Prevalence and Risk Factors of Cardiotoxicity in Elderly Cancer Patients

Background: Cancer and heart disease are the leading causes of death in older adults. Cardiotoxicity of anticancer agents may lead to under-treatment of elderly patients, resulting in suboptimal outcomes. Aim: To determine the prevalence and risk factors of cardiotoxicity in elderly patients with cancer. Patients and Methods: The study sample included one hundred (100) elderly subjects, both males and females, aged sixty years and above. The study participants were subjected to the following: comprehensive geriatric assessment (CGA), laboratory work-up (fasting blood glucose, lipid profile, and C-reactive protein), electrocardiography (ECG), and echocardiography (ECHO). Results: The prevalence of cardiotoxicity (any pattern) was 57%. Patients who experienced cardiotoxicity were older, had higher smoking index, lower body mass index, and longer cancer duration. They had higher prevalence of hypertension, diabetes, and dyslipidemia and had higher mean level of C-reactive protein. Participants who had received certain chemotherapeutic agents (e.g., Anthracycline), certain targeted therapy agents (e.g., Pertuzumab); and those who received radiotherapy (delivered to the chest) were more liable for cardiotoxicity. Cardiotoxicity was associated with malnutrition, depression and functional decline of the affected patients. Conclusion : Cardiotoxicity is common in elderly patients with cancer. It is associated with certain risk factors; such as smoking, dyslipidemia, hyperglycemia, malnutrition and certain anticancer treatments. Comprehensive geriatric assessment is essential in the management of elderly cancer patients.


Introduction
According to United Nations' report, the proportion of elderly individuals (65 years or older) is projected to increase from 10% in 2022 to 16% in 2050 [1].Aging is a major risk factor for many diseases, progressive loss of resilience and age-related multiple systems homeostatic derangements [2].Cancer stands as the leading cause of the disease burden all over the world, accounting for about 244 million disabilityadjusted life years (DALYs).This holds true for both males (137 million DALYs) and females (107 million DALYs).Following closely are coronary heart disease with around 203 million DALYs and cerebrovascular stroke with 137 million DALYs [3].Aging and cancer are closely related; both share many underlying mechanisms, risk factors and tightly interconnected biological processes [4].The high incidence of cancer in elderly has more than one mechanism.These mechanisms include prolonged lifetime exposure to carcinogenic agents, DNA damage accumulation, derangements of cellular repair mechanisms, oncogenic activation, and defects in tumor suppressor genes.A progressive senescence of immune function occurs in elderly, while an effective immune response against developing tumors may fail [5,6].Approximately 80% of adults aged 65 and above are affected by at least one cardiovascular disease (CVD) like hypertension (58%), coronary heart disease (29%), or diabetes mellitus (28%).The incidence of cardiovascular diseases among individuals aged 60 to 80 years hovers around 75-78% and surpasses 85% in those above 80 years of age [7,8].Cardiovascular risk factors, aging, and comorbidities play pivotal roles in the onset of heart disease.Among these factors, age stands out as one of the most significant contributors.Both the incidence and prevalence of cardiovascular disease significantly rise with age [2].Age-related changes in cardiovascular tissues often involve chamber hypertrophy, diminished left ventricular (LV) diastolic function leading to diastolic dysfunction, reduced LV reserve capacity, more arterial stiffness, and endothelial dysfunction.Additionally, risk factors for cardiovascular diseases are prevalent among the elderly population.Commonly observed risk factors include hypertension, diabetes mellitus, lipid disorders, obesity, and smoking.These conditions contribute significantly to the increased susceptibility of elderly individuals to cardiovascular diseases [9,10].An association between cardiovascular diseases and cancer exists, often attributed to shared risk factors.These common factors include advancing age, smoking, obesity, diabetes, high cholesterol levels, hypertension, and lack of physical activity [11].
Many cancer therapies have the potential for toxic effects on the cardiovascular system.Cardiotoxicity may cause frailty and undertreatment, resulting in suboptimal outcomes.A multi-disciplinary team based on collaboration between geriatricians, oncologists, and cardiologists is essential [12].The cardio-oncology team concentrates on preventing and managing cardiovascular complications arising from cancer therapy through three main approaches.First, treatment-based approach, which involves assessing the specific cancer treatments used, including drugs, surgeries, or radiation therapy, and understanding their potential impact on the cardiovascular system.Second, symptom/complication-based approach, the team investigates clinical manifestations such as dyspnea, chest pain, or rhythm disturbances, which are indicative of cardiovascular issues during or after cancer therapy.Third, patient characteristicbased approach, by considering individual patient factors, such as existing cardiovascular risks or established heart diseases, the team tailors their approach to address the unique cardiovascular challenges faced by each patient [13].Many unexplored areas in cardio-oncology still exist, which could open new perspectives for early detection, follow-up, and treating cardiotoxicity caused by antitumor treatments [14].Therefore, our aim was to evaluate the prevalence and risk factors associated with cardiotoxicity among elderly cancer patients who underwent various types of cancer-specific treatments.

