Background
A general decline in mortality in colorectal cancer (CRC) in recent decades is attributed to improvements in treatment, changing patterns in CRC risk factors, and screening.1,2 CRC is the one of the most common cancers among cancer survivors in the United States, where there are >1.2 million CRC survivors,3,4 most of whom are aged >60 years.5 Although surgery is the mainstay of treatment for early-stage disease, fluoropyrimidines, which include 5-FU and its oral prodrug capecitabine, are commonly used in adjuvant or neoadjuvant chemotherapy.6
Among conventional cytotoxic agents, 5-FU is the most common one that causes cardiotoxicity, second only to anthracyclines.7 Symptomatic acute cardiotoxicity occurs in up to 20% of patients treated with 5-FU and in up to 35% of patients treated with capecitabine.8 However, there is limited evidence regarding the magnitude of long-term cardiovascular disease (CVD) risk related to adjuvant chemotherapy for CRC.
Further compounding these risks, most CRC survivors are elderly and have comorbidities.9,10 In particular, the presence of factors such as obesity, tobacco exposure, and hypertension may increase the overall risk of CVD.4,11,12 Therefore, we conducted a population-based study in the New Territories West region of Hong Kong to assess the adjuvant fluoropyrimidine-based chemotherapy–related long-term CVD incidence among CRC survivors, adjusting for treatment regimens and doses, comorbidities, sociodemographic information, and their interactions.
Patients and Methods
Data Source, and Case and Outcome Definitions
Data were retrieved from the Clinical Data Analysis and Reporting System (supplemental eAppendix 1, available with this article at JNCCN.org). We identified patients diagnosed with high-risk stage II–III colorectal adenocarcinoma treated with curative surgical operations followed by adjuvant chemotherapy between January 1, 2010, and December 31, 2019, in the New Territories West region of Hong Kong. Figure 1 shows study criteria and the final number of patients in the study cohort.13 The composite primary outcome was incident CVD after CRC diagnosis index date, including ischemic heart disease, heart failure, cardiomyopathy, and stroke clinically diagnosed during inpatient hospital visits or as the cause of death after cancer diagnosis (ICD-9-CM codes in supplemental eTable 1). The validity of ICD-9-CM codes has been compared with that of ICD-10 codes, showing strong consistency.14 Prior studies from Hong Kong also showed high accuracy of ICD-9-CM codes in capturing various clinical conditions.15–18 Although Hong Kong has been transitioning to ICD-10 in the past few years, ICD-9-CM codes were used more frequently than ICD-10 for clinical records and administrative data during the study period; therefore, we used ICD-9-CM for data abstraction. Patients were excluded if they (1) had unknown demographic data or were aged <18 years, (2) developed CVD before the CRC diagnosis, or (3) had not received adjuvant chemotherapy for CRC.
Flowchart outlining inclusion and exclusion criteria for final study cohort of patients with CRC who received adjuvant chemotherapy.
Abbreviations: CRC, colorectal cancer; CVD, cardiovascular disease.
Citation: Journal of the National Comprehensive Cancer Network 20, 10; 10.6004/jnccn.2022.7042
Treatment Information
Generally, adjuvant chemotherapy is offered to patients who have stage II disease with risk factors or stage III disease. The possible adjuvant chemotherapy regimens are capecitabine alone, 5-FU alone, CAPOX (capecitabine/oxaliplatin), and FOLFOX (leucovorin/5-FU/oxaliplatin). Other treatment data included the number of cycles and any dose reduction.
Preexisting Cardiovascular Risk Factors, Comorbidities, and Other Variables
We retrieved data on the preexisting cardiovascular risk factors, including hypertension, dyslipidemia, diabetes, comorbidities, chronic obstructive pulmonary disease (COPD) or smoking, and alcohol-related diseases, using a combination of ICD-9-CM codes and the prescription of medications as appropriate (supplemental eTable 2 and eAppendix 2).19–21 We regarded the need for medical fee waiver as a surrogate for lower socioeconomic status.
