Cardiotoxicity in cancer patients treated with chemotherapy: A systematic review

Introduction

Chemotherapy cardiovascular involvement includes the development or exacerbation of cardiovascular diseases. In addition to cardiotoxicity, these patients are at increased risk of developing other cardiovascular complications, especially arrhythmias, ventricular dysfunction, systemic arterial hypertension, acute coronary syndrome, cardiomyopathy, and thromboembolic diseases.[1-4] Anthracyclines and related compounds are among the chemotherapeutic agents most associated with the development of cardiotoxicity, in addition, to these other related drugs are alkylating agents (cyclophosphamide), monoclonal antibodies (rituximab), protein kinase inhibitors, and HER2-targeted therapies (trastuzumab).[1,4]

Chemotherapeutic cardiotoxicity can be defined as any functional and/or structural alteration of the cardiovascular system induced by cytotoxic antineoplastic drugs, being measured through the reduction of the left ventricular ejection fraction (LVEF), it can manifest in an acute, subacute, or chronic form.[2,5] Cardiotoxicity represents one of the most significant adverse effects of this type of therapy. It is currently the second most common cause of morbidity and mortality in patients with the previous cancer treatment, second only to oncological causes (recurrence or secondary neoplasms).[3,4]

The appearance of chemotherapeutic cardiotoxicity may imply the interruption of chemotherapeutic treatment and, consequently, compromise the cure or adequate control of the neoplasm, in addition to the fact that heart failure may compromise the evolution of the case. It is also noteworthy that cardiotoxicity can be classified as type I, in which myocytes are affected by the toxic effects of drugs (e.g., those caused by anthracyclines) and suffer irreversible damage, and in type II, in which cardiac function is not compromised, is determined to be irreversible (such as that caused by trastuzumab).[1,4,6,7]

This review seeks to assess chemotherapeutic cardiotoxicity, so that it is possible to analyze the epidemiological aspects related to this complication, such as risk factors, the most recurrent alterations and the most commonly associated antineoplastic drugs. Furthermore, it was also possible to assess the incidence of other cardiovascular complications resulting from the use of chemotherapy.

Methods

This is a systematic review that aims to assess the profile of chemotherapy cardiotoxicity cases. For this, searches were carried out in the Scientific Electronic Library Online, virtual health library and Medical Literature Analysis and Retrieval System Online (Medline/PubMed) databases using the descriptors “Cardiotoxicity” and “Chemotherapy,” in addition to of the Boolean operator “AND,” so that it was possible to maximize the number of studies found.

The inclusion criteria defined were original articles published between 2015 and 2021 in any language with descriptors present in the title and/or abstract, while those that did not have content to achieve the proposed objective, in addition to a case report and case series, were excluded. Initially, 15,090 articles were found. Subsequently, the inclusion criteria were applied, excluding 15,010 articles [Figure 1].

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Figure 1

Study PRISMA flow diagram. Source: survey data, 2021

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After that, 80 studies were submitted for reading the title, of these 53 were selected for reading the title and abstract, of which 26 were excluded, leaving 27 studies for full reading. Then, all 27 articles were included to compose the database of this review, as they contained enough data to achieve the proposed objective. For data extraction, the Microsoft Office Excel®8 program was used to store and tabulate the data obtained.

The Kappa index was used to assess the agreement of the evaluators in the selection of articles. The value 0.8978 was obtained, which, according to Landis and Koch9, suggests excellent reliability, since the closer the value to 1, the greater the agreement of the reviewers. Therefore, it was possible to proceed with the systematic review [Table 1].

Table 1 Kappa index

Results

In Table 2, it is possible to analyze that only 2 (7.4%) studies had an impact factor lower than 1.02. With regard to the study location, a heterogeneous distribution is noted, with the United States being the country with the most number of studies, totaling 3 (11.1%). Furthermore, regarding the number of cancer patients analyzed, there were a total of 32,009 cases.

Table 2 Characteristics of the studies selected for review

From Table 3, it is observed that most of the patients analyzed were female, in which there were 27,270 (85.2%) cases, while there were 4533 (14.2%) of males, with 12 studies not included males in the sample. Breast cancer was the most frequent neoplasm, with 11,145 (34.8%) cases, followed by colorectal cancer, with 3925 (12.3%). Other reported neoplasms were lymphoma, leukemia, osteosarcoma, and sarcoma.

Table 3 Characteristics of the sample of studies included in the review

Some studies did not mention the presence of comorbidities in the sample, when analyzing this variable, cardiovascular risk was reported in 2489 (9.1%) patients, arterial hypertension in 1509 (5.5%), and diabetes mellitus in 777 (2.8%). Other comorbidities mentioned in the studies were current smoking, hyperlipidemia, chronic kidney disease, and obesity. Regarding the type of chemotherapy, anthracycline was the most prevalent, analyzed in 18 (66.7%) studies, followed by trastuzumab, in 9 (33.3%) studies.

