Original Research

Cardiotoxicity in breast cancer – Are we getting to the heart of the matter?

Zine Steenkamp, Alicia Sherriff, Cornel van Rooyen

Received: 24 Jan. 2024; Accepted: 18 July 2024; Published: 29 Nov. 2024

Copyright: © 2024. The Author(s). Licensee: AOSIS.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: The increasing awareness of chemotherapy-related cardiotoxicity has established a unique sub-speciality – cardio-oncology. However, consensus guidelines are still emerging. Patients at risk of cardiotoxicity should be identified and managed timeously to strike the balance between adequate cancer treatment and the impact of cardiovascular side-effects.

Aim: To investigate chemotherapy-induced cardiotoxicity in human epidermal growth factor receptor 2 overexpressed breast cancer patients receiving anthracyclines and/or trastuzumab.

Setting: Universitas Hospital Annex, Bloemfontein, South Africa.

Methods: This retrospective study was conducted at Universitas Hospital Annex during 2019 and 2020. Data collected included baseline left ventricular ejection fraction (LVEF) measurement, repeat LVEF prior to trastuzumab treatment and after cycles 3, 6, 9 and 12, and the presence of known cardiovascular risk factors.

Results: Thirty-one patients were evaluated. Seven (22.6%) patients were not eligible to receive trastuzumab after anthracycline treatment, and 11 (35.5%) patients were unable to complete the intended 6 months of adjuvant trastuzumab as per departmental protocol. Overall, the majority of patients (58.1%) who were planned to receive sequential anthracycline- and trastuzumab-based therapy did not complete the intended course, because of premature cessation of trastuzumab secondary to the detection of a decreasing LVEF. No significant correlation was observed between age, being overweight, laterality (left), pre-existing hypertension, diabetes mellitus, serum albumin, smoking or cardiotoxicity.

Conclusion: Cardiovascular surveillance in patients receiving potentially cardiotoxic chemotherapy is recommended, especially in our population experiencing a disproportionately higher decline in cardiac function.

Contribution: The findings emphasise the impact and raise awareness of chemotherapy-related cardiotoxicity in breast cancer treatment.

Keywords: chemotherapy-induced cardiotoxicity; anthracyclines; trastuzumab; HER2 breast cancer; left ventricular ejection fraction; cardiovascular surveillance.

Introduction

The two leading causes of death worldwide are cancer and cardiovascular disease.^1,2,3 With modern advances, 5- and 10-year breast cancer relative survival rates are approximated to be 89% and 83%, respectively, compared to a 5-year heart failure survival rate of 49.5%.^3,4,5 Unfortunately, many cancer-related treatments have adverse cardiovascular effects and with increased survivorship comes the double burden of age plus prior cancer treatment.⁶

This increasing awareness of chemotherapy-related cardiotoxicity and its identification as a distinct health problem gave rise to a unique subspeciality – cardio-oncology,^7,8 of which the main objectives are listed in Table 1.^7,9

Defining cardiotoxicity

Several different definitions of cardiotoxicity by cardiology and oncology subgroups (summarised in Table 2^10,11,12,13) and the diverse applications in clinical trials and practice cause inconsistencies in the diagnosis, management and evaluation of true prevalence.¹¹

The Department of Oncology at the Universitas Hospital Annex in Bloemfontein, South Africa, defines chemotherapy-related cardiotoxicity based on an integration of the Common Terminology Criteria for Adverse Effects (CTCAE) and the European Society of Medical Oncology (ESMO) guidelines. The European Society of Medical Oncology proposes a left ventricular ejection fraction (LVEF) cut-off of < 55%. However, CTCAE criteria define a decline in LVEF as a decrease of > 10%, irrespective of whether this value is < 55%.