Control Group
The external comparison control group was selected from among a noncancer random sample from primary care clinic registries. The external control group might represent the CVD risk in the overall population. From among 50,782 eligible adult patients in primary care, we selected a random sample of 10%, so that the case/control ratio was 1:5 (supplemental eFigure 1). The external comparison group had no history of cancer or CVD at baseline (ie, January 1, 2010) verified using ICD-9-CM codes (ie, 140–239 for cancer; CVD codes are detailed in supplemental eTable 1). Both the CRC and control groups were retrieved from the same geographic district of Hong Kong.
Statistical Analysis
We describe statistics for demographics, follow-up duration, and prevalence of characteristics. Continuous variables are presented as medians with interquartile ranges (IQRs), and differences in patient and control status were assessed using rank-sum tests. Categorical variables are presented as percentages, and differences in patient and control status were assessed using chi-square tests.
We hypothesized that exposure to fluoropyrimidine in the adjuvant setting determines the differences in CVD outcomes between patient and external control groups. We dealt with the competing risks of death and derived cause-specific hazard ratios (HRs) based on a cause-specific hazard framework (ie, censoring death when assessing CVD risk by cancer treatment).22–27 Details of the competing risk analysis are provided in supplemental eAppendix 3. Statistical analyses were performed using Stata, version 16.1 (StataCorp LLC).28,29
Results
The characteristics of the cancer cohort (n=1,037) and the control group (n=5,078) are detailed in Table 1. Median age at diagnosis for the cancer cohort was 62 years (IQR, 56–68 years); 63.6% were male. As of October 31, 2021, the median follow-up from the index date for the entire cancer survivor cohort was 5.7 years (IQR, 3.5–8.2 years), providing 5,135 person-years of follow-up. Beyond 2 months from diagnosis, 41 (3.9%) of the patients with CRC developed CVD, with a median interval to CVD of 2.3 years (IQR, 0.2–4.4 years). The incidence rate was 9.7 per 1,000 person-years (95% CI, 7.4–12.8 per 1,000 person-years). Among cancer survivors, most deaths were a result of CRC (67.4%). Supplemental eTable 3 provides the characteristics of patients with cancer who received different adjuvant chemotherapy regimens.
Patient Cohort Characteristics
Within the cancer cohort, there was a higher proportion of men (63.6% vs 51.6%; P<.001), alcohol-related disease (2.6% vs 0.7%; P<.001), fewer comorbidities (Royal College of Surgeons [RCS] score 0, 77.6% vs 50.5%; P<.001), lower medical fee waiver requirement (13.3% vs 23.2%; P<.001), fewer smokers or individuals with COPD (1.8% vs 3.3%; P=.011), less diabetes (12.9% vs 32.3%; P<.001), and less dyslipidemia or hyperlipidemia (32.6% vs 70.3%; P<.001) (Table 1).
Univariable and multivariable analyses are shown in Table 2. Multivariable analysis showed that the use of fluoropyrimidine-based adjuvant chemotherapy among patients with CRC was associated with an approximately 2-fold increase in the risk of CVD compared with the control group (adjusted cause-specific HR, 2.11; 95% CI, 1.39–3.20; P<.001). The patients with CRC who had received adjuvant chemotherapy had 1-, 5-, and 10-year cause-specific cumulative incidences (csCIs) of CVD of 2.0% (95% CI, 1.4%–3.0%), 4.5% (95% CI, 3.2%–6.3%), and 5.4% (95% CI, 3.8%–7.5%), respectively. The corresponding csCI estimates for the control group were 1.2% (95% CI, 0.9%–1.5%), 3.0% (95% CI, 2.6%–3.5%), and 3.8% (95% CI, 3.3%–4.4%), respectively (Figure 2).
Cause-Specific HRs for New-Onset CVDs
Cause-specific cumulative incidence of cardiovascular diseases in patients with CRC who received adjuvant chemotherapy (n=1,037) versus the control group (n=5,078), with death as a competing risk. Bands represent 95% confidence intervals.
Abbreviation: CRC, colorectal cancer.
