Abstract
Background
The prevalence of comorbid cardiovascular disease (CVD) among patients with colorectal cancer (CRC) has increased in the last decades. Previous studies have focused on the impact of comorbid CVD on clinical outcomes in CRC, while its impact on patients’ health-related quality of life (HRQoL) is understudied. This study, therefore, relates (new-onset) CVD to HRQoL (i.e., physical, role, cognitive, emotional, and social functioning, and two CVD-related symptom scales fatigue and dyspnea) in a two-year follow-up study among CRC patients.
Materials and methods
Newly diagnosed CRC patients from four Dutch hospitals were eligible for participation. Patients (N = 327) completed questions on HRQoL (EORTC QLQ-C30) and the presence and timing of CVDs before initial treatment (baseline) and one and two years after diagnosis.
Results
CRC patients with comorbid CVD at cancer diagnosis (n = 72, 22%) reported significantly worse physical functioning at 2-year follow-up compared with patients who never had comorbid CVD (p < .05). CRC patients with new-onset CVD (n = 36, 11%) reported worse global QoL, worse role functioning, and more fatigue at 1 and 2-year follow-up compared with patients who never had comorbid CVD. In addition, they reported more dyspnea at baseline and worse physical functioning at 2-year follow-up (p < .05). Finally, patients with new-onset CVD reported worse global quality of life at 1-year follow-up and worse role functioning and more fatigue at 2-year follow-up, compared with patients with comorbid CVD at cancer diagnosis (p < .05). All significant differences between the three groups were of clinical relevance.
Conclusions
CRC patients with CVD, specifically those with new-onset CVD, reported a significantly and clinically relevant worse HRQoL compared with those who never had comorbid CVD. These findings seem to indicate, although the number is small, that CRC patients might have cardiovascular needs that need to be addressed and that multidisciplinary care is recommended. Larger studies are needed to confirm this.
Background
Colorectal cancer (CRC) is the third most common cancer in the Netherlands, with 13,000 new diagnoses annually [Citation1]. As more than half of CRC patients are 70 years or older[Citation1], patients often have age-related comorbid medical illnesses at the time of their cancer diagnosis, with cardiovascular disease (CVD) being the most prevalent [Citation2]. Having CVD at the time of cancer diagnosis can impact cancer treatment, often resulting in less aggressive cancer treatment [Citation3–5]. Furthermore, CRC patients have a higher risk of new-onset CVD compared with noncancer controls [Citation6], and the development of CVD during cancer treatment may result in interruption or even discontinuation of treatment, potentially impacting survival [Citation4,Citation5]. Nowadays, CVD is the leading cause of noncancer death among CRC patients [Citation7].
The prevalence of CVD among CRC patients has increased in the last decades and is higher than that among the non-cancer population [Citation8]. This is possibly due to factors such as the aging population, shared lifestyle risk factors (e.g., overweight/obesity, poor diet, and smoking) [Citation9,Citation10], and the direct and indirect effects of CRC and its treatment. For example, the chemotherapeutic agents 5-fluorouracil and capecitabine have direct cardiotoxic effects that can lead to both acute and chronic CVDs [Citation6,Citation11,Citation12]. Indirectly, cancer patients generally become less physically active after their cancer diagnosis [Citation13,Citation14] increasing their risk of CVD.
The higher prevalence of CVD among CRC patients makes it increasingly important to understand its impact on CRC patients’ lives. Most studies have focused on the impact on clinical outcomes, such as adjuvant chemotherapy and survival [Citation3–5,Citation7]. However, there is a paucity of research on CVD’s impact on the health-related quality of life (HRQoL) of CRC patients [Citation15,Citation16]. In a previous study of our research group among cancer survivors at a median of 4.6 years after cancer diagnosis, CRC survivors with comorbid CVD at cancer diagnosis reported worse global quality of life (QoL), physical functioning, role functioning, fatigue, and dyspnea compared with those without CVD [Citation15]. In another study, long-term CRC survivors with CVD at the time of the study, reported worse global QoL, worse functioning, and more fatigue, pain, dyspnea, and insomnia compared with survivors without CVD [Citation16]. To our knowledge, the association between CVD at the time of CRC diagnosis and HRQoL assessed in the first two years after CRC diagnosis has not yet been examined. Also, no study examined the association between new-onset CVD and HRQoL among CRC patients. Therefore, we relate (new-onset) CVD to HRQoL in a two-year follow-up study among CRC patients. We hypothesize that CRC patients with comorbid CVD experience a worse HRQoL, with patients with new-onset CVD experiencing the worst HRQoL.
