An Assessment of Cardiac Dysfunction in Cancer Patient Receiving Chemotherapy: A Hospital-Based Non-Invasive Study

INTRODUCTION

Recent advances in cancer management have improved long-term survival. Increased longevity has been accompanied by a rise in the frequency of age-related cardiovascular (CV) disease and treatment-related cardiotoxicity. Chemotherapy-related left ventricular dysfunctions have historically been considered resistant to conventional therapy and carry a poorer prognosis than other cardiomyopathies. More recent data suggest that selected forms of chemotherapy-related cardiomyopathy are reversible to some degree but response is dependent on early detection and prompt intervention. This challenges us to develop more sophisticated risk stratification and monitoring strategies that include symptom detection, and non-invasive imaging. This paradigm also suggests that a multidisciplinary team of cardiologists and oncologists may provide more comprehensive care to this complex patient population.

Modern advancements in cancer treatment over the past few decades in cancer have resulted in improved survival in cancer patients. As a result, the effect of cancer therapy on other organ systems such as the heart is more likely to become clinically relevant and lead to cardiotoxicity. In early 1970, anthracycline was shown to exhibit cumulative dose-related cardiac dysfunction.^[1] Later on, von Hoff et al.^[1] found that cardiac function in more than 2000 anthracycline-treated patients demonstrated the relative safety of low cumulative dosages and dramatically increased incidence of congestive heart failure (CHF) at higher cumulative dosages. Consequently, the use of newer chemotherapy drugs and combination leads to improvement in patient survival from cancer but simultaneously resulted in a sharp rise in the incidence of heart failure in cancer patients. Recently, many cancer patients have a risk of developing heart disease and heart failure higher than the risk of cancer recurrence.^[2] The American College of Cardiology or American Heart Association guidelines define patients receiving chemotherapy as stage “A” heart failure.^[3] Chemotherapy can result in left ventricular dysfunction or diastolic dysfunction ranging from mild to severe reversible or irreversible life-threatening heart failure.

The CV toxicity of cancer chemotherapeutic agents is dysrhythmias, cardiomyopathic CHF, pericardial disease, and peripheral vascular disease. Chemotherapy-related cardiac dysfunction of greatest concern for cardiologists and oncologists is those directly involving myocardium. Cardiac toxicity associated with chemotherapy can range from asymptomatic subclinical abnormality, including electrocardiographic changes and temporary left ventricular ejection fraction (LVEF) decline to life-threatening congestive cardiac failure. Cardiac dysfunction if detected early can be prevented by early initiation of treatment.