Citation: Journal of the National Comprehensive Cancer Network 20, 10; 10.6004/jnccn.2022.7042
In the main analysis, we also found that age at cancer diagnosis (HR per 5-year increase, 1.16; 95% CI, 1.08–1.24; P<.001), sex (HR for male vs female, 1.40; 95% CI, 1.06–1.86; P=.020), RCS comorbidity score (HR for 1 comorbidity vs none, 1.88; 95% CI, 1.36–2.61; P<.001; HR for ≥2 comorbidities vs none, 6.61; 95% CI, 4.55–9.60; P<.001), diabetes (HR, 1.38; 95% CI, 1.04–1.84; P=.025), hypertension (HR, 3.27; 95% CI, 2.39–4.50; P<.001), and dyslipidemia/hyperlipidemia (HR, 2.53; 95% CI, 1.68–3.81; P<.001) were associated with incident CVD.
The csCI plots of individual CVD endpoints (ischemic heart disease, heart failure, cardiomyopathy, and stroke) adjusted for the same covariates (age, sex, need for medical fee waiver, preexisting cardiovascular risk factors, and RCS comorbidity score) showed a markedly higher csCI of stroke in patients with CRC than in the control group (supplemental eFigures 2–4).
Within the cancer group, the 1-, 5-, and 10-year csCIs of cancer death were 9.1% (95% CI, 6.8%–12.1%), 55.4% (95% CI, 50.5%–60.7%), and 62.5% (95% CI, 57.5%–68.0%), respectively, whereas the 1-, 5-, and 10-year csCIs of other causes of death were 3.8% (95% CI, 2.4%–5.9%), 21.1% (95% CI, 17.3%–25.7%), and 26.0% (95% CI, 21.6%–31.1%), respectively. The ratios of predicted csCI of cancer death and CVD among the cancer cohort at 1, 5, and 10 years were 3.91 (95% CI, 3.72–4.10; P<.001), 6.67 (95% CI, 6.64–6.69; P<.001), and 5.67 (95% CI, 5.66–5.67; P<.001), respectively. The corresponding ratios of other causes of death and CVD in the group at 1, 5, and 10 years were 1.59 (95% CI, 1.54–1.64; P<.001), 2.55 (95% CI, 2.54–2.55; P<.001), and 2.35 (95% CI, 2.35–2.36; P<.001), respectively (Figure 3). The control group showed a similar pattern of csCI of CVD and death, which increased with time (supplemental eFigure 5).
Cause-specific cumulative incidence of cardiovascular diseases versus other causes of death among patients with colorectal cancer. Bands represent 95% confidence intervals.
Citation: Journal of the National Comprehensive Cancer Network 20, 10; 10.6004/jnccn.2022.7042
Subgroup analysis comparing patients with CRC who received capecitabine-based versus 5-FU–based regimens revealed weak evidence of difference between the regimens (HR, 1.66; 95% CI, 0.56–4.91; P=.356), number of cycles (HR, 1.00; 95% CI, 0.86–1.16; P=.980), and chemotherapy dose reductions (HR, 0.42; 95% CI, 0.14–1.31; P=.136) in terms of incident CVD risks (Table 3). However, we found that capecitabine-based chemotherapy was associated with a higher risk of CVD when compared with the control group (supplemental eTable 4 and eFigure 6). Sensitivity analyses including additional variables or without landmark periods produced largely consistent results (supplemental eTables 5 and 6).
Cause-Specific HRs for New-Onset CVDs Among Patients With CRC
Discussion
We evaluated the long-term CVD risk among patients with high-risk stage II–III CRC in the clinically relevant time period from 2 months after surgery to 10 years, both in additive (ie, csCI) and multiplicative scales (ie, HR). We show evidence of an association between exposure to fluoropyrimidine-based adjuvant chemotherapy and higher risk of CVD in the long run among patients with high-risk stage II–III CRC when compared with the control group. The difference in CVD incidence over time between the cancer cohort and control group persisted and continued to increase.
The csCI increased the most within the first 2 years after chemotherapy. We also found that all individual CVD diagnoses were more common in patients who received chemotherapy. In particular, patients within the cancer cohort had the greatest increase in the relative risk of stroke. To our knowledge, this study is one of the first contemporary comprehensive analyses reporting long-term incident CVD events in patients with CRC after initiation of fluoropyrimidine-based chemotherapy versus control subjects.
