cancer patients, with a special inter-

est 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 ontreatment, complications of treatment and prognosis.

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