Most early definitions and classifications of chemotherapy-related cardiovascular dysfunction (CRCD) focused solely on left ventricular (LV) dysfunction. However, at least 10 distinct chemotherapy-related cardiovascular disease patterns exist, including LV systolic dysfunction, coronary artery disease (CAD), peripheral vascular disease, cardiac arrythmias, arterial hypertension, thromboembolism, pulmonary hypertension, pericardial disease, valvular disease and stroke.^9,14

Cardiotoxicity is classified based on mechanisms and pathophysiology. As indicated in Table 3, the two main types of cardiotoxicity (and those pertaining to this study) are types I and type II.^15,16,17 Treatment-related cardiotoxicity is further defined regarding the timing of onset as acute, subacute or chronic. Acute cardiotoxicity involves adverse cardiac events that develop within 1 week of chemotherapy administration, subacute cardiotoxicity develops between one week and 1 year after administration, and chronic cardiotoxicity persists more than 1 year after treatment.¹⁸

Treatment of human epidermal growth factor receptor 2-overexpressed breast cancer – Understanding the benefits

For decades, anthracycline-based chemotherapy has formed the backbone of breast cancer treatment with compelling evidence in favour of its impact on disease-free survival (DFS) and overall survival (OS).^19,20 The benefits of anthracycline-based chemotherapy may be higher in patients with high-risk disease, including human epidermal growth factor receptor 2 (HER2)-overexpressed breast cancer, which occurs in 30% of cases and is associated with increased angiogenesis, rapid proliferation, poor response to hormonal therapy and a higher risk of metastases, recurrence and mortality.^17,19 The HER2-directed monoclonal antibody, trastuzumab, is the only strategy with a proven survival benefit in HER2-overexpressed non-metastatic breast cancer, reducing the 10-year recurrence risk by 9% and mortality by 6.4%.^{17,21,22,23,24}

The protocol for treating HER2-overexpressed breast cancer at the Universitas Academic Hospital previously (and at the time of initiation of this study) involved the use of three cycles of CAF (cyclophosphamide, doxorubicin and fluorouracil), followed by three cycles of T (docetaxel) with H (trastuzumab), followed by a total of 6–12 months of trastuzumab, provided there were no contraindications to the above including, but not limited to, inadequate LVEF or a history of anthracycline-based chemotherapy.

What about the risks? Agents implicated in cardiotoxicity

Anthracyclines

Anthracyclines are the prototype of chemotherapy-induced cardiotoxicity, but their efficacy is limited by dose-dependent, cumulative and progressive myocardial dysfunction, even 20–30 years after treatment.^25,26,27 Despite extensive research, the exact mechanism of anthracycline-induced cardiotoxicity remains to be elucidated. Direct cardiac damage has been postulated to develop because of a combination of the generation of reactive oxygen species (ROS), deoxyribonucleic acid (DNA) intercalation, topoisomerase IIB-induced apoptosis, direct DNA damage, doxorubicin-iron complexes and mitochondrial toxicity.^17,28

The incidence of anthracycline-induced cardiotoxicity is difficult to ascertain because of varying definitions across clinical trials, the lack of high-quality longitudinal studies, the complexity of isolating clinical variables and risk factors, and contradictory statistics. This situation is compounded by the fact that anthracyclines are frequently used in combination regimens with radiotherapy and biological agents (e.g. trastuzumab also contributes to cardiotoxicity).²⁶

Acute anthracycline-induced cardiotoxicity is rare (< 1%), mostly involves benign arrhythmias and resolves within a week. Evidence has indicated that it is not a predictor of future heart failure.^26,27 The incidence of early-onset chronic progressive cardiotoxicity is 1.6% – 9%. Late-onset chronic progressive cardiotoxicity ranges between 5% and 48%.^29,30 Early and late anthracycline cardiotoxicity are dose dependent. The true incidence of especially late anthracycline-induced cardiomyopathy is difficult to ascertain because of a long latent period (up to 30 years), lack of surveillance guidelines for cardiovascular disease in adult cancer survivors and varying definitions of cardiotoxicity.²⁶ However, Cardinale et al. demonstrated that 98% of anthracycline-related cardiotoxicity occurred within the first year post-treatment.³¹

