A case report and review of the literature: cardiotoxicities after radiotherapy for breast cancer patients with high-risk factors of cardiovascular disease

Abstract

Cardiovascular disease (CVD) is an important adverse effect of radiotherapy and is responsible for increased morbidity and mortality in long-term survivors with breast cancer. Patients may have pre-existing cardiovascular risk factors before treatment of breast cancer, and the effects of pre-existing cardiovascular risk factors can be compounded by radiotherapy. We report a case of left breast cancer in a 63-year-old female with a high risk of CVD who was suspected of having radiation-induced myocardium injury 1 year after postoperative adjuvant therapy. Radiation oncologists should not only reduce the adverse effects by perfecting radiotherapy technology but also consider reducing other high-risk factors for CVD.

Introduction

Breast cancer is one of the common diseases in women, and its incidence rate is increasing year by year [1]. With advances in methods of diagnosis and treatment, the survival of breast cancer patients has been greatly improved, but patients still face many adverse events such as cardiovascular disease (CVD) [2]. Radiotherapy is usually used to prevent local recurrence in the chest wall, breast or axilla after surgical removal of the tumor. However, radiotherapy can also damage myocardial cells, leading to subsequent CVD. Since studies have shown that CVD has become the leading cause of death in breast cancer patients [3–5], the cardiotoxicity of breast cancer radiotherapy should be studied. Here, we report a case of breast cancer in a 63-year-old patient with a high risk of CVD who was suspected of having myocardial injury 1 year after radiotherapy. We discuss the known risk factors of CVD in women with breast cancer.

Case report

A 63-year-old woman was diagnosed as having local advanced breast cancer. Preoperative examination revealed blood glucose level of 344 mg/dL and hemoglobin A1c (HbA1C) of 10.4% without treatment, and she was admitted to the diabetes ward for adjustment of blood glucose. The patient’s body mass index (BMI) was 19.1 kg/m² and she had no cardiovascular disease prior to the diagnosis of breast cancer. She had been diagnosed with hypertension and had been treated with nifedipine of 40 mg/day for 5 years. While adjusting serum glucose, she was treated with a neoadjuvant aromatase inhibitor. After 2 weeks, blood glucose was adjusted to normal levels and was stabilized. She then underwent left total mastectomy with axillary lymphadenectomy for breast cancer (pT4bN1miM0, Stage IIIB). She received adjuvant chemotherapy (taxotere and cyclophosphamide*4 courses) 2 months after surgery and then received chest wall + subclavian irradiation at 50 Gy/25 fractions + chest wall boost at 10 Gy/5 fractions 4 months later. The dose distribution is shown in Fig. 1. The mean heart dose was 1.7 Gy. Aromatase inhibitor treatment was restarted after completion of RT.

Fig. 1.

Dose distribution

After finishing treatment, she visited a follow-up clinic once a month. After 1 year, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed increased uptake in the left ventricular apex (Fig. 2). The area of abnormal accumulation was exactly the area that had been irradiated. Radiation-induced myocardial damage was suspected. An electrocardiogram (ECG) (Fig. 3) showed ST-T wave segment abnormalities and tachycardia, and echocardiography revealed excessive contraction of the left ventricular wall. During that 1-year period, the patient’s serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels were often higher than normal. Although the patient had no symptoms such as chest pain or breathlessness, observation was recommended. The patient is still healthy and has had no subjective symptoms for 2.5 years.

Fig. 2.

PET-CT after radiotherapy 1 year

Fig. 3.

Electrocardiogram after radiotherapy 1 yearta

Discussion

Radiotherapy is one of the standard methods for treatment of breast cancer. Due to the anatomical location of the breast, part of the cardiac structure is inevitably exposed during irradiation. Radiation-induced damage to the myocardium is caused primarily by inflammatory changes in the microvasculature, leading to microthrombi and occlusion of vessels, perfusion defects and focal ischemia. This is followed by progressive myocardial cell death and fibrosis. Irradiation of endothelial cells lining large vessels also increases the expression of inflammatory molecules, predisposes to the formation of inflammatory plaque, which is more likely to rupture and cause a fatal heart attack or stroke. Cardiac mortality is an increasing important determinant of survival of breast cancer patients who have received radiation treatment.

In addition to tumors and radiation, patients themselves may also have high-risk factors for CVD. The different risk factors have an additive effect on the possibility of development of CVD and other outcomes.

High-risk factors for cardiovascular disease

Hypertension is the most common underlying risk factor for CVD.As blood pressure increases, the circulation resistance gradually increases, leading to reinforcement of ventricular contraction, compensatory myocardial hypertrophy and myocardial ischemia. On the other hand, hypertension makes the coronary wall dystrophic and destroys the vascular intima. Hypertension significantly increases the risks for heart failure, atrial fibrillation, coronary artery disease, and peripheral vascular disease [6]. The risk for these CVDs increases progressively with incremental increases in blood pressure (BP) [7, 8].

