Ashot A. Avagimyan, Lusine G. Mkrtchyan

Yerevan State Medical University after Mkhitar Heratsi

Introduction. Oncological diseases are currently one of the leading causes of death, due to the cardiovascular diseases. At the same time, modern antitumor therapy, including chemotherapy, radiation therapy, targeted therapy, allows life-saving and social adaptation of the cancer patients for decades. However, the use of anticancer therapy is limited due to their side effects. In some cases, severe cardiotoxic effects and complications (coronary heart disease, microvascular angina, systolic or diastolic myocardial dysfunction/cardiomyopathy, chronic heart failure, arterial or pulmonary hypertension, strokes, pericarditis, arrhythmias, thromboembolism of the pulmonary artery, etc.), can extremely adversely affect the prognosis of these patients.

That is why in recent years, cardiooncology has increasingly been the focus of attention of the scientists, however, many aspects of this important interdisciplinary problem are still poorly studied. Obviously, the successful treatment of the cancer patients requires the collaboration of cardiologists, oncologists, chemotherapists, radiation therapists and specialists in the field of imaging technologies. However, in our country there is still no coordination of scientific research in this area, as a result – there are no multifaceted studies, manuals and recommendations, scientific and practical programs for the prevention, diagnosis and treatment of various manifestations of cardiotoxicity. The degree of involvement in the therapeutic and diagnostic process and the level of interaction between representatives of the corresponding disciplines have not been determined yet.

The aim of study. To review the world literature on the cardiotoxicity of anticancer drugs and provide a description of the clinical case that demonstrates the importance of this problem.

Materials and methods. We used content analysis, a method of system and comparative analysis, a bibliosemantic method for studying relevant scientific research on the topic of cardiotoxicity of chemotherapeutic drugs. The data was searched in scientometric medical information databases PubMed, NCBI, Medline, ResearchGate for the key words: cardiotoxicity, cardiooncology, anthracycline cardiomyopathy, atrial fibrillation, cardiac lipomatosis, as well as on the basis of the State Medical Library of the Virmen Academy of Medical Sciences. At the end of the article, the clinical case is described.

Results. Among the all chemotherapeutic drugs with the inherent mechanisms of cardiotoxicity, which are widely used in clinical practice, are doxorubicin, paclitaxel, trastuzumab and pertuzumab. To date, the most studied field is the cardiotoxicity of anthracycline drugs. Anthracyclines are highly effective in the treatment of solid tumors and malignant diseases of the blood system, but due to their expressed side effects on the heart, failure to use them can negatively affect the prognosis. On the other hand, anthracyclines can irreversibly damage the heart, which, in turn, also influence the prognosis. For example, doxorubicin is associated with the occurrence of congestive heart failure in 5.0 % of cases when a cumulative lifespan dose of 400.0 mg/m² is reached, and the higher doses lead to the exponential increase in risk, up to 48.0 % at 700.0 mg/m². However, the susceptibility to anthracyclines in patients is very different. While many people tolerate their standard dose without any long-term complications, drug-induced cardiac toxicity in some patients may occur after the first dose. The most common pathophysiological mechanism of anthracycline cardiotoxicity is described by the oxidative stress hypothesis, which implies that the generation of reactive oxygen species and lipid peroxidation of the cell membrane damages cardiomyocytes. It is assumed that there are also other mechanisms that play a definite role in the process. Cardiotoxicity of anthracyclines can be acute, early or late. Acute cardiotoxicity is manifested mainly by the development of supraventricular arrhythmia, transient left ventricular dysfunction and electrocardiographic changes. It develops in less than 1.0 % of patients immediately after the drug infusion and is usually reversible. However, acute cardiac dysfunction may also reflect the damage of myocytes, which may ultimately develop into early or late cardiotoxicity. There is no proven tactic determining reversibility of the heart dysfunction or its progressive being; however, an increase in cardiac biomarkers may indicate a risk for patients with long-term cardiotoxicity.

Other standard chemotherapy drugs that can cause myocardial dysfunction and heart failure are cyclophosphamide, cisplatin, ifosfamide, and taxanes (docetaxel).  Cyclophosphamide cardiotoxicity is relatively rare and is primarily observed in the patients receiving large doses (>140.0 mg/kg) prior to the bone marrow transplantation. Heart failure usually occurs within a few days after the drug administration, and the risk factors include total bolus dose, old age, combination therapy with other antitumor agents and the mediastinal radiation. Some alkylating agents similar to cyclophosphamide, such as cisplatin and ifosfamide, occasionally cause heart failure due to several pathological effects, including myocardial ischemia. Additionally, chemotherapy with platinum preparations requires the administration of large intravenous volumes to avoid platinum toxicity. Namely, it is the volume overload in already existing myocardial affection (rather than direct toxicity) that often leads to a debut or recurrent episode of heart failure. Docetaxel, a drug often used in the breast cancer treatment, in combination with other anthracyclines, cyclophosphamide, or trastuzumab, has also been shown to increase the likelihood of heart failure; however, the contribution of individual drugs to the regimens involving several drugs is often difficult to assess. 

Some reports suggested that taxanes may be safer for the patients with existing left ventricular dysfunction who should avoid anthracyclines, but the absolute risks of cardiotoxicity of taxanes are still unknown. However, there are serious disputes regarding the patients with breast cancer, for whom the real advantage of using anthracyclines instead of taxanes is not as obvious as in the case of treatment of lymphoma or sarcoma. The risk/benefit assessment should include both the risk factors for individual patients and the potential efficacy based on the characteristics of the tumor.

In order to prevent the cardiological complications, it is recommended to correct all modified risk factors for cardiovascular diseases before prescribing specific antitumor drugs. When conducting chemotherapy, it is recommended to use antioxidants (curcumin, resveratrol), cytoprotectors (trimetazidine, meldonium), and sometimes inhibitors of the angiotensin-converting enzyme (perindopril, enalapril, lisinopril), statins (atorvastatin), and also α- and β-adrenoblocker carvedilol. In the desribed clinical case, the manifestation of the so-called late cardiotoxicity in the form of atrial fibrillation in a patient with left breast cancer who received polychemotherapy using doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab is depicted.

Conclusions. The combined efforts of cardiologists, oncologists, chemotherapists, radiation therapeutists and specialists in the field of imaging technologies in the development and implementation of a unified strategy for the prevention, diagnosis and treatment of cardiac complications of anticancer therapy of cancer patients is of crucial importance. The actual problems include: creation of registers for assessing the prevalence of cardiotoxic and radiation injuries of the cardiovascular system of the cancer patients receiving antitumor therapy; detection of clinical, laboratory and instrumental markers of early, subclinical affection of the cardiovascular system in the cancer patients who receive antitumor therapy; the study of the tolerability, efficacy and safety of various medications for the prevention and treatment of cardiotoxicity of the antitumor therapy; creation of methodical manuals, clinical guidelines and educational programs for doctors in managing the patients with manifestations of cardiotoxicity; preparation of an information leaflet in and the organization of health care schools for the patients receiving antitumor therapy.

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