You are on page 1of 12

Critical Reviews in Oncology/Hematology 76 (2010) 196–207

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

197
197
197
198
199
199
199
200
201
201
202
202
205
205
206
206
206
206
207

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

Trained registration clerks actively collect data on patient characteristics. arrhythmias. In 2000. accounting for 33% of the total mortality [2]. 2. these patients were included from 2002 to 2006. histology. so the proportion of elderly people with both cancer and CVD will increase [3]. Since 1993 the Eindhoven Cancer Registry collects serious comorbidity at the time of cancer diagnosis. rectum. Prognosis. The effect of CVD on treatment and overall survival was analysed by stage. cardiovascular disease can also complicate cancer treatment and (dose of) treatment might be adjusted more often. Cardiovascular diseases. prognosis. Prevelance. . Janssen-Heijnen et al. Since preoperative radiotherapy for rectal cancer was only recommended in treatment guidelines since 2002. 1. angina pectoris. Cardiovascular disease includes valvular disease. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 197 Conclusions: Many cancer patients with severe CVD have a poorer prognosis.1. topography. All rights reserved. Such research should lead to treatment guidelines for these patients. © 2009 Elsevier Ireland Ltd. the effect on cancer treatment and survival.4–11]. 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. Introduction Due to aging of the population. cardiomyopathy. 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. Prevalence and general characteristics were based on all stages of the tumours.G. Apart from affecting life expectancy. stage and information about initial treatment directly from hospital records. More research is needed for explaining the underlying factors for the decreased survival.25]. in the Netherlands. cardiovascular disease (CVD) was the number one cause of death. breast and prostate (most common tumour types) between 1995 and 2006 and aged 50 years or older were included. The hospital record is considered to be the most complete source of information on the patient’s past and current health status. Comorbidity. This area comprises 2. Keywords: Cancer. breast [12–19].L. Patients were excluded if the diagnosis of cancer was obtained at autopsy and when it did not concern a primary tumour.3 million inhabitants. (b) prevalence of cardiovascular disease in male patients. Treatment. 10 general hospitals and 2 radiotherapy institutes. Previous population-based studies have shown that patients with comorbidity among prostate [1. resulting in limited guidance about treatment and outcome in these patients. according to tumour type and age. claudicatio intermittens and cerebrovascular disease. deep vein thrombosis. 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. and colorectal cancer [20–23] were treated less aggressively and had a worse survival. according to tumour type and age. Patients diagnosed with cancer of the colon. ing comorbidity [1]. the mean age of cancer patients and the presence of comorbidity is increasing. 23% had cardiac diseases [1].M. congestive heart failure. In cancer patients aged 65 or older about 60% had one or more concomitant disease(s). non-small cell lung cancer (NSCLC). Population-based 1. small cell lung cancer (SCLC). Completeness of the registry is over 95% [27]. Patients The Eindhoven Cancer Registry collects data on all patients newly diagnosed with cancer in the southern part of the Netherlands. Patients and methods 2. myocardial infarction. (a) Prevalence of cardiovascular disease in female patients. abdominal aorta aneurysm. A slightly modified version of the Charlson comorbidity index is used for record- Fig. Elderly and especially those with comorbidity are underrepresented in clinical trials due to exclusion criteria [26].