Swain et al.²⁵ highlighted the dose-dependent nature of anthracycline-related cardiotoxicity with the incidence of cardiac events ranging between an increase of 9% for a cumulative doxorubicin dose of 250 mg/m² to 65% for 550 mg/m².²⁵ The incidence of congestive cardiac failure (CCF) also escalated exponentially with increasing cumulative doxorubicin dose, with the incidence of CCF at a cumulative dose of 500 mg/m² being 16% and 48% for 700 mg/m². However, heart failure may occur at total cumulative doxorubicin doses of < 300 mg/m² (1.5%) and even 150 mg/m² (0.2%).²⁴

Dose-conversion ratios for anthracycline derivatives are based on equivalent haemototoxicity.³² Epirubicin is commonly believed to be less cardiotoxic than doxorubicin. However, comparing randomised controlled trials on the cardiotoxicity of anthracycline derivatives found no significant difference between epirubicin and doxorubicin in clinical heart failure at equivalent doses.^33,34

Trastuzumab

Trastuzumab binds to the extracellular domain of HER2, inhibiting intracellular tyrosine kinase activation and subsequent downstream signalling pathways. Normal cardiomyocytes mediate repair induced by stress or injury via HER2 signalling of stress damage.²⁸ Contrary to type I cardiotoxicity causing structural myocyte damage, trastuzumab-mediated cardiotoxicity involves dysregulation of signal transduction pathways, inhibition of neo-angiogenesis and DNA repair.²⁸ Blockage of these pathways allows cardiac injury to accumulate, explaining the cumulative cardiotoxic risk of combination anthracycline and trastuzumab.¹⁷ Trastuzumab causes type II cardiotoxicity that is reversible with discontinuation. Occasionally, trastuzumab is restarted after cardiac abnormalities have resolved.^28,35

An outline of rates of cardiac toxicity induced by trastuzumab across trials has been reported.²⁷ Regarding the summary in Table 4, it should be noted that in the NSABP B31 and North Central Cancer Treatment Group (NCCTG) N9831 trials, 6.7% of patients did not receive trastuzumab after anthracyclines because of unacceptable decreases in protocol-specified LVEF measurements.²⁷

The evaluation of the cardiac safety of doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with or without trastuzumab (H) in the NCCTG N9831 Intergroup trial³⁶ revealed that the cumulative incidence of cardiac events was higher in the group receiving trastuzumab-containing therapy, 3.3% compared to the control group’s 0.3%. In this study, the drop in LVEF after anthracycline-based chemotherapy that precluded trastuzumab was 4.0% – 5.1%.³⁶

In the multicentre Herceptin Adjuvant (HERA) trial,³⁷ the incidence of cardiotoxicity was greater in the two groups that received adjuvant trastuzumab (0.6% vs. 0% for severe CCF and 3.04% vs. 0.53% for decreased LVEF). Furthermore, the mean cumulative anthracycline dose was higher in patients experiencing one of the defined cardiac endpoints.³⁷

Risk factors for the development of cardiotoxicity

The Framingham Heart Study established hypertension, hypercholesterolemia, obesity, diabetes and smoking as major cardiovascular disease risk factors.³⁸ Risk factors for anthracycline-induced cardiotoxicity are divided into patient-related and treatment-related factors (see Table 5).^17,18,39,40 Hypertension acts synergistically with doxorubicin as a risk factor for CCF.^39,40 Total cumulative dose of anthracyclines is the most significant risk factor for cardiac dysfunction.^18,41 The risk of chemotherapy-related cardiotoxicity increases with a cumulative doxorubicin equivalent dose of > 300 mg/m².⁴¹ The risk factors for trastuzumab-related cardiotoxicity are less well defined but include age > 50 years, concurrent or prior anthracycline or radiation exposure, obesity, arterial hypertension and prior LV dysfunction.^17,28 Three risk categories for cardiotoxicity are based on therapy- or patient-related factors (Table 5).¹³

