Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review

Abstract

Since their introduction in the 1960s, anthracyclines have been a significant breakthrough in oncology, introducing dramatic changes in the treatment of solid and hematologic malignancies. Although new-generation targeted drugs and cellular therapies are revolutionizing contemporary oncology, anthracyclines remain the cornerstone of treatment for lymphomas, acute leukemias, and soft tissue sarcomas. However, their clinical application is limited by a dose-dependent cardiotoxicity that can reduce cardiac performance and eventually lead to overt heart failure. The field of cardio-oncology has emerged to safeguard the cardiovascular health of cancer patients receiving these therapies. It focuses on controlling risk factors, implementing preventive strategies, ensuring appropriate surveillance, and managing complications. This state-of-the-art review summarizes the current indications for anthracyclines in modern oncology, explores recent evidence on pathophysiology and epidemiology, and discusses advances in cardioprotection measures in the anthracycline-treated patient. Additionally, it highlights key clinical challenges and research gaps in this area.

Keywords: anthracycline; biomarkers; cancer survivorship; diagnosis; heart failure.

Graphical abstract

Central Illustration

Trajectory of Anthracycline-Treated Patients The risk of cardiotoxicity is dynamic and changes over time, influenced by the cumulative anthracyclines and concomitant cardiotoxic therapies. Pre-existing cardiovascular disease may amplify acute and long-term effects of anthracyclines on the heart. A dedicated cardio-oncology team can attenuate the risk through continuous refinement of risk factors, the establishment of cardioprotection measures, and exercise prescriptions. Despite these efforts, some patients may still develop overt heart failure (red line), necessitating chemotherapy adjustments or cessation and guideline-directed medical therapy. More commonly, patients experience subclinical cardiotoxicity is more frequent (green line), requiring prescription of cardiovascular drugs and close surveillance. ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin 2 receptor blocker; CV = cardiovascular; GDMT = guideline-directed medical therapy; HF = heart failure.

Figure 1

Current Landscape of eBC Treatment Main treatment opportunities for early breast cancer (eBC) are depicted, differentiating between neoadjuvant or adjuvant settings. Current pharmacologic options are diverse based on estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) expression, and BRCA mutations. Numerous chemotherapy schemes, increasingly excluding anthracyclines, are used in clinical practice. AC-T = adriamycin, cyclophosphamide followed by paclitaxel; AI = aromatase inhibitor; APT = adjuvant paclitaxel + trastuzumab; CDK4/6 = cyclin-dependent kinase 4 and 6; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; eBC = early breast cancer; ER = estrogen receptor; ET = endocrine therapy; H = trastuzumab; NAT = neoadjuvant; OS = ovarian suppression; P = pertuzumab; PARP = polymeric adenosine diphosphate polymerase; pCR = pathologic complete response; PR = progesterone receptor; TC = docetaxel, cyclophosphamide; TCHP = docetaxel, carboplatin, trastuzumab, pertuzumab; T-DM1 = trastuzumab emtansine.

Figure 2

Determinants and Modifiers of Anthracycline Cardiotoxicity The risk of cardiomyopathy and heart failures (HF) increases with the cumulative dose of doxorubicin (depicted by a dashed line). A mathematical model predicts the cause-and-effect relationship between cumulative dose and HF, incorporating the size of anthracycline pools that accumulate in cardiac tissue as exposure to doxorubicin increases. Cardiotoxicity occurs at lower doses with smaller anthracycline pools or at higher doses if the patient has predisposing risk factors or undergoes cardioprotective strategies. Adapted from Minotti et al. CV = cardiovascular; HER2i = human epidermal growth factor receptor 2 inhibitor.

Figure 3

Graphical Representation of Main Cellular Pathways and Genes Involved in Susceptibility to Anthracycline Cardiotoxicity Genetic alterations that predispose individuals to anthracycline cardiotoxicity may affect drug transport across the cell membrane or its clearance from the cell. Inside mitochondria, the reduction of anthracyclines forms a superoxide anion. Polymorphism in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits may cause overproduction of ROS, which can result from alterations in iron homeostasis. At the nucleus level, DNA topoisomerase I and II relieve tension in tightly wound DNA by introducing a DNA break. Anthracyclines target the Top2b-cleaved DNA complex, causing accumulation of double-strand DNA breaks and subsequent apoptosis. Genetic variants with inherited dilated cardiomyopathy also play a role. DOX = doxorubicin; Fe = iron; HFE2 = hemojuvelin 2; ROS = reactive oxygen species; Top2 = topoisomerase 2.

Figure 4

Cardiovascular Monitoring in Cancer Patients Undergoing Anthracycline-Containing Regimens According to Risk Assessment Surveillance should be guided by baseline cardiovascular risk stratification (indicated by red, yellow, and green bullets) and any abnormal findings during follow-up. These findings may necessitate further diagnostic investigations, refinement of cardioprotective therapy, or modifications to the oncologic treatment. CMR = cardiac magnetic resonance; CTRCD = cancer therapy–related cardiac dysfunction; CV = cardiovascular; CVRF = cardiovascular risk factor; GLS = global longitudinal strain; LVEF = left ventricular ejection fraction; RT = radiotherapy; VHD = valvular heart disease.

Figure 5

Adult Cancer Survivors: Comorbidities, Risk Stratification, and CV Care Necessities A patient is considered a cancer survivor from the time of diagnosis until the end of life. With improvements in early detection and treatment, the population of cancer survivors has grown steadily. These survivors face a higher burden of CV disease compared with the general population, necessitating long-term care based on risk stratification. Establishing clinics for cancer survivors can address these needs through the prescription of healthy lifestyles and the early identification and treatment of CV comorbidities. CS = cancer survivor; other abbreviations as in Figure 4.

Figure 6

Major Preclinical/Translational/Clinical Necessities in Cardio-Oncology Research Involving Anthracycline-Treated Patients and Survivors This figure highlights the key preclinical and clinical research needs for patients treated with anthracyclines. Despite years of study, CV toxicity induced by anthracyclines still has many pathophysiological aspects uncovered. Additionally, much of clinical practice lacks support from high-quality evidence. This underscores the need for randomized controlled trials (RCTs) and collaboration efforts between clinicians and preclinical experts to address these gaps. CHIP = clonal hematopoiesis of indeterminate potential; IP = ischemic preconditioning; SGLT2i = sodium glucose co-transporter 2 inhibitor; other abbreviations as in Figure 4.

Figure 7

The Multidisciplinary Cardio-Oncology Team The expected increase in the number of cancer patients at risk of developing/worsening cardiovascular disease (CVD) necessitates an integrative multidisciplinary approach and care by dedicated specialists. Multidisciplinary cardio-oncology teams are essential for addressing the full spectrum of prevention, detection, monitoring, and treatment of cancer patients at risk of cardiotoxicity and those with concomitant CVDs. CV = cardiovascular; CTR-CVT = cancer treatment–related cardiovascular toxicity.