The clinical TNM stage was used when surgery was the dependent variable. When interaction was found between CVD and other dependent variables. 2008 for the patients who were still alive. Pathological tumour stage was classified in four categories based on the pathological/post-operative TNM classification. gender and SES as independent variables. The study population consisted of all cancer patients with CVD (also those with 2 or more comorbid conditions of which one consisted of CVD). Statistical analyses The age-specific prevalence of CVD for each tumour type was calculated separately for men and women. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 Table 1 Patient characteristics according to type of cancer and the presence of cardiovascular disease. An exception has been made for patients with colorectal cancer because the majority underwent surgery and cTNM is generally not determined. CVD Male (%) 6–64–11–19 7–62–13–18 SES = socioeconomic status: 1 = low. In addition to passive follow-up from the hospital records. an elderly or nursing home). medium and high socioeconomic status. except for the relationship with stage among rectum carcinoma (p = 0. CVD 1037 (25) 3079 (75) NSCLC CVD No. 4 = living in an institution. and a separate category of patients who were institutionalized (i. because surgery decisions are based on this tumour stage. CVD 2175 (30) 5019 (70) 75 69 Rectum CVD No. SCLC as limited or extensive disease.10). 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.13). The crude survival was calculated and the independent prognostic effect of CVD was estimated by using Cox regression models. models were fitted with ‘receiving therapy’ as dependent variable and CVD. For all analyses the reference population consisted of cancer patients with other comorbid conditions than CVD. this information was actively obtained from the Municipal personal records database that registers vital status. c Limited–extensive. Cancer treatment was defined as surgery. Stagesa 1–2–3–4 (%) COPD (%) DM (%) SES 1–2–3–4 (%) 38–44–12–6 43–43–9–5 11 5 24 9 38–32–18–12 27–39–29–5 61 46 17–39–26–18 15–38–26–21 15 9 21 10 33–37–22–8 28–36–30–6 73 67 71 56 30–30–22–18 28–28–24–20 16 9 19 9 33–36–24–7 25–40–31–4 3071 (34) 5939 (66) 70 67 84 77 34–66b 32–68b 30 26 15 8 35–39–21–5 31–41–25–3 SCLC CVD No. Surgery did not comprise diagnostic operations and biopsies. data on household income and economical value of the house are available from fiscal data.e. Patients were categorized as: low. 2 = middle. 2008. Differences in treatment between patients with and without CVD were tested with the chi-square test. 2. COPD or DM and cancer patients without comorbid conditions. 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. Age was included as a categorical variable because there was no linear relation between treatment and age. CVD 2736 (32) 5799 (68) 72 69 14 11 12 8 28–38–28–6 23–37–36–4 Tumour type and presence of CVD N (%) Median age (years) Breast CVD No. That for lung cancer was classified in two categories: NSCLC as localized (stages I and II) or non-localized (stages III and IV). CVD + DM. All variables have a significant different distribution between the CVD and no CVD group (Chi-square p < 0. the results were stratified per variable outcome. Univariate differences in survival were evaluated with the log rank test. Logistic regression analysis was used to evaluate the independent influence of CVD on treatment of cancer. Survival time was defined as the time from diagnosis to death or January 1st. CVD 1494 (15) 8707 (85) 74 63 Colon CVD No. CVD 687 (33) 1383 (67) 70 65 77 65 40–60c 44–56c 29 22 17 8 41–39–15–5 34–40–22–4 Prostate CVD No. Follow-up of all patients was completed until January 1st. age. Clinical TNM was used when pathological TNM was not available. The proportional hazard assumption of CVD was evaluated by applying Kaplan–Meier curves. The . 3 = high. CVD + COPD. Janssen-Heijnen et al.198 M. a Unknown stage excluded (ranging from 2% to 18% among the various cancer types). For each tumour type and stage.2.G. b Loclaized–non-localized. surgery plus adjuvant therapy and combined chemoradiation therapy (the latter only for SCLC).L.

. 1999). The SAS computer package (version 8. nodal status and differentiation grade (model B).G. In model C treatment was included to investigate whether the effect of CVD on prognosis could be explained by differences in treatment. earlier stages at diagnosis were found in case of NSCLC.L. Patients with CVD had more extensive disease in case of SCLC and breast cancer. (C) localized NSCLC.. Cary. The influence of cardiovascular disease on treatment Fig. gender. NC. Among patients with pT2 or pT3 rectal cancer the proportion receiving preoperative radiotherapy was clearly lower among patients with both CVD and diabetes (Fig.M. 2. 1a and b shows that the prevalence of CVD was higher among men and among patients with lung or colon cancer. Fig. 3. SES. 2B). (A) colon cancer stage III. CVD + COPD and CVD + DM in each age group. tumour size. 2 shows the influence of CVD. (E) breast cancer. Janssen-Heijnen et al. 199 In contrast. Cancer patients with CVD had a significantly lower SES than patients without CVD.2. unadjusted) were adjusted for age. Treatment of cancer according to age and comorbidity. (D) SCLC limited disease. Patients with CVD were older and were significantly more often male. 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. Table 1 gives baseline characteristics of cancer patients with CVD and cancer patients without CVD. 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. colon and rectal cancer. USA. Hazard ratios with 95% confidence intervals were reported. (B) rectal cancer pT2–pT3. 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. T1–T2. 3. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 hazard rates for death (model A. Results 3. (F) prostate cancer stages I–II.2) was used for all statistical analyses (SAS Institute Inc.1. 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). Patient characteristics Fig.

Among patients with prostate cancer. Patients older than 65 with limited SCLC received less combined radiotherapy (RT) and CT if CVD was present (Fig. The effect of CVD did not reach statistical significance at the 0. and surgery in case of prostate cancer.1 times higher risk of dying compared to patients without CVD for most tumour types (Table 3). / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 Fig. (Continued). SES and gender almost all effects of CVD on treatment disappeared except for the lower proportion undergoing surgery for prostate cancer (Table 2). Fig. The combination of CVD and COPD led to less surgery in patients with NSCLC or prostate cancer. colon cancer (stages I–II) and limited SCLC the effect of CVD on survival was different for the age groups and was therefore presented sep- . Janssen-Heijnen et al. 3.2–2. The influence of cardiovascular disease on survival Fig. 3 shows survival curves according to age and CVD.L.G. and differentiation grade) patients with CVD experienced a 1.3.200 M. breast and prostate cancer patients with CVD aged 50–64 had a prognosis that was comparable to the agecohort without CVD that was 10 years older. rectum. gender. Further adjustment for treatment did not clearly change the odds ratios for dying. 2. The presence of additional COPD or diabetes led to a further increased risk of dying (Table 3). 2C). The proportion of patients with stage I or II prostate cancer undergoing surgery decreased when CVD was present (age groups 50–64 and 65–74. Breast cancer patients undergoing lumpectomy with both CVD and COPD received adjuvant radiotherapy less often. SES. SCLC (except those aged 75 or older) and for patients with breast cancer. patients with CVD and diabetes had a lower chance of receiving preoperative RT in case of rectal cancer. The proportion undergoing surgery of patients with localized NSCLC was lower among patients with combined CVD and COPD (Fig. 2D). When considering the effect of additional comorbid conditions. tumour size. 2F). and these proportions were even lower when COPD of diabetes were also present.05 level for patients with NSCLC. and also to less chemoradiation in SCLC. Among breast cancer patients undergoing lumpectomy the proportion receiving adjuvant radiotherapy was significantly lower for those with combined CVD + COPD or CVD + DM (Fig. After adjustment for age. After adjustment for other prognostic variables (age. 2E). nodal status. Colon.