Cardiac surveillance

Cardio-oncology is a fairly new concept, and organised services and guidelines are just emerging, with a lack of consensus guidelines concerning screening and management. Other barriers to the implementation of a successful cardio-oncology programme include a lack of resources, personnel, skills and timeous access to care. Consequently, patients with asymptomatic chemotherapy-induced cardiac disease such as LV dysfunction present late (e.g. in overt heart failure), limiting effective interventions.⁴² The British Society for Echocardiography (BSE) and British Cardio-Oncology Society (BC-OS) recently published guidelines regarding definitions, imaging and clinical decision-making considerations regarding anthracyclines and/or trastuzumab treatment and emphasised early detection and the need for specialised cardio-oncology services.⁴³

Because cardiovascular abnormalities are often detected when the changes are irreversible, diagnostic modalities able to detect early alterations in potentially reversible pathways are becoming increasingly appealing.⁴⁴ Of note is that current guidelines and definitions concentrate on a reduction in LVEF, which usually occurs later in the disease process. A better approach would be to identify subclinical cardiotoxicity before it manifests as a decrease in LVEF or cardiac dysfunction. Early detection and treatment allow recovery of some myocardial function before irreversible heart failure ensues.^44,45

The aim of this study was to create awareness about cardio-oncology and the need for closer cardiac surveillance in cancer patients receiving cardiotoxic chemotherapy and to quantify the burden of treatment-induced cardiotoxicity in our patient population.

Methods

Study design

A retrospective analysis of the prevalence and risk factors of acute and subacute chemotherapy-induced cardiotoxicity and its impact on planned treatment in non-metastatic HER2-overexpressed breast cancer patients treated with anthracyclines and/or trastuzumab was conducted. Furthermore, surveillance practices regarding imaging modalities, use of biomarkers, and ECG and symptom reporting were reviewed.

Study population

The study population included all new patients diagnosed with histologically confirmed non-metastatic HER2-overexpressed breast cancer treated with neoadjuvant or adjuvant anthracycline-based chemotherapy with or without trastuzumab at the Universitas Hospital Annex, Department of Oncology, in 2019 and 2020. Chemotherapy consisted of three cycles CAF (cyclophosphamide 600 mg/m², doxorubicin 50 mg/m², 5-fluorouracil 600 mg/m² IV 3-weekly) or FEC (doxorubicin replaced by epirubicin 90 mg/m²), followed by three cycles of docetaxel (75 mg/m² – 85 mg/m² IV 3-weekly) with trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg IV 3-weekly) if there were no contraindications and LVEF was acceptable.

The specific study population and time frame were selected as trastuzumab was only approved for non-metastatic HER2-overexpressed breast cancer patients at the Universitas Annex in November 2018. Trastuzumab is known to cause type II (reversible) cardiotoxicity and has synergistic cardiotoxic effects with anthracyclines. The departmental protocol for patients receiving trastuzumab is to monitor LVEF 3 monthly during treatment. Current departmental protocol dictates that patients receiving anthracycline-based chemotherapy only require a baseline normal LVEF measurement as these patients receive 3–6 cycles of anthracyclines (cumulative doxorubicin dose of 150 mg/m² – 300 mg/m²). This dose is considered to be within the recommended tolerable limits for avoiding anthracycline-induced cardiotoxicity (cumulative doxorubicin dose < 450 mg/m²). However, anthracycline-related cardiotoxicity may occur at lower doses (e.g., a cumulative doxorubicin dose of 150 mg/m²) and without monitoring, its incidence in our setting is unknown. Therefore, this population of patients receiving trastuzumab has an objective and systematically measured parameter of cardiotoxicity (LVEF).

Definition of cardiotoxicity

For the purpose of this study, cardiotoxicity was defined according to protocols applied at the Department of Oncology, Universitas Hospital Annex, Bloemfontein, South Africa, including the following:

• interim LVEF (measured by transthoracic echocardiography or multigated acquisition [MUGA] scanning) < 55%;
• asymptomatic decrease in LVEF of > 10% from baseline; or
• symptomatic heart failure and LVEF < 55%.

Data collection

Left ventricular ejection fraction was recorded at baseline, after three cycles of CAF/ECF prior to trastuzumab (H) and after 3, 6, 9, 12, 15 and 17 cycles trastuzumab, respectively, where applicable. Left ventricular ejection fraction was determined by MUGA or echocardiography. Any other abnormalities detected on cardiac imaging were recorded. When two modalities were used to assess LVEF, we conservatively used the lower value.

