Z. Tlegenova1, S. Balmagambetova1, B. Zholdin1, G. Kurmanalina1, I. Talipova1,A. Koishybayev1, G. Sultanbekova1, K. Kubenova2, M. Baspayeva2,S. Madinova2, A. Amanova1
Tlegenova Z. Balmagambetova S. Zholdin B. Kurmanalina G. Talipova I. Koishybayev A. Sultanbekova G. Kubenova K. Baspayeva M.Madinova S. Amanova A. Cardiotoxicity of Anthracycline-Based Chemotherapy in Breast Cancer Patients: A Case Series.
Annotation
In Kazakhstan, breast cancer remains the leading cause of cancer morbidity and mortality among women. The presented case series aims to summarize cardiovascular events that resulted in discontinuation or suspension of anthracycline-based chemotherapy during an ongoing project on studying the cardiotoxic effects.
Case 1: Classic acute cardiotoxicity with asystole. Patient Sh., 46 years old, was admitted with a baseline left ventricular ejection fraction (LVEF) of 64% and global longitudinal strain (GLS) of 22.4%. After the first dose of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, the patient experienced two episodes of asystole. Trimetazidine was prescribed at a dose of 80 mg. Eventually, Sh. completed the courses of anthracycline therapy after a 1-month delay at a cumulative dose of 455 mg/m2.
Case 2: Subacute cardiotoxicity with ventricular extrasystole. Patient Zh., aged 47, developed single, paired, and group ventricular extrasystoles after the 2nd course of chemotherapy with doxorubicin 200 mg/m2 (23 days after admission). Carvedilol was prescribed at 25 mg twice daily and Trimetazidine at 80 mg once a day. After one month of monitoring, ventricular extrasystoles disappeared. The patient completed chemotherapy at a cumulative dose of 400 mg/m2, with a 1-month delay.
Case 3: Severe cardiotoxicity due to pre-existing cardiovascular disease with discontinuation of chemotherapy. Patient M., aged 58, was referred to the very high-risk group for developing atrial fibrillation and heart failure with an LVEF of 51%. M. received Enalapril 5 mg twice daily, Bisoprolol 5 mg, Eplerenone 50 mg, Dapagliflozin 10 mg, and Dabigatran 150 mg twice daily. After three months, anthracycline therapy was canceled at a cumulative dose of 260 mg/m2 due to deterioration of the patient's condition (LVEF 41%).
Conclusion: Discontinuation or delay of vitally needed chemotherapy in breast cancer patients deteriorates their prognosis for survival. Patients should be constantly monitored during and after anticancer treatment.
Keywords: anthracyclines, chemotherapy, cardiotoxicity, Kazakhstan, case series
Introduction
Breast cancer (BC) poses a significant health challenge globally, with predictions indicating a substantial increase in new cases and deaths by 2040. In Kazakhstan, BC remains the primary cause of cancer morbidity and mortality among women, with a notable increase in prevalence and incidence rates over recent years. Despite advancements in early detection and antitumor pharmacological treatments, BC survivors often grapple with the physical consequences of cancer and its therapies, resulting in functional and cognitive impairments. Notably, BC survivors face a heightened risk of developing heart failure (HF) within five years of diagnosis compared to the general population.
Cardiovascular complications in cancer patients encompass a wide spectrum of conditions, including coronary artery disease, hypertension, arrhythmias, stroke, and venous thromboembolism. Among the various cardiotoxic effects of chemotherapy, cancer therapy-related cardiac dysfunction (CTRCD) represents a significant concern, with left ventricular dysfunction (LVD) being the most prevalent and serious manifestation.
Anthracyclines, widely utilized in BC treatment, induce dose-dependent cardiotoxicity characterized by HF and arrhythmias. On the other hand, pharmaceuticals like trastuzumab and vascular endothelial growth factor (VEGF) inhibitors contribute to reversible myocardial dysfunction. The incidence of HF escalates with increasing cumulative doses of anthracyclines, emphasizing the importance of careful monitoring and dose management during treatment.