Materials and methods
Setting, participants, and data collection
For this study, we performed secondary analyses on the PROCORE data, a prospective population-based study examining the impact of CRC and its treatment on patient-reported outcomes. Invited patients were newly diagnosed with CRC as a primary tumor between January 2016 and January 2019 in four Dutch hospitals: Elisabeth-TweeSteden hospital, Catharina hospital, Elkerliek hospital, and Máxima Medical Centre. Exclusion criteria were: (1) previous diagnosis with a different carcinoma, except for basal cell carcinoma of the skin, (2) cognitive impairments, and (3) inability to read or write Dutch. PROCORE was approved by the certified Medical Ethic Committee of Medical Research Ethics Committees United (registration number: NL51119.060.14).
Details of the data collection have previously been described [Citation17]. In brief, data collection was performed within Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship (PROFILES), a registry for the physical and psychosocial impact of cancer and its treatment [Citation18]. PROFILES is directly linked to the Netherlands Cancer Registry (NCR) that collects data from all newly diagnosed cancer patients [Citation1]. Eligible patients were invited to participate by their research nurse or case manager shortly after diagnosis, before the start of initial treatment (baseline). Follow-up questionnaires were sent four weeks after surgery (when applicable), and one and two years after diagnosis.
Measures
Sociodemographic and clinical characteristics
Sociodemographic (i.e., age, sex) and clinical (i.e., clinical stage, treatment) information was available from the NCR [Citation1]. Non-CVD comorbidity was assessed with the adapted Self-administered Comorbidity Questionnaire (SCQ) [Citation19]. Questions on partner status and educational level were self-reported.
Comorbid CVD
Patients were asked to indicate if they (ever) had ≥1 of the following CVDs: myocardial infarction, stroke/transient ischemic attack, heart failure, arrhythmias, hypertension, hypercholesterolemia, and other CVDs (open item). In addition, based on patients’ answers on the open item, four categories were made: (coronary) artery disease, angina pectoris, valvular heart disease, and other CVD (e.g., aneurysm, endocarditis lenta). The questionnaire also included the month and year of CVD diagnosis. On the basis of the presence and timing of the CVD diagnosis, three groups were made: (1) CRC patients without CVD, (2) patients with CVD at CRC diagnosis, and (3) patients with new-onset CVD (i.e., those who developed CVD in the first two years after their CRC diagnosis). The mere presence of hypertension or hypercholesterolemia was insufficient to be classified as having CVD.
Health-related quality of life
We used the EORTC QLQ-C30 (Version 3.0) to assess HRQoL [Citation20], and focused on the global QoL scale, the five functioning scales (i.e., physical, role, cognitive, emotional, and social functioning), and two symptoms known to be impacted by CVD (fatigue and dyspnea) [Citation21]. Each item is scored from (1) ‘not at all’ to (4) ‘very much’, except for the global QoL items, which range from (1) ‘very poor’ to (7) ‘excellent’. Scores were linearly transformed to a 0–100 scale [Citation22]: higher scores on the functioning scales and global QoL indicate better functioning/QoL, higher scores on symptom scales indicate more complaints.
Statistical analyses
NCR data on patient characteristics enabled us to compare eligible patients and respondents, using t tests for continuous variables and chi-square (or Fisher’s exact) tests for categorical variables. Frequency distributions of CVD types were calculated among CRC patients with CVD at cancer diagnosis and new-onset CVD. Furthermore, ANOVA analyses were conducted to compare differences in baseline patient characteristics among (1) CRC patients without CVD, (2) patients with CVD at CRC diagnosis, and (3) patients with new-onset CVD.
Differences in HRQoL between the three groups were examined using linear mixed models (LMM), with maximum likelihood estimation and an unstructured covariance matrix with a 2-level structure (i.e., repeated time points [lower level], patients [higher level]). Analyses were done separately for each time point and HRQoL and were adjusted for a priori determined confounding variables such as age, sex, cancer stage, and number of non-CVD comorbidities. As cancer stage and cancer treatment are closely related and we want to avoid multicollinearity, we opted to include the cancer stage as a covariate, in line with our previous study [Citation15]. Clinically relevant differences in HRQoL were determined using the evidence-based guidelines for EORTC QLQ-C30 differences [Citation23].
Analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 24.0, IBM Corps, Armonk, NY). p Values <.05 were considered significant.