undergone lumpectomy Adjuvant radiotherapy CVD CVD + COPD CVD + DM 0.3) 1. Adjustment has been made for age.3–0.7 (0.4) SCLC limited disease CT + RT CVD CVD + COPD CVD + DM 0.1. which is reflected by the results of the present study.7) 0.4–20.4) 0.4 (0.8 (0.5–1.4–6.5–1.1–0.7–1. The generation of oxidative stress has been associated with hyperlipidemia.0) Prostate cancer stages I–II Surgery CVD CVD + COPD CDV + DM 0.6) 0.0 (0. Table 3).6) a b Reference group consisted of patients without CVD.1 (0.8 (0. Hyperlipidemia is associated with colon cancer and CVD.9 (0.2 (0. Among patients with stage I or II colon cancer over 65 years old.4) 0.2–0. Furthermore.7 (0.4–1. Tumour and stage Therapy Comorbiditya Unadjusted OR (95% CI) Adjusted ORb (95% CI) Colon cancer stages I–II Surgery CVD CVD + COPD CVD + DM 0. The effect on survival was less clear among patients with lung cancer.3 (0.4) 0. since 2002 Preoperative RT CVD CVD + COPD CVD + DM 1.2–1.7) NSCLC localized disease Surgery CVD CVD + COPD CVD + DM 0.7 (0.7) 0.8) 0. In breast.1 (0.1) 0.4 (0.4 (0.2–0.2–1.6) 0.3–14. hypertension and smoking. arately.1–0.2 (0.6) 1.4 (0.6) 0. M0.5 (0.5 (0.5 times higher.6) 0. Janssen-Heijnen et al.3 (0.4) 2.8) 1.2–0.6–2. and gender. Patients with CVD were often treated less aggressively.1–0.0 (0.0–0.5–1. the HR for dying was higher for patients with CVD in combination with either COPD or DM.5 (0.4–1.L.2) 0.7) 2.4) 0. the opposite was seen among patients with SCLC or breast cancer.0–0.0) 0.2–0.2–0.M. Discussion Over one fourth of all cancer patients aged 50 or older also suffered from cardiovascular diseases.9) 1.4) 0.1.5) 0.2–0.2–0.6–0.3 (0.5–1.3 (0. according to tumour type and treatment. Oxidative stress has a central role in the initiation of atherosclerosis and cancer.4 (0. male gender and increasing age are also risk factors for developing CVD [33].6–10. whereas smoking is associated with lung cancer and CVD.5 (0.7–1. CVD + COPD and CVD + DM. the lowest .1–0.4 (0.8) Rectal cancer T2 + T3.4 (0.9 (0.0 (0. For many tumour types.0) 2. This means that these (elderly) patients are at risk for cancer and therefore the prevalence of patients with both cancer and CVD has increased. COPD or DM. The high prevalence of CVD in patients with lung or colon cancer can be explained by similarity in risk factors [24. colon.5) 1.1 (0.3–2. the risk of dying for those with CVD compared to those without CVD was over 1.2–0.5–2. 4.4 (0.3–0.7) 1.8) 0.5 (0.29–31]. The prevalence of CVD among cancer patients was higher than that among general patients aged 55 or older admitted to Dutch hospitals [28].3) 1. among patients with prostate cancer.0 (0.3 (0. As previous studies showed.5 (0. which could hardly be explained by differences in treatment. rectal and prostate cancer survival curves of patients with CVD aged 50–64 were comparable to those of patients without CVD but within an age-cohort of 10 years older.4–4. Finally.8) 0.G.4–0. socioeconomic status.5–0. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 201 Table 2 Odds Ratios (OR) for receiving treatment for patients with CVD.1–1. and was especially high for stage I or II colon cancer patients with both CVD and COPD (HR up to 4.6) 0.3) 0.3–3. 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 = 2.8–1.6 (0.3–0.5) Rectal cancer stages I–II Surgery CVD CVD + COPD CVD + DM 0.1 (0.4 (0.1) 0. the increased mortality risks for CVD were most marked among younger patients (Table 3).7 (0. Ross et al.4) and for stage I or II prostate cancer (HR up to 6.8 (0.8 (0.0). 4.3–1.5–1.8 (0.4 (0.9) 0.4) 0. CVD had an independent effect on survival.2 (0.1 (0. especially elderly and in case COPD or diabetes was present in combination with CVD.9) 0.2) 1.5) Colon cancer stage III Adjuvant chemotherapy CVD CVD + COPD CVD + DM 0.6) 0. Prevalence of cardiovascular diseases Due to new treatment modalities CVD has become a chronic disease and patients have a considerable life expectancy.4–1.4–0. have reviewed the concept of similarities in the pathways of CVD and cancer [32]. T1–T2.4) 1.3–0.7–1. especially those aged 75 or older and those with lung or colon cancer.7) 0.1 (0.4) 0.6 (0.8) 0. Although patients with NSCLC.5 (0. colon or rectal cancer were diagnosed in an earlier stage when CVD was present.5–2.0) Breast cancer stages I–III.