The 2022 Cardio-Oncology Guidelines offer updated definitions of asymptomatic CTRCD, aiding in early detection and intervention. These guidelines emphasize the role of clinical risk factors in assessing the potential cardiotoxicity of chemotherapy and advocate for stratifying patients' cardiovascular risk at baseline to guide treatment decisions effectively.
Chemotherapeutic regimens for BC patients are tailored based on disease status and risk factors. Trastuzumab is commonly administered every three weeks for up to 18 courses, while anthracycline-based chemotherapy remains the primary option for HER2-negative patients. The presented case series aims to analyze cardiovascular events leading to anthracycline-based chemotherapy discontinuation or suspension in breast cancer patients at the Aktobe Oncologic Center.
Among 128 enrolled BC patients treated with anthracyclines and/or trastuzumab, we observed three cases necessitating chemotherapy cessation due to cardiovascular events. These cases underscore the importance of vigilant monitoring and personalized management strategies to mitigate cardiotoxicity risks during breast cancer treatment.
Case Series Report
Case 1: Classic Acute Cardiotoxicity with Asystole
Patient Sh., a 46-year-old female diagnosed with ST IIB T3NxM0 breast cancer, had no cardiovascular (CV) diseases in her medical history but presented with risk factors upon admission to the Chemotherapy division on March 17, 2022. Baseline left ventricular ejection fraction (LVEF) was 64%, and global longitudinal strain (GLS) was 22.4%. Primary biomarker values at baseline were as follows: cardiac Troponin I (cTnI) - 0.1 ng/ml and B-type natriuretic peptide (BNP) - 43.8 pg/ml. Despite the initial assessment indicating low risk for forthcoming anthracycline therapy, the patient experienced two episodes of asystole at Holter monitoring (HM) shortly after receiving the first dose of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC regimen). As these episodes occurred less than a week after administration, they were classified as acute cardiotoxicity. After relieving acute episodes, observation was prolonged, and Holter data returned to normal values within a week. The patient was prescribed Trimetazidine at a dose of 80 mg. Over a year of observation, LVEF decreased from 64% to 58%, and GLS decreased from -22.4% to -15.3%, representing a significant reduction of 31.7%. Despite this, Sh. completed anthracycline therapy after a 1-month delay at a cumulative dose of 455 mg/m2. Notably, the patient was not transferred to other risk groups as there were no indications for allocation to the high- or very high-risk, or moderate-risk group. This case highlights the importance of understanding patients' baseline allocation into risk groups for guiding treatment decisions.
Case 2: Subacute Cardiotoxicity with Ventricular Extrasystole
Patient Zh., a 47-year-old female newly diagnosed with invasive breast carcinoma, was admitted to the division on November 5, 2021. The baseline risk of cardiotoxic complications was estimated as low. After the second course of chemotherapy with doxorubicin 200 mg/m2 (23 days after admission), the patient reported interruptions in heart function. Holter monitoring revealed single, paired, and group ventricular extrasystoles (VES), totaling 10,895, with a maximum of 1,211 per hour. See Table 1 for summary data on arrhythmias.
Table 1.
These data are also presented graphically (Figure 1.)
Figure 1: Holter Monitoring Summary
Dynamic 24-hour ECG examination was conducted using three channels for 23 hours and 42 minutes. The main rhythm observed is sinus. A total of 118,376 QRS complexes were recorded. The maximum heart rate recorded was 170 beats/min during walking, while the minimum heart rate was 47 beats/min during sleep. The average heart rate over the monitoring period was 83 beats/min. Increased ectopic activity was noted, with single ventricular extrasystoles (VES) totaling 10,895. The maximum number of VES occurred at 23:00, with 1,211 instances. Bigeminy was observed in 88 instances, while trigeminy occurred 932 times. Additionally, 64 instances of single VES were recorded. ST analysis revealed no ischemic changes in the ST segment.
Carvedilol was prescribed at a dose of 25 mg twice daily, and Trimetazidine at a dose of 80 mg once daily. Cardioprotectants were continued until normalization of Holter monitoring performance. Upon one month of monitoring, no VES were observed during control Holter monitoring. The patient completed chemotherapy at a cumulative dose of 400 mg/m2, with a 1-month delay. After 12 months of monitoring, no signs of developed cancer therapy-related cardiac dysfunction (CTRCD) were observed, except for B-type natriuretic peptide (BNP) levels indicating incremental subclinical cardiotoxicity (refer to Table 2).