Results
Sociodemographic and clinical characteristics
Of the 713 invited CRC patients, 68% (n = 483) completed the questionnaire at baseline, 52% (n = 374) at 1-year follow-up, and 49% (n = 347) at 2-year follow-up. A full flow chart of the study has previously been published [Citation17]. Compared with all eligible patients, respondents were younger, more often male, more likely to receive chemotherapy, and less likely to undergo surgery (p < .05) [Citation17]. In addition, they were less often diagnosed with rectosigmoid cancer, more often had stage III cancer, and less often stage IV cancer (p < .05, data not shown).
Of 397 patients who completed baseline and 1 or 2-year follow-up, 65 patients were excluded as they were previously diagnosed with cancer, had already started treatment at baseline, and/or had missing data on CVD. Of the final sample (n = 327), nearly a quarter of patients (n = 72, 22%) had comorbid CVD at the time of cancer diagnosis, and 11% (n = 36) developed CVD during the 2-year follow-up (). CRC patients with comorbid CVD at diagnosis were older, less often had no non-CVD comorbidities (p = .04), more often had at least two non-CVD comorbidities (p = .004), and more often had hypertension (p < .001), hypercholesterolemia (p < .001), or both (p < .001) compared with patients who never had comorbid CVD (n = 219, 67%). Furthermore, CRC patients with new-onset CVD more often had at least two non-CVD comorbidities (p = .002) and more often had hypertension (p = .01) and both hypertension and hypercholesterolemia (p = .048) compared with those without CVD. Finally, CRC patients with comorbid CVD at diagnosis more often had hypercholesterolemia (p < .001) and both hypertension and hypercholesterolemia (p = .03) compared with CRC patients with new-onset CVD.
Table 1. Baseline characteristics of colorectal cancer patients, stratified by CVD status.
Prevalence of comorbid CVD
Of the total sample, 76% (n = 248) had no comorbid CVD at the time of cancer diagnosis, 18% (n = 60) had one CVD, and 6% (n = 19) had two or more CVDs at cancer diagnosis. The most prevalent CVDs at cancer diagnosis were cardiac arrhythmias (n = 27, 8%), stroke or transient ischemic attack (n = 27, 8%), and myocardial infarction (n = 22, 7%).
During two-year follow-up, 11% (n = 36) reported new-onset CVD: 9% (n = 29) developed one CVD and 2% (n = 7) developed two or more CVDs. Of those with new-onset CVD, 81% (n = 29) did not have a CVD at time of cancer diagnosis, while 19% (n = 7) already had at least one CVD. The most prevalent new-onset CVDs for the total group were cardiac arrhythmias (n = 13, 4%), myocardial infarction (n = 9, 3%), stroke or transient ischemic attack (n = 6, 2%), and heart failure (n = 6, 2%).
Comorbid CVD and HRQoL
CRC patients with comorbid CVD at cancer diagnosis reported significantly worse physical functioning (p = .006) of small clinical relevance at 2-year follow-up compared with patients who never had comorbid CVD (). No other differences in HRQoL were found between the two groups. In contrast, several differences in HRQoL were found between CRC patients with new-onset CVD and patients who never had comorbid CVD. Specifically, patients with new-onset CVD reported worse global QoL (p = .001 and p = .002), worse role functioning (p = .008 and p < .001), and more fatigue (p = .009 and p = .004) at 1 and 2-year follow-up, respectively. In addition, they reported more dyspnea at baseline (p = .008) and worse physical functioning at 2-year follow-up (p = .001). Differences were of small clinical relevance, except for those in global QoL which were of medium clinical relevance. Finally, patients with new-onset CVD reported worse global QoL at 1-year follow-up (p = .048) and worse role functioning (p = .02), and more fatigue (p = .03) at 2-year follow-up, compared with patients with comorbid CVD at cancer diagnosis. These differences were of small clinical relevance. Of the patients with new-onset CVD, seven patients had a CVD prior to their CRC diagnosis and developed a new CVD after their CRC diagnosis. Sensitivity analyses were performed excluding these seven patients, when comparing the three groups: (1) CRC patients without CVD, (2) patients with CVD at CRC diagnosis, and (3) patients with new-onset CVD (minus seven patients with prior CVD). Sensitivity analyses showed similar results (data not shown). That is, CRC patients with new-onset CVD still showed poorer HRQoL compared with CRC patients without CVD and patients with CVD at CRC diagnosis, although some results were no longer significant.