MATERIALS AND METHODS

RESULTS

A total of 50 patients were enrolled in the study, who received 3–6 therapeutic cycles each. Among these 50, two patients were lost to follow-up and two patients received radiation therapy. Hence, these were excluded from the study. In these patients, the analysis of cardiac dysfunction was done pre- and post-chemotherapy. The remaining 46 patients constituted 25 with breast cancer, 16 non-Hodgkin’s Lymphoma, four Hodgkin’s lymphoma, and one patient with stomach cancer. Cardiac risk factors such as hypertension, type II diabetes mellitus, obesity, dyslipidaemia, and smoking were present in 17 patients before the start of chemotherapy. Few patients among these had more than one risk factor. About 26% of the population was obese. About 73% of patients with cardiac dysfunction had one or more cardiac risk factors. There was statistically no significant association observed in breathlessness on exertion (BOE) when compared pre-chemotherapy versus post-chemotherapy with P = 0.332. The symptom of AOE was compared pre- and post-chemotherapy and the association was statistically non-significant with P = 0.50. The symptom of palpitation was compared pre- and post-chemotherapy and the association was statistically non-significant with P = 1.000. Fatigability was noted in a significant number (n = 8) of patients prechemotherapy as well as (n = 13) post-chemotherapy and the association was statistically significant with P = 0.021. The cardinal symptoms of CV system involvement, namely, BOE, AOE, fatigability, and palpitation were studied in pre- and post-chemotherapy. Although the number of patients having symptoms increased post-chemotherapy, the difference was statistically significant only in the case of fatigability. Post-chemotherapy, more number of patients had evidence of cardiac dysfunction on the basis of history and physical examination but a statistically significant association was found only in fatigability, pallor, oedema, and rales and a total number of patients having clinical heart failure were 10% (n = 5) of the study population. The most common ECG changes observed post-chemotherapy were ST-T changes in four patients out of a total of six patients having ECG alteration. These four patients further underwent stress thallium and coronary angiography revealing no abnormality. Cardiac arrhythmia was present in two patients in the form of atrial fibrillation (AF) with controlled ventricular rate and sinus bradycardia. However, a statistically significant association for ECG alterations was not established. Chest X-ray changes were assessed for cardiomegaly. There was a statistically non-significant association between pre- and post-chemotherapy on chest X-rays in terms of cardiomegaly. Post-chemotherapy cardiac dysfunction in terms of decrease in EF more than 10% was observed in 24% (n = 11) of patients; out of these, 11% (n = 5) were clinical and 13% (n = 6) were subclinical. Symptomatic cardiac dysfunction occurred in 11% (n = 5) patients; out of these, 6.5% (n = 3) patients were in the TAC chemotherapy receiving group and 4.3% (n = 2) in the CHOP chemotherapy receiving group and all were receiving doxorubicin dose range from 300 to 540 mg. The distribution of patients receiving doxorubicin and epirubicin-based chemotherapy was 73.91% (n = 34) and 23.91% (n = 11), respectively. Out of this, cardiac dysfunction was observed in 19.56% (n = 9) and 4.3% (n = 2), respectively. The comparison of diastolic dysfunction between two chemotherapy agents was statistically not significant as per Fisher’s exact test (P = 0.701). Doxorubicin was given in the cumulative dose of 270–375 mg for 16 patients, 450–480 mg for eight patients, and a cumulative dose of 510–600 mg for ten patients. Among these, in 270–375 mg cumulative dose, 1 patient (6.2%) had clinical cardiac dysfunction while 3 patients (18.7%) had subclinical cardiac dysfunction. In the cumulative dose of 450–480 mg, 2 patients (25%) had clinical cardiac dysfunction. In the cumulative dose range of 510–600 mg, 2 patients (20%) had clinical cardiac dysfunction and 1 patient (10%) had subclinical cardiac dysfunction.

DISCUSSION

Cardiac dysfunction is one of the dreaded complications of the chemotherapy agent anthracycline. It adds to the comorbidity of cancer. The small increase in the risk of common and serious adverse health events, such as cardiac disease, has important public health implications. Effective steps taken at the proper time; can prevent the onset or exacerbation of these complications. This study was carried out to detect cardiac dysfunction in patients receiving chemotherapy. In this study, 46 patients receiving chemotherapy for breast cancer, non-Hodgkin’s Lymphoma, Hodgkin’s Lymphoma, and stomach cancer were studied. They received anthracycline-based chemotherapy which included doxorubicin and epirubicin. Different risk factors were studied such as hypertension, type 2 diabetes mellitus, obesity, dyslipidaemia, and smoking. About 73% of patients with cardiac dysfunction had one or more cardiac risk factors. Similar risk factors were studied by Ryberg et al.^[6] and Piccirillo et al.^[7] which showed a significantly increased risk of cardiac dysfunction in the presence of these risk factors. Patients were 16–70 years of age with a mean age of 36 years and 51 years, respectively, for males and females. The mean age of the total study population was 46.27 ± 14.71 years. Mean age in Khattry et al.^[8] was 44 years. There was no statistically significant association of cardiac symptoms such as BOE, AOE, and palpitation pre- and post-chemotherapy. However, there was an increase in the number of symptoms in the post-chemotherapy group. The increase in fatigability in the post-chemotherapy group was statistically significant. This may be due to side effects of chemotherapy agents or associated malignancy. In this study, ECG showed ST and T wave changes in 8.6% (n = 4) patients. On further evaluation, coronary angiography in two patients and stress thallium in two patients were done. There was no evidence of coronary artery disease. Cardiac arrhythmia such as AF and sinus tachycardia was present in 4.3% (n = 2) patients. Similar non-specific ST and T wave changes had been described by Galderisi et al.^[9] 5-Fluorouracil has been associated with ECG signs of myocardial ischemia and less frequently with arrhythmias as studied by Hrovatin et al.^[10] In Shan et al.^[11] the study, chronic anthracycline cardiotoxicity manifests often as life-threatening arrhythmias. There was no significant association of cardiomegaly on chest X-rays in pre- and post-chemotherapy received patients. No other significant X-ray changes were present. This observation was consistent with the study by Khattry et al.^[8]