The following risk factors were assessed for correlation with the incidence of cardiotoxicity: (1) age (> 64 years); (2) pre-existing hypertension; (3) pre-existing CAD; (4) diabetes mellitus (sub-stratified into type 1 or 2); (5) pre-existing hyperlipidaemia; (6) smoking (sub-stratified according to number of pack years); (7) obesity (BMI > 30 kg/m²); (8) radiation therapy received; and (9) pre-chemotherpay LVEF. In this study, pre-existing hypertension was defined as a patient giving a history of hypertension and using anti-hypertensive medication, systolic blood pressure >140 mmHg or diastolic blood pressure > 90 mmHg on two separate occasions > 6 h apart. Pre-existing CAD was defined as a history of myocardial infarction, coronary artery bypass surgery or coronary artery stenting and/or CAD diagnosed by a cardiologist, including myocardial ischaemia, angina or infarction.

Statistical analysis

Statistical analysis was performed by the Department of Biostatistics, University of the Free State (UFS), using Statistical Analysis Software (SAS), version 9.4 (SAS Institute Inc., Cary, NC). Continuous variables were summarised by medians, minimum, maximum or percentiles. Categorical variables were summarised by frequencies and percentages. Differences between groups were evaluated using the chi-square or Fischer’s exact test for unpaired data. The percentage of patients who developed cardiotoxicity was expressed as a percentage of the sample population, and results were subcategorised according to the timing of its development (i.e. chemotherapy cycle). The impact of cardiotoxicity was assessed by analysing the number and percentage of patients who no longer qualified for trastuzumab after anthracycline-only treatment or required early cessation of trastuzumab (i.e. not receiving treatment for the intended 6 months) because of cardiotoxicity.

Ethical considerations

The Health Sciences Research Ethics Committee (HSREC) of the UFS approved the study (reference number: UFS-HSD2021/0276/2606). The Free State province Department of Health and the Head of the Department of Oncology gave permission for the research. Because of the retrospective nature of the study and because only patient records were used, informed consent was not required.

Results

Patient characteristics

Thirty-one patients met the inclusion criteria. The median age was 52 years (range 26–83 years). Pertaining to cardiovascular risk factors, pre-existing hypertension and diabetes mellitus were present in 16 (51.6%) and two (6.5%) patients, respectively. Two (6.6%) patients reported to be smokers. The median BMI was 29 kg/m², and 14 (45.2%) patients were obese (BMI > 30 kg/m²).

Baseline cardiac function

The median baseline LVEF documented was 66% (range 52% – 86%). Thirty (96.8%) of the 31 patients had a baseline cardiac assessment performed with MUGA scanning. Three (9.7%) patients had documented abnormalities on baseline LVEF assessment, including an enlarged left ventricle, LV hypertrophy but normal wall motion, and a prominent thoracic aorta, respectively.

Anthracycline dose

Eighteen (58.1%) patients had three cycles of CAF with doxorubicin at 50 mg/m² per dose. Three (9.7%) patients had three cycles of dose-equivalent CEF with epirubicin at 90 mg/m². Seven patients had a combination of doxorubicin and equivalent dose epirubicin. Three patients received three cycles of reduced-dose CAF at 75% of the normal dose (37 mg/m² per dose). Reasons for reduced-dose doxorubicin included elderly or frail patients and one patient with baseline neutropenia.

Cardiac function post-anthracycline and pre-trastuzumab

The median LVEF after anthracycline therapy prior to initiation of trastuzumab was 63% (range 42% – 79%), corresponding to an average decrease in LVEF of 3%. One patient with a baseline LVEF of 52% had a 10% decrease in cardiac function following anthracycline-based therapy. The imaging modality used most frequently at this point for LVEF assessment was MUGA (n = 27 patients). Three patients had other abnormalities detected by imaging, including eccentric LV hypertrophy combined with right ventricular dilation and a prominent right atrium, and an enlarged right ventricle with decreased wall motion detected on MUGA. In the latter, a confirmatory echocardiogram demonstrated an LVEF of 53%.