Figure 1. Health-related quality of life among colorectal cancer patients, stratified by cardiovascular disease status. A higher score on the scales indicates better functioning or more fatigue and dyspnea. NOTE: for clear visibility, the scales of global quality of life and the functioning scales in this figure range from 50–100 and the scales of fatigue and dyspnea range from 0–50, while scores of the EORTC QLQ-C30 range from 0–100. *Significant difference between CRC patients with comorbid CVD at cancer diagnosis versus CRC patients who never had comorbid CVD, †significant difference between CRC patients with new-onset CVD versus CRC patients who never had comorbid CVD, ‡significant difference between CRC patients with new-onset CVD versus CRC patients with comorbid CVD at cancer diagnosis.
Sensitivity analyses
The group of patients with comorbid CVD at cancer diagnosis is a heterogenous group regarding time since CVD diagnosis (range 0–51 years ago). Therefore, we conducted sensitivity analyses and compared HRQoL among (1) patients who never had comorbid CVD, (2) patients with comorbid CVD diagnosis up to 5 years before CRC diagnosis (n = 42), and (3) patients with comorbid CVD diagnosis more than 5 years before CRC diagnosis (n = 28) (n = 2 had missing data on the time of CVD diagnosis). Patients with comorbid CVD diagnosis ‘more than 5 years’ before CRC diagnosis reported significantly worse physical functioning at baseline (84.6 vs. 93.6; p = .003) and 2-year follow-up (78.0 vs. 90.0; p = .001) and worse role functioning at baseline (89.4 vs. 76.8; p = .001) compared with patients who never had comorbid CVD. These differences were of small clinical relevance. Furthermore, they reported worse role functioning at baseline (76.8 vs. 90.5; p = .001) and worse physical functioning at 2-year follow-up (78.0 vs. 84.1; p = 0.01) compared with patients with comorbid CVD diagnosis ‘up to 5 years’ before CRC diagnosis. Both differences were of small clinical relevance. Finally, no differences were found between patients with comorbid CVD diagnosis up to 5 years before CRC diagnosis and those who never had comorbid CVD.
Discussion
In this prospective, population-based study, CRC patients with comorbid CVD, specifically those with new-onset CVD, experienced a significantly and clinically relevant worse HRQoL compared with CRC patients who never had comorbid CVD. In addition, patients with new-onset CVD reported worse HRQoL compared with patients who had comorbid CVD at cancer diagnosis. Exclusion of CRC patients (n = 7) who had CVD at diagnosis as well as developed new-onset CVD attenuated the results, although the direction remained similar. This is likely due to loss of power, but may also indicate that those seven patients showed the poorest HRQoL. Despite our rather small sample size, the results are in line with our hypothesis and two other studies [Citation15,Citation16]. In the first study, done by our research group, CRC survivors who were at a median of 4.6 years after the cancer diagnosis, reported worse global QoL, physical functioning, role functioning, fatigue, and dyspnea compared with those without CVD [Citation15]. In the other study, CRC survivors with CVD at the time of the study reported worse global QoL, worse functioning, and worse symptoms including fatigue and dyspnea [Citation16]. However, both studies did not assess the timing of CVD diagnosis and therefore could not distinguish between comorbid CVD already present at cancer diagnosis and new-onset CVD. Also, both studies were done among long-term CRC survivors, while we examined the association between (new-onset) CVD and HRQoL from CRC diagnosis until 2-year follow-up.
Two findings of our sensitivity analyses were that patients with comorbid CVD ‘more than 5 years’ before CRC diagnosis reported worse role functioning at baseline and worse physical functioning at 2-year follow-up compared with patients with comorbid CVD diagnosis ‘up to 5 years’ before CRC diagnosis. Also, there were no differences between patients with comorbid CVD diagnosis ‘up to 5 years’ before CRC diagnosis and those without comorbid CVD. We find it difficult to offer a sensible explanation for these surprising findings. A possible explanation is improved cardiovascular treatment [Citation24]. Patients with comorbid CVD diagnosis ‘up to 5 years’ before cancer diagnosis may have received better cardiovascular treatment, resulting in less symptoms. This may also explain the lack of significant differences between patients with comorbid CVD diagnosis ‘up to 5 years’ before CRC diagnosis and those without CVD.