In this study, five out of 46 patients (11%) who received doxorubicin were clinically diagnosed with heart failure. Minow et al.^[12] also reported heart failure in 0.4–9% of patients who received doxorubicin. In Khattry et al.,^[8] clinical heart failure was observed in 3% of the study population. This may be attributed to the average age in our study population being more; also, more cardiac risk factors were present in the study population. Khattry et al.^[8] studied cardiotoxicity in low cumulative doses of doxorubicin.

The incidence of subclinical cardiac dysfunction in this study was 13% (n = 6). In our study, diagnosis of subclinical cardiac dysfunction was done on the basis of falls in LVEF more than 10% or LVEF <50% as measured by 2D echocardiography. In Khattry et al.^[8] study, subclinical cardiac dysfunction was present in 27% of patients. Agarwala et al.^[13] observed that 40% of children receiving doxorubicin-based chemotherapy developed subclinical cardiac dysfunction. Mohta et al.^[14] observed that 30% of the paediatric patients had significant cardiac dysfunction on echocardiographic evaluation at a mean cumulative dose of 365 mg/m². Similarly, in Dresdale et al.,^[15] out of 87 asymptomatic patients who received 430 mg/m² of doxorubicin 21% showed abnormal LVEF at rest by radionuclide angiogram. Subclinical cardiac dysfunction was low in our study may be due to different assessment methods, that is, we measured LVEF by echocardiography while another used radionuclide angiogram. In our study, 54% (25) of patients had breast cancer. Out of this, cardiac dysfunction was present in 20% (n = 5). Among these five patients, two got Docetaxel, doxorubicin and cyclophosphamide (TAC), one received doxorubicin and cyclophosphamide (AC), and two received 5 fluorouracil, epirubicin and cyclophosphamide (FEC) chemotherapy. In our study, the distribution of patients receiving doxorubicin and epirubicin-based chemotherapy was 73.91% (n = 34) and 23.91% (n = 11), respectively. Out of these patients, cardiac dysfunction was observed in 26.47 (n = 9 out of 34) and 18.18 (n = 2 out of 11), respectively. The comparison of cardiac dysfunction between two chemotherapy agents was statistically not significant. There was significant cardiac dysfunction observed in different studies as discussed in a meta-analysis by Smith et al.^[16]

In this study, we compared the cumulative dose of doxorubicin in the range of 270–375 mg, 450–480 mg, and 510–600 mg. It was observed that in the cumulative dose range of 270–375 mg, 6.2% had clinical cardiac dysfunction and 18.7% had subclinical cardiac dysfunction. In the dose range of 450–480 mg, 25% had clinical cardiac dysfunction. In the cumulative dose of 510–600 mg, 20% had clinical cardiac dysfunction and 10% had subclinical cardiac dysfunction. In the study by Khattry et al.,^[8] 16% developed subclinical cardiac dysfunction at the cumulative dose of 300 mg and 28.8% developed clinical cardiac dysfunction at the cumulative dose of 450 mg. These findings were in concordance with our study in the mentioned cumulative dose range. Lefrak et al. studied cardiac dysfunction in the cumulative dose of 500–550 mg, 551–600 mg, and more than 600 mg.^[17] He noted that the clinical cardiac dysfunction increased from 4% to 18% when the cumulative dose increased from 500 mg to 600 mg.

CONCLUSION

Modifiable risk factors such as hypertension, type 2 diabetes mellitus, obesity, smoking, and dyslipidaemia predispose cancer patients to increased cardiac toxicity of the chemotherapeutic drugs/regimens such as anthracycline. Steps for optimal control of the risk factors and modified cancer chemotherapy regimens if possible should be adopted to prevent cardiac toxicity. Non-invasive investigations such as echocardiography should be freely used at various intervals of cancer treatment to detect early cardiac dysfunction.