When analyzing the presence of cardiotoxicity in the analyzed patients, five studies did not present any case. In total, 2,255 (8.3%) cases of cardiotoxicity were recorded, and the study by Wittayanukorn et al.[36] had only cases of cardiotoxicity in its sample, and the causes were later evaluated. In addition to cardiotoxicity, other outcomes were evaluated, such as the development of arrhythmia (n = 522), acute coronary syndrome (n = 185), diastolic dysfunction (n = 184), cardiomyopathy (n = 161), and arterial hypertension (n = 89) after chemotherapy [Table 4].

Table 4 Cardiotoxicity and related factors

Regarding the risk factors for the development of cardiotoxicity, only nine studies evaluated this, and the presence of arterial hypertension was mentioned by three studies, being the most cited factor. From Table 4, it can be observed that there were 16 deaths from cardiovascular causes, two of these cases were due to cardiotoxicity.

Discussion

This review showed a higher prevalence of female patients in the analyzed studies, with breast cancer and colorectal cancer being, respectively, the most prevalent in the sample. Likewise, chemotherapy with anthracycline combined or not with trastuzumab was the most frequent. In fact, breast cancer is currently the most commonly diagnosed malignancy in the world, followed by lung cancer and colorectal cancer, respectively.[37]

Anthracyclines are antineoplastic agents commonly used in adjuvant or neoadjuvant therapy, as well as in the treatment of metastases. This class of drugs, represented by doxorubicin, epirubicin and others, forms a complex with DNA, inhibiting the synthesis of nucleic acids and proteins, through cleavage by topoisomerase II, which results in its cytotoxic activity. The mechanisms of cardiotoxicity described for this class involve lipid peroxidation, oxidative stress, apoptosis and necrosis of cardiac cells, in addition to the impairment of proteins and transcription factors relevant to the heart, resulting in a negative balance of sarcomeric proteins and an imbalance in cardiac function.[1,3,38]

In the study, it was possible to observe the presence of cardiovascular risk factors in cancer patients, such as systemic arterial hypertension, diabetes mellitus, smoking, hyperlipidemia, obesity, and chronic kidney disease. In addition to these, it is known that other factors such as inflammatory diseases, chronic obstructive pulmonary disease, and the presence of cancer are associated with high cardiovascular risk.[39] Therefore, care with the identification and control of cardiovascular risk factors should be redoubled in patients undergoing chemotherapy with potential for cardiotoxicity.[40,41]

Cardiotoxicity was recorded in 8.3% of cancer patients who underwent chemotherapy, similar to the study by Volkova and Russell[42] observed that anthracycline can induce heart failure in up to 8.7% of cases, while Curigliano et al.[43] reported that in patients treated with trastuzumab the cardiotoxicity is up to 3.8% and with cyclophosphamide it varies between 7 and 28%. The increased risk for the development of cardiotoxicity associated with the use of anthracyclines is related to younger patients, the female sex, the rapid rate of drug infusion, the high cumulative dose, and the presence of hypocalcemia, hypomagnesemia, and previous cardiovascular diseases, such as coronary heart disease and hypertension.[40] Consistent with these facts, this study found risk factors associated with chemotherapy cardiotoxicity, such as the presence of systemic arterial hypertension.

The study by Wittayanukorn et al.[36] evaluated reports of chemotherapy-related cardiotoxicity in breast cancer patients in the United States, identifying 937 cases. The most prevalent drug was trastuzumab in combination with doxorubicin or cyclophosphamide, with 25% of the total reports being associated with death or disability. Such findings are in agreement with the study by Chen et al.,[44] which presents evidence demonstrating that the use of anthracyclines with trastuzumab increases the risk of heart failure, while the study by Seidman et al.[45] demonstrates an association of the use of anthracyclines with cyclophosphamide and trastuzumab with the incidence of dysfunction heart. In addition to these outcomes, this review also demonstrates the occurrence of arrhythmias, acute coronary syndrome and cardiomyopathy in patients undergoing chemotherapy, evidencing the existing cardiovascular risk.

In view of all these factors discussed, it is important to reaffirm the need to know the cardiotoxic effects of chemotherapy, as well as the cardiovascular risk that the patient presents, so that the likelihood of poor treatment outcomes is combated. In addition, the cardiovascular risks and cardiotoxicity demonstrated in this work may help the surveillance of adverse events in cancer patients undergoing chemotherapy, as well as guide future studies.

Conclusions

Cardiotoxicity was highlighted as relevant in most studies, presenting a percentage of review cases in this review, in addition to cardiovascular manifestations such as coronary syndrome and systemic arterial hypertension from chemotherapy. Finally, regarding the types of chemotherapy, the most prevalent was anthracycline followed by trastuzumab.