Table 2: Patient Monitoring Recommendations
The patient requires scrutinized monitoring during follow-up according to the principles outlined in the European Society of Cardiology (ESC) cardio-oncology Guidelines 2022.
Case 3: Severe Cardiotoxicity Due to Pre-existing Cardiovascular Disease with Discontinuation of Chemotherapy
Among our cohort of 128 patients, three (2.3%) had a recorded history of cardiovascular disease. However, only one patient, M., aged 58, was referred to the very high-risk group due to a history of atrial fibrillation and heart failure with a left ventricular ejection fraction (LVEF) of 51%. M. has been experiencing arterial hypertension (AH) since 2000, with atrial fibrillation diagnosed in 2010. In 2017, heart failure with a reduced LVEF of 38% was diagnosed. With treatment for atrial fibrillation and heart failure, LVEF eventually improved to 51% (heart failure with improved LVEF). Breast carcinoma was newly diagnosed in 2021. Please refer to Figure 2 for a comprehensive overview of the patient's medical history.
Figure 2: Patient Medical Examination and Cardioprotective Therapy
The patient underwent examination by a cardiologist, with the following findings:
Arterial hypertension stage 1, risk category 4.
Permanent form of atrial fibrillation, with a CHA2DS2-VASc score of 3 points*.
Heart failure (HF) with improved left ventricular ejection fraction (LVEF) of 51%, classified as New York Heart Association (NYHA) class II.
Transthoracic echocardiography (TTE) with speckle tracking performed as of October 18, 2022, revealed:
Enlargement of both atria.
Reduced pumping and contractile functions of the left ventricle (LV), with LVEF of 51%.
Reduced global longitudinal deformation (-12.6%).
LV myocardial hypertrophy.
Mild aortic regurgitation.
Mitral regurgitation of 2nd degree.
Tricuspid regurgitation grade 1.5.
Minimal regurgitation on the pulmonary valve.
Pulmonary hypertension with pulmonary artery systolic pressure (PASP) of 41 mmHg.
Echo-enhanced interventricular septum (IVS) with a small amount of fluid in the pericardial cavity. No fluid detected in pleural cavities.
Considering the patient's LVEF of 50-55%, clinical signs of chronic heart failure, arterial hypertension, and increased cardiac markers, M. was categorized into the very high-risk group. As she was HER2-negative, anthracycline therapy was planned. Per European Society of Cardiology (ESC) Guidelines, cardioprotective therapy was initiated before chemotherapy, including Enalapril 5 mg twice daily, Bisoprolol 5 mg, Eplerenone 50 mg, Dapagliflozin 10 mg, and Dabigatran 150 mg twice daily.
During TTE follow-up after three months, LVEF declined to 41%, with worsening valvular regurgitation and pulmonary hypertension. Anthracycline therapy was discontinued at a cumulative dose of 260 mg/m2 due to the deterioration of the patient's condition (LVEF 41%). Anticancer treatment continued with Tamoxifen (antihormonal treatment) and courses of radiation therapy at a total focal dose of 66 Gray. Please refer to Table 3 for cardiotoxicity monitoring data for patient M.
*The CHA2DS2-VASc score assesses the risk of stroke in patients with atrial fibrillation.
Table 3.
____________________
* The CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 y.o., diabetes mellitus, stroke or transient ischemic attack (TIA), vascular disease, age 65 to 74 y.o., sex category) score is a validated tool to predict the risk of stroke and systemic emboli in patients with non-valvular atrial fibrillation.
Conclusion
Discontinuation, suspension, or delay of vital chemotherapy in breast cancer (BC) patients significantly worsens their prognosis for survival. The development of cancer therapy-related cardiac dysfunction (CTRCD) during or after chemotherapy is a leading cause of decreased quality of life post-treatment. Cardiotoxicity can manifest in patients at any time, regardless of their baseline risks. Therefore, it is imperative to monitor all BC patients continuously during and after treatment, adhering to the principles outlined in the European Society of Cardiology (ESC) cardio-oncology Guidelines 2022.