Subsequent cardiac function

The median LVEF after three cycles of trastuzumab for qualifying patients was 60.5% (range 49% – 70%), representing a further 2.5% decrease in the average LVEF. Changes in LVEF after three cycles of trastuzumab are illustrated in Figure 1. For patients eligible to continue with trastuzumab, the median LVEF after six cycles was 64%. Although this appears to represent an average increase in LVEF, it should be noted that only 12 of the 31 patients had an adequate LVEF to be eligible to complete six cycles of trastuzumab. Only two patients had a repeat LVEF assessment after cycle eight of trastuzumab, with an LVEF of 65% (MUGA) and 64% (echocardiography), respectively.

FIGURE 1: Change in left ventricular ejection fraction percentage points after anthracycline-based chemotherapy.

Impact of cardiotoxicity

The impact of cardiotoxicity on treatment intent was measured by the number of patients who were not eligible to receive trastuzumab after anthracycline treatment, which was 22.6%. The percentage of patients who did not complete the intended 6 months of trastuzumab treatment amounted to an additional 35.5%. Thus, a total of 58.1% (18 patients) did not receive the optimal intended course of treatment because of the development of cardiotoxicity. Therefore, only 41.9% of patients received intended chemotherapy. Table 6 summarises the percentage of the original study population still receiving intended chemotherapy at measured cycles.

Surveillance practices

An analysis of surveillance practices indicated that MUGA was the most common imaging modality used to determine LVEF at our institution. Biomarkers (cardiac troponins or proBNP) were not determined, and electrocardiography (ECG) was not performed.

Correlation of risk factors to develop cardiotoxicity

Age

Nineteen (61.3%) patients older than 50 years did not receive the intended cycles of trastuzumab because of cardiotoxicity. However, no statistically significant difference was found that confirmed a correlation between age and cardiotoxicity (p = 0.5158).

Body mass index

The percentage of patients unable to receive trastuzumab stratified by BMI category was 50.0%, 75.0%, 33.3% and 60.0% for BMI categories underweight (< 18.5 kg/m²), normal weight (18.5 kg/m² – 24.9 kg/m²), overweight (25.0 kg/m² – 29.9 kg/m²) and obese (> 30 kg/m²), respectively. Using Monte Carlo estimates for Fischer’s exact test, no statistically significant association was found between BMI and cardiotoxicity (p = 0.5138).

Pre-existing hypertension

In the study population, pre-existing hypertension was also not found to correlate with cardiotoxicity (p = 0.3473). Of the patients who developed cardiotoxicity, 66.7% did not have a pre-existing history of hypertension.

Pre-existing diabetes mellitus

Pre-existing diabetes mellitus was noted in only two patients, with one developing cardiotoxicity. Consequently, inferences could not be drawn regarding the association between diabetes and cardiotoxicity.

Pre-existing coronary artery disease

There were no comparative results to correlate pre-existing CAD with cardiotoxicity, as its occurrence was not recorded for any patients.

Smoking history

Although both patients with a smoking history (n = 2; 100%) developed cardiotoxicity, 55.1% (n = 16/29) of non-smokers developed cardiotoxicity. This known risk factor for cardiovascular disease was not associated with a significant risk of developing cardiotoxicity (p = 0.4968).

Pre-chemotherapy cardiac function and abnormalities detected on imaging

The median pre-chemotherapy LVEF was 66%. Three patients had other abnormalities detected on pre-chemotherapy cardiac imaging evaluation, of which only one developed cardiotoxicity. The abnormality noted in this case was a prominent aorta for further workup. The remaining two patients with LV hypertrophy and an enlarged left ventricle, respectively, did not develop cardiotoxicity.

Type of anthracycline used

Three patients received epirubicin alone (total dose 270 mg/m²), of which one (33.3%) developed cardiotoxicity. Two patients received two cycles epirubicin and one cycle doxorubicin, of which one (50.0%) developed cardiotoxicity. Five patients received two cycles doxorubicin and one cycle epirubicin, with two (40.0%) experiencing decreased LVEF.