The increased prevalence of comorbid CVD among CRC patients may be the result of the aging population [Citation8], shared lifestyle risk factors (e.g., obesity, physical inactivity, smoking) [Citation9,Citation10], and the direct or indirect cardiotoxic effect of cancer treatment [Citation6,Citation11,Citation12]. Receiving a CVD diagnosis induced by cancer treatment may have a synergetic or accumulative effect in lowering patients’ HRQoL. In addition, there is emerging evidence of not merely shared lifestyle factors but also biological mechanisms such as inflammatory markers and oxidative stress, that may link CVD and (colorectal) cancer [Citation25]. However, the bi-directional association between CVD and cancer [Citation26] remains complex and more studies are needed to (further) elucidate the interrelationship between these two lethal conditions. Future longitudinal research should include CVD and (colorectal) cancer populations simultaneously to examine their development.
The increased number of CRC patients with comorbid CVD and the findings of this study highlight the importance of addressing cardiovascular needs of CRC patients to optimize patients’ health and wellbeing. Cardio-oncology, a new discipline, focuses on the involvement of cardiologists in cancer care, including the management of cardiovascular complications of cancer therapy and the overall care of cancer patients from cancer diagnosis to survivorship [Citation27]. Given the shared lifestyle risk factors for CRC and CVD, the management of CVD in CRC should also include interventions to support a healthy lifestyle, before, during, and after cancer treatment [Citation28]. Furthermore, psychological risk factors should be considered, as psychological factors such as anxiety have been linked to an increased risk for new-onset CVD among cancer survivors [Citation29,Citation30].
Several study limitations should be mentioned. First, we neither assess CVD the severity nor the worsening of CVDs during the course of the study. Furthermore, CVD status was measured by self-report. While several studies have shown that self-reported questionnaires are valid to assess comorbid conditions [Citation31,Citation32], recall bias may occur, which is influenced by several factors including older age and lower educational level [Citation32]. Given our patient population and the fact that CVD was sometimes diagnosed many years ago, some patients may have had problems recalling (the date of) their CVD diagnosis. In addition, patients lost to follow-up could have stopped participating because of CVD development, increased CVD severity or CVD-related death. Its effect on our findings is unclear, as this could have led to an underestimation or overestimation of the effect. The inclusion of more CRC patients with CVD may result in a larger difference in HRQoL; i.e., lower scores compared to CRC patients without CVD. Alternatively, if these deceased CRC patients with new-onset CVD are categorized as having no CVD in our analyses (they deceased prior to filling out information on their changed CVD status), our findings may be overestimated. Furthermore, eligible patients and participants of this study differed in some patient characteristics. Also, patients willing to participate in a cohort study generally have a higher HRQoL, better survival, and more often no comorbidities compared with nonparticipants, and therefore represent a healthier population [Citation33]. Correspondingly, patients might drop out of the study due to similar reasons, possibly resulting in selection bias. As the Rour study consists of secondary data analyses, numbers are too small to draw firm conclusions. In contrast to the limitations, the major strengths of this study are the pretreatment assessment of CVD, including the date of diagnosis, and the prospective design, which enabled us to examine both comorbid CVD at diagnosis and new-onset CVD. In addition, this study is, to our knowledge, the first to relate both comorbid CVD at CRC diagnosis and new-onset CVD to HRQoL from CRC diagnosis until 2-year follow-up.
In conclusion, this prospective, population-based study from diagnosis until 2-year follow-up showed that CRC patients with comorbid CVD, specifically those with new-onset CVD, experienced a significantly and clinically relevant worse HRQoL compared with those without comorbid CVD. While numbers are small, findings seem to indicate that CRC patients might have cardiovascular needs that need to be addressed and that multidisciplinary care is recommended. Larger studies need to confirm this.
Ethics approval
The PROCORE study was approved by the certified Medical Ethic Committee of Medical Research Ethics Committees United (registration number: NL51119.060.14).
Consent to participate
Informed consent was obtained from all individual participants included in the study.
Consent for publication
Patients signed informed consent regarding publishing their data.
Acknowledgments
We would like to thank all patients and their doctors for their (ongoing) participation in PROCORE. Special thanks go to C. Rolf, MD, and F. van Heest, MD, who were willing to function as independent advisors and to answer questions of patients. In addition, we want to thank the following hospitals for their collaboration: Elisabeth-Twistedness hospital, Tilburg; Catharina hospital, Eindhoven; Elkerliek hospital, Helmond; Máxima Medical Centre, Eindhoven and Veldhoven.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The data that support the findings of this study are available from the PROFILES registry (www.profilesregistry.nl).
Additional information
Funding
References
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