Patients and methods
A cross sectional study comprised one hundred (100) elderly participants, men, and women, aged sixty years and above, who were diagnosed with cancer.The sample size was calculated using Power Analysis and Sample Size System (PASS) 11 program, setting alpha error at 5%, margin of error at 5%, and the power of the test 80%.The research protocol has been approved by the Ethics Board of Ain Shams University (Study Protocol Approval Code: FMASU MD 01/2018).Every participant provided their consent by signing an informed written permission form.The study sample was collected from the inpatient wards and outpatient clinics of National Cancer Institute, Cairo, Egypt.Medical records were reviewed; and all patients enrolled in the study had normal cardiovascular assessment at baseline.Additionally, patients who had previous history of heart disease two years or more before diagnosis of cancer were excluded.All the study participants were subjected to the following: (1) Comprehensive Geriatric Assessment (CGA) including: • Medical history and physical examination.• Body mass index (BMI) calculation [15].• Screening for dementia: using the Arabic version [16] of the Minimental state examination (MMSE) [17].

Statistical analysis
The gathered data underwent a thorough review, coding, and tabulation before being input into a computer using the Statistical Package for the Social Sciences (IBM SPSS 20.0).Quantitative parametric data were presented as mean and standard deviation (±SD), while quantitative nonparametric data were represented as median and interquartile range.To compare quantitative variables, t-tests were employed for comparing two groups, while ANOVA was used for comparing three groups.For qualitative variables, the Chi-square test was utilized.The significance level was determined based on P value (Probability) as follows: P>0.05 (insignificant), P<0.05 (significant), and P<0.01 (highly significant).