Cancer might be detected earlier because patients with CVD are under surveillance which might lead to earlier diagnosis of cancer. This might lead to diagnosis of previously unknown CVD. Chemoradiation Fig.2. Janssen-Heijnen et al. A lesser adherence to breast cancer screening program in patients with CVD and their relatively lower socioeconomic status may play a role. Also. especially when it concerns high risk surgery. This could explain the higher prevalence of CVD in early stage NSCLC and colorectal cancer patients. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 prevalence of CVD was found in breast and prostate cancer patients [34. while Yancik et al. 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. Therefore the threshold to avoid surgery is relatively low. In contrast. Fleming et al.3. Gonzalez et al. [17] concluded that comorbidity did not have any influence on disease stage in breast cancer patients. (B) Colon cancer stage III. colorectal and prostate cancer patients was associated with a more advanced stage at the time of diagnosis. Cardiovascular disease and treatment No association was found between cancer treatment and CVD after adjusting for confounding factors. (D) Localized NSCLC. (C) Rectal cancer stages I–II. 4. We can only postulate why breast cancer is more frequently diagnosed with advanced stage in patients with CVD. [37] showed that comorbidity (measured with Charlson comorbidity index) in breast. (F) Breast cancer stages I–III. whereas NSCLC and colorectal cancer patients were more often diagnosed with localized disease. (E) Limited SCLC.L.G. Crude survival according to the presence of cardiovascular disease and age. cancer patients diagnosed with a resectable tumour undergo preoperative examinations. (A) Colon cancer stages I–II. “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.202 M. 3.35]. In patients with prostate cancer alternative treatment plans are widely available with results comparable to surgery. . except for patients with prostate cancer and SCLC. cancer might also be detected later because complaints of cancer are assigned to CVD. (G) Prostate cancer stages I–II. [36] showed that breast cancer patients with CVD had 13% lower odds of being diagnosed with advanced breast cancer. 4. Three population-based American studies have shown conflicting results with respect to the influence of comorbidity on stage of cancer.

the specific effect of CVD was not investigated in these studies.L. 3. also showed a significant association with adjusted treatment in patients with rectal cancer. . SCLC. especially in those with deep vein thrombosis and COPD [38]. Complications after surgery can be expected in colorectal cancer patients with comorbidity. In the present study this did not result in refraining from surgery in colorectal cancer patients with CVD.G. in case of limited SCLC gives a high rate of treatment-related complications and. however. Previous studies have shown that patients with comorbidity received chemotherapy significantly less often [20–22]. Janssen-Heijnen et al. CVD in combination with other comorbidity (diabetes or COPD). any comorbidity and high age are commonly used as contraindications to chemoradiotherapy. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 203 Fig. However. (Continued).M. while its benefits are clear but relatively small. This can probably be explained by the fact that surgery is often inevitable for preventing life-threatening complications of colorectal cancer. In this study also no relation was found between colon cancer patients with CVD and the receipt of adjuvant chemotherapy. NSCLC and breast cancer. also in patients with CVD.