Severity of impact

Of the 18 patients who developed cardiotoxicity, the notes reflected signs of CCF for only one patient and negative findings for an additional two patients. For the majority of patients, signs and symptoms of cardiac failure were not recorded in their clinical notes.

Discussion

This study demonstrated that 58.1% of patientswho were planned to receive sequential anthracycline- and trastuzumab-based therapy, did not complete the intended course, because of premature cessation of trastuzumab secondary to the detection of a decreasing LVEF. Consequently, the full benefit of targeted therapy (trastuzumab) was not achieved, which has been reported to significantly reduce breast cancer-specific mortality and recurrence and improve OS by 37% and DFS by 40% in HER2-overexpressed breast cancer.^22,46 Furthermore, a decreased LVEF is known to be associated with the future development of symptomatic heart failure and impaired quality of life and life expectancy, counteracting the survival gains achieved by anthracyclines and trastuzumab in HER2-overexpressed breast cancer.

More than a fifth (n = 7; 22.6%) of patients developed type I cardiotoxicity as they presented with a decline in LVEF following treatment with anthracycline (prior to the initiation of trastuzumab). This finding was significant as the median doxorubicin-equivalent dose was 150 mg/m², which was notably less than traditional thresholds (cumulative doxorubicin dose 300 mg/m² – 450 mg/m²) reported as a risk factor for anthracycline-induced cardiotoxicity. Furthermore, this type of cardiotoxicity is irreversible.²⁵

Acute anthracycline cardiotoxicity is rare (< 1%), transient (resolving within a week) and involves benign arrhythmias. However, the authors cannot comment on its prevalence because (1) it was uncertain at which exact point a decline in LVEF developed; (2) ECGs were not recorded for these patients; and (3) surveillance was done only by means of LVEF measurements obtained 3 weeks after the last chemotherapy, prior to initiation of the next cycle. Therefore, in accordance with previous findings, the type I cardiotoxicity in this population could be described as subacute.^25,26,27 Evaluation of cardiac function after 1 week by ECG and possibly biomarkers may assist in identifying and sub-classifying early onset cardiotoxicity as acute and subacute and in determining whether acute cardiotoxicity is predictive of subsequent cardiotoxicity.

An additional 35.5% of patients experienced a decline in LVEF after initiating trastuzumab, although it was difficult to evaluate the weight of contribution of anthracyclines (type I), trastuzumab (type II – reversible) or these drugs combined. Follow-up LVEF measurements after completion of systemic therapy would be valuable to assess cardiac function recovery and quantify patients with reversible declines in LVEF, early-onset chronic progressive cardiotoxicity, chronic cardiotoxicity (> 1 year after treatment) or late-onset chronic progressive cardiotoxicity.^27,29

When comparing our findings to other studies, including a study by Swain et al. in which only 0.2% of patients receiving a cumulative doxorubicin dose of 150 mg/m² developed cardiotoxicity,²⁵ the prevalence of cardiotoxicity in our population was substantially higher.

Although data relating to the prevalence of anthracycline-induced cardiotoxicity in other African and low-middle-income countries are limited, the following studies suggest that the incidence of cardiotoxicity in our study population (22.6%) remains higher. In one study from Morocco (n = 90), the incidence of severe cardiotoxicity (defined as a decrease in LVEF of more than 10% or an LVEF of less than 40%) was 4.2%.⁴⁷ A further two studies in the Philippines and Brazil, defining cardiotoxicity as an LVEF of less than 53% or a decline of more than 10% from baseline, indicated prevalence rates of 9.68% (n = 341) and 16.1% (n = 112), respectively.^48,49

As noted, the lack of a uniform definition of chemotherapy-induced cardiotoxicity hampers comparison regarding its true incidence, which is further complicated by treatment with different chemotherapy regimens. The urgency for a global standardised definition of cardiotoxicity is evident. Moreover, guidelines relating to cardiovascular surveillance in patients receiving chemotherapy should take into consideration the resource constraints of low- to middle-income regions.