Results
The study sample comprised one hundred (100) elderly participants, men and women, sixty years and above, the mean age of the participants was 68.8 years, 50% of participants were smokers (mean smoking index=37), and 14% were obese.Most prevalent cancer type among our study participants was breast cancer (32%) and most of the participants had a cancer stage of 2 or 3. Hypertension, diabetes mellitus, and COPD were the most prevalent associated comorbidities among the studied population; as shown in table (1).Various modalities of cancer treatment were received by the study participants.70% of our study participants underwent surgical treatment, 92% received chemotherapy (with mean duration of 2.38 years), 58% received radiotherapy (most common site of radiotherapy was chest radiotherapy), 40% received hormonal therapy, and 30% received targeted therapy.Combined chemo/radiotherapy was used in 55% of participants, while combined chemo/targeted therapy was used in 30% of participants.Most common types of anti-cancer agents used among the study population were Anthracycline (Doxorubicin) (67%), Paclitaxel (37%), Trastuzumab (26%), Cyclophosphamide (22%) and 5-Fluorouracil (18%).Cardiotoxicity was found in 57% of study participants.The pattern of the observed cardiotoxicity included: low EF (59.65%), symptomatic diastolic dysfunction (57.89%), myocardial ischemia (45.61%),QTc interval prolongation (21.05%) and arrhythmias (14.04%).This is shown in table (2).Study participants who experienced cardiotoxicity (any pattern) were older, had higher smoking index, lower body mass index, and longer cancer duration.They had higher prevalence of diabetes, hypertension and dyslipidemia and had higher mean value of fasting blood glucose and C-reactive protein.They also showed higher prevalence of depression, malnutrition, and functional impairment.This is illustrated in table (3).With regards to treatment-related cardiotoxicity, as presented in table (4), participants who experienced cardiotoxicity were those patients who received certain chemotherapy agents (namely Anthracycline, 5-Fluorouracil, Capecitabine, Arsenic trioxide, and Lapatinib); patients who received certain targeted therapy agents (namely Pertuzumab and Trastuzumab); and patients who received radiotherapy (most commonly radiotherapy to the chest).Participants who experienced cardiotoxicity received longer duration of chemotherapy.Participants who were treated with hormonal therapy experienced less cardiotoxicity.Regression analysis was done to determine the risk factors independently associated with cardiotoxicity, as shown in table (5).According to the results, the risk factors independently associated with cardiotoxicity, in the studied population, were high smoking index, dyslipidemia (low HDL), high fasting blood glucose, malnutrition and previous treatment with Pertuzumab.

Discussion
Cancer and heart disease stand as the primary causes of mortality among individuals over 60 years of age.The involvement of geriatricians in these specialized fields holds particular importance.Geriatric cardiology and geriatric oncology have become crucial allies due to advancements in cancer and cardiovascular treatments, leading to an overall increase in life expectancy [23].
The aim of this work was to assess the prevalence and potential risk factors associated with cardiotoxicity among elderly cancer patients who underwent cancer-specific treatments.The study was carried out on 100 elderly participants, men and women, sixty years and above; diagnosed with cancer.
Our study participants who experienced cardiotoxicity (any pattern) were older, had higher smoking index, lower body mass index, and longer cancer duration.They had higher prevalence of diabetes, hypertension and dyslipidemia.Most of these are well known cardiac risk factors, as reported in the previous studies [24,25].
It has been observed that the presence of several cardiovascular risk factors in cancer patients, including hypertension, diabetes, a history of smoking, and dyslipidemia, is associated with a significantly higher risk of cardiac adverse events [26].Similarly, retrospective study suggested that cardiovascular disease risk factors, such as history of hypertension and diabetes, also increase the risk of developing medicationrelated cardiotoxicity (e.g., Anthracyclines use) [27].
A strong link between inflammation, heart disease and cancer has been reported in numerous previous studies.In our study, participants who experienced cardiotoxicity had higher mean value of C-reactive protein.
Similarly, a study evaluated inflammatory factors such as high-sensitivity C-reactive protein and demonstrated that these markers were associated with an increased risk of developing heart failure and new-onset cancer [28].
Previous studies revealed a greater risk of cardiovascular disease in obese individuals.Among our study participants, and in contrast to these studies, lower body mass index was associated with more cardiotoxicity.This may have some explanations.First, lower BMI is associated with cancer cachexia, longer cancer duration, poorer health, and therefore more cardiovascular toxicity/complications.Second, looking at patients who didn't develop cardiotoxicity, their mean BMI was 26.67 (i.e., just overweight), and many studies reported better outcomes in these

Conclusion
Cardiotoxicity is common in elderly cancer patients, and it has different patterns.Smoking, dyslipidemia, and hyperglycemia are important risk factors for cardiotoxicity.Certain anticancer therapies increase the risk of cardiotoxicity.Cardiotoxicity is associated with depression, malnutrition, and functional decline of the geriatric patients, highlighting the importance of comprehensive geriatric assessment in elderly cancer patients.

Limitations of the study
We recognize that this study had certain limitations.One of the limitations was its small sample size.It could be better to measure other cardiac biomarkers (such as troponin and brain natriuretic peptide; BNP) to add intensity to cardiotoxicity diagnosis.