Acknowledgments
This work was conducted as part of a scientific project funded by the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan, titled "Development of a Program for Early Diagnosis and Treatment of Cardiotoxic Complications Caused by Breast Cancer Chemotherapy" (IRN AP09259524, state registration No. 0121RK00565).
Conflict of Interest
The authors declare that they have no conflicts of interest.
References:
Table 1. Summary data on arrhythmias during the Holter monitoring in patient Zh.
|
Ventricular activity |
||||||||
|
Time |
Max HR |
Min HR |
Average HR |
Total complexes |
Total VES |
Single VES |
Bigeminy |
Trigeminy |
|
Total |
0 |
0 |
83 |
118376 |
10895 |
10895 |
88 |
932 |
|
10:45 – 12:00 12:00 – 13:00 13:00 – 14:00 14:00 – 15:00 |
148 133 137 147 |
64 60 68 78 |
89 85 95 101 |
6669 5129 5703 6065 |
344 505 321 233 |
344 505 321 233 |
3 2 4 0 |
17 32 11 5 |
|
15:00 – 16:00 16:00 – 17:00 17:00 – 18:00 18:00 – 19:00 |
103 119 93 140 |
75 51 62 64 |
83 77 72 91 |
4962 4597 4342 5474 |
538 316 670 184 |
538 316 670 184 |
0 2 23 2 |
9 8 31 5 |
|
19:00 – 20:00 20:00 – 21:00 21:00 – 22:00 22:00 – 23:00 |
126 137 110 123 |
67 59 74 74 |
94 94 56 91 |
5624 5656 3371 5457 |
155 147 108 257 |
155 147 108 257 |
3 0 0 1 |
6 2 7 20 |
|
23:00 – 00:00 00:00 – 01:00 01:00 – 02:00 02:00 – 03:00 |
117 107 114 102 |
70 50 47 59 |
81 79 68 70 |
4857 4741 4056 4194 |
1211 1098 671 595 |
1211 1098 671 595 |
28 19 1 0 |
80 83 53 78 |
|
03:00 – 04:00 04:00 – 05:00 05:00 – 06:00 06:00 – 07:00 |
94 93 125 102 |
61 60 55 58 |
69 69 70 68 |
4148 4118 4174 4070 |
632 588 706 757 |
632 588 706 757 |
0 0 0 0 |
99 92 96 99 |
|
07:00 – 08:00 08:00 – 09:00 09:00 – 10:00 10:00 – 10:28 |
128 170 157 117 |
53 73 81 80 |
74 125 112 97 |
4421 7500 6720 2328 |
668 109 65 17 |
668 109 65 17 |
0 0 0 0 |
88 7 6 1 |
Figure 1. Data on Holter monitoring in patient Zh.
Table 2. Monitoring of possible CTRCD development in patient Zh.
|
Cardiotoxicity monitoring: |
visit 1 |
visit 2 (3 months after the treatment commencement) |
visit 3 (6 months after the treatment commencement) |
visit 4 (9 months after the treatment commencement) |
visit 5 (12 months after the treatment commencement) |
|
cTnI, ng/ml |
0.1 |
0.1 |
0.1 |
0.1 |
0.1 |
|
BNP, pg/ml |
49.64 |
53.20 |
38.20 |
56.38 |
99.54 |
|
CRP, mg/ml |
2.98 |
3.41 |
4.28 |
3.87 |
1.80 |
|
D-dimer, mg/l |
3.22 |
2.43 |
0.27 |
0.22 |
0.23 |
|
LVEF, % |
57 |
56 |
55 |
55 |
56 |
|
GLS, % |
-14.3 |
-16.7 |
-14.6 |
-17.8 |
-15.8 |
Figure 2. Case 3 graphical presentation.
Z. Tlegenova1, S. Balmagambetova1, B. Zholdin1, G. Kurmanalina1, I. Talipova1,A. Koishybayev1, G. Sultanbekova1, K. Kubenova2, M. Baspayeva2,S. Madinova2, A. Amanova1
List of references
Additional files