A previous study reported that among CRC survivors, 1.6% and 0% had new-onset self-reported myocardial infarction and heart failure, respectively, at 3 years after diagnosis.30 Another study that assessed an older group (80% were aged ≥70 y) of patients with stages I–III CRC (most without adjuvant chemotherapy) detected a higher cumulative incidence of CVD of 23% at 3 years and 57% at 10 years after the cancer diagnosis.31 In a recent study that assessed the risk for myocardial infarction in patients with gastrointestinal cancer treated with 5-FU compared with age- and sex-matched noncancer control subjects, the 6-month and 1-year cumulative incidences of myocardial infarction were 0.7% and 0.9% versus 0.3% and 0.6% in the control group, respectively.32 The discrepancies among these studies are likely related to the differences in the study populations, endpoint definitions, and methodologies.
Our study is unique because we assessed well-defined CVD endpoints from patients who were diagnosed with high-risk stage II–III CRC treated with adjuvant chemotherapy. We provided cumulative incidence estimates of clinically relevant time points up to 10 years based on the flexible parametric competing risk analysis, which allowed us to evaluate the trajectory and competing risks of cancer death and noncancer death and the influence of various patient characteristics. Importantly, a population-based study using SEER-Medicare data revealed that the occurrence of comorbid conditions before CRC diagnosis was common and contributed to increased death in patients.33 However, it remains unclear how established cardiovascular risk factors influence fluoropyrimidine cardiotoxicity. Our study built on the previous work by adjusting for comorbidities and common cardiovascular risk factors, including tobacco and alcohol use.
There remains uncertainty about the role of cardioprotective medications (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and diuretics) for patients treated with fluoropyrimidine in terms of their subsequent risk of CVD.34,35 Our study assessed the baseline use of these medications and found that none were associated with a reduced risk of CVD. This is a finding supplementary to the main results largely because of lack of information about indications of the prescriptions, dosages, and adherence to medications.
Some studies found that cardiovascular risk is increased with continuous infusions compared with bolus regimens, suggesting that cardiotoxicity might be influenced by plasma exposure over time (ie, the administration schedule).36–38 However, we detected no statistically significant difference between capecitabine-based and 5-FU–based chemotherapy in their association with CVD risk. This is consistent with results of another study assessing patients with gastrointestinal cancers, in which capecitabine and 5-FU were largely similar in terms of the timing and type of cardiotoxicity.39
Our analysis detected that CVD was more common among older patients and patients with more comorbidities. Intuitively, elderly patients tend to have more comorbidities and reduced cardiovascular reserve. This could lead to a higher chance of cardiac decompensation after receipt of chemotherapy. This may explain why most CVD cases are detected within the first 2 years, when the physiologic (related to the postoperative recovery and adjuvant chemotherapy) and emotional stress is high.
Mechanisms responsible for fluoropyrimidine-related cardiotoxicity are multifactorial.7,40 Fluoropyrimidine treatment can lead to endothelial damage, which can increase secretion of vasoconstrictors,41,42 disturb production of nitric oxide,43 activate apoptosis in endothelial cells and myocytes,44,45 and trigger thrombosis due to platelet clumps and fibrin formations.46 Endothelial dysfunction and primary smooth muscle dysfunction result in coronary artery spasm, which is an important mechanism implicated in myocardial ischemia and damage.47,48 Fluoropyrimidine treatment is also associated with enhanced oxidative stress due to the formation of reactive oxygen species, lipid peroxidation, and the decrease in glutathione level, with myocytes being especially susceptible to cellular damage due to their numerous mitochondria.44 Furthermore, fluoropyrimidine can lead to disruption of erythrocyte metabolism, with a subsequent change in the cellular structures, integrity, and functioning.49 The ability of erythrocytes to deliver and transport oxygen is decreased.50 Insufficient oxygen supply and associated ischemic injury to metabolically active organs such as the heart can occur as a result.