1–1.4–2.4–3.0 (1.8 (1.2–1.6) 1.7–1. c No adjustment for treatment has been made.0) 1.0) 3.2 (0.1 (0.8) 1.9–3.0) c Rectum T2–T3.7–3.3 (0.9) 1.3) 1.8) 2.4) 1. When interaction was present with age the hazard ratios are shown according to age group.6) 1.6) 1.5–3.2 (1.2) 2.1 (1. HT.4–2.5) 1.0) 2.3–2.6) 1.7 (1.6) 1.9–1.8) 1.6 (0.9) 1.8 (1.1 (0.7) 2.4 (1.6–3.4 (1.0–1.8) 2.6–3.8) 1.3 (1.3) 2.0–1.7) 1.2–4.1) 1. CVD + DM according to tumour type and stage.9–1.9) 2. since 2002 CVD CVD + COPD CVD + DM 1.6) 1.5 (0. M0.7 (2.6–2. CVD + DM are presented.4–4.3) 1.8–8. nodal status.7) 2.4 (0. COPD or DM.5 (1.8–2.2) 1.4) 1.4–4.2) 2. CVD + COPD. in model B adjustment has been made for age. breast cancer patients undergoing lumpectomy: adjuvant RT (yes/no).4–4.2 (1.2–11.5) 3.4 (1.4) 2.7) 3.0–1.8) 1.8) 1. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 Table 3 Hazard ratios (HR) for overall mortality for CVD.2–1.8) 1.7) 2.3 (0.4–2.8 (1.8) 6.8) 2.6–1.L.5–2. b Adjustment has been made for the following treatment according to tumour type: colon III: adjuvant CT (yes/no).9–3.9–8.0 (1.7–2.7) 2.9) 3.9 (0.9–2.0) 2.0–1.5–2.0) 2.9) 1.3) 1.2 (1.6 (0.2–6.7) SCLC limited CVD 50–64d 65–74 75+ CVD + COPD 50–64d 65–74 75+ CVD + DM 50–64d 65–74 75 1.5) 0.4–2.4–1.7) Rectum I–II CVD CVD + COPD CVD + DM 1.2–2.1–1.0 (1.2–1.1) 1.2 (1.0 (1.4–4.1) 1.9 (1. undergone lumpectomy CVD CVD + COPD CVD + DM Prostate I–II CVD 50–64d 65–74 75+ CVD + COPD 50–64d 65–74 75+ CVD + DM 50–64d 65–74 75+ c c In model A the unadjusted hazard ratios for CVD.9 (0.4–2. RT and no therapy.4) 1.7–1.0 (0. Janssen-Heijnen et al.7 (1.1–1. .9–8.1–1. differentiation grade.7–1.6–2.2–12.7–1.8–11.7 (3.3–1.9 (1.4 (1.1 (0.2–8.9–3.1 (0.2–3.3 (1.1–12.7–3.3–3.4–2.5) 1.6 (1.4 (1.7) 1.9–3.9 (1.7) 1.7) 1.0) 1.2) 1.6) 2.4–2.3 (0.6) 2.7) 1.9) 1.3 (1.9) 2.6) 1.3 (1.2 (1.1 (0.0) 1.4) 1.3–1. CT + RT and no therapy.4 (1.8–2.2) 2.6) 2.204 M.5–2.0–1.4–3.9 (1.7–1.6–5.1) 2.6) 0.8 (1. In model C additional adjustment has been made for treatment.7–1.9–1.9–1.1) 1.0–3.3 (0.8) 1. prostate: surgery.3) 2.5 (0.7 (0. no therapy.4 (0.4–2.2) 1. T1–T2.9–3.0) 1. RT.5 (1.8 (2.9–2.4) 1.4) 2.1 (1.0 (1.4) 2.7) 4.5) 0.7) 2.1 (0.1–1.0) 6.8–2.2 (1.5–2.1–1.5–3.8) 1.4 (2.7–3.5) NSCLC local CVD CVD + COPD CVD + DM 1. a Reference group consisted of patients without CVD.6 (1.7) 3.3–13. because majority (>95%) of the patients underwent surgery.4 (1.G.4) 1.5 (1.3 (1.1–1.7 (0.3 (0.9) 1.0–1.0 (2. Tumour and stage Comorbiditya Colon I–II CVD 50–64d 65–74 75+ CVD + COPD 50–64d 65–74 75+ CVD + DM 50–64d 65–74 75+ Model A HR (95% CI) Model B adjusted HR (95% CI) 1.1) 3.2 (2.6 (2. d Interaction with age was present.0) 1.5) 2.0–1.4–2.5 (0.3 (1.3) 1.2–2. socioeconomic status.4 (1.8) 1.2 (1.8 (1.8) 2. gender.5 (1.3 (0.1) 1.2) Model Cb adjusted HR (95% CI) c c c Colon III CVD CVD + COPD CVD + DM 1.4) 6.0–1.0 (0.1 (1.4 (0.0) 1.2 (0.4 (0.3 (1.8) Breast I–III.0) 5.7 (1.1 (1.1–2.5–2.3) 1.7 (1.3 (1.1) 1.2 (0.0) 1.2–2.6 (1.2–3.0 (0.1–1.7 (0. NSCLC local: surgery. SCLC limited: CT.9) 1.7–1.9 (1.0 (1.2 (1.7) 1.1–8.8) 2.3) 1.1 (0.5 (1.7–5.4–2.1 (3.0–1.6–1.3 (1.4–6.3) 2.8) 1.7) 2. CVD + COPD.3–2.3) 3. tumour size.5 (3.6–2.4) 1.9–1.6 (1.3 (1.7 (1.8 (0.9 (1.7) 1.8–2.1 (0.0–9.2–9.6–6.4–4.4 (1.3 (1.4 (1.5 (1.1–4.1 (1.8 (0.1) 1.3 (1.4 (1.7–1.3–1.6–1.7) 1.0 (1.0–3.