Because of the additional contribution of trastuzumab-related type II cardiotoxicity superimposed by anthracycline risk, separating the individual contributions of these agents is problematic. In one of the largest trials (HERA) involving 5102 participants, the incidence of an asymptomatic decline in LVEF was 7.1% in patients receiving adjuvant trastuzumab after AC-T.⁴⁶ This is considerably lower than the incidence of 58.1% observed in our study population.⁵⁰ Until recently, our patients received CAF and not AC-T, and the combination of anthracyclines with fluorouracil and cyclophosphamide may play a role in the development of cardiac dysfunction. The treatment regimen in the FinHer trial⁵¹ was more comparable to our institutional protocol, in that it used three cycles of FEC (fluorouracil, epirubicin and cyclophosphamide) combined with trastuzumab. In this study, the incidence of an asymptomatic decline in LVEF was 8.6%.⁵¹ It is clear that in both comparisons, the percentage of patients in our study who experienced an asymptomatic decline in LVEF was significantly higher.

It could be hypothesised that an increased prevalence of major cardiovascular risk factors as defined by the Framingham Heart Study³⁸ may explain the increased prevalence of cardiac dysfunction in our study population. However, no statistically significant correlation between hypertension, diabetes, obesity or smoking and the development of cardiotoxicity was observed in our study population.

Despite an evaluation of conventional risk factors, our data failed to identify a statistically significant reason for the disproportionately high decline in cardiac function among the patients in this study. Feasible explanations include the possibility that the influence of fluorouracil was not as small as assumed, dietary deficiencies in our unique African population not reflected by BMI but rather serum albumin or other unidentified risk factors. A lack of answers prompted us to amend our protocol to incorporate serum albumin, which was determined at baseline for all patients and compared to the development of cardiotoxicity. Hypoalbuminaemia is defined as a serum albumin level of < 35 g/L.⁵² However, we observed no statistically significant correlation with the development of cardiac dysfunction.

Limitations of the study

We acknowledge the small sample size, which limited the ability to extrapolate findings to a larger population of patients and accurately identify statistically significant risk factors for cardiotoxicity. Furthermore, varying definitions of cardiotoxicity and differing chemotherapy regimens cause comparison across studies to be challenging. Additionally, the first cardiotoxicity guidelines only emerged in 2012 and many of the studies cited had been conducted earlier. However, recognising these limitations reinforces the need for further research in cardio-oncology.

Conclusion

A paradigm shift from seeing cancer as a death sentence to cancer as a chronic disease that requires follow-up in terms of cardiovascular complications is necessary.⁶ This study highlights the need for better definitions and standardised guidelines for cardiovascular monitoring in patients receiving potentially cardiotoxic chemotherapeutic agents, especially in our unique population of patients who appear to experience disproportionately higher declines in cardiac function. Furthermore, alternative, accessible and cost-effective methods for early detection and monitoring of cardiotoxicity are crucial.

Regrettably, this study failed to identify a specific reason for the disproportionately high rates of cardiac dysfunction in our population based on known cardiovascular risk factors or nutritional deficiencies. However, it emphasised the fact that other risk factors need to be investigated to identify and appropriately manage patients at risk. Other areas to be explored include the use of biomarker testing (high-sensitivity troponins), three-dimensional (3D) echocardiography with global longitudinal strain measurement, combined cardio-oncology assessment and genetic testing.

Acknowledgements

The authors thank Dr. Daleen Struwig, medical writer and editor, Faculty of Health Sciences, University of the Free State, for the technical and editorial preparation of the article.

The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

The research question, study design and methodology were formulated by Z.S. and A.S. Z.S. was responsible for data collection, project administration, presentation of results and writing the first draft of the article. C.v.R. performed the statistical analyses and assisted with the interpretation of results. A.S. and C.v.R. contributed to reviewing and editing of the article. All the authors approved the final manuscript.

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Data are available from the corresponding author, Z.S., upon reasonable request.

The views and opinions expressed in this article are those of the authors and are the product of professional research. It does not necessarily reflect the official policy or position of any affiliated institution, funder, agency or that of the publisher. The authors are responsible for this article’s results, findings and content.

References