Stroke was found to be the CVD that had the greatest relative difference between patients with cancer and the control subjects. This suggests that some other mechanisms may play a role in CVD incidence in at least some patients. Ischemia in particular may be related to the underlying hypercoagulable state of malignancy, causing small-vessel thrombosis.51,52 In addition, anemia secondary to chemotherapy-related bone marrow suppression or nutritional deficiency may contribute to the ischemic state.53–55 Risk factors for CRC, such as obesity and sedentary lifestyle, may also contribute to CVD.56 Moreover, cancer survivors may experience chronic fatigue and have reduced exercise capacity, further contributing to CVD.57
The American Cancer Society and ESMO guidelines, along with the European Society of Cardiology position paper, are not very specific regarding the screening methods and frequencies.4,40,58 Generally, it was suggested that patients with cancer with preexisting CVD should have optimal control of cardiovascular risk factors and close monitoring during and after fluoropyrimidine treatment. Our study found that the risk for incident CVD is highest within 5 years after diagnosis, especially in the first 2 years, and the events continue to occur along the survivorship, albeit at a slower rate. Long-term risk-adapted surveillance of CRC survivors that accounts for their baseline CVD risk factors and exposure to chemotherapy is advisable.
Our study has several strengths. First, we identified that active cancer itself may increase the CVD risk, which can confound the association between cancer treatment and CVD. Therefore, we only included patients who had undergone a radical resection and were being treated with adjuvant chemotherapy. Second, we compared the incident CVD risk of our cohort with that of a control group without cancer and not against a group with CRC treated with radical resection alone. This reduces the risk of confounding by indication. Third, because of the heavily subsidized healthcare system in Hong Kong, patients with chronic diseases and serious conditions (eg, myocardial infarction) are mostly treated in the public healthcare system.59 Therefore, the Hong Kong Hospital Authority data should have captured nearly all the hospital-managed CVD outcomes, together with the corresponding dates.
Our study’s limitations include the lack of details regarding chemotherapy dosing and whether particular drugs were omitted from the regimen. As such, it is difficult to draw strong conclusions on the dose–response relationship between drug exposure and CVD incidence and the CVD risks associated with different regimens. To mitigate this, we adjusted for chemotherapy dose reduction and the number of chemotherapy cycles, which were surrogates for dosages. Information such as level of physical exercise and performance status was not readily available in our database, and we acknowledge that these may be contributing factors to CVD. Additionally, some ICD-9-CM codes, such as those for medical conditions, alcoholism, and smoking, may be undercoded, leading to the problems of underdiagnosis or misclassification. However, when possible, we used medication prescriptions to supplement diagnoses (eg, antidiabetic medications for diabetes). Finally, our study was based on an Asian cohort, and one should be careful when generalizing our findings to other populations, which can have different demographics, cardiovascular risk factor profiles, and susceptibilities to cancer treatment toxicities.
Conclusions
In this Asian population-based study, we detected a 2-fold increase in the risk of incident CVD among survivors of high-risk stage II–III CRC without preexisting CVD with exposure to adjuvant fluoropyrimidine-based chemotherapy. We also found that most CVD events occurred soon after diagnosis and treatment. Together, these findings highlight the importance of pretreatment screening for CVD risk factors, periodic monitoring of cardiac function, and timely intervention to minimize the risk of CVD during and after cancer treatment and throughout cancer survivorship.
Acknowledgments
We thank King-Fung Tsang (Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong) for clerical support and data retrieval.
References
- 1.↑
Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116:544–573.
- 2.↑
Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin 2019;69:363–385.
- 3.↑
Bluethmann SM, Mariotto AB, Rowland JH. Anticipating the “Silver Tsunami”: prevalence trajectories and comorbidity burden among older cancer survivors in the United States. Cancer Epidemiol Biomarkers Prev 2016;25:1029–1036.
- 4.↑
El-Shami K, Oeffinger KC, Erb NL, et al. American Cancer Society colorectal cancer survivorship care guidelines. CA Cancer J Clin 2015;65:428–455.
- 6.↑
Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 1.2022. Accessed March 17, 2021. To view the most recent version, visit https://www.NCCN.org
- 7.↑
Sara JD, Kaur J, Khodadadi R, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol 2018;10:1758835918780140.