Diabetes is an independent risk factor for CVD [9]. Long-term hyperglycemia can cause vascular endothelial cell dysfunction and systemic inflammatory reaction and it increases vascular wall arteriosclerosis. Besides, diabetes often occurs alongside hypertension, dyslipidemia and obesity, which can promote coronary arteriosclerosis, leading to cardiovascular pathological lesions and high risk of CVD.

The biological pathway of radiation to the heart is similar to the pathological process of hypertension and diabetes, and radiotherapy may, therefore, be more likely to have an additive effect on patients with hypertension and diabetes, increasing the absolute risk of CVD.

Overweight or obesity is also associated with an increased risk of cardiac disease [10]. With an increase of cholesterol, invading monocytes transform into activated macrophages and form fatty streaks, thereby initiating the process of atherosclerosis. Some studies have suggested that BMI affects breast cancer outcomes [11].

Drug-induced cardiotoxicity

The availability of anti-tumor drugs in recent years has greatly reduced morbidity and mortality rates and has prolonged survival time of cancer patients. However, at the same time, anti-tumor drugs can cause significant cardiotoxicity, which has become an important cause of cancer patients’ illness and even death [12]. Lage et al. [13] reported that taxotere played a direct role in the development of myocardial toxicity. Treatment with cyclophosphamide can result in cardiomyopathy, myocardial infarction, and heart failure by altering contractility, damaging the endothelium and enhancing pro-inflammatory/pro-apoptotic activities, and the cardiotoxicity is dose-related [14]. Anthracyclines and trastuzumab, which are commonly used for treatment of breast cancer, have been reported to cause cardiomyopathy, congestive cardiac failure, arrhythmia and acute ECG alterations [15].

For endocrine therapy drugs, an increased risk of heart failure and cardiomyopathy was reported for patients who were treated with an aromatase inhibitor alone or sequentially after tamoxifen [16]. Radiotherapy combined with treatment with an aromatase inhibitor might reduce left ventricular diastolic function compared with that in the case of radiotherapy alone.

Strategies

The increase in incidence of heart disease is proportional to the increase in the mean dose of radiotherapy to the heart [17]. We protect the heart by minimizing the exposure irradiation dose and irradiated volume for the heart using high precision irradiation technology (such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT)). However, if the patient has many other high-risk factors of CVD at the same time, radiotherapy may lead to changes in cardiac function even if the does is not high. Reduction of CVD risk factors and timely detection of CVD are important.

CVD risk reduction includes treatment of modifiable risk factors such as hypertension and diabetes. Active control of blood pressure, blood glucose level and cholesterol level is important for the prevention of cardiovascular disease. In addition, people with a high risk of CVD should be assessed and appropriately managed for dyslipidemia, smoking, abdominal obesity, sedentary behavior, and unhealthy eating habits. The effects of these on cardiovascular event rates caused by radiotherapy are substantial.

ECG abnormalities are important factors for diagnosing radiation-induced heart injury (RIHD) [18]. The main manifestations are ST segment depression, conduction block, arrhythmia, and increased heart rate. Echocardiography also has advantages for the diagnosis of cardiac injury by enabling evaluation of cardiac function. Myocardial scintigraphy allows assessment of myocardial perfusion and viability. Cardiac magnetic resonance (CMR) imaging is sensitive for detection of not only established morphologic and functional abnormalities but also myocardial edema, inflammation, and focal fibrosis as well as interstitial fibrosis and vascular remodeling. A previous study revealed that focal increased uptake in the basal myocardium on FDG-PET in patients after radiotherapy [19], and it has been used after stereotactic lung and esophageal radiotherapy to indicate RIHD [19, 20]. In future clinical studies, FDG-PET could be considered for monitoring early changes in cardiac function and radiation-induced cardiotoxicity for patients with breast cancer. These tools are all excellent for evaluating cardiotoxicity.

Conclusion

Radiotherapy for breast cancer has potential cardiotoxicity, and it increases the risk of an adverse cardiac event in patients who have pre-existing cardiovascular risk factors before treatment. It is important to integrate programs for assessing and addressing cardiovascular risks. Therefore, when formulating a treatment plan for patients, considering implementation of preventive interventions, improvement in the patient’s state, and reduction of high-risk factors can help to reduce adverse cardiac reactions caused by treatment, reduce medical costs, and improve the survival benefit and quality of life of patients receiving radiotherapy.

Funding

None.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from the patient.

Ethical approval

All procedures performed in studies involving human participant were in accordance with the ethical standards of the institutional research committee. For this type of study, formal consent is not required.