this effect did not reach significancy at the 0.05 level. [41]. This information (except for age. The lower proportion of patients with NSCLC and both CVD + COPD undergoing surgery in this study was therefore not surprising.M. . minor adjustments in treatment regimens were not registered (i. This is in conformity with the results of JanssenHeijnen et al. prior treatment.4. 4. time between administration and the kind of chemotherapy. Also severity of the disease. gender. Previous studies. we could not differentiate between less severe and more severe conditions. differentiation grade. This is in line with the results of previous studies [11. Another strength of this study was the reliable source of information: medical records. socioeconomic status. this statement needs to be evaluated in prospective studies. Janssen-Heijnen et al. 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]. adjustments in cardiovascular treatment. dose. In the present study a worse survival was seen among patients with CVD for localized NSCLC. Radiotherapy in addition to chemotherapy does not only improve survival (cancer mortality is reduced with 14%.e. more contraindications for anti-cancer treatment and a higher rate of treatment-related complications such as cardiovascular events. other comorbid conditions and type of surgery needs to be evaluated [39]. After adjustment for age. 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. With regard to receiving adjuvant chemotherapy we did not have information on completion or early termination of the treatment. 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. where older patients and those with comorbidity were omitted from surgery [4–6].5. In agreement with the American study.19. presence of comorbidity and type of surgery) is not registered by the cancer registry. Unfortunately. However. but can also lead to a small increase in treatment-related death [43–46].e. prostate and colorectal cancer patients. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 Our study showed that rectal cancer patients with CVD and diabetes were less likely to receive preoperative radiotherapy. 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. and a standardized method for extracting data from the medical records by trained registrars [27]. treatment of the comorbid condition and complications are not routinely registered in the cancer registry. Ludbrook et al. 205 most patients with a more lethal tumour type die from cancer before they become at risk of dying from CVD.40].49]. For considering cardiac risk in non-cardiac surgery not only the presence of pre-existing cardiovascular disease needs to be identified. the cancer registry only registers severe comorbid conditions with a possible effect on prognosis. we could conclude that the increased risk of dying for patients with CVD could hardly be explained by less aggressive treatment.23. chemotherapeutic regimens or surgical procedures). Therefore. although no reduction was observed in patients above 70 years) and local tumour control. However. 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. 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]. by adjusting our survival analyses for treatment.L. stability. In elderly breast cancer patients undergoing lumpectomy a physician has to outweigh the benefits of adjuvant RT in the perspective of life expectancy. In contrast. among other considerations. 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. The decision to perform surgery in prostate cancer patients is. related to life expectancy. A third strength was the inclusion of unselected patients. This means that other factors play an important role. Also we were only able to register treatment modalities. tumour size and nodal status. This is comparable to other studies. In our study no influence was found of CVD on the proportion of patients with localized NSCLC undergoing surgery. functional capacity.15. causes of death. especially for those with localized disease [50]. excess mortality due to cardiovascular disease and death due to complications of treatment could not be investigated. [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. we found an effect of CVD on risk of mortality among breast cancer patients. 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. 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. costs of radiation and adverse effects [47]. however. have found that NSCLC patients with COPD underwent surgery less often compared to patients without COPD [25. age. Therefore. A limitation of this study was that information about the severity of the comorbid condition was lacking. Of course. breast cancer). 4.G.