- 8.↑
Polk A, Vaage-Nilsen M, Vistisen K, et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev 2013;39:974–984.
- 9.↑
Gross CP, Guo Z, McAvay GJ, et al. Multimorbidity and survival in older persons with colorectal cancer. J Am Geriatr Soc 2006;54:1898–1904.
- 10.↑
Luque-Fernandez MA, Gonçalves K, Salamanca-Fernández E, et al. Multimorbidity and short-term overall mortality among colorectal cancer patients in Spain: a population-based cohort study. Eur J Cancer 2020;129:4–14.
- 11.↑
Sinicrope FA, Foster NR, Yothers G, et al. Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy. Cancer 2013;119:1528–1536.
- 12.↑
Westmaas JL, Alcaraz KI, Berg CJ, et al. Prevalence and correlates of smoking and cessation-related behavior among survivors of ten cancers: findings from a nationwide survey nine years after diagnosis. Cancer Epidemiol Biomarkers Prev 2014;23:1783–1792.
- 13.↑
Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332.
- 14.↑
Quan H, Li B, Saunders LD, et al. Assessing validity of ICD-9-CM and ICD-10 administrative data in recording clinical conditions in a unique dually coded database. Health Serv Res 2008;43:1424–1441.
- 15.↑
Wong MCS, Jiang JY, Tang JL, et al. Health services research in the public healthcare system in Hong Kong: an analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data. BMC Health Serv Res 2008;8:138.
- 16.↑
Wong OF, Ho PL, Lam SK. Retrospective review of clinical presentations, microbiology, and outcomes of patients with psoas abscess. Hong Kong Med J 2013;19:416–423.
- 17.↑
Chan EW, Lau WCY, Leung WK, et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology 2015;149:586–595.e3.
- 18.↑
Wong AYS, Root A, Douglas IJ, et al. Cardiovascular outcomes associated with use of clarithromycin: population based study. BMJ 2016;352:h6926.
- 19.↑
Grundy SM, Pasternak R, Greenland P, et al. Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 1999;100:1481–1492.
- 20.↑
Vaccarino V, Badimon L, Bremner JD, et al. Depression and coronary heart disease: 2018 position paper of the ESC working group on coronary pathophysiology and microcirculation. Eur Heart J 2020;41:1687–1696.
- 21.↑
Poulsen AH, Christensen S, McLaughlin JK, et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br J Cancer 2009;100:1503–1507.
- 23.↑
Pintilie M. Competing Risks: A Practical Perspective. Hoboken, NJ: John Wiley & Sons Ltd.;2006.
- 24.↑
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988;16:1141–1154.
- 25.↑
Andersen PK, Geskus RB, de Witte T, et al. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol 2012;41:861–870.
- 26.↑
Geskus RB. Data Analysis with Competing Risks and Intermediate States. Boca Raton, FL: CRC Press;2016.
- 27.↑
Kipourou DK, Charvat H, Rachet B, et al. Estimation of the adjusted cause-specific cumulative probability using flexible regression models for the cause-specific hazards. Stat Med 2019;38:3896–3910.
- 28.↑
Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988;332:83–85.
- 30.↑
Hawkes AL, Lynch BM, Owen N, et al. Lifestyle factors associated concurrently and prospectively with co-morbid cardiovascular disease in a population-based cohort of colorectal cancer survivors. Eur J Cancer 2011;47:267–276.
- 31.↑
Kenzik KM, Balentine C, Richman J, et al. New-onset cardiovascular morbidity in older adults with stage I to III colorectal cancer. J Clin Oncol 2018;36:609–616.
- 32.↑
Shanmuganathan JWD, Kragholm K, Tayal B, et al. Risk for myocardial infarction following 5-fluorouracil treatment in patients with gastrointestinal cancer: a nationwide registry-based study. JACC CardioOncol 2021;3:725–733.
- 33.↑
Li X, Li Y, Zhang T, et al. Role of cardioprotective agents on chemotherapy-induced heart failure: a systematic review and network meta-analysis of randomized controlled trials. Pharmacol Res 2020;151:104577.
- 35.↑
Zamorano JL, Gottfridsson C, Asteggiano R, et al. The cancer patient and cardiology. Eur J Heart Fail 2020;22:2290–2309.