and consequences of undertreatment. causes. Mineo TC. Cancer 2002. Kurth T. Terrell FL. J Clin Epidemiol 2008:28. [8] Satariano WA. Int J Epidemiol 1993. [24] Ambrogi V. Adjuvant treatment recommendations in older women with breast cancer: a survey of oncologists. Louwman MW.24:4184–9. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 Furthermore. [10] Hall HI. Narayan S. DuChane J. Yates JW.95:2308–15. Hortobagyi GN. Ryu JK. 5. Ries LA. This work was carried out with grants from the Dutch Cancer Society (KWF). Wesley MN. J Clin Oncol 2006.23:3112–24. Factors associated with surgical and radiation therapy for early stage breast cancer in older women.L.23: 811–7. Risk of cardiovascular mortality in prostate cancer patients in the Rotterdam randomized screening trial. J Clin Oncol 2007. Vlastos AT. Tomlinson G. Impact of comorbidity on treatment and prognosis of prostate cancer patients: a population-based study. Broering JM. Cancer 2007. Jacobsen J. et al. Repelaer van Driel OJ. Carroll PR. Breast cancer treatment guidelines in older women.8:22–30. Hogel J.206 M. Thompson T. Verheij CD. Rapiti E. [5] Hall WH. Eur J Cardiothorac Surg 2003. Norgaard M. Coebergh JW. Verheij CD. Elkin E. Kau SW. Prognoses en Implicaties Voor Zorgvraag. et al. Co-morbidities and survival of men with localized prostate cancer treated with surgery or radiation therapy. [4] Fowler Jr JE. Jani AB. [26] Townsley CA. complications of treatment. Alibhai SM.22:369–76. [11] Houterman S. Edwards BK. Hammer E. Crit Rev Oncol Hematol 2005. [28] Schram MT.59:218–25. Naeim A. recurrence or progression and cause of death. [14] Giordano SH.175:1326–31. Kessler LG. no information was available on social support. Siu LL. Br J Surg 2005. McAvay GJ. [27] Schouten LJ. Blagojevic S. [6] Marr PL. Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study. J Natl Cancer Inst 1996. Crit Rev Oncol Hematol 2006. Janssen-Heijnen et al. Coebergh JW. [3] Driver JA. [13] Cronin-Fenton DP. Herbert R. Krahn MD. Potosky AL. [15] Houterman S.156:1714–8. Van Den Eeden SK. Selvin S. gender. 2004. 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. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. van de Lisdonk EH. Knottnerus JA. such as motive for non-adherence to guidelines. Houterman S. [25] Dy SM. Naglie G. [16] Hurria A.61:255–60. Haddad K. Coebergh JW.109:2410–9. Comorbidity and survival of Danish breast cancer patients from 1995 to 2005. Cancer 1998. preference of patient. Wedding U. Prognostic impact of increasing age and comorbidity in cancer patients: a population-based approach. J Cancer Res Clin Oncol 2004. Satariano WA. Pistolese GR. Therefore. J Urol 1996. Elkin EP. Arredondo SA. Crit Rev Oncol Hematol 2007. cancer patients with severe CVD need to be discussed in multidisciplinary meetings in the presence of a cardiologist. Prostate Cancer Prostatic Dis 2005.88:716–26. de Koning HJ. Ragland KE. Djousse L. van den Berg HA. References [1] Janssen-Heijnen ML. Bondy ML. . Schroder FH. Frijters D. [7] Otto SJ. Nayfield SG. [17] Yancik R. Jager JJ. J Urol 2006. J Clin Oncol 2005. Completeness of cancer registration in Limburg. Havlik RJ.130:664–70. whereas these factors also play a role in deciding whether or not to undergo a certain treatment [12]. Vlastos G. Kanker in Nederland: Trends. [2] Signaleringscommissie Kanker. van Halteren AH. Pompeo E. The Netherlands. Continued undertreatment of older men with localized prostate cancer. J Clin Oncol 2005. Janssen-Heijnen ML. [23] Rieker RJ. Lemmens VE. et al. Rohrig B. [18] Ballard-Barbash R. Renfroe DL.16:767–72. [19] Nagel G.83:1180–8. Adjuvant treatment for elderly patients with stage III colon cancer in the southern Netherlands is affected by socioeconomic status. The impact of age and comorbidity on survival outcomes and treatment patterns in prostate cancer. [22] Lemmens VE. Houterman S. Ann Oncol 2005.337:a2467.387:72–6. Comorbid illnesses and health care utilization among medicare beneficiaries with lung cancer. Amsterdam: KWF Kankerbestrijding. Janssen-Heijnen ML. Sharkey P. Co-morbidity leads to altered treatment and worse survival of elderly patients with colorectal cancer. Conflict of interest None Acknowledgements The authors thank the registration team of the Eindhoven Cancer Registry for their dedicated data collection. Langenbecks Arch Surg 2002. Hendrikx AJ. Older female cancer patients: importance. [9] Schwartz KL. The impact of comorbidity on the overall survival and the cause of death in patients after colorectal cancer resection. Tinetti ME. JAMA 2001. Maas HA. Theriault RL. Cause of death in men diagnosed with prostate carcinoma. van den Brandt PA. Harlan LC.25:1858–69. The impact of cardiovascular comorbidity on the outcome of surgery for stage I and II non-small-cell lung cancer. et al. [20] Gross CP. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. Hoppener P. Wu AW. Logroscino G. Vreugdenhil G. [12] Bouchardy C. transportation availability and time spent by the physician. The impact of comorbidity on the survival of postmenopausal women with breast cancer. The impact of chronic illnesses on the use and effectiveness of adjuvant chemotherapy for colon cancer. Janssen-Heijnen ML. Janssen-Heijnen ML.G. Br J Cancer 2004. Ragland KE.58:60–7. Br J Cancer 2005:2007. Schmid E.92:615–23.62:860–5. Comorbidity has negligible impact on treatment and complications but influences survival in breast cancer patients. Van Den Eeden SK. Comorbidity and primary treatment for localized prostate cancer: data from CaPSURE. and comorbidity. Selby R. Eisele R. [21] Lemmens VE.55:231–40. Crit Rev Oncol Hematol 2006. Guo Z. Setting and registry characteristics affect the prevalence and nature of multimorbidity in the elderly.285:885–92. Elia S.90: 2332–7. Coebergh JW. Urology 2003. Gaziano JM. Repelaer van Driel OJ. The underlying factors for the decreased survival in these patients should be systematically addressed. Katenkamp D. Vijayakumar S. Initial treatment for prostate carcinoma in relation to comorbidity and symptoms. BMJ 2008.23:783–91.

72:153–84.43:132–40.25:4137–45. The pathophysiology of cigarette smoking and cardiovascular disease: an update. van den Borne BE. Chen K. Crit Rev Oncol Hematol 2007. J Am Coll Cardiol 2004. Page NC.43:2194–202.31:192–9. Oehlschlaeger S. [42] Ludbrook JJ. Pursley HG. Galusha DH. Tierney RM. Eur J Cancer 2006. et al. Langer C.23:458–66. Mink PJ. Truong PT. Int J Radiat Oncol Biol Phys 2003. Ned Tijdschr Geneeskd 2005. Socinski MA.L. Janssen-Heijnen et al. Janssen-Heijnen ML. Payne D. [32] Ross JS. Gridelli C.22:3099–103. Arriagada R. Schairer C. [39] Mangano DT. Pavlov D. Mamun AA. 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. / Critical Reviews in Oncology/Hematology 76 (2010) 196–207 [29] Ambrose JA. Peeters A. Perioperative cardiac morbidity. J Natl Cancer Inst 2006. Biesma B. Which conditions contributing to the Charlson score predict survival after radical prostatectomy? J Urol 2004.327:1618–24. and a worse overall survival in the elderly patient. J Clin Oncol 2007. Eur J Cancer 2007. Maione P. and risk of colon and rectal cancer in a cohort of Swedish men. Bogart JA. A cardiovascular life history. N Engl J Med 1992. Effectiveness of radiation therapy for older women with early breast cancer. Litz R.94:913–20. 1995 to 2002.M.25:1898–907. et al. Since 2000 she is coordinating large population-based projects in which the prevalence of comorbidity in cancer patients is studied. The influence of age and comorbidity on receiving radiotherapy as part of primary treatment for cancer in South Netherlands. Oei SB. Houterman S. Which comorbid conditions predict complications after surgery for colorectal cancer? World J Surg 2007. Dietary fat and cancer. .43:1731–7. Limited-stage small-cell lung cancer: the current status of combined-modality therapy. Donovan MJ.42:2590–7.G. Ihde DC. complications of treatment and prognosis. Breitbart RE. Cancer 2006. Roetzheim RG. J Clin Oncol 2004. Koch R. Eur Heart J 2002. a different treatment strategy in case of primary tumours above the diaphragm. [35] Vulto AJ. Comorbidity as a predictor of stage of illness for patients with breast cancer. Smith GL.62:172–8. Newman B. [41] Janssen-Heijnen ML. van Doormaal JJ. J Clin Oncol 1992. Pal N. [37] Gonzalez EC. obesity. et al. Med Care 2005. Biography Maryska Janssen-Heijnen is working as a senior epidemiologist at the Eindhoven Cancer Registry. [40] van de Schans SA. [33] Fokkema MR. [38] Lemmens VE. Bergkvist L. MacNeil MV. Coebergh JW. Comorbid illness and the early detection of cancer. Devesa SS. Carroll L. Schild SE. COPD in cancer patients: higher prevalence in the elderly. [31] Larsson SC. 9B):63S–70S. Van Durme DJ.149:2607–12. as well as the influence of increasing age and comorbidity on treatment.98:681–90. Pignon JP. [30] Kushi L. Lemmens VE.96:1311–21. Froehner M. Probabilities of death from breast cancer and other causes among female breast cancer patients.10:890–5. Differential prognostic impact of comorbidity. Ferrante JM. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. with a special interest in elderly patients with comorbidity. South Med J 2001. Negligible influence of comorbidity on prognosis of patients with small cell lung cancer: a population-based study in the Netherlands. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A metaanalysis. Willekens F. Wirth MP. et al. Louwman MW. et al. Bonneux L. A life course analysis of the original Framingham Heart Study cohort. She focuses on prognostic factors for cancer patients. Barua RS.106:2734–42.113(Suppl.947:271–92. Muskiet FA. Lifestyle intervention for the prevention of cardiovascular disease. Ann N Y Acad Sci 2001. Smith BD. discussion 92-3. Biesma B. Rutegard J.55:1321–30. Lung cancer in the elderly. [36] Fleming ST. Giovannucci E. Stagliano NE. Anesthesiology 1990. Am J Med 2002. J Clin Oncol 2007. Bekelman JE. Ginsburg GS.171:697–9. Rossi A. [34] Read WL. Wolk A. Lemmens VE. Warde P. J Natl Cancer Inst 2004. et al. Physical activity. Gross CP. Haffty BG. Atherosclerosis and cancer: common molecular pathways of disease development and progression. Janssen-Heijnen ML.