- 36.↑
Kosmas C, Kallistratos MS, Kopterides P, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 2008;134:75–82.
- 37.↑
Khan MA, Masood N, Husain N, et al. A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) and 5-FU based chemotherapy regimens in Pakistani adult cancer patients at Shaukat Khanum Memorial Cancer Hospital & Research Center. J Pak Med Assoc 2012;62:430–434.
- 38.↑
Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol 2006;58:487–493.
- 39.↑
Khan K, Rane JK, Cunningham D, et al. Efficacy and cardiotoxic safety profile of raltitrexed in fluoropyrimidines-pretreated or high-risk cardiac patients with GI malignancies: large single-center experience. Clin Colorectal Cancer 2019;18:64–71.e1.
- 40.↑
Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768–2801.
- 41.↑
Thyss A, Gaspard MH, Marsault R, et al. Very high endothelin plasma levels in patients with 5-FU cardiotoxicity [letter]. Ann Oncol 1992;3:88.
- 42.↑
Seker M, Isen HC, Çevirme N, et al. Role of urotensin-2 in 5-fluorouracil-related arterial vasoconstriction in cancer patients. Oncol Res Treat 2018;41:545–549.
- 43.↑
Morbidelli L, Donnini S, Ziche M. Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents. Cardiooncology 2016;2:3.
- 44.↑
Focaccetti C, Bruno A, Magnani E, et al. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One 2015;10:e0115686.
- 45.↑
Lamberti M, Porto S, Zappavigna S, et al. A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives. Toxicol Lett 2014;227:151–156.
- 46.↑
Kinhult S, Albertsson M, Eskilsson J, et al. Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation. Scanning 2001;23:1–8.
- 47.↑
Bathina JD, Yusuf SW. 5-fluorouracil-induced coronary vasospasm. J Cardiovasc Med (Hagerstown) 2010;11:281–284.
- 48.↑
Chong JH, Ghosh AK. Coronary artery vasospasm induced by 5-fluorouracil: proposed mechanisms, existing management options and future directions. Interv Cardiol 2019;14:89–94.
- 49.↑
Spasojević I, Maksimović V, Zakrzewska J, et al. Effects of 5-fluorouracil on erythrocytes in relation to its cardiotoxicity: membrane structure and functioning. J Chem Inf Model 2005;45:1680–1685.
- 50.↑
Spasojević I, Jelić S, Zakrzewska J, et al. Decreased oxygen transfer capacity of erythrocytes as a cause of 5-fluorouracil related ischemia. Molecules 2008;14:53–67.
- 51.↑
Caine GJ, Stonelake PS, Lip GYH, et al. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia 2002;4:465–473.
- 52.↑
Khorana AA, Dalal M, Lin J, et al. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 2013;119:648–655.
- 53.↑
Ravasco P, Monteiro-Grillo I, Vidal PM, et al. Nutritional deterioration in cancer: the role of disease and diet. Clin Oncol (R Coll Radiol) 2003;15:443–450.
- 54.↑
Birgegård G, Aapro MS, Bokemeyer C, et al. Cancer-related anemia: pathogenesis, prevalence and treatment. Oncology 2005;68(Suppl 1):3–11.
- 55.↑
Ravasco P, Monteiro-Grillo I, Vidal PM, et al. Cancer: disease and nutrition are key determinants of patients’ quality of life. Support Care Cancer 2004;12:246–252.
- 56.↑
Veettil SK, Wong TY, Loo YS, et al. Role of diet in colorectal cancer incidence: umbrella review of meta-analyses of prospective observational studies. JAMA Netw Open 2021;4:e2037341.
- 57.↑
Schneider EC, Malin JL, Kahn KL, et al. Surviving colorectal cancer: patient-reported symptoms 4 years after diagnosis. Cancer 2007;110:2075–2082.
- 58.↑
Curigliano G, Lenihan D, Fradley M, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol 2020;31:171–190.
- 59.↑
Lee CP. Health care system and pharmacy practice in Hong Kong. Can J Hosp Pharm 2018;71:140–148.
